risk of drug interactions involving herbal and citrus products · risk of drug interactions...
TRANSCRIPT
1
Risk of Drug Interactions Involving
Herbal and Citrus Products Shiew-Mei Huang PhD
Deputy Director for ScienceOffice of Clinical Pharmacology
Center for Drug Evaluation and ResearchFood and Drug AdministrationShiewmeihuangfdahhsgov
Health Canada International Symposium onDrug Food and Natural Health Product Interactions
February 9 2006Gatineau Quebec
2
bull 2000000number of serious ADRs yearly
Adverse Drug Reactions-Marketed Drugs
lt JAMA 19982791200ndash1205 Arch Intern Med 1995155(18)1949ndash1956gt
bull 136000000000annual cost in dollars associated with ADRs
bull 4-6ranking of serious ADRs as causes of death
bull 100000annual number of ADR-related deaths
3
0
20
40
60
80
100
Use
Total 18-44ymen
45-64ymen
gt 65 ymen
18-44ywomen
45-64ywomen
gt 65 ywomen
Use of Medications by Sex and Age
Any Usegt 5 drugsgt 10 drugs
lt JAMA 2002287337-344 gt
Why are there so many ADRs
4lt Eisenberg DM et al JAMA 280 (18) 1569 1998gt
bull 15 millions are at risk for potential adverse interactions
bull One in five Americans (184) take prescription medicationsconcurrent with at least 1 herbal product a high-dose vitamin or both
bull Use of botanicals has increased
(including 3 millions 65 years or older)
Evaluation of Evaluation of DrugDrug--DrugDrugInteractionsInteractions
--When are they significantWhen are they significant--
6
bull Draft Guidance for Industry Drug Interaction Studies mdash Study Design Data Analysis and Implications for Dosing and Labeling (expected publication 1Q 2006)
lt httpwwwfdagovcderguidanceindexhtmhttpwwwfdagovcdermapp40004pdfhttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
bull Reviewer Guide Good Review Practices (April 2004)
bull ldquoDrug Interactions in Drug Developmentrdquo website (expected one-line 1Q 2006)lthttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
Tools available Tools available
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
2
bull 2000000number of serious ADRs yearly
Adverse Drug Reactions-Marketed Drugs
lt JAMA 19982791200ndash1205 Arch Intern Med 1995155(18)1949ndash1956gt
bull 136000000000annual cost in dollars associated with ADRs
bull 4-6ranking of serious ADRs as causes of death
bull 100000annual number of ADR-related deaths
3
0
20
40
60
80
100
Use
Total 18-44ymen
45-64ymen
gt 65 ymen
18-44ywomen
45-64ywomen
gt 65 ywomen
Use of Medications by Sex and Age
Any Usegt 5 drugsgt 10 drugs
lt JAMA 2002287337-344 gt
Why are there so many ADRs
4lt Eisenberg DM et al JAMA 280 (18) 1569 1998gt
bull 15 millions are at risk for potential adverse interactions
bull One in five Americans (184) take prescription medicationsconcurrent with at least 1 herbal product a high-dose vitamin or both
bull Use of botanicals has increased
(including 3 millions 65 years or older)
Evaluation of Evaluation of DrugDrug--DrugDrugInteractionsInteractions
--When are they significantWhen are they significant--
6
bull Draft Guidance for Industry Drug Interaction Studies mdash Study Design Data Analysis and Implications for Dosing and Labeling (expected publication 1Q 2006)
lt httpwwwfdagovcderguidanceindexhtmhttpwwwfdagovcdermapp40004pdfhttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
bull Reviewer Guide Good Review Practices (April 2004)
bull ldquoDrug Interactions in Drug Developmentrdquo website (expected one-line 1Q 2006)lthttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
Tools available Tools available
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
3
0
20
40
60
80
100
Use
Total 18-44ymen
45-64ymen
gt 65 ymen
18-44ywomen
45-64ywomen
gt 65 ywomen
Use of Medications by Sex and Age
Any Usegt 5 drugsgt 10 drugs
lt JAMA 2002287337-344 gt
Why are there so many ADRs
4lt Eisenberg DM et al JAMA 280 (18) 1569 1998gt
bull 15 millions are at risk for potential adverse interactions
bull One in five Americans (184) take prescription medicationsconcurrent with at least 1 herbal product a high-dose vitamin or both
bull Use of botanicals has increased
(including 3 millions 65 years or older)
Evaluation of Evaluation of DrugDrug--DrugDrugInteractionsInteractions
--When are they significantWhen are they significant--
6
bull Draft Guidance for Industry Drug Interaction Studies mdash Study Design Data Analysis and Implications for Dosing and Labeling (expected publication 1Q 2006)
lt httpwwwfdagovcderguidanceindexhtmhttpwwwfdagovcdermapp40004pdfhttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
bull Reviewer Guide Good Review Practices (April 2004)
bull ldquoDrug Interactions in Drug Developmentrdquo website (expected one-line 1Q 2006)lthttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
Tools available Tools available
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
4lt Eisenberg DM et al JAMA 280 (18) 1569 1998gt
bull 15 millions are at risk for potential adverse interactions
bull One in five Americans (184) take prescription medicationsconcurrent with at least 1 herbal product a high-dose vitamin or both
bull Use of botanicals has increased
(including 3 millions 65 years or older)
Evaluation of Evaluation of DrugDrug--DrugDrugInteractionsInteractions
--When are they significantWhen are they significant--
6
bull Draft Guidance for Industry Drug Interaction Studies mdash Study Design Data Analysis and Implications for Dosing and Labeling (expected publication 1Q 2006)
lt httpwwwfdagovcderguidanceindexhtmhttpwwwfdagovcdermapp40004pdfhttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
bull Reviewer Guide Good Review Practices (April 2004)
bull ldquoDrug Interactions in Drug Developmentrdquo website (expected one-line 1Q 2006)lthttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
Tools available Tools available
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
Evaluation of Evaluation of DrugDrug--DrugDrugInteractionsInteractions
--When are they significantWhen are they significant--
6
bull Draft Guidance for Industry Drug Interaction Studies mdash Study Design Data Analysis and Implications for Dosing and Labeling (expected publication 1Q 2006)
lt httpwwwfdagovcderguidanceindexhtmhttpwwwfdagovcdermapp40004pdfhttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
bull Reviewer Guide Good Review Practices (April 2004)
bull ldquoDrug Interactions in Drug Developmentrdquo website (expected one-line 1Q 2006)lthttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
Tools available Tools available
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
6
bull Draft Guidance for Industry Drug Interaction Studies mdash Study Design Data Analysis and Implications for Dosing and Labeling (expected publication 1Q 2006)
lt httpwwwfdagovcderguidanceindexhtmhttpwwwfdagovcdermapp40004pdfhttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
bull Reviewer Guide Good Review Practices (April 2004)
bull ldquoDrug Interactions in Drug Developmentrdquo website (expected one-line 1Q 2006)lthttpwwwfdagovcderdrugdrugInteractionsdefaulthtmgt
Tools available Tools available
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
7
Key messages1 Metabolism drug-interaction info
key to benefitrisk assessment2 Integrated approach may reduce
number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to be useful and consistent
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
8
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
9
Labeled dose AUC or effective concentration (100)
Safety (Adverse Effect) Curve
Efficacy Curve
80 170R
espo
nse
(PD
)
Dose AUC or Concentration (PK)[Exposure]
Adapted from Huang SM Lesko LJ Williams RL J Clin Pharmacol 39 1006-1014 1999
Therapeutic Range
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
10
Labeling Impact- Drug-Drug Interactions -
bull Concomitant Medications The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (eg ketoconazole itraconazole ritonavir indinavir and erythromycin) (see WARNINGS PRECAUTIONS Drug Interactions )
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
11
Labeling Impact- Drug-Drug Interactions (2) -
bull For ritonavir a single dose of 25 mg LEVITRA should not be exceeded in a 72-hour period
bull For indinavir ketoconazole 400 mg daily and itraconazole 400 mg daily a single dose of 25 mg LEVITRA should not be exceeded in a 24-hour period
bull For ketoconazole 200 mg daily itraconazole 200 mg daily and erythromycin a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
Evaluation of Evaluation of DrugDrug--HerbHerbInteractionsInteractions
--When are they significantWhen are they significant--
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
13
Key Questions To Ask On Drug-Drug Interactions
1 Will an NME alter exposure to other drugs
2 Will other drugs alter exposure to the NME
3 Are these alterations in exposure significant enough to warrant dose adjustment
Questions on Drug-Botanical Interactions
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
Evaluation of DrugEvaluation of Drug--Herb Herb InteractionsInteractions--Which herbsWhich herbs--
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
15
St Johnrsquos Wort
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
16
St Johnrsquos wort (2)bull Cases of rejection of heart transplant patients on St Johnrsquos wort
ltRuschitzka F et al Lancet 355 548-549 February 12 2000gt
0
5
10
15
Cyc
los p
orin
e
Car
bam
azep
i ne
Sild
enaf
il
OC SSRI
bull Up to 2001 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 39 case reports
ltChen M Drug-Herb Interactions Eds Lam Huang Hall Taylor amp Francis in pressgt
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
17
bull St Johnrsquos wort decreasedindinavir plasma levels
St Johnrsquos wort (3)-effect on CYPs-
0
2
4
6
8
10
12
14
0 1 2 3 4 5
ltPiscitelli S et al Lancet Feb 2000gt
CYP2D625
CYP2C15
CYP1A23
CYP2E13
CYP3A54
bull Acute St Johnrsquos wort had little effects on major CYPs(CYP1A2 2D6 2C9 3A)bull Chronic St Johnrsquos Wort induced CYP3AltWang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20gt
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
18
bull Fexofenadine levels were slightly increased by acute St John wort dosing and reduced during chronic dosing
bull Consistent with an increase in immunodetectable CYP3A4 and P-gp in intestinal biopsies following 14 days treatment with St Johnrsquos wort (Duumlrr et al CPT 68 598 2000)
Wang Z et al Clin Pharmacol Ther 200170317-26 Clin Pharmacol Ther 200271414-20
St Johnrsquos wort (4)- Effect on P-gp -
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
19
bull More breakthrough bleeding occurred in St Johnrsquos Wort phase
bull 8 weeks of St Johnrsquos Wort decreasednorethindrone levels and ethinyl estradiol t12
Nu m
b er o
f Su b
j ect
s
bull Higher midazolamclearance for thosewith breakthrough bleeding
(216+ 67 vs 98 +37) 0
1
2
3
4
5
6
7
ControlSJW
lt Gorski JC et al Clin Pharmacol Ther 2003 Dec74(6)525-35 gt
St Johnrsquos wort (5)- Effect on OC -
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
bullbull Specific studies to understand Specific studies to understand mechanisms of interactionsmechanisms of interactions
bullbull Case reportsCase reports-- systematic evaluation of reportssystematic evaluation of reports
-- herbrsquos effects on specific probes for herbrsquos effects on specific probes for
-- herbrsquos effects on specific drugsherbrsquos effects on specific drugs
enzymes and transporters enzymes and transporters ltin vitro and in vivo studiesgtltin vitro and in vivo studiesgt
St Johnrsquos wort (6)
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
21
bull Labeling of newly approved drugs
St Johnrsquos wort (7)- Regulatory Impact-
bull FDA Health Advisory on ldquoconcomitant use with protease inhibitors or NNRTI is not recommendedrdquolthttpwwwfdagovcderdrugadvisorystjworthtmgt
bull Labeling revision of marketed drug products
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
22
When do we include St Johnrsquos Wort inthe drug labeling
Cytochrome P450 3A andor P-gp substrates and where the products effectiveness may be reduced upon co-administration of St Johns Wort
St Johnrsquos wort (8)- Regulatory Impact-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
23
bull 55 drug products with St Johnrsquos wortin the labeling
- 2 based on actual clinical studies
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- St Johnrsquos wort -
- 2 not related to the products (concurrent OC use)
- others based on reports andor mechanistic reasons
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
24
PRECAUTIONS Herbal products containing St Johnrsquos Wort (hypericumperforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
Current Labeling- St Johnrsquos wort and OC -
httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwfdagovcderguidance5197dftpdf
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
25
Other botanical products
Echinacea
ltGorski Huang Pinto Hamman Hilligoss Zaheer Desai Miller Hall Clin Pharmacol 2004 Jan75(1)89-100 gt
bull Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites
bull The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites
bull Study to evaluate the effects on OC ongoing
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
26
Other botanical products
Ginkgo Biloba
ltYin OQ et al Pharmacogenetics 2004 Dec14(12)841-50gt
bull Ginkgo Biloba extract induced CYP2C19
bull AUC ratio (omeprazole5-OH omeprazole) decreased by 68 the extent of interactions appear to be CYP2C19 genotype-dependent
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
27
How do we address possible drug dietary supplement interactions
Clinical protocol- Participants will be excluded for the following reasons hellip use of prescription or over-the-counter medications including herbal products or alcohol within two weeks prior to enrollment
Protocol Design
ltProtocol for FDAIndiana echinacea- cytochrome P450 interaction study results in Clin Pharmacol2004 Jan75(1)89-100 gt
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
28
Grape fruit juice
Interactions with Citrus FruitJuices
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
29
Fexo
fena
dine
i trac
ona z
ole
prav
ast a
ti nc y
clos
por i
nni
mod
ipi n
em
i da z
olam
t ri a
z ol a
ms a
quin
a vir
ator
vas t
atin
f el o
dipi
net e
r fe n
adi n
em
i sol
dipi
nebu
s pir
one
l ova
s tat
ins i
mva
s tat
i n
-100
0
100
200
300
400
500
A
UC
incr
ease
ove
r ba
selin
e
Grapefruit Juice - Drug Interactions900 1500 1600
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
30
Grapefruit JuicePost-marketing reports (FDA)
Calcium channel blockersHMG Co-A
reductase inhibitors
Non-sedating antihistamines
Othersbull Up to 2004 FDArsquos Adverse Event Reporting System (AERS) in CDER indicated up to 40 case reports
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
31
Case ReportLovastatin and Grapefruit Juice (1)
bull muscle pain and high CPK (gt40 ooo UL)
bull 60 yo male with hypertension chronic lower extremity venous stasisedema renal insufficienty non-insulin dependent diabetes mellitus and familial history of hyperlipidemia
bull changed his usual orange juice to grapefruit juice
ltPiazza-Hepp T in ldquoldquoHerb-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt
bull taking lovastatin concurrent with gemfibrozil amlodipine metoprolol glyburide trovafloxacin vitamine E metformin aspirin ciprofloxacin
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
32
bull started IV fluid dc lovastatin and gemfibrozilcreatinine (5 mgdL) gradually back on other meds
bull CPK to 1017 improved on muscle weakness
bull Physician concluded drug interactions betweengrapefruit and lovastatin and gemfibrozil=gt told the patient to avoid grapefruit juice
bull ICU for rhabdomyolysis with acute renal failure overlapping with chronic renal failure
Case ReportLovastatin and Grapefruit Juice (2)
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
33
bull while traveling in Florida took nifedipine with grapefruit juice experiences extreme fatigue dizziness vertigo decreased appetite disorientation bull hospitalized juice stopped recovered
bull Back home took nifedipine with grapefruit juice again experiences a similar but milder grapefruit and lovastatin and gemfibrozil=gt pharmacist suspected an interaction between
nifedipine and grapefruit juice
bull 92 yo female with hypertension took nifedipine 30 mg daily for 4 years
Case ReportNifedipine and Grapefruit Juice
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
34
bull 35 drug products with grapefruit juice in the labeling
- 50 reported clinical data
lt As summarized in Huang S-M Lesko LJ Temple R in ldquoherbal-drug interactionsrdquo eds Lam Huang Hall Taylor amp Francis in pressgt httpwwwaccessdatafdagovscriptscderdrugsatfdahttpwwwpdrelcompdrstatichtmpath=pdrelpdr57300800htm
Current Labeling- Grapefruit juice -
- grapefruit juice considered ldquomoderateCYP3A inhibitorrdquo- CYP class labeling
- others based on reports andor mechanistic reasons
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
35
When do we include grapefruit juice inthe drug labeling
Cytochrome P450 3A substrates with low oral bioavailability (due to enteric first pass)
Regulatory Impact
Dosage and AdministrationGrapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine (Neoral) thus should be avoided
lthttpwwwpdrelcompdrstatichtmpath=pdrelpdr57301293htmPDRCON01 1199 updategt
WarningsPrecautionsTo avoid possible serious side effects avoid drinking large quantities of grapefruit juice(more than on quart daily) while on simvastatin (ZOCOR) (see hellipMuscle)
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
36
Health Canada on GFJbull Certain drugs and health products used in the
treatment of the following medical conditions are known to cause this effectAngina Anxiety Cancer Convulsions Depression Erectile dysfunction Gastrointestinal reflux High blood pressure High lipid (cholesterol) levels HIVAIDS Infections Irregular heart rhythms Organ graft rejections Psychotic problems
bull Avoid taking any drug with grapefruit juiceuntil you have asked your doctor or pharmacist if it is safe to do so
bull if you are taking medication for any of the conditions listed above DO NOT drink grapefruit juice or eat grapefruit in any form until you have talked to your doctor and your pharmacist about the potential for an adverse reaction
lthttpwwwhc-scgccaahc-ascmediaadvisories-avis20022002_49_ehtml
lthttpwwwhc-scgccaiyh-vsvfood-alimentgrapefruit-pamplemousse_ehtml last update Jan 2006gt
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
37
Grapefruit juiceApple juiceOrange juice
Interactions with Citrus FruitJuices
- Effects on transporters
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
38
Effect of various juices on fexofenadine (n=10)
(12 L over 3 hours) in a randomized 5-way crossoverltBailey D et al ASCPT presentation 2001 Dresser GK et al Clin pharmacol Ther 2002 Jan 71(1)11-20 2005 Mar77(3)170-7 gt
Effect on OATP gt P-gp
HOURS0 2 4 6 8
0
100
200
300WATERDIL GFJGFJOJAJ
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
39
Calcium-fortified Orange juiceOther interactions with citrus fruit
ltNeuhofel AL et al J Clin Pharmacol April 2002 Wallace AW et al J Clin Pharmacol Jan and May 2003gt
0102030405060708090
100
control levo- gati- cipro-
Cm
ax (
of c
ontr
ol)
Evaluation of -floxacins from various studies (n=15-16)
Chelation + transporter
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
40
Cranberry Juice
September 2003 Current Problems in Pharmacovigilanceldquo by British Committee on Safety of Medicines
Other interactions with
httpwwwmcagovukourworkmonitorsafequalmedcurrentproblemscpsept2003pdf
- patients taking warfarin should limit or avoiddrinking cranberry juice
- five reports one fatal-- involved a man whose INR gt50 six weeks after starting cranberry juice
Effect on CYP2C9
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
41
How do we address possible drug-juice interactions
Protocol Design
ldquoFor at least two weeks prior to the start of the study until its conclusion volunteers will not be allowed to eat any food or drink any beverage containing alcohol grapefruit or grapefruit juice apple or orange juice vegetables from the mustard green family (eg kale broccoli watercress collard greens kohlrabi brussels sprouts mustard) and charbroiled meatsrdquo
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
42
Related to Drug- Natural Product Interactions
1 Metabolism drug-interaction infokey to benefitrisk assessment
2 Integrated approach may reduce number of unnecessary studies andoptimize knowledge
3 Study designdata analysis key toimportant information for proper labeling
4 Need to establish ldquoTherapeutic equivalenceboundariesrdquo (no effect boundaries)
5 Labeling language needs to beuseful and consistent
NMErsquos exposure-response needs to be well-defined
Studies may not be needed- from known info
NMErsquos clearance pathway needs to be well-defined
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
43
Jerry Collins Soloman Sobel John Strong
Sophia Abraham Sayed Al-Habet Raman BawejaSang Chung Philip Colangelo Paul HeppShiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei QiuNam Atik Rahman Kellie Reynolds Xiaoxiong WeiLei K Zhang Jenny H Zheng
David M Green David FruchtHon Sum Ko Toni Stifano
Drug Interactions working group
Robert Temple Janet Norden
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
44
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
45
Questions
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
46
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
47
Update on Botanical INDrsquos
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
bullbull Total of 242 ApplicationsTotal of 242 Applicationsbullbull 192 INDs (23 active) 50 pre192 INDs (23 active) 50 pre--INDs INDs bullbull 50 inlsquorsquo9050 inlsquorsquo90--rsquo98 192 inlsquorsquo99rsquo98 192 inlsquorsquo99--rsquo05rsquo05bullbull 2~3 new submmonth in recent yrs 2~3 new submmonth in recent yrs bullbull 40 commercial 60 research40 commercial 60 researchbullbull 23 single herb 13 multiple herbs23 single herb 13 multiple herbs
Botanical Applications in FDABotanical Applications in FDA(as of June 1 2005)(as of June 1 2005)
ltShaw Chen CDER FDA November 2005gt
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
49
Botanical Applications at FDABotanical Applications at FDAGrowing over the YearsGrowing over the Years
020406080
100120
1982-89 1990-94 Jan 95 -July 00
Aug 00 -May 04
Jun 04 -May 05
Botanical Applications 1982-2005
Annual AvePeriod Total
ltShaw Chen CDER FDA November 2005gt
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
Botanical Applications in FDABotanical Applications in FDA
05
10152025303540
Cardior
enal
Neuro
psyc
hOnc
ology
Imag
ingAne
sthab
use
GI-Coa
gulat
ionEnd
ocr-m
etab
Anti-in
fectiv
eAnti
-vira
lDerm
-den
talAnti
-infla
mmPulm
-Alle
rgy
Repro
ducti
veSpe
cial P
ath
Botanical Applications by Therapeutic Classes
pINDIND
ltShaw Chen CDER FDA November 2005gt
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
51
Drug-Drug Interactions- Labeling Implications -
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
52
bull All relevant informationhellip should be included inthe PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section of thelabeling
bull The clinical consequences hellip should be placedin DRUG INTERACTIONS WARNINGS ANDPRECAUTIONS BOXED WARNINGSCONTRAINDICATIONS or DOSAGE ANDADMINISTRATION sections as appropriate
bull When the data resulted in recommendations for dosage adjustments contraindications warnings these recommendations should also be included in ldquoHIGHLIGHTSrdquo
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
53
Drug- Natural Product Interactions
- Current Labeling examples -
Physiciansrsquo Desk Reference at httppdrelthomsonhccompdrellibrarianA catalog of FDA approved drug products httpwwwaccessdatafdagovscriptscderdrugsatfdaCDER New and Generic Drug Approvals 1998-2004 httpwwwfdagovcderapprovalindexhtm
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
54
Cyclosporine
DOSAGE amp ADMINSTRATION
Grapefruit and grapefruit juice affect metabolism increasing blood concentration of cyclosporine thus should be avoided
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
55
FexofenadineInteractions with Fruit Juices
Fruit juices such as grapefruit orange and applemay reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skinwheals and flares coupled with population pharmacokinetic analysis helliphelliphellip Therefore to maximize the effects offexofenadine it is recommended that ALLEGRA-D 24 HOUR should be taken with water
httpwwwfdagovcderfoilabel200421704lblpdf
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
56
Levonorgestrel and Ethinyl Estradiol
Herbal products containing St Johns wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids This may also result in breakthrough bleeding
httppdrelthomsonhccompdrellibrarianPFDefaultActionIdpdrcommonIndexSearchTranslatorPDRPRE01el200421704lblpdf
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
57
Isotretinoin
CONTRAINDICATIONS and WARNING
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St Johns wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St Johns wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns wort (see PRECAUTIONS)1
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
58
WarfarinPRECAUTIONS
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN Few adequate well-controlled studies exist evaluating the potential for metabolic andor pharmacologic interactions between botanicals and COUMADIN Due to a lack of manufacturing standardization with botanical medicinal preparations the amount of active ingredients may vary This could further confound the ability to assess potential interactions and effects on anticoagulation It is good practice to monitor the patientrsquos response with additional PTINR determinations when initiating or discontinuing botanicals
httpwwwfdagovcderfoilabel2005009218s101lblpdf
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
59
Warfarin (2)Information for Patients
Patients should be advised Strict adherence to prescribed dosage schedule is necessaryDo not take or discontinue any other medication including salicylates (eg aspirin and topical analgesics) other over-the-counter medications and botanical (herbal) products (eg bromelains coenzyme Q10 danshen dong quai garlic Ginkgo biloba ginseng and St Johnrsquos wort)except on advice of the physician
httpwwwfdagovcderfoilabel2005009218s101lblpdf
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
60
St Johnrsquos wort Products
FTC Warning ON Herbal Outlook or similar product (Panda) St Johns Kava Kava (ForMor) httpwwwftcgovopa200106cureallhtm
WARNING St Johns Wort can have potentially dangerous interactions with some prescription drugs Consult your physician before taking St Johns Wort if you are currently taking anticoagulants oral contraceptives antidepressants anti-seizure medications drugs to treat HIV or prevent transplant rejection or any other prescription drug
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-
61
References for Draft Guidance on Drug Interactionsbull Guidance for industry In vivo metabolismdrug interactions Study design data analysis
and recommendation for dosing and labeling (Issued 11241999 Posted 11241999) httpwwwfdagovcderguidanceindexhtm httpwwwfdagovcderguidance2635fnlpdf
bull Tucker Houston and Huang Clin Pharm Ther August 2001 70(2)103bull Bjornsson Callaghan Einolf et al J Clin Pharmacol May 2003 43(5)443bull Yuan Madani Wei Reynolds Huang Drug Metab Disp December 2002 30(12) 1311 bull Labeling guidance httpwwwfdagovcderguidance6005dftpdf (Jan 2006)bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology
Subcommittee meeting Issues and challenges in the evaluation and labeling of drug interaction potentials of NME Rockville MD April 23 2003 httpwwwfdagovohrmsdocketsac03slides3947s2htm httpwwwfdagovohrmsdocketsac03transcripts3947T2htm
bull FDA Advisory Committee for pharmaceutical sciences and Clinical Pharmacology Subcommittee meeting Issues drug interaction concept paper Rockville MD November 3 2004 httpwwwfdagovohrmsdocketsac04briefing2004-4079b1htmhttpwwwfdagovohrmsdocketsac04slides2004-4079s1htmhttpwwwfdagovohrmsdocketsac04transcripts2004-4079T1htm
bull Huang S-M Lesko LJ J Clin Pharmacology June 2004bull Huang S-M Hall S Watkins P et al Clin Pharmacol Ther Jan 2004bull Huang S-M Temple R Lesko LJ in ldquoBotanical ndash Drug Interactions Scientific and
Regulatory Challengesrdquo Ed Lam F Huang S-M Hall S Taylor and Francis in pressbull CDER Drug Interactions Website (available 1Q
httpwwwfdagovcderdrugdrugInteractionsdefaulthtm )
- Risk of Drug Interactions Involving Herbal and Citrus Products
- Evaluation of Drug-Drug Interactions-When are they significant-
- Tools available
- Labeling Impact- Drug-Drug Interactions -
- Labeling Impact- Drug-Drug Interactions (2) -
- Evaluation of Drug-Herb Interactions-When are they significant-
- Evaluation of Drug-Herb Interactions-Which herbs-
- Grapefruit Juice - Drug Interactions
- Health Canada on GFJ
- Effect of various juices on fexofenadine (n=10)
- Botanical Applications in FDA(as of June 1 2005)
- Botanical Applications at FDAGrowing over the Years
- Botanical Applications in FDA
-