epidemiology risk factors for hcv - learning express toys...– seizure meds: almost all...

1

Emerging Antiviral Agents and New Strategies for Treating

Hepatitis C Infection

Zane Saul MDChief, Infectious Diseases

Bridgeport Hospital

Learning Objectives:

1. Discuss AASLD consensus guidelines for managing HCV and HIV co-infection.

2. Assess the role of newly approved and emerging therapies for the treatment HCV infection.

3. Summarize the efficacy and tolerability of available treatment strategies for hepatitis C.

4. Identify common side effects and drug interactions of the direct-acting antiviral medications.

Epidemiology• 3.9-4.1 million Americans are HCV Ab+

– May be as high as 7 million

• 2.7-3.2 million are chronically infected

• Highest prevalence in 30-54 yo

• Highest prevalence in African Americans and Hispanics

CDC. MMWR 1998 47(RR-19):1-38

Alter M. NEJM 1999 341:546-52

Armstrong GL. Ann Intern Med 2006 144:705-14

Risk Factors for HCV

• Injection drug use (60%)

• Blood transfusion before 1992

• Multiple sex partners

• Iatrogenic (hemodialysis, re-use of vials, etc)

• Intranasal cocaine

• Piercing, tattooing, scarification

• Unknown (10%)

SCREENING FOR HEP C

• CDC suggests to screen all “baby boomers” born between 1945-1965

• May have experimented with IV Drugs• Blood transfusions before 1992• Military Veterans• US Preventative Services Task Force

suggests only testing baby boomers with history of IDU or transfusion

2

WHY SCREEN NOW ?

• Screening tests are widely available

• Treatment is much easier and effective

• Most people living with Hep C don’t know they have it

WHO TO TREAT

• Treat ALL patients except those with limited life expectancy < 12 months due to non-liver related co-morbid conditions

• Goal is virologic cure SVR, undetectable viral load at least 12 weeks after completion of therapy

• Goal is to reduce all cause mortality including end stage liver disease and HCC

WHY TREAT NOW

• Rates of cure > 90%

• Decrease rate of fibrosis by up to 70%

• 50% cirrhosis resolved

• 70% reduction in risk of HCC

HIGHEST PRIORITY TO TREAT

• Highest risk for severe complications of HCV

• Advanced fibrosis F3 or decompensated cirrhosis

• Organ transplant- 75% not cured at time of transplant will relapse in 6 months, goal is to pre-treat with SVR x 28 days pre-transplant

• Extra liver disease related to HCV, Vasculitis or Kidney disease

HIGH PRIORITY

• Moderate fibrosis• HIV co-infection, exacerbate

progression to fibrosis• HBV co-infection, 1.4% pop. • Other coexistent liver disease, NASH• Diabetes with Insulin resistance,

unknown cause• Debilitating fatigue

HIGH RISK OF TRANSMISSION WHERE

TREATMENT MAY REDUCE

• MSM unsafe sex practices

• Active IDU

• Incarceration

• Hemodialysis patients

3

EXPERIENCE TO NOW

• Interferon and Rib for 48 weeks with max efficacy of 40%, intolerable side effects and high relapse rates

• 2011 Ist Generation PI much better efficacy, also intolerable side effects

• 2013 New agents with better efficacy and tolerability and many with shorter durations of treatment

Side Effects of PegIFN/Ribavirin

• Depression ranging from mild to suicidality

• Irritability, aggressive behavior

• Worsening of mania• Fatigue• Insomnia• Myalgias, fever, flu-like

symptoms• Hair loss• Cytopenias“Interferon Man”

Slide courtesy Chia Wang

2011 NEW PI

• Many problems were found

• Unbearable side effects: Rash, Anorectal pain/burning, Anemia

• Large pill burden

• Significant drug-drug interactions

• Cost quite high

SOFOSBUVIR (Sovaldi)

• Polymerase inhibitor

• Pan-Genotypic activity

• High barrier to resistance

• Single tablet in combination with other meds

• Price is high but < total cost of care of complications of liver disease

• Headache, nausea and fatigue most common side effects

SOFOSBUVIR

• Substrate of P-gp • Drugs that are potent P-gp inducers in the

intestine may decrease SOF concentration and lead to failure

• Avoid with anticonvulsants (Tegretol, dilantin, phenobarb) Rifampin and rifabutin, St John’s wort, and Tipranavir

• No dose adjustment for methadone, cyclosporine and other HIV drugs

SIMEPREVIR (Olysio)

• New generation Protease inhibitor• Polymorphism at Genotype 1A Q80K

mutation will make drug less effective• Used in Genotype 1 and 4 • Price less than cost of liver disease• Rash, nausea, muscle pain and

indigestion most common• One pill daily with food

4

SIMEPREVIR

• Primary enzyme involved in metabolism is CYP3A

• Drugs with moderate or strong inhibitors of CYP3A may increase plasma concentration of SIM

• Moderate or strong inducers may reduce levels of SIM and affect efficacy

• HIV PI, NNRTI and Cobi should not be used

clinicaloptions.com/hepatitisAll-Oral Therapy for HCV: A New Era Begins

Elimination of HCV in the US: Infected Population, 2013

3200

1600

63

PWID, homeless, immigrants, incarcerated, veterans

Viremic HCV Infections[1,2] Diagnosed[3] Treated[4]

1. Denniston MM, et al. Ann Intern Med. 2014;160:293-300. 2. Chak E, et al. Liver Int. 2011;31:1090-1101.3. Denniston MM, et al. Hepatology. 2012;55:1652-1661. 4. Razavir H, et al. Hepatology. 2013;57:2164-2170.

3500

3000

2500

2000

1500

1000

500

0

Tota

l In

div

idu

als

(0

00

)


Despite Declining HCV Infections, Healthcare Costs Will Increase due to ESLD

Razavir H, et al. Hepatology. 2013;57:2164-2170.

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Pre

vale

nce

(M

illio

ns)

16

14

12

10

8

6

4

2

0

Health

care Co

st ($ Billio

n)


Increasing Use of High SVR Therapy (~ 90%) Will Eliminate HCV in the US by 2029

No more pts

available to treat

200,000Treated

150,000

100,000

50,000

0

160,000

120,000

80,000

40,000

0

Cured

Razavir H, et al. Hepatology. 2013;57:2164-2170.

HARVONI

• Studies ION 1, 2, 3 with cure rates of 94 to 99%

• Side effects HA, Insomnia, Nausea

• No dose adjustments needed for Renal failure

HARVONI

• Newly FDA approved combination STR of Sofosbuvir (polymerase inhibitor) and Ledipasvir (NS5A inhibitor)

• First approved treatment with NO INFN or RIB

• Approved for Genotype 1

5

HARVONI• Genotype 1 TxN , no cirrhosis, baseline

VL < 6 million = 8weeks, $63,000

• Genotype 1 TxN with cirrhosis, 12 weeks or Genotype 1 TE, no cirrhosis 12 weeks= $94,000

• Genotype 1 , TxE with cirrhosis, 24 weeks =189,000

SVR > 90%

Toxicity

Tolerability

Short duration

One size fits all: pangenotypic

High barrier to resistance

Requirements for HCV Therapy

No drug–drug interactions

Low pill burden


Tx naive

100

80

60

40

20

0

SV

R1

2 (

%)

Previous Tx (incl PI) failures

ION 1, 2, and 3: Sofosbuvir/Ledipasvir ±RBV in Tx-Naive Pts and Previous Failures

8 wks adequate for noncirrhotic treatment-naive pts

RBV provides no benefit

No SOF resistance observed; most virologic failures have LDV resistance

1. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 2. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.3. Kowdley KV, et al. N Engl J Med. 2014;370:1879-1888.

n/N =108/109

99

S/L

24 Wks[2]

110/111

99

S/L+R

94

102/109

S/L

107/111

96

S/L+R

12 Wks[2]

98

212/217

99

215/217

S/L S/L+R

24 Wks[1]

99

211/212

97

211/217

S/L S/L+R

12 Wks[1]

94

202/215

93

201/216

95

8 Wks[3] 12 Wks[3]

S/L S/L+R S/L

206/216


ION 2: Sofosbuvir/Ledipasvir ± RBV Is Effective in Pts With Previous PI Failure

No cross-resistance with PI and either SOF or LDV

P/R failure

PI failure

40/43

62/66

45/47

62/64

58/58

49/50

58/59

51/51

12 Wks 24 Wks

SOF/LDV + RBV SOF/LDV + RBVSOF/LDV SOF/LDV

SV

R1

2 (

%)

100

80

60

40

20

0

93 94 96 97 1009898100

Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

n/N =


Sofosbuvir/Ledipasvir: FDA-Approved Indication

*8-wk duration can be considered in treatment-naive pts without cirrhosis who have pretreatment HCV RNA < 6 million IU/mL.†Treatment-experienced pts who have failed treatment with pegIFN/RBV ± HCV PI.

Sofosbuvir/ledipasvir [package insert]. October 2014.

Population Recommended Treatment Duration

Treatment naive with or without cirrhosis 12 wks*

Treatment experienced† without cirrhosis 12 wks

Treatment experienced† with cirrhosis 24 wks


Safety and DDIs With SOF/LDV

Safety/tolerability[1]

– Treatment-related AEs: 45% SOF/LDV vs 71% SOF/LDV + RBV

– Without RBV:

– < 1% d/c due to AEs

– < 1% serious AEs

– Headache, fatigue: ~ 20%

– Nausea, diarrhea: ~ 8% to 10%

– Almost no anemia

DDIs[2]

– St John’s wort

– Rifampin

– Acid reducing agents: high pH reduces LDV absorption

– Statins: coadministration with rosuvastatin not recommended

– Seizure meds: almost all contraindicated

– Digoxin: be careful—may increase levels

– ARVs: most okay; careful with TDF and check them all

1. Alqahtani S, et al. AASLD 2014. Abstract 1944. Note that these data were available in abstract form only at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.2. Sofosbuvir/ledipasvir [package insert]. October 2014.

6

HARVONI TOLERABLE DRUGS

• Methadone

• Oral contraceptives

• Tacrolimus

• Cyclosporine

• MANY HIV REGIMENS

VIEKIRA PAK• 3 Direct acting agents with Ritonavir

• Paritaprevir (Protease, Genotype 1-6) plus Ombitasvir (NS5A, Genotype 1-6) plus ritonavir combined in 2 tab daily

PLUS

• Dasabuvir (polymerase, Genotype 1)

• 1 tab bid

Indicated in Genotype 1 including patients with Cirrhosis , HIV, Liver transplant

VIEKIRA PAK

• Studied in Genotype 1 only

• 12 weeks in TxN or TxE with no decompensated liver disease

• 24 weeks in Compensated liver disease, HIV or Transplant

• SVR > 90%

• With RBV 1A, Without RBV 1B no cirrhosis


SAPPHIRE I & II: PTV/RTV/OBV + DSV + RBV for 12 Wks in Noncirrhotic Pts

5 drugs (3 pills): 3 pills in the morning + RBV, 1 pill in the evening + RBV

Very well tolerated (vs placebo), few virologic failures but usually with multiclass resistance

1. Feld J, et al. N Engl J Med. 2014;370:1594-1603. 2. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

100

80

60

40

20

0

SV

R1

2 (

%)

95

307/322

GT1a

98

148/151

96

455/473

All GT1b

SAPPHIRE I: Naive Pts[1]

n/N =

100

80

60

40

20

0

SV

R1

2 (

%)

96

166/173

GT1a

97

119/123

96

286/297

All GT1b

SAPPHIRE II: P/R Failures (49% Nulls)[2]

n/N =


Ribavirin-Free Therapy in GT1b

GT1b Tx Naive

99

99

PEARL-III[2]

1. Andreone P, et al. Gastroenterology. 2014;147:359-365. 2. Ferenci P, et al. N Engl J Med. 2014;370:1983-1992.

3 DAAs + RBV (n = 91)

3 DAAs (n = 95)GT1b

Tx Experienced

Wk 12

100

97

SVR12, %

PEARL-II[1]

GT1a Tx Naive

90

97

PEARL-IV[2]

3 DAAs + RBV (n = 210)

3 DAAs (n = 209)

3 DAAs + RBV (n = 100)

3 DAAs (n = 205)

RBV needed for GT1a, not necessary for GT1b noncirrhotics


Event, % 3 DAAs + RBV 3 DAAs P Value

Any AE 84 75 < .05

Serious AE 2 1 NS

Headache 25 26 NS

Fatigue 29 29 NS

Diarrhea 7 11 NS

Nausea 14 9 < .05

Pruritus 11 6 < .05

Hemoglobin < 10 g/dL 7 0 < .05

Bilirubin > 3 x ULN 5 0.5 NS

Safety and DDIs With 3 DAAs ± RBV

Ferenci P, et al. N Engl J Med. 2014;370:1983-1992.

DDIs: relatively similar to first-generation PIs (CYP3A) check the label and other resources (eg, University of Liverpool Web site)

7


COSMOS: Sofosbuvir + Simeprevir ± RBV in Tx-Naive and Tx-Experienced GT1 Pts

No breakthrough on therapy, 6 relapses, 9 nonvirologic failures

Efficacy of 12 wks similar to 24 wks; RBV provided no additional benefit

Recently FDA approved: 12 wks in noncirhotics, 24 wks for cirrhotics; no RBV

100

80

60

40

20

0

SV

R1

2 (

%)

Cohort 2: F3/4 Null Responders/Naives

19/24

S+S+R S+S

93

14/15

79

Cohort 1: F0-2 Null Responders

96 93

S+S+R S+S

26/27 13/14

12 Wks

93 93

S+SS+S+R

25/27 13/14

93

28/30

100

16/16

S+SS+S+R

Lawitz E, et al. Lancet. 2014;[Epub ahead of print].

24 Wks 12 Wks 24 Wks

n/N =


GT1 GT1a GT1b

Efficacy of SOF + SMV ± RBV in Real-World Settings

1. Jensen DM, et al. AASLD 2014. Abstract 45. 2. Dieterich D, et al. AASLD 2014. Abstract 46.

HCV-TARGET: Prospective Observational Cohort Study: Adjusted SVR4 in GT1 HCV Pts[1]

TRIO: Prospective Observational Cohort Study: SVR12 in Tx-Naive GT1 HCV Pts[2]

SV

R4

(%

)

100

80

60

40

20

0

8380

SMV + SOF ± RBV

SV

R1

2 (

%)

132 85n =

92

36

SOF + SMV SOF + SMV + RBV

All Pts Tx-Naive Pts

Tx-Exp’d Pts

86 87 89 8785 86100

80

60

40

20

0

NEW GUIDELINES• AASLD, IDSA and IAS-USA new guidelines

developed

• Differs from European guidelines

• Suggest Directly acting agents

• All oral regimens possible

• Options for interferon intolerant or unwilling

• Special populations including Cirrhosis, HIV and Transplant patients

INITIAL TREATMENT GENOTYPE 1

• HARVONI 12 WEEKS

• VIEKIRA PAK and RBV 12-24 WEEKS

• SOF PLUS SIM WITH OR WITHOUT

• RBV 12 TO 24 WEEKS

GENOTYPE 2

• Easier genotype to treat

• SOF + RBV 12 weeks

• SVR 94%

• RBV weight based

• 16 WEEKS IF CIRRHOSIS

GENOTYPE 3

• SOF + RBV 24 weeks

OR

• SOF + PEG INFN/RBV 12 weeks

• SVR for 24 weeks much better in most studies up to 90%

8

GENOTYPE 4

• Less common genotype

• HARVONI 12 WEEKS

• VIEKIRA PACK PLUS RBV 12 WEEKS

• SOF+ /RBV 24 weeks

GENOTYPE 5 OR 6

• SOF + RBV/INFN 12 weeks

OR

• INFN/RBV alone 48 weeks

PREVIOUS FAILURES OR NON RESPONDERS

• Genotype 1: SOF + SIM w/without RBV 12 weeks or

HARVONI 12 WEEKS OR VIEKIRA PAK PLUS RBV

• Genotype 2: SOF + RBV 12 weeks or SOF + INFN/RBV 12 weeks

• Genotype 3: SOF + RB 24 weeks or SOF + INFN/RBV 24 weeks

• Genotype 4: SOF + RIB 24 weeks OR HARVONI OR VPAK PLUS RIB

HIV COINFECTION

• Naïve: HARVONI, VPAK PLUS RBV

• SOF + SIM +/- RBV, only if on certain HIV meds.


The Pt Perspective on All-Oral Therapy: Patient One Acquired HCV in childhood

Asymptomatic until 2012

Previous failure on 2 IFN-based regimens

– Depression on IFN with significant impact on work and home life

– Required growth factors

Became symptomatic in 2012 with series of GI bleeds

– Required hospitalization


Patient One

Ineligible for many clinical trials due to advanced disease; eventually entered SOLAR trial, received SOF/LDV + RBV x 24 wks

– Liver function normal, HCV RNA undetectable within 4 wks

Hospitalized again for GI bleed

Underwent OLT in early 2014

HCV and hemophilia are now cured

No adverse effects of antirejection therapy

The pt has experienced a return to health with substantial benefit for family and professional life

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Patient Two

Pt has heart condition and diabetes

Diagnosed in 2012 with HCV after his endocrinologist noted elevated liver enzymes, referred to specialist care

– Shocked by diagnosis

Mild GT1a HCV disease with minimal fibrosis

Not eligible for IFN due to comorbidities

Diagnosis affected his relationship with his partner and his professional life as an MD

Pt was keen to begin therapy


Patient Two

Began therapy in early 2014 with SOF + SMV x 12 wks

– Approval of insurance coverage delayed therapy by 2 mos

The pt was concerned treatment would be long and difficult and that AEs would be hard to manage

Experienced no AEs or interruption to his daily routine

HCV remained negative throughout treatment; pt achieved SVR12 recently; AST/ALT are normal

Treatment has removed anxiety about disclosure at work

CONCLUSIONS

• Many new available regimens that are better tolerated, less pills and now all oral regimens

• Pharmacist must help take active role in managing drug interactions and helping to educate and assist with side effects.

• Cost of care is being debated but still quite better then long term cost of care of chronic liver disease

NEWEST HURDLES $$$

• Initial approval by insurance was slow but many have gotten approval and have been treated

• Now Insurance companies, Medicaid and Pharmacy medication managers are implementing strict criteria for use.

• Asking to document advanced disease, fibrosis, cirrhosis or other complications

NEW HURDLES $$$$

• We need to all work together for the good of the patient

• Guidelines state all non-terminal patients should be treated, not being reflected in Insurance approvals

• We need to be ADVOCATES for our patients

LETS CURE HCV

• Newer treatments with better tolerability and near 100% efficacy for SVR are here now, with more to come

• As a medical community we need to fight hard for all patients to get treated

• WE CAN ERADICATE HCV !!!

• ESTIMATED BY 2029 !

10

1. Chronic infection with HCV leads to cirrhosis and cancer in what time frame?

1. Weeks

2. Months

3. Years

4. Decades

5. Not sure

2. Which of the following is a side effect of interferon?

1. Fatigue

2. Depression

3. Flu like symptoms

4. Hair loss

5. All of the above

6. Not sure

3. Which agent has activity against all genotypes of HCV?

1. Ribavirin

2. Sofosbuvir

3. Tenofovir

4. Ledipasvir

5. None of the above

6. Not sure

4. The efficacy of Harvoni in leading to SVR in treatment naïve patients with genotype 1 is:

1. 40%

2. 60%

3. 80%

4. Nearly 100%

5. Not sure

5. Which of the following is true with regards to treatment of HCV with newer agents in patients also infected with HIV?

1. Newer treatments are not very effective due to HIV.

2. Newer treatments are not very tolerable due to side effects.

3. Newer treatments will have a dangerous impact on the immune system.

4. Treatment options are limited by drug interactions with HIV meds but are still effective.

5. Not sure

Questions?

1

PHARMACY COMPOUNDING:

Update on Trends & Regulations

Michael Roberge, RPhCertified Compounding Pharmacist

Owner, Compounded Solutions in Pharmacy LLC Monroe, CT

Learning Objectives

• Define pharmacy compounding and its role within a pharmacy practice

• Discuss basic components involved in quality pharmacy compounding

• Explain compliance issues with the current regulatory requirements for compounding

• List resources available for pharmacists with regards to helping a patient with compounded products

Disclosure

Michael Roberge R.Ph Owner

Compounded Solutions in Pharmacy, LLCMonroe, CT

(203) 445-9171 or 877-Rx NEEDS

What is aCompounding Pharmacist?

• Specially trained pharmacist• Problem solver preparing customized

medications to help meet unique physician and patient needs.

• Ultimate goal - help the patient & MD achieve optimal therapeutic outcome.

Michael Roberge, RPh

PERSONALIZEDMEDICINE

Improve Therapeutic Outcomes……by solving problems:

• Medication not commercially available (discontinued or backordered)

• Customization of active ingredient(s) /strength(s)

• Dosage Form Alterations

Palatability: flavoring

Convenience : combinations

• Reduction of adverse side effects : suppositories, transdermals

• Avoidance of dyes, preservatives, specific inactives

• Combinations or Sustained-Release therapies to improve compliance

2

CompoundingAs defined in the NABP Model State Pharmacy Act:

• The preparation, mixing, assembling, packaging, or labeling of a drug or device (i) as a result of a practitioner’s prescription drug order or initiative based on the Practitioner / Patient / Pharmacist relationship in the course of professional practice, or (ii) for the purpose of or as an incident to research, teaching, or chemical analysis, and not for resale or dispensing.

• Compounding also includes the preparation of drugs or devices in anticipation of prescription drug orders based on routine, observed patterns.

ManufacturingAs defined in the NABP Model State Pharmacy Act:

• The production, preparation, conversion, or processing of a drug or device

• Any packaging or repackaging of the substance(s) or labeling or relabeling of its container

• Promotion and marketing of such Drugs or Devices.

• Preparation and promotion of commercially available products from bulk compounds for resaleby the pharmacies, practitioners, or other persons.

COMPOUNDING OUTSOURCING MANUFACTURING

• Making the formula match the patient’s needs

• Administer the drug to the sight of action in themost effective dosage form available

• Patient’s needs in mind or for specific in-office procedure

• Regulated by the state

• Shipping out of CT limited to 5%

• Out sourcing - Large volume compounding dispensed without patient specific data

• Shipped across state borders

• Regulated by the FDA under 503B

• No specific patient in mind when drug is produced

• Has prescribers matching patients to the product available

• Economic considerations limit choices in drug dosages and dosage forms

• Regulated by the FDA

Quality & Safety in ConnecticutCompounding Pharmacies

State of Connecticut

CONTINUES to Enforce

USP 797 Guidelines for

Sterile Compounding &

USP 795 for

Non-Sterile Compounding(not all states enforce USP Guidelines)

State of CT Inspection

• State Inspection criteria same as retail pharmacies

• Plus 795/797 inspector

• Post NECC, CT added inspectors to focus on sterile compounding.

• Typically a minimum of 2 full days with 2 inspectors going through all the required documentation.

• State is also inspecting Hospital Pharmacies for

795/797 compliance

• Expect same standard to be applied to any

pharmacy that compounds at any level.

Compounding Pharmacist knowledge base responsibility

• Trained & proficient in compounding

• CE’s pertinent to compounding

• Knowledge of: 795,797,1151,1160,1163,1176,1191,1265 & all applicable state & federal laws

• NIOSH

3

General Principals• Personnel training is well documented

• Proper storage of quality ingredients from reliable sources

• OSHA labeling & MSDS available

• Equipment maintained & used properly

• Environment maintained to protect personnel & prevent cross-contamination

• Limited personnel access to compounding area

• Processes are clear and reproducible

• All aspects are well documented

• Procedures & records exists for researching & correcting problems

Process Criteria

• Preparation suitability

• Formulation records (master & specific)

• Ingredient verified via CofA, MSDS, FDA

• Proper environment for each formula

• Equipment clean & operational

• BUD established

• Proper hygiene & garb

• Critical processes & final product verified by pharmacist

• Packaging & labeling comply with law & includes “this is a compounded preparation”

Facility & Equipment

• Dedicate space for compounding

• Temp & Humidity monitored and recorded

• Nothing on the floor

• Equipment cleaned & maintained regularly

• Everything is documented

Ingredient Selection & Storage

• USP, NF, FCC whenever possible

• Manufactured in FDA-registered facilities

• Adhere to mfg expiration dates (if no expdate, assign date < 3 yrs from receipt)

• Not on “Do Not Compound” list for humans

• All ingredients properly stored and labeled

795 Compounding Categories

• SIMPLE:

USP monograph

Peer-reviewed journal

Reconstitution of commercially available product per mfg

directions

• MODERATE:Special calculations or procedures

Stability data unavailable

• COMPLEX

Special training, equipment & procedures

Personnel Training

• Anyone involved in process needs proper training

• Read USP795

• Understand process requirements

• Training documented and reviewed annually

4

USP 795 Stability & BUD• Assigned conservatively based on drug-specific & general

stability data as well as supportive literature

• Refer to manufacturer’s literature when available

• Without manufacturer’s literature or supportive data:

NonAqueous: earliest API exp. or 6 months max

Aqueous Oral: 14 days max

Aqueous Topical/Mucosal or SemiSolids: 30 day max

USP 797 GUIDELINESHIGH LIGHTS

1. Must be prepared by licensed pharmacists certified in aseptic compounding

2. Air & Surface Sampling Required

3. Room Certifications

4. QA testing

5. Beyond Use Dating

797 Personnel Requirements

• Properly trained to perform & document duties

− aseptic hand cleaning & garbing

− achieve & maintain sterility within ISO 5 environment

− select, measure & manipulate ingredients

− handle sterile products aseptically

Low Risk CSP’s

− Transfer, measure & mix of <3 commercially manufactured sterile products

− < 2 entries into any sterile container

− BUD without documented stability/sterility testing:

48 hrs (rm temp), 14 days (fridge), or 45 days (frozen)

− If product compounded in ISO5 equipment which is NOT located within ISO7 environment, product must be administered within 12 hrs

− Annual media tests completed & documented

Medium Risk CSP’s

• Multiple sterile ingredients combined for multiple patients or single patient on multiple occasions.

• Extended time to complete (dissolution or mixing)

• BUD without documented stability/sterility testing:


• Annual Media Tests completed and documented

High Risk CSP’s

• Non-sterile ingredient(s)

• Use of equipment or ingredients that have been exposed to environment worse than ISO5

• BUD without documented stability/sterility testing:


• Sterility testing for autoclaved CSP’s not required for batches < 25 units

• Sterility by filtration must be performed using 0.22 micron filter in an ISO5 environment or better.

• Semi-Annual Media Tests completed and documented

5

Special Conditions

• Immediate-Use CSP’s

• Hazardous Drug CSP’s

• Radiopharmaceutical CSP’s

• Allergen Extract CSP’s

Sterilization• Verification of testing & monitoring of personnel &

environment

• API determined to be stable under chosen method

• Glass & metal devices dry heat sterilized

• Filter integrity tested after use

• Autoclaving at 121 degrees, 15 psi, for 20-60 minutes

• Dry-heat sterilization reserved for special cases

Environmental Quality

• ISO 5 workspace within ISO 7 buffer area with >0.02-0.05” water column pos pressure to ante-room

• ISO 8 ante-room for garbing, storage and prep with >0.02-0.05” water column pos pressure to unclassified areas

• ACPH (air changes per hour) > 30

• Constructed of approved materials (non-porous)

Environmental Sampling

• Environmental sampling @ recertification (q 6 mo), facility or equip servicing, and/or issue response

• Nonviable: tests performance of system

• Pressure Differential: Meter installed to measure positive pressure between classified areas. Readings monitored and recorded daily

• Viable: Surface sampling with contact plates & volumetric air sampling > every 6 months

Environmental Maintenance

• ISO 5 area: each shift, each batch, after spill or suspected contamination, after 30 minutes of ongoing compounding.

• ISO 7 & ISO 8 work surfaces cleaned daily

(counters & easily cleanable work surfaces)

• Floors: Daily

• Walls, Ceilings, storage shelves: Monthly

CONNECTICUTREGULATION CHANGE

EFFECTIVE 7/1/14

STATE OF CT MANUFACTURING LICENSE REQUIRED TO DISPENSE COMPOUNDED

MEDICATIONS TO MEDICAL FACILITIES/OFFICES

PHARMACY REQUIRED TO CREATE & MAINTAIN A SEPARATE FILING SYSTEM FOR MEDICATIONS

DISPENSED TO MEDICAL FACILITIES/OFFICES

LIMITED TO A TWO WEEK SUPPLY

6

Clinical Trials

• Double Blinded Research

• Phase I Clinicals

“Pharmacies producing drugs for clinical studiesunder an IND must adhere to the requirementsin the IND and are subject to all requirements andregulations applicable to INDs”*

*www.fda.gov/downloads/Drugs/.../Guidances/ucm070273.pdf

FDA COMPOUNDING QUALITY ACT

Outsourcing Facilities or 503Bexempt from labeling requirementsCGMP requirementsinterstate commerce allowedlarge volume batches allowed

Commonly Compounded Non-Sterile Medications

• Bio-Identical Hormones

(Bi-Est, Tri-Est, Progesterone, Testosterone, DHEA, etc)

• Transdermal Creams (NSAIDS, Corticosteroids, Anxiolytics, etc)

• Mupirocin Nasal Spray

• Nail Fungus Solutions (Fluconazole, Itraconazole, Zinc, etc)

• Pain Gels

-ketamine

-gabapentin

-cyclobenzaprine

-amitriptyline

-baclofen

• Salicylic Acid 70% Ointment

Commonly Compounded Sterile Medications

Injections

• TriMix or Triple P

• Intrathecal pain meds

Bladder Irrigations

• Gentamicin

• DMSO/Lidocaine

Ophthalmics

• PF

• Combinations

Commonly OrderedOffice-Use Medications

• Tetracaine solution or gel (Pontocaine)

• Cantharidin Solutions

• Salicylic Acid 70% Ointment

• Dexamethasone Injections

• Benzocaine/Lidocaine/Tetracaine Gels

1. Pharmaceutical compounding includes preparation of drug dosage forms for all of the following except:

1. Animals

2. Resale by physicians

3. Clinical research

4. In anticipation of routine ordering patterns

5. Not sure

7

2. Which condition is considered a basic required component of quality compounding?

1. Well documented personnel training

2. Reproducible process

3. Certificate of Analysis for all ingredients

4. All of the above

5. Not sure

3. Which of the following is not a requirement for ingredient selection in compounding?

1. MSDS available

2. FDA-registered source for manufacturer

3. Documentation of storage conditions

4. NDC number recognized by patient’s insurance company

5. Not sure

4. Which ingredient is not on the NIOSH Hazardous chemicals list?

1. Salicylic Acid

2. Chlorambucil

3. Progesterone

4. Warfarin Sodium

5. Not sure

5. Which of the following is an acceptable sterilization method for an aqueous suspension?

1. Filtration through 0.22 micron sterile filter

2. Autoclaving at 121 degrees Celsius & 15 psi for 20-60 minutes

3. Dry Heat sterilization at 250 degrees Celsius for 30 minutes

4. Autoclaving at 100 degrees Celsius & 20 psi for 15 minutes

5. Not sure

Questions???

For more information

Michael Roberge

(203) 268-4964

[email protected]

1

ACC/AHA Guideline on the Treatment of Blood Cholesterol:

Update for Pharmacists

C. Michael White, PharmD, FCP, FCCPProfessor and Head, Pharmacy Practice, UCONN

Co-Director, HOPE Collaborative Group, UCONN/Hartford Hospital

Learning Objectives

• At the conclusion of the lecture and post-lecture study, the successful learner will be able to:– Discuss the ACC/AHA recommendations in terms of

key differences from previous guidelines.

– Identify the four patient groups that may benefit from statin therapy as a result of guideline recommendations.

– Differentiate statins in terms of intensity, efficacy, and drug interactions.

– Utilize the risk calculator and make treatment recommendations based on a patient case.

Lipid Lowdown• LDL = bad cholesterol

– LDL carries most (70%) cholesterol to periphery– Strongly correlated with atherosclerosis

• Triglycerides:– <150mg/dL is normal, >500mgdL can increase risk of

pancreatitis– 20% of triglycerides delivered via VLDL

• VLDL is atherogenic like LDL-C

• HDL = good cholesterol, higher amounts better – <40mg/dL = bad– >60mg/dL = protective

Formulas

• Total cholesterol = LDL + HDL + VLDL– VLDL = (Triglycerides/5)

• Non-HDL = LDL + VLDL

• Non-HDL = Total Cholesterol – HDL

AHA/ACC Lipid Guidelines

White CM. Drug Topics 2014;2:53-60

AHA/ACC Risk Calculatorhttp://my.americanheart.org/professional/StatementsGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jspthen click on web based risk calculator in upper right.

2

Patient Case– Tony Arroz is a 58 year old African American

male who comes in for a healthy check visit at your community pharmacy. He receives a point of care lipid profile after a 12-hour fast and has his blood pressure taken. His total cholesterol is 206mg/dL, LDL is 143mg/dL, HDL is 53mg/dL, and his resting blood pressure is 150/82 mmHg. He is on no medications, does not have diabetes, does not smoke, and has no ASCVD

Mr. Arroz Risk Calculation

Variable Guidance Value Entered

Gender M or F M

Age Years 58

Ethnicity AA or WH AA

Total C mg/dL 206

HDL C mg/dL 53

SBP mmHg 150

HTN Dx Y of N N

DM Dx Y or N N

Smoker Y or N N

Your 10-Year Risk % 9.9

10-Year Risk at Your Age with Optimal Risk Levels

% 5.5

Where is Mr. Arroz?


A

B

C

D

AHA/ACC Lipid Guidelines


Therapy Impact on Intermediate Outcomes

Summary Lipid Effects

Drug LDL TG HDL

All Around Winners

Statins - 35-58% - 10-25% + 7-12%

Niacin - 15-30% - 30-60% + 20-30%

LDL Specialists

Resins - 15-20% - 4% + 4%

Ezetimibe - 15-20% - 4% + 4%

Triglyceride Specialists

Fibrates +/- 5% - 30-60% + 5%

Omega-3 FA +/- 5% - 30-60% + 5%

Dose IndependentDose Dependent Effects

3

LDL Lowering – Statin/Statin Combo

White CM. US Pharm 1998;23:HS19-28., Stein E, JACC 2001;37:291A., Paoletti R ACC 2001. AHFS 2013.

Drug <25% 25 -35% 35 -40% 40 -45% 45 -50% 50 –55%

55 –60%

Fluva, Lova, Prava

10 -20mg

20 -40mg

80mg

Simva 5mg 10mg 20mg 40mg 80mg

Pitava 1mg 1mg 2mg 3mg 4mg

Atorva 10mg 10mg 10mg 20mg 40mg 80mg

Niacin + Simva

500/20 mg

500/20 mg

500/20 mg

1000/20 mg

1000/40mg

2000/40mg

Rosuva 5mg 5mg 10mg 10mg 20mg 40mg 80mg

Ezet + Simva

10/10 mg

10/10 mg

10/10 mg

10/10 mg

10/20 mg

10/40 mg

10/80 mg

Intensity of Statin Therapy in primary and secondary prevention


Impact on Final Health Outcomes

Statin vs. Placebo: Landmark Clinical Trials

• Primary Prevention: WOSCOPS, AFCAPS/TexCAPS, ASCOT-LLA, JUPITER – Prava, lova, atorva, rosuva reduce cardiac events

• JUPITER: LDL goal near 100mg/dL may be better than 130mg/dL

• Secondary prevention: CARE, LIPID, 4S, HPS, GREACE– Prava, simva, atorva reduce mortality and recurrent

events

50

Secondary preventionPrimary prevention

CARE-Rx

4S-Rx

LIPID-Rx

CARE-PL

LIPID-PL

4S-PL

AFCAPS-Rx

AFCAPS-PL

WOSCOPS-RxWOSCOPS-PL

70 90 110 130 150 170 190 210

0

5

10

15

20

25

LDL-C Lowering With Statins: Reduced CHD Events

LDL Cholesterol (mg/dL)

Illingworth DR. Med Clin North Am. 2000;84:23-42.

High vs. Low Intensity Statins: Landmark Clinical Trials

• Secondary Prevention Trials• PROVE-IT Trial

– Prava 40mg vs Atora 80mg– LDL 90-100mg/dL vs. 60-70mg/dL

• TNT Trial– Atorva 10mg vs. Atorva 80mg– LDL 90-100mg/dL vs. 60-70mg/dL

• LOWER IS BETTER

4

PROVE-IT: Final LDL Level

Pravastatin 40 mg (IQR) (n=1973)

Atorvastatin 80 mg (IQR) (n=2003)

p

Final LDL cholesterol (mg/dL)

95(79-113)

62 (50-79) <0.001

Cannon CP et al. N Engl J Med 2004. Available at: http://www.nejm.org.

IQR=Interquartile range

PROVE-IT: Final Health Outcomes

Primary end point Pravastatin 40 mg (n=1973)

Atorvastatin 80 mg (n=2003)

Relative risk reduction, %

p

Mortality, MI, UA, PCI, CABG, Stroke

26.3% 22.4% 16% 0.005

Cannon CP et al. N Engl J Med 2004. Available at: http://www.nejm.org.

Secondary end points

All-cause mortality 3.2% 2.2% 28% 0.07

Revascularization 18.8% 16.3% 14% 0.04

Statin + Adjunctive Therapy• Adjunctive therapies improve lipid effects over

statins alone– Up to November 2014, did not impact final

cardiovascular health outcomes (death, MI, ACS, stroke, revascularization)

• Niacin + Simva vs. Simva alone– AIM-HIGH and HPS-THRIVE Trials

• Fenofibrate + Statin vs. Statin alone (diabetics)– ACCORD Trial

• Torcetrapib + Atorva vs. Atorva Alone– ILLUMINATE Trial

Statin + Niacin• AIM-HIGH – Secondary Prevention Trial• 3414 participants in US and Canada with a history of

cardiovascular disease, low HDL cholesterol, and high triglycerides

• Simvastatin + Placebo vs. Simvastatin + Niacin ER (doses up to 2000mg/day)

• Additional LDL lowering, 25% high HDL, lower triglycerides– LDL-cholesterol levels maintained at the target range

between 40 and 80 mg/dL – Simva + niacin ER did not reduce the five-component

end point [MI, stroke, hospitalizations for ACS, or revascularization]

• 5.8% in the high-dose-niacin group vs 5.6% in placebo group (p=NS)

– 28 strokes (1.6%) reported with simva + niacin ER vs. 12 strokes (0.7%) in the control group (p=NS)

Statin + Ezetimibe: IMPROVE-IT Trial

Clinical Outcomes Simva 40 mgn=9077 (%)

Ezet 10mg/Simva 40mg, n=9067 (%)

P-value

Primary end point (CV death, MI, UA, PCI/CABG, or stroke)

34.7% 32.7% 0.016

All-cause death 15.3% 15.4% 0.782MI 14.8% 13.1% 0.002Stroke 4.8% 4.2% 0.052Ischemic stroke 4.1% 3.4% 0.008Unstable angina 1.9% 2.1% 0.618Coronary revascularization

23.4% 21.8% 0.107

1. Pts enrolled <10d from ACS2. LDL reduced from 95mg/dL to 70mg/dL (Simva 40mg)

or 53mg/dL (Simva 40mg + Ezetimibe 10mg)3. Follow-up 2.5-7y

Cannon C. AHA November 2014

Non-Statin Monotherapy and Final Health Outcomes

• Fibrates in Diabetes– FIELD Trial

• Diabetics with higher triglycerides & low HDL but without markedly elevated LDL

• Fenofibrate 200mg daily vs. placebo• Nonfatal MI [HR 0.76 (0.62-0.94)], revascularization [HR 0.80

(0.70-0.92)]• Total mortality [HR 1.11 (0.95-1.29). P=0.18]

– VA-HIT + Helsinki Heart Study• Benefits in diabetic & metabolic syndrome patients with higher

triglycerides & low HDL but without markedly elevated LDL• Gemfibrozil vs. placebo• Significant reductions in cardiac events and cardiovascular

mortality

FIELD Inv. Lancet 2005.

5

Non-Statin Monotherapy and Final Health Outcomes

• Niacin monotherapy– Meta-analysis of 11 clinical trials (n= 9959)

– Niacin can reduce cardiovascular events by 34% and coronary heart disease events by 25% vs. placebo

Lavigne PM. JACC 2012.

What Statins and Doses are Needed in Mr Arroz?


A B

C = A or B

D = A + B

Intensity of Statin Therapy in primary and secondary

prevention


Statins: Patient Management

Drug Therapy: Statins• Contraindications

– Pregnancy, breastfeeding (category X)

– Active liver disease or high unexplained liver transaminases (AST, ALT, LDH)

• Fatty liver can raise liver transaminases and is treated with statins

• LFTs checked at baseline and when clinically indicated– If baseline LFT >3X ULN, find out reason

– Normal: AST 0-35mg/dL, ALT 5-40mg/dL, LDH 50-150mg/dL

– If any follow-up LFT >3X ULN, hold statin until resolution and reinitiate with another statin, lower the dose, or use another class

– No resolution of LFT elevation, liver biopsy

• Pravastatin, rosuvastatin, simvastatin has lower risk of LFT elevation/hepatotoxicity than atorvastatin

• Greater risk with concurrent fibrate or niacin use

White CM. J Clin Pharmacol 2002;42:963-70.

Persistent ALT > 3 × ULN Frequency by % LDL-C Reduction

Ref: Prescribing Information and Summary Basis of Approval documents.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

% p

ersi

sten

t A

LT >

3 ×

UL

N

% LDL-C reduction

Fluva 20-80mg

Lova 20-80mg

Simva 10-40mg

Atorva 10-80mg

Rosuva 5-40mgPrava 20-80mg

6

Proteinuria

• Incidence 1.1% rosuvastatin vs. 0.4% other statins

• Excretion of α-1 & β-2 microglobulin, not albumin

– Reduced reabsorption of small proteins usually reabsorbed in kidney tubules

• If hematuria (blood in urine), halt statin therapy til resolved and switch to another statin or another class

Muscle Toxicity• Myalgia

– Muscle pain• Test CK (normal 10-150u/L Male 10-130u/L Female)

– If CK in myopathy range >10X ULN (1300u/L female, 1500u/L male), stop therapy– If >3X ULN, test weekly til 10X ULN or normalization

• Rhabdomyolysis– Seldom occurs without myalgia preceding it

• Counsel to contact physician if myalgia, especially with fever and malaise– Severe muscle breakdown– Myoglobinemia and myoglobinuria common

• Brownish or black urine– CPK increased >10,000 u/L– Can cause renal failure– Can cause prolonged muscle weakness needing rehabilitation

• Greater risk of rhabdomyolysis with simvastatin and lovastatin than hydrophilic statins (atorvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin)

• Greater risk with concurrent fibrate, daptomycin, colchicine, niacin or for simvastatin or lovastatin use of CYP3A4 inhibitors

AHFS 2001, FDA NDAC Advisory Panel (7/13/00 from www.FDA.gov)

Intra-Muscle IC50 for Synthesis

Prava vs Simva

– 399X - protein

– 228X - ATP

– 98X - CK

– 111X - MTT

•MTT = marker of mitochondrial dehodrogenase activity

•Adding mevalonic acid lactone normalized synthesis

Masters BA. Toxicol ApplPharmacol1995;131:163-74.

Metabolic Pathways & Rhabdomyolysis

• Lova, simva, and atorva are CYP 3A4 substrates– Inhibitors of CYP 3A4 increase risk of rhabdomyolysis

with lova + simva but not shown with atorva

– Lova and simva are contraindicated or have maximum dosing limits with CYP3A4 inhibitors

– CYP3A4 inhibitors: Azole antifungals (ketoconazole, itraconazole), macrolides (erythromycin, clarithromycin, trandeolamycin), cyclosporin, nefazodone, nondihydropyridine CCBs (diltiazem, verapamil), protease inhibitors (saquinavir, indinavir, ritonavir, amprenavir), amiodarone, dronedarone

– 93% of rhabdomyolysis cases occur w/ concurrent CYP3A4 inhibitors White CM. US Pharm 1998;23:HS19-HS30.

Omar MA. Ann Pharmacother 2001;35:1096-107.

Simvastatin or Lovastatin + CYP3A4 Drug Interactions

• FDA revised product labeling:– Do not use with itraconazole, ketoconazole,

erythromycin, clarithromycin, protease inhibitors, nefazodone, or >1qt of grapefruit juice

– Use 10mg of simvastatin or 20mg of lovastatin with cyclosporine

– Use 20mg of simvastatin or 40mg of lovastatin with amiodarone or verapamil

Simvastatin and CYP 3A4

• In clinical trials incidence of myopathy/rhabdomyolysis on simvastatin was 13/21,224 pts or 0.061%– Incidence was 0.63% if drug used with

verapamil and 6.0% if drug used with amiodarone

7

CYP3A4 Inhibitors Extent of

White CM. Conn Med 2000;64:533-5

Diltiazem + LovastatinHigh Variability in Interaction Magnitude

Lovastatin AUC (% control)

Aznie NE. Clin Pharmacol Ther 1998;64:369-72.

Statin/Fibrate Combinations

Prueksaritanont T, et al. Drug Metab Disp 2002;30:1280.

HydroxysimvastatinHydroxyacid

Lactone

Simvastatin

Gemfibrozil with Simvastatin

• Pts (n=10) on simva alone and then on simva after 3 days of gemfibrozil

• Gemfibrozil is not a CYP3A4 inhibitor (no intx with midazolam or cyclosporin)

Hackman JT. Clin Pharmacol Ther 2000;68:122-9.

Simva Acid AUC

Effect of Gemfibrozil on Statin Plasma Concentrations

Ratio of AUC in gemfibrozil-treated patients to AUC in placebo patients

Effect of Gemfibrozil and Fenofibrate on Rosuvastatin Plasma Concentrations

Ratio of rosuvastatin AUC in fibrate-treated patients to AUC in placebo-treated patients

8

Pitavastatin

• Normal doses 1-4mg• Substrate for Uridine Diphosphate

Glucuronosyltransferase (UGT)– Pitava contraindicated with cyclosporin– Max dose 2mg with rifampin– Max dose 1mg with erythromycin– Atazanavir, lopinavir, ritonavir have minor

interaction

Dosing Pearls: Absorption

• Bioavailability of lovastatin 50% by food– High fiber meals reduce bioavailability

– Dose with dinner for most food with least fiber

• Can’t use lovastatin with bile acid sequestrants– Both need dosing with meals

White CM. US Pharm 1998;23:HS19-HS30.

Dosing Pearls: Half-Life

• Short half-life drugs (fluvastatin, pravastatin) should optimally be dosed QHS– This is because night is the optimal time for

circadian activation of HMG CoA reductase

• Others can be dosed at any time

White CM. US Pharm 1998;23:HS19-HS30., Martin PD. Data on File AstraZeneca.

Non-Statins: Patient Management

Non-Statin Lipid Impact

LDL TG HDL

Niacin -15 to -25% -20 to -50% +15 to +35%

Ezetimibe -15 to -20% -5 to -8% +3 to +5%

BAS -15 to -30% 0 to -10% +3 to +5%

Lomitapide -30 to -40% -40 to -50% -7%

Mipomerson -25% -18% +15%

Lipid Apheresis -50 to -68% 0% 0%

Fibric Acid Deriv -30 to +10% -30 to -60% +9 to +20%

Omega-3 FAs -5 to +44% -30 to -60% +5 to +10%

White CM. Drug Topics. Feb 2014

Classics for LDL ReductionUse in Renal Dx

Pregnancy/ Breastfeeding

Drug Intx GI ADEs Notes

BAS Yes Pregnancy: Cat BBreastfeed: Safe

Absorption of lipid and diabetes meds, levothyroxine, contraceptives, olmesartan, digoxin, and warfarin

+++Constipation, Bloating

1. Colesevelam < Drug Intx Risk and Less Vitamin A, D, E, K Absorption Blocking2. No use in Gastroparesis3. Use ColesevelamSuspension in Dysphagia

Niacin Use Caution

Pregnancy: Cat CBreastfeed: Possible Use

None +++ Dyspepsia, Nausea.Contraindwith PUD

1. Uric Acid and Transient Serum Glucose Conc2. False + for catecholamines or glucose in urine

Ezetimibe Yes Pregnancy: Cat CBreastfeed: Possible Use

Ezet + Feno = Increased Gallbladder RiskEzet Cyclosporin

+ Diarrhea 1. Only one dose (10mg)2. Not Recommended in LFTs but not Contraind


9

Other Lipid DrugsUse in Renal Dx

Pregnancy/ Breastfeeding

Drug Intx GI ADEs Notes

Lomitapide Yes Pregnancy: Cat XBreastfeed: Do not use

Contra w/ CYP3A4 inh. Blocks CYP3A4 and PGP

++++ Diarrhea, Nausea, Flatulence

1. Supplement Fat Soluble Vits2. Can Raise LFTs

Mipomerson No use in Severe RenalDx, Dialysis,Proteinuria

Pregnancy: Cat BBreastfeed: Use Caution

None No 1. SQ Dosing Only2. No Use in Fatty Liver Dx

Fibric AcidDerivatives

Gemfib: YesFeno: DoseAlter, Contraind in Severe Dx

Pregnancy: Cat CBreastfeed: Contraind

1. Statins2. Warfarin INR3. BAS Fibrate4. Gemfib Repaglinide5. Fenofib + Colchicine Myopathy6. Fenofib + Ezet Gallbladder Risk

Gemfib +++ (Dyspepsia, Diarrhea, Flatulence)Fenofib +

No Use in Gallbladder DxPatients


Molecular comparison

Niacin

• Niacin, nicotinic acid, and Vit B3– Synonymous terms– Niacinamide and nicotinamide are not niacin

• Contraindications– Active liver disease or baseline unexplained liver

transaminases >3X ULN• If due to fatty liver, can use niacin• Monitor LFTs Q12 weeks for 1 year

– DC if LFTs >3X ULN

– History of severe hemorrhaging– Severe pre-existing hypotension

Niacin: Side Effects• Flushing and pruritus (itching)

– Prostaglandin mediated vasodilation– Occurs within 20 min of ingestion, lasts 30-60 min– Aspirin premedication >30 minutes before niacin can

help– Avoid hot drinks at the same time as niacin ingestion– Sustained release products reduce intensity– Tolerance occurs, titrate dose slowly over time (Q2

weeks)

• GI upset– Take with food

Natural Products With Evidence to Show Lipid Effects Conclusions

• LDL and VLDL are bad cholesterol, increase heart risk– Use NCP ATP guidelines to determine targets for LDL

and non-HDL cholesterol • Statins are first line therapy to achieve LDL and

non-HDL goals– Unknown if any therapy gives additional benefits when

added to optimal statin therapy – Maximize statin dose or switch between statins before

leaving statin class or using adjunctive therapy• Niacin is a reasonable alternative therapy if statins

cannot be used

10

Conclusions

• Three statins (simva, lova, atorva) are CYP3A4 substrates and one (pitava) is a UGT substrate– Myriad of inhibitors that increase muscle risk

• Counsel on statin muscle symptoms and check CK when symptoms arise– Warnings if CK is >3X ULN, DC if 10X ULN

• Three statins have targeted ingestion times– Lova at dinner, prava and fluva at bedtime

1. According to the new ACC/AHA guidelines what would be the most appropriate LDL goal for a 63 year old male with a past medical history of a peripheral vascular disease?

1. LDL goal <70

2. LDL goal <100

3. LDL goal <130

4. No LDL goals are recommended

5. Not sure

2. What is the appropriate statin intensity for a 42 year old man with an LDL of 200 mg/dL per the ACC/AHA guidelines?

1. Low-intensity statin

2. Moderate-intensity statin

3. High-intensity statin

4. Statin therapy is not indicated

5. Not sure

3. The ACC/AHA guidelines recommend that everyone with elevated triglycerides should be treated:

1. With a fibrate

2. With high intensity statin therapy

3. With an Omega 3 preparation

4. They make no recommendation for treating triglycerides

5. Not sure

4. When using the ACC/AHA risk assessment calculator, one must factor in at least:

1. BMI and diastolic blood pressure

2. Systolic and diastolic blood pressure

3. Total cholesterol and HDL

4. Marital status

5. Not sure QUESTIONS?

1

Examining Current and Proposed Pharmacy Law Issues in CT

John Gadea, Jr, RPhDirector, Drug Control DivisionDepartment of Consumer ProtectionHartford, CT

Learning Objectives

• Recognize recent pharmacy inspection findings and trends

• Discuss the future of the CT Medical Marijuana Program

• Summarize opioid abuse issues including the responsibility of the pharmacist

• Discuss the CT Business Status Application and its benefits

• Summarize current and proposed legislation and regulations affecting pharmacy practice

Department of Consumer ProtectionDrug Control Division

Drug Control Division:

Compliance, Investigations, Enforcement, Education.• Agents (RPh)

Prescription Monitoring Program

Medical Marijuana Program

Board Administrator ‐ Commission of Pharmacy

Pharmacy Inspections

Inspections

Pharmacy

• Routine

• Special Inspections

• Findings

– Messy working environments

• Staffing ?

– Technician Ratios

Sterile Compounding

2

Information/Inspection

• Package has been modified several times, never released. Nearly ready, being taken into the field.

• Point of Contact for Hospital Based Issues, Questions or Inspections regarding USP 797:

Daniel Carpenter, Drug Control Agent • 860‐713‐6065

• [email protected]

Information/Inspection

Compliance

• Identify – to genus level

• Remediate – by choosing an appropriate agent to kill the growth.

• Eliminate – this is shown by subsequent environmental retesting showing that the organisms have been eliminated by No EM growth.

Diversion

Areas of ConcernCommunity Pharmacy:• Quantities from inventory• Aware of orders vs usage• Messy work environments

Hospitals:• Ambulance Controlled Substance Kits.

– Proper Inspections of Containers.– Proper Review of Documentation.

• Aware of Patient Response to Medications.• Quantities from inventory• Aware of orders vs usage

Where Pharmacist Can Help

• Vigilance– Patient Responses.– Purchases.– Odd situations.

• Compliance– Adherence to policies and regulations.

• Education– Public.– Patients.– Co‐professionals (nurses, pharmacists, technicians, physicians)

• Opioid antagonists

3

Medical Marijuana

Debilitating Medical Conditions Recognized by the Law

• Cancer

• Glaucoma

• Positive status for human immunodeficiency virus or acquired immune deficiency syndrome

• Parkinson’s disease

• Multiple sclerosis

• Damage to the nervous tissue of the spinal cord with objective neurological indication of intractable spasticity

• Epilepsy

• Cachexia

• Wasting Syndrome

• Crohn’s disease

• Post‐traumatic stress disorder

Pending Debilitating Medical Conditions:

• Post‐Laminectomy Syndrome

• Severe Psoriasis and Psoriatic Arthritis

• Sickle Cell Disease

Quick Facts

• Number of Patients – Registered: 3600

• Number of Certifying Physicians: 200

• Automated Certification/Registration process:

– Started

Medical Marijuana Pharmacology

‐ marijuana is fat soluble‐ effects may persist or reoccur for 12‐24 hours‐ the ability to drive a car or a plane, other motor performance tasks, alertness and the ability to concentrate may be affected for hours to days

Producer Product Label Dosage Forms

• Wax

• Tincture

• Vapor cartridge (is there any controversy with these?)

• Shatter

• Concentrated Oil Blend

• Plant material

• Sublingual

• Oral

4

Product Examples Testing

• Active ingredients

• Pesticides

• Heavy metals

– Arsenic, Cadmium, Lead, Mercury

• Mycotoxins

• Microbiologicals

Next

• Patient (MMP) is admitted into a:

– Acute Care facility,

– Long Tern Care facility,

– Hospice,

• The ‘Institution of Hospice’– Institution,

– Home.

– Policy applies to all facilities

Factors to Consider

• Will your facility allow a marijuana product to be used in your facility?– Schedule 1 ‐ Federal

– Schedule 2 ‐ CT

• Most facilities do not allow smoking on the premises.

• Many facilities do not allow personal medications to be used.

• No use of non formulary drugs.

Factors to Consider

• Federal Courts have told the FDA that e‐cigarettes should be seen as tobacco products.

– Vaporization.

• Equivalency between dosage forms.

• Constant communication between patient, physicians, facility, dispensary (pharmacist).

– Anticipatory actions.

Factors to Consider

• How to get product to the patient (Legally).

– Caregiver (If the patient has one).

– Obtaining a caregiver if the patient does not have one at the time of admission.

– Proper planning goes a long way.

• Develop the appropriate policies and procedures.

• Pending Legislation

5

Establishment of standards

• Expiration dates.

• Stability testing.

• Storage requirements,

– Recent issue with botulism with non‐refrigerated product.

Drug Studies

• Data Collection

• Trial of Products

• Improved dosage forms

– Non smoking

Drug Waste

• Commercial methods

• Home/Personally generated drug waste

– Community based methods

• The Community Take Back Program

• DEA Take Back Program

• Drop Box Program

– Home disposal

Commercial Drug Waste

• Drug Control Compliance

• DEA Compliance

• DEEP Compliant Methods

• Cannot use Home Waste exemption and Personal Waste Medication exemption for the disposal of commercially generated waste.

Home/Personally generated drug waste– Community based methods

• The Community Take Back Program– originally established by CVS and NERC

– Handed off to Drug Control

– Some excellent programs such as Southington

• DEA Take Back Program– Copied community based programs

– No longer available

• Drop Box Program– In CT only available in a Police Department

– Home disposal

• Most cost effective

• Most efficient

• DEEP approved

The DEA waste regulations

• Why

– Good

• applies nationwide

• Not actual mandated

– Bad

• Does not show an indication of understanding of medical practice in most settings.

• Once regulations passed, DEA no longer has to conduct DEA Drug Take Back Program

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Reasons why not to place Drop Boxes anywhere but Police Departments

• The Fed Regs say ‘in the pharmacy’.– Blueprint.– Access/security.– Pharmacist “already monitors controlled substances”.

• In ECFs‐responsibility of Provider Pharmacy.• Contamination of pharmacy area.• Reuse of Product.• Diversion.• Accountability of waste bags.• Waste

– Waste generator.– Waste Hauler.

• Once these regs were passed DEA no longer has to conduct DEA/Community Drug Take Back Programs

• Example‐UConn Pilot Waste Program

Connecticut's Drop Box Program

• 57 Municipal Police Departments

• Handled as Abandoned Property.

• 2014 approximately 21,000 pounds.

• No cost to the general fund.

• Several boxes donated by private sector,– Bunker Hill Pharmacy, CVS, others.

• Partnered with local community groups

• Covanta‐waste handling and disposal company.– Wheelabrator‐ Bridgeport

Pending Legislation

Legislation

The Governor’s Bill:– An Act Concerning Substance Abuse and Opioid Overdose Prevention

• Continuing Education: prescribing controlled substances and pain management.

• Live Data

• Physician Delegate (Licensed by DPH)

• Mandatory review prior to prescribing a greater than 72 hour supply

• Review chronic C/S medication every 90 days

• Pharmacist Prescribing of opiate antagonist.

Legislation

Medical Marijuana Bill:

– Provides Lab employees with immunity.

– Provides a mechanism for under 18 yo.

– Immunity to administering nurses.

– Allow delivery from dispensary facilities to institutions. (If allowed by the institutions).

– Establishes mechanisms for research programs.

Emergency Service Locator for Consumers

Smart Phone VersionDepartment of Consumer Protection

Drug Control Divisionhttp://businessstatus.ct.gov

7

Introduction

THESE ARE INSTRUCTIONS FOR CONSUMERS.THIS TOOL WILL ALLOW USERS TO ACCESS

THE CONNECTICUT SERVICES LOCATOR DATABASE VIA SMART PHONES. THE

PROGRAM IS WEB BASED AND ACCESSIBLE THRU THE INTERNET ON SMART PHONES AND

COMPUTERS.Please proceed to the following url:

http://BusinessStatus.ct.gov

Smart Phone

O The software in the website will adjust to most web browsers on Smart Phones (iPhone, Android Phones, Windows Phone, and others.) such as Safari, Firefox, Chrome, etc.

O The next few slides will be demonstrating the use of the website on a Smart Phone

Smart PhoneFigure 1 Currently Pharmacies are

identified in the system but Medical Oxygen Providers, Gasoline Stations and Grocery Stores will soon be included. Choose the type of Service Provider from the Drop Down.

The system defaults to a 10 mile radius from either your current location or an address that you may enter. You may change the 10 mile default to any mile distance.

From the Smart Phones, it is best to use “By distance from current location” using your GPS. However, the “By Distance from Address” option does work.

Smart PhoneFigure 2 Once you have your choices (identified in figure 1 and

2) the following screen will be visible (figure 3). This screen will be composed of a list of pharmacies. (Or oxygen retailers, grocery and gasoline stations depending on which list you have chosen).

A view of the list will indicate if the business is: Open- Will be highlighted in GREEN Closed- Will be highlighted in RED Unknown (if open or closed)- Will have no color Whether the business has:

Phone Power

Any other information such as hours of operation etc. Distance to the business from the entered

address/current location.

NOTE: This information is the responsibility of the business to keep current and relevant.

Prior to a potential weather event or other statewide emergency, which may affect these businesses, the Department will re-classify every business to UNKNOWN status approximately 24 – 48 hours prior to event occurring.

Web Browser

Figure 2 Select an available

retailer (green-highlighted entry) from the list.

Proceed to the screen shown in Figure 3

Smart PhoneFigure 3

The button located to the right of “Transportation method” can be used to identify three methods of transportation: Walking; Bicycling; and Driving.

After choosing the Transportation Method, select the “Get Directions” button.

8

Smart PhoneFigure 4

The directions from either your current location or the entered address are demonstrated on a Google map and in writing.

RetailerBusiness StatusDuring Crisis

Department of Consumer ProtectionDrug Control Division

ANDFood and Standards Division

Introduction

THIS TOOL WILL ALLOW BUSINESS USERS TO ACCESS THE CONNECTICUT SERVICES

LOCATOR DATABASE. THE PROGRAM IS WEB BASED AND ACCESSIBLE THRU THE INTERNET

ON SMART PHONES AND COMPUTERS.

Please proceed to the following url:http://BusinessStatus.ct.gov

THESE ARE INSTRUCTIONS FOR BUSINESSES TO ACCESS THE CONNECTICUT SERVICES LOCATOR DATABASE FOR OXYGEN DISTRIBUTORS, GROCERY STORES AND GAS STATIONS ONLY.

THIS PROCEDURE WILL GUIDE YOU THRU THE REQUIRED STEPS FOR THE PROCESS: THE FIRST IS THE INITIAL LOG-IN. THE SECOND IS THE SUBSEQUENT LOG-IN ONCE

YOU HAVE IDENTIFIED THE BUSINESS YOU ARE TIED TO.

WHAT THE SERVICE WILL LOOK LIKE FOR THE CONSUMER.

Retailer Instructions

The link for a Business to create an account:https://www.biznet.ct.gov

This URL is not posted publicly.

Oxygen distributors, Grocery Stores and Gas Stations will have to create an account in the Biznet System if they do not already have one.

Once the URL is entered the following screen will be visible:

INITIAL LOG‐IN INITIAL LOG‐INO If you are on this

screen (Figure 1), please select “Emergency Services” link.

O Once you select this link, Figure 2 will be visible (next page).

Figure 1

9

ACCOUNT ACCESSPlease follow the instructions on this page: (Figure 2) If you already have a BizNet

Account, please enter your email and your established password.

If you do not have a BizNetaccount, you must create one to use this product. Select “Create New Account” button and follow instructions.

Once you have established your account, you may log on to the screen seen in Figure 2, entering your e mail address and password. Figure 2

ACCOUNT ACCESS

After logging in, you will see the screen in Figure 3. Select “Business Profile”.

IF YOU ARE LOGGING IN FOR THE FIRST TIME, Please enter the information as it appears on your credential provided by the Department of Consumer Protection in figure 4.

Figure 3

ACCOUNT ACCESS

Please enter the information requested as found on the registration from the Department of Consumer Protection.

Once you have added your information please click the “Add New Business Type” button.

Figure 4

ACCOUNT ACCESS Select your “Business Type” from the

drop down menu. Enter your credential number in the

format; The three letter prefix

The period, ‘.’ Any zeros in the

license/registration as issued by the Department of Consumer Protection.

Once you have added the information please click the “Save” button.

Please note that any information that you provide about the business may be reset by the Department of Consumer Protection.

ACCOUNT ACCESS

Please Note:This information is very important to consumers and your business. Care must be taken to ensure that you are on the correct business page and you have made the correct entries and updates.

Once you have previously logged on and identified your business, the next time you log in and click on Business Statusidentified on figure 3, your previously identified business will be seen in your next screen. Please see screen, figure 5, below.

ACCOUNT ACCESS

Figure 5 From this screen you may

create a new business profile. Proceed to edit the information or delete record.

To edit the record, click on the binoculars image under EDIT and you will see a new screen (Figure 6, next page).

Figure 5

10

ACCOUNT ACCESS

Figure 6 From this screen you may

add a new business type or make any changes to the visible data. You may also edit the status information or delete record.

To edit the status information, click on the binoculars image under EDIT and you will see a new screen, (figure 7, next page).

ACCOUNT ACCESS

Figure 7

On this screen you may change the status of your business, and/or whether you have phone service or power.

You may also add comments such as changes in business hours, powered by generator, etc.

Make sure to save any changes. These changes may be instituted as often as you would like.

ACCOUNT MAINTENANCE

Figure 7 To modify the individuals

having access to this business entity’s information, click on the Business Accounts located in the middle of the header.

Once “Business Accounts” is selected. A new screen will appear (see figure 8next page).

ACCOUNT MAINTENANCE

Figure 8

On this screen, you will see the account identifier (email address) of the person establishing the account. You may add email addresses for other individuals.

For example, if you are the business entity manager, you may add other authorized employees and possibly a district manager. When completed, select on the “Continue” button to save the entries.

ACCOUNT MAINTENANCE

Figure 9 While on this same screen

you may also delete the authorization(s) previously granted. Again, when completed, click on the “Continue” button to save the entries. It should be noted that the system will not allow you to delete your own account. Please see Figure 9 and note the red warning indicating that you cannot delete your own account.

Questions?

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