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The Science of Prescribing Informa3on
Kellie Schoolar Reynolds, Pharm.D. Deputy Division Director, Division of Clinical Pharmacology IV
Office of Clinical Pharmacology Office of Transla=onal Sciences
Center for Drug Evalua=on and Research, FDA
Disclaimer
• The opinions expressed in this presenta=on are the presenter’s and do not necessarily reflect the official views of the Food and Drug Administra=on (FDA)
• The presenter has no disclosures related to the content of this presenta=on
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Prescribing Informa3on Goals
• FDA’s primary communica=on tool – safe and effec=ve use of a drug
• Inform health care providers – prescribe drugs – counsel pa=ents
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Prescribing Informa3on Data Source
• Drug company submits data – Chemistry – Preclinical – Clinical
• FDA reviews data • Process con=nues post-‐marke=ng (some changes are ini=ated by FDA)
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Prescribing Informa3on Format and Presenta3on
Clear Communica3on Concise and Complete
ART and
SCIENCE 5
The Basics • PLR = Physician Labeling Rule (2006)
– Designed to make informa=on easier for health care providers to access, read, and use.
• Parts – Highlights – Table of Contents – Full Prescribing Informa=on
• Considera=ons – Avoid redundancy – Use cross references – Use ac=onable language
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Highlights
• Concise (half page) summary
• Crucial prescribing informa=on, based on – Knowledge of clinical seYng – Judgment
• Based on Full Prescribing Informa=on • Succinct, relevant, complete
– Ex: risk, consequences, ac=ons to mi=gate or prevent
• Direc=ve Language
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Highlights Headings
• Limita=ons Statement
• Product Names and Date of Ini=al Approval
• Boxed Warning • Recent Major Changes • Indica=ons and Usage • Dosage and Administra=on
• Dosage Forms and Strengths
• Contraindica=ons • Warnings and Precau=ons
• Adverse Reac=ons • Drug Interac=ons • Use in Specific Popula=ons
• Pa=ent Counseling Informa=on (reference)
• Revision Date 8
Highlights Headings A few notes on specific content • Ini=al US Approval • Boxed Warning (If any) • Recent Major Changes • Dosage and Administra=on
• Contraindica=ons • Warnings and Precau=ons • Adverse Reac=ons • Drug Interac=ons • Use in Specific Popula=ons
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Highlights Example of Drug interac3on informa3on in Highlights
Lurasidone hydrochloride (LATUDA®)-‐-‐ • DOSAGE AND ADMINISTRATION
– Concomitant Use of a Moderate CYP3A4 inhibitor (e.g., dil=azem): LATUDA dose should be reduced to half of the original dose level. Recommended star=ng dose is 20 mg per day. Maximum recommended dose is 80 mg per day.
– Concomitant Use of a Moderate CYP3A4 inducer: It may be necessary to increase the dose of LATUDA.
• CONTRAINDICATIONS – Concomitant use with a strong CYP3A4 inhibitor (e.g., ketoconazole).
– Concomitant use with a strong CYP3A4 inducer (e.g., rifampin).
Highlights sec3on Example of Warnings and Precau3ons
UNITUXIN™ (dinutuximab) injec3on, for intravenous use WARNINGS AND PRECAUTIONS • Capillary leak syndrome and hypotension: Administer required prehydra=on and monitor pa=ents closely during treatment. Depending upon severity, manage by interrup=on, infusion rate reduc=on, or permanent discon=nua=on. (5.3, 5.4)
• Infec=on: Interrupt un=l resolu=on of systemic infec=on. (5.5)
• Neurological Disorders of the Eye: Interrupt for dilated pupil with sluggish light reflex or other visual disturbances and permanently discon=nue for recurrent eye disorders or loss of vision. (5.6)
• Bone marrow suppression: Monitor peripheral blood counts during Unituxin therapy. (5.7) • Electrolyte abnormali=es: Monitor serum electrolytes closely. (5.8)
• Atypical hemoly=c uremic syndrome: Permanently discon=nue Unituxin and ins=tute suppor=ve management. (5.9)
• Embryo-‐Fetal toxicity: May cause fetal harm. Advise females of reproduc=ve poten=al of poten=al risk to a fetus and to use effec=ve contracep=on. (5.10, 8.1, 8.3)
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Full Prescribing Informa3on
Boxed Warning
1. Indica=ons and Usage 2. Dosage and Administra=on
3. Dosage Forms and Strengths 4. Contraindica=ons 5. Warnings and Precau=ons
6. Adverse Reac=ons 7. Drug Interac=ons 8. Use in Specific Popula=ons 9. Drug Abuse and Dependence
10. Overdosage
11. Descrip=on 12. Clinical Pharmacology
13. Nonclinical Toxicology 14. Clinical Studies
15. References
16. How Supplied/Storage and Handling
17. Pa=ent Counseling Informa=on
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Full Prescribing Informa3on
• Consistent numbering for sec=ons – Skip number if sec=on is not included
• Limit redundancy – Same informa=on may appear with different level of detail in different sec=ons
– Cross reference • Clear Language
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Labeling Review Process
• CDER has a defined process for labeling review • Process includes
– Timeline with milestones – Oversight by Project Manager
– Reviewer and team leader roles
– Labeling mee=ngs – Study Endpoint and Labeling Development team input
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ART and SCIENCE
Drug Interac=on Informa=on – Complicated science – Impact on many sec=ons of prescribing informa=on
– Poten=al for harm – Same informa=on affects at least two drugs
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Physician Percep3on of Drug Interac3on Informa3on
• Some informa=on is intui=ve, universally appreciated, ingrained – Aspirin and oral an=coagulants – MAO inhibitors and SSRIs
• Clinicians are otherwise overwhelmed – Sheer number of drug interac=ons – Complexity of mechanisms and terminology
• Adapted from informa=on presented by David Juurlink (University of Toronto) at FDA Clinical Pharmacology Advisory Comminee Mee=ng on 9/25/2013
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Physician percep3on-‐ What is wrong with drug interac3on informa3on in Prescribing Informa3on?
• Confusing structure • Too much informa=on • Wrong informa=on • No conveyance of risk • No real guidance
• Adapted from informa=on presented by David Juurlink (University of Toronto) at FDA Clinical Pharmacology Advisory Comminee Mee=ng on 9/25/2013
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Ideal drug interac3on informa3on
• Easy to access and navigate • Minimal pharmacology jargon • Structured in a clinically intui=ve way • Imparts sense of severity or risk
• Provides risk management instruc=ons • Does not include unnecessary informa=on • Up to date
• Adapted from informa=on presented by David Juurlink (University of Toronto) at FDA Clinical Pharmacology Advisory Comminee Mee=ng on 9/25/2013
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Prescribing Informa3on Parts that include Drug Interac3on Informa3on (1)
Labeling Loca=on Drug Interac=on (DI) Informa=on
Highlights
Highlights Headings • Typical DI informa=on: contraindica=ons, dose adjustments, and poten=al for serious DI
• May be a short statement regarding general poten=al for DI
Full Prescribing Informa=on Sec=ons (2) Dosage and Administra=on
Specific dose adjustments for drug that is subject of labeling
(4) Contraindica=ons List coadministered drugs that are contraindicated because combina=on is dangerous and risk clearly outweighs benefit
Prescribing Informa3on Sec3ons that include Drug Interac3on Informa3on (2)
Labeling Loca=on DI Informa=on
Full Prescribing Informa=on Sec=ons
(5) Warnings and Precau=ons
Known or predicted DI with serious or clinically significant outcomes. Examples:
• Sildenafil with ritonavir (11 fold increase in sildenafil AUC, reports of decreased blood pressure and syncope)
• Viekira Pak and mul=ple other drugs (loss of therapeu=c effect and possible resistance, and possible clinically significant adverse reac=ons)
(7) Drug Interac=ons
Drugs that interact or are predicted to interact in a clinically significant way. Includes prac=cal instruc=ons for managing DI. May also include brief informa=on about mechanisms of DI.
(12) Clinical Pharmacology
Present summary of results of in vitro drug metabolism, in vitro DI, and in vivo DI studies.
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Drug Interac3on Study Results
• Content – Results from drug interac=on studies – Study design informa=on (Level of detail varies)
• Ra=onale – supports the drug interac=on management informa=on that is useful to clinicians
– may be useful to clinical pharmacologists or clinical pharmacists who provide drug interac=on management informa=on to the prescribers
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Drug Interac3on Study Results Tables (Clinical Pharmacology Sec3on) • Posaconazole (effect of coadministered drugs on posaconazole in healthy volunteers) – Coadministered drug (postulated mechanism)
– Dose and schedule for both drugs – Percent change in mean Cmax and AUC (and 90% confidence intervals)
Note-‐ The table on the next slide is one example of the type of table that is used to convey drug interac:on informa:on. It is not a template or required format.
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Drug Interac3on Study Results Forest Plot (Clinical Pharmacology Sec3on) • Apixaban (effect of coadministered drugs on apixaban pharmacokine=cs) – Coadministered drug (mechanism; dose)
– Plot illustrates “fold-‐change and 90% CI” for Cmax and AUC – Ver=cal lines indicate “no effect” boundary (not a characteris=c of all Forest plots)
– Recommenda=on-‐ cross reference to sec=on 7 (Drug Interac=ons)
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Apixaban Drug Interac=on Study Results: Forest Plot
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Drug interac3on predic3ons • Tamsulosin hydrochloride (Flomax®)-‐ substrate for CYP3A4 and
CYP2D6.
• The following informa=on is in the labeling (paragraph) – Ketoconazole (strong CYP3A4 inhibitor) 400 mg qd x 5d ↑ Cmax 2.2 x and AUC
2.8 x.
– Effect of moderate CYP3A4 inhibitor not evaluated
– Paroxe=ne (strong CYP2D6 inhibitor) 20 mg qd x 9d ↑ Cmax 1.3 x and AUC 1.6x.
– Similar effect expected for CYP2D6 PMs and EMs – Poten=al for significant ↑ exposure when CYP2D6 PMs receive strong CYP3A4
inhibitor (Don’t use with strong CYP3A4 inhibitors)
– Effect of moderate CYP2D6 inhibitor not evaluated
– Effect of coadminister of both CYP3A4 and CYP2D6 inhibitors not evaluated. Poten=al for significant increase.
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Drug interac3on management
• Informa=on for clinicians – Alter therapy (dose adjust; don’t coadminister) – Specific monitoring instruc=ons
• Instruc=ons are based on – Study results or predic=on – Exposure-‐response (efficacy and safety)
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Dosage and Administra3on • Guanfacine (Intuniv®)
• Dose adjustment in pa=ents taking concomitant CYP3A4 inhibitors or inducers
Comedica=ons Scenarios
Ini=ate Intuniv when taking comedica=ons
Con=nue Intuniv when adding a medica=on
Stop a comedica=on when con=nuing Intuniv
Strong CYP3A inhibitors
Intuniv dose should be limited to 2 mg/day
Intuniv dose should be decreased by half
Intuniv dose should be doubled based on pa=ent tolerability. The maximum dose should not exceed 4 mg/day.
Strong CYP3A4 inducers
Intuniv dose may be =trated up to 8 mg/day. Consider faster =tra=on (e.g., in increments of 2 mg/week)
Consider increase in Intuniv dose gradually in 1-‐2 weeks to 2 fold of the original dose based on pa=ent tolerability
Intuniv dose should be decreased by half in 1-‐2 weeks based on pa=ent tolerability. The maximum dose should not exceed 4 mg/day.
Contraindica3ons • Darunavir (Prezista)-‐ Table in contraindica=ons sec=on. 2 of 9 rows shown. • Co-‐administra=on of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent
on CYP3A for clearance and for which elevated plasma concentra=ons are associated with serious and/or life-‐threatening events (narrow therapeu=c index).
Drug Class Drugs within class that are contraindicated with Prezista/ritonavir
Clinical Comment
Ergot deriva=ves Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine
Poten=al for serious and/or life threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremi=es and other =ssues.
An=-‐mycobacterial Rifampin Rifampin is a potent inducer of CYP450 metabolism. PREZISTA/ritonavir should not be used in combina=on with rifampin, as this may cause significant decreases in darunavir plasma concentra=ons. This may result in loss of therapeu=c effect to PREZISTA.
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Darunavir • Table (Drug Interac=on Sec=on)
– Established and Other Poten=ally Significant Drug Interac=ons: Altera=ons in Dose or Regimen May be Recommended Based on Drug Interac=on Studies or Predicted Interac=on (cross reference to table with study results)
• Columns – Concomitant drug class: drug name – Effect on concentra=on of darunavir or concomitant drug
– Clinical comment
Note-‐ The table on the next slide is one example of the type of table that is used to convey drug interac:on informa:on. It is not a template or required format.
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Some clinical comments in the darunavir prescribing informa3on
(interac=on with lopinavir/ritonavir)
• Appropriate doses of the combina=on have not been established. Hence, it is not recommended to co-‐administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
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Some clinical comments in the darunavir prescribing informa3on (interac=on with rifabu=n)
• Dose reduc=on of rifabu=n by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in pa=ents receiving this combina=on and further dose reduc=on of rifabu=n may be necessary.
Ideal drug interac3on informa3on in labeling Are we there, yet? • Easy to access and navigate • Minimal pharmacology jargon • Structured in a clinically intui=ve way • Imparts sense of severity or risk
• Provides risk management instruc=ons • Does not include unnecessary informa=on • Up to date • Adapted from informa=on presented by David Juurlink (University of Toronto) at FDA Clinical Pharmacology Advisory
Comminee Mee=ng on 9/25/2013
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Labeling changes (1)
• Safety Labeling Changes under FDAAA – New safety informa=on that becomes available ater approval of product
– New informa=on is related to serious risk
– May include a class of drugs – Defined process and =meline
FDAAA-‐ Food and Drug Administra:on Amendments Act of 2007
Guidance:
hnp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInforma=on/Guidances/UCM250783.pdf
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Labeling changes (2)
Ini=ated by FDA or Drug Sponsor Mechanism of submission varies based on type of change
• Sponsor submits change – Prior approval labeling supplement – Changes being effected labeling supplement
– Annual report
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Resources Link to PLR Requirements of Prescribing Informa=on and Labeling Guidances hnp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInforma=on/LawsActsandRules/ucm084159.htm
Some guidances address specific sec=ons of labeling Adverse Reac=ons
Dosage and Administra=on
Warnings and Precau=ons, Contraindica=ons, and Boxed Warnings
Clinical Pharmacology (drat)
Pregnancy, Lacta=on, Reproduc=ve Poten=al (new drat guidance; 12/2014)
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How are we doing?
• YOU can help OCP achieve its goal of translating its regulatory reviews into understandable and actionable labeling language
• Provide feedback on the quality, clarity and utility of the professional and consumer drug labeling you are using
EMAIL: OCP@FDA.HHS.GOV
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