new physician’s labeling: where is the safety information?

New Physician’s New Physician’s Labeling: Where is the Labeling: Where is the

Safety Information?Safety Information?Rosemary Roberts, MD, FAAP

DirectorDirectorOffice of Counter-Terrorism and Office of Counter-Terrorism and

Pediatric Drug DevelopmentPediatric Drug DevelopmentCDERCDER

March 22, 2006

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Rx LabelingRx Labeling DefinitionsDefinitions

LabelLabel: Written, printed, or graphic matter: Written, printed, or graphic matteron the immediate container of the drug on the immediate container of the drug productproduct

LabelingLabeling: Includes all labels, as well as: Includes all labels, as well asother written, printed, or graphic matterother written, printed, or graphic matteraccompanying the productaccompanying the product

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LabelingLabeling

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Rx LabelingRx Labeling21 CFR 201.5621 CFR 201.56

a)a)Labeling is a summary of essential Labeling is a summary of essential scientific information needed for safe scientific information needed for safe and effective use of the drugand effective use of the drug

b)b)Informative, accurate and neither Informative, accurate and neither promotional in tone nor false or promotional in tone nor false or misleadingmisleading

c)c) Based on data derived from human Based on data derived from human experience (whenever possible)experience (whenever possible)

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BackgroundBackground

Previous labeling regulations finalized Previous labeling regulations finalized in 1979in 1979

Increase in amount and complexity of Increase in amount and complexity of drug information drug information

Goal - more informative and Goal - more informative and accessible labeling, resulting in a accessible labeling, resulting in a better risk communication and better risk communication and management toolmanagement tool

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BackgroundBackground

Development process included Development process included Focus groups, National physician Focus groups, National physician

survey, Public meeting, Written survey, Public meeting, Written comments comments

Proposed rule issued December 2000Proposed rule issued December 2000

Final rule published January 24, 2006Final rule published January 24, 2006

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Content InnovationsContent Innovations HighlightsHighlights

Limited to ½ pageLimited to ½ page Bulleted Boxed Warning and IndicationsBulleted Boxed Warning and Indications

Table of Contents (“Contents”)Table of Contents (“Contents”) Allows easy reference to full prescribing information Allows easy reference to full prescribing information

(FPI)(FPI) Facilitates hyperlinks in electronic formatsFacilitates hyperlinks in electronic formats

Identifies and Dates “Recent Major Changes”Identifies and Dates “Recent Major Changes” Captures Captures Indications, D&A, Boxed Warning, CI and W&PIndications, D&A, Boxed Warning, CI and W&P Referenced inReferenced in Highlights Highlights; margin mark in FPI; margin mark in FPI

Added date of initial US approvalAdded date of initial US approval

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Imdicon safely and effectively. See full prescribing information for Imdicon. IMDICON® (cholinasol) CAPSULES Initial U.S. Approval: 2000

WARNING: LIFE-THREATENING HEMATOLOGICAL ADVERSE REACTIONS

See full prescribing information for complete boxed warning. Monitor for hematological adverse reactions every 2 weeks for first 3 months of treatment (5.2). Discontinue Imdicon immediately if any of the following occur: Neutropenia/agranulocytosis (5.1) Thrombotic thrombocytopenic purpura (5.1) Aplastic anemia (5.1) ----------------------------RECENT MAJOR CHANGES-------------------------- Indications and Usage, Coronary Stenting (1.2) 2/200X Dosage and Administration, Coronary Stenting (2.2) 2/200X ----------------------------INDICATIONS AND USAGE--------------------------- Imdicon is an adenosine diphosphate (ADP) antagonist platelet aggregation inhibitor indicated for: Reducing the risk of thrombotic stroke in patients who have experienced

stroke precursors or who have had a completed thrombotic stroke (1.1) Reducing the incidence of subacute coronary stent thrombosis, when

used with aspirin (1.2) Important limitations: For stroke, Imdicon should be reserved for patients who are intolerant of

or allergic to aspirin or who have failed aspirin therapy (1.1) ----------------------DOSAGE AND ADMINISTRATION----------------------- Stroke: 50 mg once daily with food. (2.1) Coronary Stenting: 50 mg once daily with food, with antiplatelet doses

of aspirin, for up to 30 days following stent implantation (2.2) Discontinue in renally impaired patients if hemorrhagic or hematopoietic problems are encountered (2.3, 8.6, 12.3)

---------------------DOSAGE FORMS AND STRENGTHS---------------------- Capsules: 50 mg (3)

-------------------------------CONTRAINDICATIONS------------------------------ Hematopoietic disorders or a history of TTP or aplastic anemia (4) Hemostatic disorder or active bleeding (4) Severe hepatic impairment (4, 8.7) -----------------------WARNINGS AND PRECAUTIONS------------------------ Neutropenia (2.4 % incidence; may occur suddenly; typically resolves

within 1-2 weeks of discontinuation), thrombotic thrombocytopenic purpura (TTP), aplastic anemia, agranulocytosis, pancytopenia, leukemia, and thrombocytopenia can occur (5.1)

Monitor for hematological adverse reactions every 2 weeks through the third month of treatment (5.2)

------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence >2%) are diarrhea, nausea, dyspepsia, rash, gastrointestinal pain, neutropenia, and purpura (6.1). To report SUSPECTED ADVERSE REACTIONS, contact (manufacturer) at (phone # and Web address) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS------------------------------- Anticoagulants: Discontinue prior to switching to Imdicon (5.3, 7.1) Phenytoin: Elevated phenytoin levels have been reported. Monitor

levels. (7.2) -----------------------USE IN SPECIFIC POPULATIONS------------------------ Hepatic impairment: Dose may need adjustment. Contraindicated in

severe hepatic disease (4, 8.7, 12.3) Renal impairment: Dose may need adjustment (2.3, 8.6, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 5/200X

Example of Highlights for a Fictitious DrugExample of Highlights for a Fictitious Drug

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Old Format LabelingOld Format Labeling

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Highlights of New LabelingHighlights of New Labeling Limitations Limitations

StatementStatement Product Names and Product Names and

Date of Initial US Date of Initial US ApprovalApproval

Boxed WarningBoxed Warning Major Recent Major Recent

ChangesChanges Indications and Indications and

UsageUsage Dosage & Dosage &

AdministrationAdministration Dosage Forms & Dosage Forms &

StrengthsStrengths

ContraindicationsContraindications Warnings & Warnings &

PrecautionsPrecautions Adverse ReactionsAdverse Reactions Drug InteractionsDrug Interactions Use in Specific Use in Specific

PopulationsPopulations Patient Counseling Patient Counseling

Information Information StatementStatement

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Revised: 5/200X


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Contents and Full Prescribing Contents and Full Prescribing Information (FPI)Information (FPI)

Boxed WarningBoxed Warning 1 Indications & Usage1 Indications & Usage 2 Dosage & 2 Dosage &

AdministrationAdministration 3 Dosage Forms & 3 Dosage Forms &

StrengthsStrengths 4 Contraindications4 Contraindications 5 Warnings & Precautions5 Warnings & Precautions 6 Adverse Reactions6 Adverse Reactions 7 Drug Interactions7 Drug Interactions 8 Use in Specific 8 Use in Specific

PopulationsPopulations 9 Drug Abuse & 9 Drug Abuse &

DependenceDependence

10 Overdosage10 Overdosage 11 Description11 Description 12 Clinical 12 Clinical

PharmacologyPharmacology 13 Nonclinical 13 Nonclinical

ToxicologyToxicology 14 Clinical Studies14 Clinical Studies 15 References15 References 16 How 16 How

Supplied/Storage & Supplied/Storage & HandlingHandling

17 Patient Counseling 17 Patient Counseling InformationInformation

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Example of Contents for a Fictitious DrugExample of Contents for a Fictitious Drug FULL PRESCRIBING INFORMATION: CONTENTS* WARNING – LIFE-THREATENING HEMATOLOGICAL ADVERSE REACTIONS 1 INDICATIONS AND USAGE

1.1 Thrombotic Stroke 1.2 Coronary Stenting

2 DOSAGE AND ADMINISTRATION 2.1 Thrombotic Stroke 2.2 Coronary Stenting 2.3 Renally Impaired Patients

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Hematological Adverse Reactions 5.2 Monitoring for Hematological Adverse Reactions 5.3 Anticoagulant Drugs 5.4 Bleeding Precautions 5.5 Monitoring: Liver Function Tests

6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience

7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs 7.2 Phenytoin 7.3 Antipyrine and Other Drugs Metabolized Hepatically 7.4 Aspirin and Other Non-Steroidal Anti-Inflammatory Drugs 7.5 Cimetidine 7.6 Theophylline 7.7 Propranolol 7.8 Antacids 7.9 Digoxin 7.10 Phenobarbital 7.11 Other Concomitant Drug Therapy 7.12 Food Interaction

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Thrombotic Stroke 14.2 Coronary Stenting 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

17.1 Importance of Monitoring 17.2 Bleeding 17.3 Hematological Adverse Reactions 17.4 FDA-Approved Patient Labeling

*Sections or subsections omitted from the full prescribing information are not listed.

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ContraindicationsContraindications 21 CFR 201.57(c)(5)21 CFR 201.57(c)(5)

Describe those situations in which the drug should not be used because the risk of use clearly outweighs any possible therapeutic benefit

Known hazards and NOT theoretical possibilities

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ImdiconImdicon(cholinasol)(cholinasol)

ContraindicationsContraindications

Hematopoietic disorders or a Hematopoietic disorders or a history of history of TTP or aplastic TTP or aplastic anemiaanemia

Hemostatic disorder or active Hemostatic disorder or active bleedingbleeding

Severe hepatic impairmentSevere hepatic impairment

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Warnings and PrecautionsWarnings and Precautions 21 CFR 201.57(c)(6)21 CFR 201.57(c)(6)

Include clinically significant ARs Include clinically significant ARs observedobserved in in association with the use of a drug for which association with the use of a drug for which there is reasonable evidence of a there is reasonable evidence of a causalcausal association between drug and the AR (a causal association between drug and the AR (a causal relationship need not have been established)relationship need not have been established)

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Serious AR; orSerious AR; or

Otherwise clinically significantOtherwise clinically significant Require discontinuationRequire discontinuation Dosage or regimen adjustmentDosage or regimen adjustment Significantly affect patient compliance; orSignificantly affect patient compliance; or

Product interferes with a laboratory Product interferes with a laboratory testtest

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Include an AR which can be Include an AR which can be expectedexpected to to occur with a drug based on observations occur with a drug based on observations from other members of the drug class or from other members of the drug class or animal studiesanimal studies Serious or otherwise clinically significant AR; Serious or otherwise clinically significant AR;

and eitherand either Based on what is known about the Based on what is known about the

pharmacology, chemistry, or drug class, it pharmacology, chemistry, or drug class, it seems likely that an AR will occur with the seems likely that an AR will occur with the drug; or drug; or

animal data raises substantial concern for an animal data raises substantial concern for an AR in humansAR in humans

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Other factors to consider whether Other factors to consider whether to include an AR in this section:to include an AR in this section: IndicationIndication IncidenceIncidence Ability to manage or prevent an Ability to manage or prevent an

adverse reaction (through patient adverse reaction (through patient monitoring, dose selection or monitoring, dose selection or titration, avoiding a concomitant titration, avoiding a concomitant therapy)therapy)

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Neutropenia (2.4% incidence; may Neutropenia (2.4% incidence; may occur suddenly; typically resolves occur suddenly; typically resolves within 1-2 weeks of discontinuation), within 1-2 weeks of discontinuation), thrombotic thrombocytopenic purpura thrombotic thrombocytopenic purpura (TTP), aplastic anemia, agranulocytosis, (TTP), aplastic anemia, agranulocytosis, pancytopenia, leukemia, and pancytopenia, leukemia, and thrombocytopenia can occur (5.1)thrombocytopenia can occur (5.1)

Monitor for hematological adverse Monitor for hematological adverse reactions every 2 weeks through the reactions every 2 weeks through the third month of treatment (5.2)third month of treatment (5.2)

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Boxed WarningBoxed Warning21 CFR 201.57(c)(1)21 CFR 201.57(c)(1)

When to use a boxed warning:When to use a boxed warning: Adverse reaction (AR) so serious in proportion Adverse reaction (AR) so serious in proportion

to the potential benefit from the drug that it to the potential benefit from the drug that it is essential the AR be considered in assessing is essential the AR be considered in assessing the risks and benefits of using the drug; ORthe risks and benefits of using the drug; OR

Serious adverse reaction that can be Serious adverse reaction that can be prevented or reduced by appropriate use of prevented or reduced by appropriate use of the drug; ORthe drug; OR

Drug approved with restrictions to assure Drug approved with restrictions to assure safe use; distribution or use restrictionsafe use; distribution or use restriction

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Boxed WarningBoxed Warning 21 CFR 201.57(c)(1)21 CFR 201.57(c)(1)

Ordinarily based on clinical data, but serious Ordinarily based on clinical data, but serious animal toxicity may also be the basis in absence of animal toxicity may also be the basis in absence of clinical dataclinical data

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Revised: 5/200X


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WARNING: LIFE-THREATENING HEMATOLOGICAL WARNING: LIFE-THREATENING HEMATOLOGICAL ADVERSE REACTIONSADVERSE REACTIONS

See full prescribing information for complete See full prescribing information for complete boxed warningboxed warning

Monitor for hematological adverse reactions Monitor for hematological adverse reactions every 2 weeks for first 3 months of every 2 weeks for first 3 months of treatment (5.2). Discontinue Imdicon treatment (5.2). Discontinue Imdicon immediately if any of the following occur:immediately if any of the following occur:

Neutropenia/agranulocytosis (5.1)Neutropenia/agranulocytosis (5.1) Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura

(5.1)(5.1) Aplastic anemia (5.1)Aplastic anemia (5.1)

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Boxed Warnings: Balancing the Boxed Warnings: Balancing the Risk/BenefitRisk/Benefit

Multi-layered processMulti-layered process Internal: statisticians, toxicology, Internal: statisticians, toxicology,

safety reviewer, medical reviews, safety reviewer, medical reviews, clinical pharmacologyclinical pharmacology

External: Advisory Committee inputExternal: Advisory Committee input Consensus decision Consensus decision Iterative process with the sponsorIterative process with the sponsor

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Resources on FDA’s WebsiteResources on FDA’s WebsiteDedicated Web pageDedicated Web page

http://www.fda.gov/cder/regulatory/physLabel/default.htmhttp://www.fda.gov/cder/regulatory/physLabel/default.htm

Final ruleFinal rule

Guidance for IndustryGuidance for Industry Implementing the new labeling content and format (draft)Implementing the new labeling content and format (draft) Adverse reactions section (final)Adverse reactions section (final) Clinical studies section (final)Clinical studies section (final) Warnings and Precautions, Contraindications and Boxed Warnings and Precautions, Contraindications and Boxed

Warning sections (draft)Warning sections (draft)

Examples of labeling in the new format for fictitious drugsExamples of labeling in the new format for fictitious drugs

Information sheets for healthcare professionals and Information sheets for healthcare professionals and consumersconsumers

http://www.fda.gov/cder/regulatory/physLabel/default.htm

new physician’s labeling: where is the safety information?

Documents

safety information

coronary stenting

risk of thrombotic stroke

completed thrombotic

complete boxed warning

pagebulleted boxed warning

aspirin therapy

rx labeling definitionslabel