Joint Dermatologic and Ophthalmic Drugs

Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004

RISK MANAGEMENT RISK MANAGEMENT OPTIONS FOR PREGNANCY OPTIONS FOR PREGNANCY

PREVENTIONPREVENTION

RISK MANAGEMENT RISK MANAGEMENT OPTIONS FOR PREGNANCY OPTIONS FOR PREGNANCY

PREVENTIONPREVENTION

Kathleen Uhl, MDPregnancy Labeling

US Food & Drug Administration

Kathleen Uhl, MDPregnancy Labeling

US Food & Drug Administration

2Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004

ObjectivesObjectivesObjectivesObjectives

• General principles of a teratogen• Decision making regarding

pregnancy prevention strategies• Existing strategies for pregnancy &

fetal exposure prevention

• General principles of a teratogen• Decision making regarding

pregnancy prevention strategies• Existing strategies for pregnancy &

fetal exposure prevention


TeratogenTeratogenTeratogenTeratogen

• What is a teratogen?– An agent or factor that causes:

• birth defect or congenital malformation

• abnormal development in an exposed embryo or fetus

• What is a teratogen?– An agent or factor that causes:

• birth defect or congenital malformation

• abnormal development in an exposed embryo or fetus


““Teratogenic Exposure”Teratogenic Exposure”““Teratogenic Exposure”Teratogenic Exposure”

• Teratogenic potential at clinical doses used in humans

• Teratogenic effect is not 100%• Other factors contribute

– Genetic susceptibility• If given at a high enough dose even

“benign” agents can be teratogenic– Glucose

• Teratogenic potential at clinical doses used in humans

• Teratogenic effect is not 100%• Other factors contribute

– Genetic susceptibility• If given at a high enough dose even

“benign” agents can be teratogenic– Glucose


Developmental AbnormalitiesDevelopmental AbnormalitiesDevelopmental AbnormalitiesDevelopmental Abnormalities

• Structural abnormalities– Skeletal or soft tissue malformations

• Fetal and infant mortality– Miscarriage, stillbirth, embryolethality

• Impairment of physiologic function– Endocrinopathy, deafness,

neurodevelopmental effects, impairment of reproduction function

• Altered growth– Growth retardation or enhancement, delayed or

early maturation

• Structural abnormalities– Skeletal or soft tissue malformations

• Fetal and infant mortality– Miscarriage, stillbirth, embryolethality

• Impairment of physiologic function– Endocrinopathy, deafness,

neurodevelopmental effects, impairment of reproduction function

• Altered growth– Growth retardation or enhancement, delayed or

early maturation


Is a drug a teratogen?Is a drug a teratogen?Is a drug a teratogen?Is a drug a teratogen?

• Animal data• Totality of evidence from animals:

– Highly suspected human teratogens– Not yet proven to be a human

teratogen

• Animal data• Totality of evidence from animals:

– Highly suspected human teratogens– Not yet proven to be a human

teratogen


• Human data– Adverse event reports– Medical literature – Pregnancy exposure registries or

other postmarketing studies– Peer reviewed assessments

• OTIS, TERIS

• Human data– Adverse event reports– Medical literature – Pregnancy exposure registries or

other postmarketing studies– Peer reviewed assessments

• OTIS, TERIS

Is a drug a teratogen?Is a drug a teratogen?Is a drug a teratogen?Is a drug a teratogen?

Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004

Decision Making for Decision Making for Pregnancy Prevention Pregnancy Prevention Decision Making for Decision Making for

Pregnancy Prevention Pregnancy Prevention


Decision MakingDecision Making Tiers of ConcernTiers of Concern

Decision MakingDecision Making Tiers of ConcernTiers of Concern

• No or low• Highly suspect teratogens• Known human teratogens

– Frequency – high vs. low– Severity– Reversibility– Critical time of exposure

• No or low• Highly suspect teratogens• Known human teratogens

– Frequency – high vs. low– Severity– Reversibility– Critical time of exposure


Decision MakingDecision Making What is the Risk?What is the Risk?

Decision MakingDecision Making What is the Risk?What is the Risk?

• Frequency of event• Severity of outcome

- Not all birth defects are equal- Major congenital anomaly (incompatible with

life vs. surgically correctable vs. cosmetic) - Reversibility

• Type of abnormality- Structural malformations, mortality, impaired

physiologic function, altered growth • Timing of exposure• Severity and type of outcomes affect

perception of “badness”

• Frequency of event• Severity of outcome

- Not all birth defects are equal- Major congenital anomaly (incompatible with

life vs. surgically correctable vs. cosmetic) - Reversibility

• Type of abnormality- Structural malformations, mortality, impaired

physiologic function, altered growth • Timing of exposure• Severity and type of outcomes affect

perception of “badness”


• Does maternal disease increase risk for birth defects (e.g., diabetes)?

• What are the consequences of untreated maternal disease (e.g., seizure disorders)?

• What are the benefits of treatment?

• Does maternal disease increase risk for birth defects (e.g., diabetes)?

• What are the consequences of untreated maternal disease (e.g., seizure disorders)?

• What are the benefits of treatment?

Decision Making Decision Making Maternal DiseaseMaternal Disease

Decision Making Decision Making Maternal DiseaseMaternal Disease


Decision MakingDecision MakingRange of OptionsRange of Options

Decision MakingDecision MakingRange of OptionsRange of Options

Warfarin• Toxicity well known• Risk is relatively low

(low rates)• Timing

– 6-9 weeks• Use in FCBP low• Comprehensive care

Warfarin• Toxicity well known• Risk is relatively low

(low rates)• Timing

– 6-9 weeks• Use in FCBP low• Comprehensive care

Isotretinoin• Toxicity known +/-• Risk is large

(high rates)• Timing

– 3-5 weeks• Use in FCBP high• Targeted care

Isotretinoin• Toxicity known +/-• Risk is large

(high rates)• Timing

– 3-5 weeks• Use in FCBP high• Targeted care


Isotretinoin TeratogenicityIsotretinoin TeratogenicityIsotretinoin TeratogenicityIsotretinoin Teratogenicity

• Structural malformations– Craniofacial, cardiac, thymus,

CNS– 20-30% exposed fetuses

• Functional impairment– Intellectual impairment

• Mortality– Increased spontaneous abortion &

premature birth• Critical period of exposure • Single dose teratogenic• Unique pharmacokinetics

• Structural malformations– Craniofacial, cardiac, thymus,

CNS– 20-30% exposed fetuses

• Functional impairment– Intellectual impairment

• Mortality– Increased spontaneous abortion &

premature birth• Critical period of exposure • Single dose teratogenic• Unique pharmacokinetics

Schardein JL, 2000


Goals of Pregnancy PreventionGoals of Pregnancy PreventionGoals of Pregnancy PreventionGoals of Pregnancy Prevention

1. Pregnant women do not receive drug2. Females of childbearing potential do

not get pregnant while taking drug

1. Pregnant women do not receive drug2. Females of childbearing potential do

not get pregnant while taking drug


Label is Most Applied ToolLabel is Most Applied ToolCRF 201.57CRF 201.57

Label is Most Applied ToolLabel is Most Applied ToolCRF 201.57CRF 201.57

• Decision making process considers:– Disease to be treated – Population of intended use– Frequency of event– Severity of event

• Benefits of drug use outweigh potential risks– Labeled as Category “D”– Wording in “Warnings” section

• Benefits do not outweigh potential risks– Drug should not to be used in pregnancy– Labeled as Category “X”– Wording in “Contraindications” section

• Decision making process considers:– Disease to be treated – Population of intended use– Frequency of event– Severity of event

• Benefits of drug use outweigh potential risks– Labeled as Category “D”– Wording in “Warnings” section

• Benefits do not outweigh potential risks– Drug should not to be used in pregnancy– Labeled as Category “X”– Wording in “Contraindications” section


““Contraindicated” DrugsContraindicated” Drugs““Contraindicated” DrugsContraindicated” Drugs

• Known human teratogen– Systemic retinoids

(e.g., isotretinoin)– Thalidomide– Warfarin– Antimetabolites

(e.g., methotrexate)– Testosterone

• Known human teratogen– Systemic retinoids

(e.g., isotretinoin)– Thalidomide– Warfarin– Antimetabolites

(e.g., methotrexate)– Testosterone

• Highly suspect human teratogen– Ribavirin– Bosentan– Statins

• Highly suspect human teratogen– Ribavirin– Bosentan– Statins


Labeling Beyond “X”Labeling Beyond “X”InformationalInformational

Labeling Beyond “X”Labeling Beyond “X”InformationalInformational

• Black Box– Must go into all advertising

• “Warnings”• Informed Consent

– Advised or included• Medication Guide

– Required issuance

• Black Box– Must go into all advertising

• “Warnings”• Informed Consent

– Advised or included• Medication Guide

– Required issuance


Labeling Beyond “X”Labeling Beyond “X” Active InterventionsActive Interventions

Labeling Beyond “X”Labeling Beyond “X” Active InterventionsActive Interventions

• Pregnancy testing• Contraceptive use

Require health care provider and/or patient to actively DO something

• Pregnancy testing• Contraceptive use

Require health care provider and/or patient to actively DO something


• Before starting drug– Timing relative to starting drug– Number of tests prior to starting drug

• Continued testing during drug therapy– Periodic or specific (monthly)

• Testing after completing drug therapy– For how long?

• Test specifics– Sensitivity– Urine or Blood– Accredited laboratory vs. doctor’s office vs. home

pregnancy testing

• Before starting drug– Timing relative to starting drug– Number of tests prior to starting drug

• Continued testing during drug therapy– Periodic or specific (monthly)

• Testing after completing drug therapy– For how long?

• Test specifics– Sensitivity– Urine or Blood– Accredited laboratory vs. doctor’s office vs. home

pregnancy testing

PREGNANCY TESTSPREGNANCY TESTSPREGNANCY TESTSPREGNANCY TESTS


• Before starting drug– Timing relative to starting drug

• Continued use during drug therapy• Contraception after completing drug

therapy– For how long?

• Contraception specifics– Acceptable methods, e.g., “primary methods”– Number of methods

• Before starting drug– Timing relative to starting drug

• Continued use during drug therapy• Contraception after completing drug

therapy– For how long?

• Contraception specifics– Acceptable methods, e.g., “primary methods”– Number of methods

CONTRACEPTIONCONTRACEPTIONCONTRACEPTIONCONTRACEPTION


ADDITIONAL PREGNANCY ADDITIONAL PREGNANCY PREVENTION STRATEGIESPREVENTION STRATEGIESADDITIONAL PREGNANCY ADDITIONAL PREGNANCY PREVENTION STRATEGIESPREVENTION STRATEGIES

• Limited Supply• Prohibited refills• Links• Real time documentation• Registration• Limited Distribution

• Limited Supply• Prohibited refills• Links• Real time documentation• Registration• Limited Distribution


Ultimate Pathway Ultimate Pathway to Preventionto Prevention

Ultimate Pathway Ultimate Pathway to Preventionto Prevention

Patient and prescriber understand the risk and actively work to mitigate it:

• Adequately informed of risk• Understand the risk• Demonstrate behavior consistent with

risk

Patient and prescriber understand the risk and actively work to mitigate it:

• Adequately informed of risk• Understand the risk• Demonstrate behavior consistent with

risk


Pregnancy Prevention Pregnancy Prevention StrategiesStrategies

Pregnancy Prevention Pregnancy Prevention StrategiesStrategies

• Very complex• Not all teratogens are equal• Pregnancy Prevention = prevent fetal

exposure– At drug initiation– With continued drug use

• Must tailor pregnancy prevention to the specific drug

• One size does NOT fit all

• Very complex• Not all teratogens are equal• Pregnancy Prevention = prevent fetal

exposure– At drug initiation– With continued drug use

• Must tailor pregnancy prevention to the specific drug

• One size does NOT fit all

Joint Dermatologic and Ophthalmic Drugs

Health & Medicine

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