joint dermatologic and ophthalmic drugs
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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
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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
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3Joint 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
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
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4Joint 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
““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
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5Joint 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
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
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6Joint 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
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
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7Joint 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
• 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?
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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
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9Joint 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 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
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10Joint 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 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”
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11Joint 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
• 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
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12Joint 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 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
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13Joint 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
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
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14Joint 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
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
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15Joint 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
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
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16Joint 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
““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
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17Joint 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
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
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18Joint 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
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
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19Joint 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
• 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
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20Joint 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
• 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
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21Joint 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
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
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22Joint 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
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
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23Joint 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
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