1. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 RISK MANAGEMENT OPTIONS FOR PREGNANCY PREVENTION Kathleen Uhl, MD Pregnancy Labeling US Food & Drug Administration Kathleen Uhl, MD Pregnancy Labeling US Food & Drug Administration

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

3. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 3 TeratogenTeratogen 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

4. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 4 “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

5. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 5 Developmental 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

6. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 6 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

7. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 7 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?

8. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 Decision Making for Pregnancy Prevention

9. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 9 Decision Making Tiers 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

10. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 10 Decision Making 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”

11. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 11 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 Maternal Disease

12. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 12 Decision Making Range 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

13. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 13 Isotretinoin 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

14. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 14 Goals of Pregnancy Prevention 1.Pregnant women do not receive drug 2.Females of childbearing potential do not get pregnant while taking drug 1.Pregnant women do not receive drug 2.Females of childbearing potential do not get pregnant while taking drug

15. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 15 Label is Most Applied Tool CRF 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

16. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 16 “Contraindicated” 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

17. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 17 Labeling Beyond “X” Informational 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

18. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 18 Labeling Beyond “X” Active 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

19. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 19 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 TESTS

20. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 20 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 CONTRACEPTIONCONTRACEPTION

21. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 21 ADDITIONAL PREGNANCY PREVENTION STRATEGIES Limited Supply Prohibited refills Links Real time documentation Registration Limited Distribution Limited Supply Prohibited refills Links Real time documentation Registration Limited Distribution

22. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 22 Ultimate Pathway to 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

23. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 23 Pregnancy Prevention Strategies 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