RISK MANAGEMENT OPTIONS FOR PREGNANCY PREVENTION

1. RISK MANAGEMENT OPTIONS FOR PREGNANCY PREVENTION Kathleen Uhl, MD Pregnancy Labeling US Food & Drug Administration

2. Objectives • General principles of a teratogen • Decision making regarding pregnancy prevention strategies • Existing strategies for pregnancy & fetal exposure prevention

3. Teratogen • What is a teratogen? • An agent or factor that causes: • birth defect or congenital malformation • abnormal development in an exposed embryo or fetus

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

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

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

7. Is a drug a teratogen? • Human data • Adverse event reports • Medical literature • Pregnancy exposure registries or other postmarketing studies • Peer reviewed assessments • OTIS, TERIS

8. Decision Making for Pregnancy Prevention

9. Decision MakingTiers of Concern • No or low • Highly suspect teratogens • Known human teratogens • Frequency – high vs. low • Severity • Reversibility • Critical time of exposure

10. Decision MakingWhat 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”

11. Decision Making Maternal Disease • 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?

12. 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 Decision MakingRange of Options

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 Schardein JL, 2000

14. Goals of Pregnancy Prevention • Pregnant women do not receive drug • Females of childbearing potential do not get pregnant while taking drug

15. Label is Most Applied ToolCRF 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

16. Known human teratogen Systemic retinoids (e.g., isotretinoin) Thalidomide Warfarin Antimetabolites (e.g., methotrexate) Testosterone Highly suspect human teratogen Ribavirin Bosentan Statins “Contraindicated” Drugs

17. Labeling Beyond “X”Informational • Black Box • Must go into all advertising • “Warnings” • Informed Consent • Advised or included • Medication Guide • Required issuance

18. Labeling Beyond “X”Active Interventions • Pregnancy testing • Contraceptive use Require health care provider and/or patient to actively DO something

19. PREGNANCY TESTS • 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

20. CONTRACEPTION • 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

21. ADDITIONAL PREGNANCY PREVENTION STRATEGIES • Limited Supply • Prohibited refills • Links • Real time documentation • Registration • Limited Distribution

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

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