Joint Dermatologic and Ophthalmic Drugs

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Joint Dermatologic and Ophthalmic Drugs

  1. 1. Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 RISK MANAGEMENTRISK MANAGEMENT OPTIONS FOR PREGNANCYOPTIONS FOR PREGNANCY PREVENTIONPREVENTION Kathleen Uhl, MD Pregnancy Labeling US Food & Drug Administration
  2. 2. 2 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 ObjectivesObjectives • General principles of a teratogen • Decision making regarding pregnancy prevention strategies • Existing strategies for pregnancy & fetal exposure prevention
  3. 3. 3 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 TeratogenTeratogen • What is a teratogen? –An agent or factor that causes: • birth defect or congenital malformation • abnormal development in an exposed embryo or fetus
  4. 4. 4 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 ““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
  5. 5. 5 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Developmental 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
  6. 6. 6 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 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
  7. 7. 7 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand 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 Is a drug a teratogen?Is a drug a teratogen?
  8. 8. Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Decision Making forDecision Making for Pregnancy PreventionPregnancy Prevention
  9. 9. 9 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 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
  10. 10. 10 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 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”
  11. 11. 11 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand 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? Decision MakingDecision Making Maternal DiseaseMaternal Disease
  12. 12. 12 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Decision MakingDecision Making Range of OptionsRange of Options 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. 13. 13 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Isotretinoin 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 Schardein JL, 2000
  14. 14. 14 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Goals of Pregnancy PreventionGoals of Pregnancy Prevention 1. Pregnant women do not receive drug 2. Females of childbearing potential do not get pregnant while taking drug
  15. 15. 15 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Label is Most Applied ToolLabel is Most Applied Tool CRF 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
  16. 16. 16 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 ““Contraindicated” DrugsContraindicated” Drugs • Known human teratogen – Systemic retinoids (e.g., isotretinoin) – Thalidomide – Warfarin – Antimetabolites (e.g., methotrexate) – Testosterone • Highly suspect human teratogen – Ribavirin – Bosentan – Statins
  17. 17. 17 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Labeling Beyond “X”Labeling Beyond “X” InformationalInformational • Black Box – Must go into all advertising • “Warnings” • Informed Consent – Advised or included • Medication Guide – Required issuance
  18. 18. 18 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Labeling Beyond “X”Labeling Beyond “X” Active InterventionsActive Interventions • Pregnancy testing • Contraceptive use Require health care provider and/or patient to actively DO something
  19. 19. 19 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand 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 PREGNANCY TESTSPREGNANCY TESTS
  20. 20. 20 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand 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 CONTRACEPTIONCONTRACEPTION
  21. 21. 21 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 ADDITIONAL PREGNANCYADDITIONAL PREGNANCY PREVENTION STRATEGIESPREVENTION STRATEGIES • Limited Supply • Prohibited refills • Links • Real time documentation • Registration • Limited Distribution
  22. 22. 22 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Ultimate PathwayUltimate 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
  23. 23. 23 Joint Dermatologic and Ophthalmic Drugs & Drug SafetyJoint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committeeand Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004 Pregnancy PreventionPregnancy 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

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