RISK MANAGEMENT OPTIONS FOR PREGNANCY PREVENTION

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RISK MANAGEMENT OPTIONS FOR PREGNANCY PREVENTION

• Kathleen Uhl, MD
• Pregnancy Labeling
• US Food Drug Administration

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Objectives

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

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Teratogen

• 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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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

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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

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Is a drug a teratogen?

• Animal data
• Totality of evidence from animals
• Highly suspected human teratogens
• Not yet proven to be a human teratogen

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Is a drug a teratogen?

• Human data
• Adverse event reports
• Medical literature
• Pregnancy exposure registries or other
  postmarketing studies
• Peer reviewed assessments
• OTIS, TERIS

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Decision Making for Pregnancy Prevention
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Decision Making Tiers of Concern

• No or low
• Highly suspect teratogens
• Known human teratogens
• Frequency high vs. low
• Severity
• Reversibility
• Critical time of exposure

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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

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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?

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Decision MakingRange of Options

• Isotretinoin
• Toxicity known /-
• Risk is large
• (high rates)
• Timing
• 3-5 weeks
• Use in FCBP high
• Targeted care

• Warfarin
• Toxicity well known
• Risk is relatively low (low rates)
• Timing
• 6-9 weeks
• Use in FCBP low
• Comprehensive care

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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
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Goals of Pregnancy Prevention

• Pregnant women do not receive drug
• Females of childbearing potential do not get
  pregnant while taking drug

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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

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Contraindicated Drugs

• Known human teratogen
• Systemic retinoids (e.g., isotretinoin)
• Thalidomide
• Warfarin
• Antimetabolites (e.g., methotrexate)
• Testosterone

• Highly suspect human teratogen
• Ribavirin
• Bosentan
• Statins

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Labeling Beyond XInformational

• Black Box
• Must go into all advertising
• Warnings
• Informed Consent
• Advised or included
• Medication Guide
• Required issuance

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Labeling Beyond X Active Interventions

• Pregnancy testing
• Contraceptive use
• Require health care provider and/or patient to
  actively DO something

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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. doctors office vs.
  home pregnancy testing

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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

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ADDITIONAL PREGNANCY PREVENTION STRATEGIES

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

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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

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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