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Mevacor Daily lovastatin Tablets, 20 mg Merck


Joint Meeting of the Nonprescription Drugs and. Endocrinologic and Metabolic Drugs ... Elevated ALT and/or AST at least on two occasions 6 to 18 months apart ... – PowerPoint PPT presentation

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Title: Mevacor Daily lovastatin Tablets, 20 mg Merck

Mevacor Daily (lovastatin)Tablets, 20 mgMerck
Co., Inc.
  • Joint Meeting of the Nonprescription Drugs and
  • Endocrinologic and Metabolic Drugs Advisory
  • Silver Spring, Maryland
  • December 13, 2007
  • Shewit Bezabeh MD, MPH
  • Division of Drug Risk Evaluation,
  • Office of Surveillance and Epidemiology

Center for Drug Evaluation and Research
  • Regulatory background
  • January, 2005 AC meeting, the NDA was
    non-approvable due to several deficiencies
  • One deficiency - lack of adequate safety data of
    lovastatin in patients with asymptomatic liver
  • Applicant submitted A study of potential
    hepatotoxicity of Lovastatin in Kaiser
    Permanente Northern California (KPNC) liver
    disease population

  • Objective of presentation
  • Review of the submitted population study
  • Discuss the studys strengths
  • Major limitations
  • Channeling bias
  • Heterogeneity of baseline liver disease
  • Surveillance bias
  • Study results
  • FDAs Review and Conclusions

KPNC study
  • A retrospective cohort observational study
  • KPNC is an integrated health plan with gt 3.2
    million members and an electronic information

KPNC study
  • Population HMO members with liver disease or
    evidence of hepatic dysfunction
  • Study Period January 1, 1995 to June 30, 2004

KPNC study
  • Inception Cohort
  • Adults with evidence of liver disease at
    baseline or
  • High risk for liver disease due to either
    elevated liver test or presence of a selected
  • 13 months of continuous membership
  • No statin exposure 1 yr prior to study entry

KPNC study
  • Inclusion Criteria
  • Presence of at least one of the following
  • Elevated ALT and/or AST at least on two occasions
    6 to 18 months apart
  • Diagnosis of liver disease
  • Chronic Viral hepatitis
  • Metabolic disorders (Wilsons disease,
  • Other Chronic Liver Diseases e.g. chronic liver
    disease, alcoholic fatty liver, biliary cirrhosis

KPNC study
  • Exclusion Criteria
  • Past Hx of the following diagnosis
  • Drug-induced liver disease
  • Disorders of bilirubin excretion
  • Cancer (except non-melanoma skin)

Study Outcomes
  • Primary
  • Hys Rule (ALT gt 3x ULN, Total Bili gt 2x ULN
    and AP 1.5 ULN)
  • Secondary
  • Liver injury (ALT 3X ULN or Bili 3x ULN)
  • Cirrhosis (automated medical records)
  • Liver Failure (automated medical records)

Data analysis
  • Major Analysis Primary and secondary outcomes
  • Incidence rate ratios (IRR)
  • IRR IR (exposed) / IR (unexposed)
  • Multivariate analysis
  • adjustments for potential confounders
  • Age
  • Gender
  • General health status
  • Concomitant medications

Data analysis
  • Secondary and sensitivity analyses
  • Liver disease etiology subgroup
  • Dose-response (cumulative amount or cumulative
    number of days)
  • Lovastatin discontinuation
  • Channeling bias sub-study
  • Analysis for confounders age, gender, general
    health status and concomitant medications)

Study Results Demographic Data
Primary Outcome
  • Based on per person-days exposure
  • unadjusted for all potential confounders
  • Exposure to Lovastatin was associated with
    72 decrease in the risk of achieving Hys Rule

Secondary Outcome
  • Laboratory diagnosis
  • unadjusted for all potential confounders

Secondary Composite Outcome
  • Combined secondary outcome are not mutually
    exclusive (1st occurrence of a liver injury,
    cirrhosis, or liver-failure)
  • unadjusted for all potential confounders

Conclusions by Study Authors
  • Fewer adverse outcomes in KPNC patients with
    baseline liver disease who were exposed to
    lovastatin compared to non exposed.
  • Lovastatin exposure appears to be protective of
    adverse outcomes in liver disease patients.

Authors Conclusions - Continued
  • Sub-study and sensitivity analyses
  • Little evidence for channeling bias (or
    confounding by contraindication)
  • No significant evidence of lovastatin
    discontinuation in liver disease patients
  • Sensitivity analyses did not alter the conclusions

FDA Analysis Study Limitations
  • Channeling Bias
  • - lovastatin preferentially prescribed (or
    channeled) to individuals at low risk for liver
    disease due to prominent labeling for risk of
  • - lovastatin preferentially avoided in patients
    at high risk for liver toxicity

FDA Analysis Study Limitations
  • Channeling Bias (continued)
  • - unable to address / adjust for this issue
    given limitations of administrative data
  • - results in residual confounding

FDA Analysis Study Limitations
  • Channeling Bias (continued)
  • - Of 6391 patients with both
    hypercholesterol-emia (LDL gt 160 mg/dL) and
    liver disease, only 2746 ( 43) were treated with
  • No explanation was provided why 57 of
    hypercholesterolemic (LDL gt 160 mg/dL) patients
    did not receive lovastatin suggesting
    confounding by diagnosis.

FDA Analysis Study Limitations
  • 2. Baseline liver disease
  • The cohort of patients with liver disease
    consisted multiple potentially disparate clinical
    entities, resulting in clinical heterogeneity and
    disparate outcomes
  • Misclassification
  • Stratification

FDA Analysis Study Limitations
FDA Analysis Study Limitations
  • 3. Surveillance bias
  • Tendency to discontinue lovastatin after a
    positive test or after a liver disease diagnosis
  • Surveillance bias Sub Study showed increased
    frequency of liver enzyme testing in subjects
    with liver disease
  • lovastatin exposed had 46 more LFT testing
    compared to non-exposed
  • Impact of differential surveillance on study
    outcome is not clear

Overall Conclusions
  • A well conducted large study
  • Most of the limitations are associated with
    observational studies
  • Evidence of channeling
  • Disparate baseline disease
  • Surveillance bias

Summary Conclusions
  • The studys findings are consistent with results
    of other published studies and suggest that
    exposure to lovastatin in patients with baseline
    liver abnormalities do not appear to increase the
    risk of hepatotoxicity.

Summary Conclusions
  • Because of the limitations and nature
    (retrospective observational) of the study, a
    clinically significant hepatotoxic effect of
    lovastatin cannot be ruled out.
  • Furthermore, it is not possible to determine if
    there is a protective role for lovastatin in the
    setting of baseline liver disease.

  • CDER Review Team
  • Mark Avigan, M.D., C.M. Division of Drug Risk
  • Allen Brinker M.D., M.S. Division of Drug Risk
  • Eileen Craig, M.D., Division of Metabolic and
    Endocrine Products