SLIDES FOR NDA 21213 ADVISORY COMMITTEE PRESENTATION

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SLIDES FORNDA 21-213 ADVISORY COMMITTEE
PRESENTATION
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Joint Advisory Committee MeetingFDA Presentations

• Clinical Efficacy and Safety Review
• Mary H. Parks, MD (DMEDP)
• Review of Actual-Use Trials
• Andrea Leonard-Segal, MD (DOTCDP)
• Drug-Drug and Drug-Food Interactions
• Jim Wei, PhD (OCPB)
• Label Comprehension
• Karen Lechter, JD, PhD (DDMAC)

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Joint Advisory Committee Meeting on
Nonprescription Availability of Lovastatin 10 mg

• Thursday, July 13, 2000
• Mary H. Parks, MD
• Division of Metabolic and Endocrine Drug Products
• Center for Drug Evaluation and Research

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NDA 21-213

• Sponsors rationale for nonprescription
  lovastatin
• Definition of the OTC-target population
• Clinical studies reviewed in DMEDP
• Efficacy of lovastatin 10 mg
• Safety of lovastatin
• Conclusion benefit-risk relationship of
  nonprescription lovastatin

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Sponsors Rationale
MRFIT. JAMA. 19862562823-2828.
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NCEP Recommendations

• Initial Treatment
• dietary modification
• exercise
• CHD risk factor reduction
• Drug Treatment
• HDL-C levellt35 mg/dL OR ? 2 risk factors
• LDL-C level of ? 160 mg/dL

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AFCAPS/TexCAPS

• 5-year randomized, double-blinded,
  placebo-controlled trial
• lovastatin 20-40 mg
• eligibility criteria
• men gt 45 yrs age and postmenopausal women
• total-C 180-264 mg/dL
• LDL-C 130-190 mg/dL
• HDL-C lt 45 mg/dL for men lt 47 mg/dL for women
• Two-thirds of cohort had ? 2 CHD risk factors
• Based on NCEP Guidelines, 17 of the 6,605 study
  cohort qualified for drug treatment

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AFCAPS/TexCAPS

• Primary composite endpoint
• Fatal or nonfatal MI
• Unstable angina
• Sudden cardiac death

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AFCAPS/TexCAPSPrimary Endpoint Results

• After 5 yrs with 70 completion rate
• LOVASTATIN 3.5
• PLACEBO 5.5
• Plt.0001

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OTC-Target Population Sponsors Definition

• Males gt 40 years and postmenopausal females
• No CVD, DM or significant HTN
• Not on prescription lipid-lowering drug
• Total-C 200 - 240 mg/dL
• LDL-C ? 130 mg/dL
• Does not include HDL-C
• Based on NHANES III, the estimated OTC-eligible
  population is 15.5 million.

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Clinical Studies Reviewed

• Protocol 075 (The Efficacy Study)
• Protocol 076 (The Pharmacy Study)
• Protocol 079 (Restricted Access Study)
• AFCAPS OTC-eligible Population

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Issues Addressed

• Efficacy
• LDL-C reduction
• Clinical cardiovascular benefit
• Safety
• Clinical trials
• Postmarketing

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EfficacyLDL-C Reduction
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Clinical Studies Reviewed

• Protocol 075
• Blinded, Diet, Placebo-Controlled Study
• 12-hour fasting serum lipids
• Weeks 0, 6, 12
• Protocol 076
• Open-label, No diet, Uncontrolled Study
• ?2-hour fasting fingerstick lipids
• Weeks 0, 8, 16, 24
• Protocol 079
• Open-label, No diet, Uncontrolled Study
• ?6-hour fasting fingerstick lipids
• Weeks 0, 8

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Study Adherence by Week

0
6
12
0
8
16
24
0
8
P075
P076
P079
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LDL Change from BaselineCompleters
8 wks
8 wks
12 wks
91 completers at wk 12
79 completers at wk 8
63 completers at wk 8
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LDL-C ReductionConclusions

• Compliant and adherent individuals
• 18 reduction in LDL
• Actual nonprescription setting
• poor drug adherence
• gt30 dropouts by Week 8 and 24 in the actual-use
  studies

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EfficacyClinical Cardiovascular Benefit
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Clinical Cardiovascular Benefit?

• Does LDL-C lowering with lovastatin 10 mg in the
  OTC-target population confer clinical benefit?
• No evidence from controlled clinical trials.

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Clinical Cardiovascular Benefit?

• 6,605 AFCAPS total cohort

Total-C 200-240 mg/dL LDL-C ? 130 mg/dL no DM or
significant HTN
2,800 excluded
3,805 OTC-eligible
no HDL-C criterion is imposed
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AFCAPS/TexCAPS OTC-Eligible Subgroup Post-Hoc
Analysis

• LOVASTATIN (n1,884) 3.0
• PLACEBO (n1,921) 5.3

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AFCAPS OTC-Target Population?

• Different lovastatin dose
• AFCAPS/TexCAPS 20-40mg
• 51.5 of the AFCAPS subgroup required treatment
  with 40 mg per day to achieve an LDL-C lt 110
  mg/dL
• OTC-Target population 10 mg

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AFCAPS OTC-Target Population?
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AFCAPS OTC-Target Population?AFCAPS Subgroup
Event Rates by Baseline HDL-C
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AFCAPS OTC-Target Population?
Proportion of population with HDL gt 40
NHANES
AFCAPS
P075
P076
P079
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AFCAPS OTC-target populationAdherence to Drug?
3 months
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Clinical Cardiovascular BenefitConclusions

• AFCAPS not representative of OTC-target
  population
• HDL-C
• Poor adherence to drug treatment
• AFCAPS 5yr - 70 completers
• Actual use 3 mos - 40 completers

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SafetyClinical Trials
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Safety of Lovastatin 10 mgClinical Trials

• 10 mg dose
• Comparable to placebo
• Incidence of myalgias lt 2 in all studies
• No cases of rhabdomyolysis, myoglobinuria, or
  hepatic toxicity
• Discontinuation of medication due to reported AEs
  higher in the actual-use studies vs controlled,
  clinical trials

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Safety - Clinical Trials

• 20-80 mg dose (AFCAPS and EXCEL)
• consecutive 3x ULN liver enzyme elevation
• lt1 20-40 mg daily dose
• 1.5 80 mg daily dose
• myopathy (symptoms and CPK gt 10 ULN)
• 0.1 40 mg daily dose
• 0.2 80 mg daily dose
• one case of rhabdomyolysis for 20 mg dose

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Limitations of Safety Assessments

• Clinical Trials
• exclusion of patients on interacting drugs
• exclusion of patients with co-morbid conditions
• scheduled MD visits and monitoring

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SafetySpontaneous Reports
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Postmarketing Safety Concerns

• Liver failure
• Rhabdomyolysis
• - drug-drug interaction
• - drug-food interaction

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Liver Failure

• Case Definition
• Unduplicated U.S. cases of
• clinical diagnosis of liver failure or
• receipt of liver transplant
• Time period
• From marketing 8/31/87 to 2/25/00

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Background Rate vs. Reporting Rate

• Estimated background rate of idiopathic liver
  failure is 1 per million person-years
• Estimated four-year reporting rate is 1.4 per
  million PYE for lovastatin-associated liver
  failure (1987-1990)

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Rhabdomyolysis

• Case definition
• Unduplicated U.S. cases
• Clinical diagnosis of rhabdomyolysis
• CPK gt 10,000 IU/L
• Time period
• From marketing 8/31/87 to 4/4/00
• Background rate for this AE unknown

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191 Cases RhabdomyolysisPercent of Cases
Reported by Dose
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Dispensed Prescriptions for Lovastatin in U.S.
1999 (Total Rx 3,177,000)
72
72
Rxs
24
24
4
4
Source IMS HEALTH National Prescription Audit TM
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RhabdomyolysisDrug-Drug Interactions
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Reported Drug-Drug Interactions With Lovastatin

• Erythromycin
• Clarithromycin
• Nefazodone
• Danazol
• Cyclosporine
• Metabolized through the CYP3A4 isoenzyme

• Itraconazole
• Ketoconazole
• Mibefradil
• (98 withdrawal)
• Gemfibrozil
• Niacin

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Reported Drug-Food InteractionGrapefruit Juice

• One case report
• lovastatin 80 mg and gemfibrozil 1200 mg gt 5
  years
• baseline renal impairment
• onset 2 wks after initiating grapefruit juice

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RhabdomyolysisConclusions

• Most reported cases associated with drug-drug
  interactions
• Many interactions are due to competition for
  CYP3A4 metabolic pathway

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Product Label - Interacting Drugs

• Do not use product if also on
• erythromycin or clarithromycin
• ketoconazole or itraconazole
• nefazodone
• cyclosporine
• protease inhibitors
• niacin or gemfibrozil
• Rx statin drugs (simvastatin,pravastatin,
  fluvastatin, atorvastatin, cerivastatin,
  lovastatin)
• List not complete and likely to increase
• Challenging to consumers

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Drugs Withdrawn from U.S. Market Due to CYP3A4

• Seldane (terfenadine) -1997
• Posicor (mibefradil) -1998
• Hismanal (astemizole) -1999
• Propulsid (cisapride) - 2000

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CYP3A4 Drug Withdrawals

• Withdrawn despite
• Changes to the label warnings
• Dear Healthcare Professional letters
• Black box warnings

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Safety of OTC LovastatinConclusions

• Dependent upon
• Consumer comprehension of label
• Use of product according to label instructions
• No self-titration to higher doses
• No use by individuals at risk for drug-related
  toxicity in unrestricted OTC setting
• drug-drug interactions
• drug-food interactions
• co-morbid medical conditions

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Summary of Issues Addressed

• LDL-C reduction
• lowers LDL-C but effectiveness in OTC-population
  diminished by poor drug adherence
• Clinical Cardiovascular Benefit
• no established benefit of drug treatment in
  OTC-Target population
• any benefit offset by poor drug adherence
• Safety
• drug-drug/drug-food interactions
• unrestricted/unsupervised OTC environment

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Conclusion

• What is the balance of benefit versus risk of
  nonprescription lovastatin?