DRAFT SLIDES FOR NDA 21-198 ADVISORY COMMITTEE PRESENTATIONS

1. DRAFT SLIDES FOR NDA 21-198 ADVISORY COMMITTEE PRESENTATIONS

2. Joint Advisory Committee MeetingFDA Presentations • Clinical Efficacy and Safety • Mary H. Parks, MD (DMEDP) • Actual-Use Trials • Daiva Shetty, MD (DOTCDP) • Label Comprehension Studies • Karen Lechter, JD, PhD (DDMAC)

3. Joint Advisory Committee Meeting on Nonprescription Availability of Pravastatin 10 mg Friday, July 14, 2000 Mary H. Parks, MD Division of Metabolic and Endocrine Drug Products Center for Drug Evaluation and Research

4. NDA 21-198 • Sponsor’s rationale for nonprescription Pravastatin • Definition of the OTC-target population • Clinical studies reviewed in DMEDP • Safety of Pravastatin • Conclusions: benefit-risk relationship of nonprescription pravastatin

5. Sponsor’s Rationale MRFIT. JAMA. 1986;256:2823-2828.

6. Sponsor’s Rationale • Clinical trials demonstrate reduction in cardiovascular events with lipid-lowering drugs • primary and secondary prevention • across a broad range of cholesterol levels

7. Sponsor’s Rationale • Inadequate treatment of population to NCEP Goals • < 2 CHD risk factors present • treatment goal: LDL-C<160 mg/dL •  2 CHD risk factors present • treatment goal: LDL-C<130 mg/dL • established CHD • treatment goal: LDL-C<100 mg/dL

8. Sponsor’s Rationale • Consumer interest • low-fat, diet foods • dietary supplements • Unrestricted access to pravastatin provides an adjunct for lowering cholesterol

9. OTC-Target PopulationSponsor’s Definition • Who should use: • told by MD to lower cholesterol but not on drug treatment • total-C 200-240 mg/dL, LDL-C > 130 mg/dL • Who should NOT use: • presence of CHD or DM • on prescription lipid-lowering drug • children and pregnant women

10. Clinical Studies Reviewed • 10 and 40 mg placebo-controlled studies • PREDICT (Pravachol Experience in a Documented Consumer-Use Trial) • 24-wk, randomized, open-label • Rx vs OTC pravastatin groups • OPTIONS (OTC Pravachol in an Observed Naturalistic Setting) • 12-wk, open-label, uncontrolled • OTC pravastatin in HMO setting

11. Issues Addressed • LDL-C reduction • Necessity of MD involvement • Adherence to drug treatment • Clinical cardiovascular benefit • Safety • Clinical trials • Postmarketing

12. LDL-C Reduction

13. LDL-C Reduction • 18-22% LDL-C reduction • placebo-controlled studies • diet enforced • in non OTC-target population

14. PREDICTQualified and Treated Randomization to OTC or Rx group Study Physician Consult treatment guidelines applied Qualified for Treatment Qualified and Treated Subgroup 15% of OTC and 19% of Rx group

15. PREDICTTreatment Guidelines

16. LDL-C ReductionPREDICT • Qualified and treated subgroups • 18% required dose titration to 20 or 40 mg to achieve NCEP goals • 17-18% LDL reduction for both OTC and Rx patients

17. PREDICTQualified and Treated Randomization RX n=1948 OTC n=1924 499 treated 355 treated Qualified and Treated 253 (50.7% of treated) Qualified and Treated 352 (99.2% of treated)

18. NECESSITY OF PHYSICIAN INVOLVEMENT

19. PREDICTStudy Drug Discontinuation

20. PREDICTMD Recommended Discontinuations

21. Necessity of MD Involvement • OTC self-selection • overtreatment • undertreatment • inappropriate treatment

22. Adherence to Therapy

23. OPTIONSSubject Disposition n=2207 n=782 n=404 n=321 n=156

24. Clinical Cardiovascular Benefit

25. Clinical Cardiovascular Benefit? • not demonstrated: • in OTC target population • for OTC product and dose • in OTC setting

26. SafetyClinical Trials

27. Safety - Clinical Trials • 10 mg dose • No rhabdomyolysis, myoglobinuria, or hepatic toxicity • Incidence of myalgias < 2% • Incidence of hepatic enzyme elevation similar between pravastatin and placebo (< 2%) • Discontinuation of medication due to reported AEs higher in the OTC group vs Rx group (PREDICT)

28. Safety - Clinical Trials • 40 mg dose • 3 placebo-controlled trials of ~ 5yrs • consecutive 3x ULN liver enzyme rates < 1% for pravastatin; no significant difference to placebo • no cases of hepatic failure • 1 case of reported rhabdomyolysis

29. Limitations of Safety Assessments • Clinical Trials • exclusion of patients on interacting drugs • exclusion of patients with co-morbid conditions • scheduled MD visits and safety monitoring

30. Safety - Spontaneous Reports • Liver Failure • Rhabdomyolysis

31. Liver Failure • Case definition • clinical diagnosis of liver failure stated by reporter • liver transplant • Reporting time period • from marketing until 2/25/00

32. Liver Failure • 13 Cases • 8 domestic, 5 foreign • dose • 10 mg (3 cases), 20 mg (6), 40 mg (1), unknown (3) • 10 unconfounded cases

33. Liver Failure • No increase from background rate of idiopathic liver failure

34. Rhabdomyolysis • Case definition • clinical diagnosis of rhabdomyolysis • CPK > 10,000 IU/L • Reporting time period • marketing until April-May 2000 • Background rate unknown for this AE

35. Rhabdomyolysis35 Cases

36. Dispensed Prescriptions for Pravastatin in U.S. 1999 (Total Rx = 12,871,000) 64% Rxs 27% 9% Source: IMS HEALTH National Prescription Audit

37. Rhabdomyolysis • True incidence rate unknown but risk exists • Potential increased risk • concomitant use with certain medications • fibrates, cyclosporine, erythromycin • co-morbid medical conditions • Cases may increase with increase use of 10 mg dose in OTC setting

38. Safety of OTC Pravastatin • Dependent upon: • Comprehension of label • Following label instructions • No self-titration • No use by high-risk individuals in the unrestricted, unsupervised OTC setting • drug-drug interactions • co-morbid medical conditions

39. Summary of Issues Addressed • LDL-C reduction • Adherence to drug treatment • Necessity of MD involvement • Clinical cardiovascular benefit • Safety

40. Conclusion What is the balance of benefit versus risk of nonprescription pravastatin?