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René Belder, MD

René Belder, MD. Executive Director Clinical Development and Life Cycle Management Cardiovascular / Metabolics. 7asdf. Pravachol Safety. Pravachol Extensive Worldwide Safety Experience. Clinical Trial Experience Extensively studied since 1986 in over 200 clinical trials

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René Belder, MD

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  1. René Belder, MD Executive Director Clinical Development and Life Cycle Management Cardiovascular / Metabolics 7asdf

  2. Pravachol Safety

  3. Pravachol Extensive Worldwide Safety Experience • Clinical Trial Experience • Extensively studied since 1986 in over 200 clinical trials • Well established efficacy and safety at doses up to160 mg (4x highest prescription dose; 16x proposed OTC dose) • >100,000 patient years in placebo-controlled morbidity and mortality studies (> 50,000 on pravastatin) • Long-term safety data in excess of 5 years • Post Marketing Experience • Available in 68 countries for up to 10 years • More than22 million patient years of exposure

  4. Special Safety Considerations For OTC Use • Drug interactions • Musculoskeletal • Hepatobiliary • Overdose • Pregnancy

  5. Safety Considerations Drug Interactions

  6. Pravachol: No Clinically Relevant Pharmacokinetic Drug Interactions • Not significantly metabolized by cytochrome P450 3A4 • No significant interactions in standard PK studies (e.g. digoxin, warfarin, cimetidine) • Inhibitors of p-glycoprotein may cause small increases in pravastatin levels • Has linear pharmacokinetics over 10-160 mg dose range • No warning for drug interactions in proposed OTC label

  7. Lack of Drug Interactions with Pravastatin 25x 20x Increase in Statin AUC withInteracting Drug 15x 10x 5x 0 Pravastatin Lovastatin Simvastatin

  8. Safety Considerations Musculoskeletal

  9. Rhabdomyolysis • Clinical Diagnosis + CK > 10,000 IU/L • Multiple known risk factors for rhabdomyolysis* • Infections • Metabolic disorders • Collagen / vascular disease • Trauma hyper / hypothermia / toxins • Drugs (165 identified e.g., fibrates) • Background incidence unknown • Rare cases associated with statin use * Crit Care Clin 1999;15:415-28. Weiner SL: Pg 571-99. Grenvik A. Textbook of Critical Care. WB Saunders. 2000:160-90.

  10. Rhabdomyolysis Reported During Pravastatin Use • Clinical Trials • No cases of confirmed rhabdomyolysis • One reported case - CK < 2 x ULN • Serious musculoskeletal events similar to placebo (0.2%) • Post Marketing Surveillance* 10-40 mg dose • Very rare: 0.3 cases per 100,000 patient years • 57 cases meeting definition • 17 cases CK level unknown • Most cases (n=47; 64%) confounded by concomitant conditions • 15 cases associated with fibrates (2 clofibrate, 2 gemfibrozil, 11 bezafibrate) * Data collected up to May 31, 1999

  11. Post-Marketing Cases of Rhabdomyolysis ShowNo Apparent Relationship to Dose or Country Distribution by DoseCases Per Million Tablets Distributed* Distribution by CountryCases Per Million Tablets Distributed n=43 n=13 n=4 n=21 n=43 n=7 n=3  10 mg 20 mg 40 mg U.S. Japan France Other * Dose unknown in 18 cases

  12. Rhabdomyolysis Summary • Cases reported with pravastatin use are very rare(0.3 cases per 100,000 patient years) • Many confounding factors; background incidence unknown • No apparent relationship to dose or country • No increased risk to be expected due to lack of drug interactions • Proposed OTC label provides appropriate warnings and instructions to patients • Stop use and ask your doctor if you have unusual muscle pain or weakness not caused by cold, flu, recent injury or sprain. This is very important if you also feel weak or have a fever

  13. Safety Considerations Hepatobiliary System

  14. Pravachol Liver Monitoring Label History:Reduction of Monitoring Requirements Over Time • Baseline, Week 6, 12, 20, 28, 36, periodicallyor dose elevation • Baseline, Week 6, 12, periodicallyor dose elevation • Baseline, Week 12or dose elevation • Supports elimination of liver function monitoring • 1991: NDA Approval(Class Labeling)900 treated patients • 1994: Post Marketing Experience7.5 million patient years • 1996: West of Scotland Coronary Prevention Study (WOSCOPS)3,302 treated patients • 2000: PRAVA 3CARE, LIPID, WOSCOPS9,895 treated patients>50,000 patient yearsof exposure

  15. Post Baseline ALT Abnormalities ALT Pravastatin 40 mg* (n=9,185) Placebo (n=9,152) (%) (%) > 3 x ULN, £ 5 x ULN 0.9 1.0 > 5 x ULN, £ 7 x ULN 0.3 0.2 > 7 x ULN, £ 9 x ULN < 0.1 < 0.1 > 9 x ULN 0.2 0.1 No Statistically Significant Differences Between Pravastatin and Placebo in Abnormalities of ALT Data from pooled analysis of WOSCOPS, CARE and LIPID * p=NS pravastatin vs. placebo for all comparisons

  16. Post Baseline ALT Abnormalities ALT Pravastatin 40 mg* (n=317) Placebo (n=262) (%) (%) > 3 x ULN, £ 5 x ULN 3.5 6.1 > 5 x ULN, £ 7 x ULN 1.3 0.8 > 7 x ULN, £ 9 x ULN 0 0 > 9 x ULN 0.3 0.4 No Statistically Significant Differences Between Pravastatin and Placebo in Abnormalities of ALT in Subjects with an Elevated Baseline Value Data from pooled analysis of WOSCOPS, CARE and LIPID * p=NS pravastatin vs. placebo for all comparisons

  17. Pravachol Hepatobiliary Safety • Clinical trial database • 9,895 patients treated for up to 7 years, of whom > 5,000 treated over 5 years • No signal of drug or dose related hepatotoxicity • Post Marketing Surveillance • > 22 million patient years of exposure • Very rare cases of liver failure; most confounded by predisposing conditions and multiple concomitant medications • Proposed OTC label doses not recommend LFT monitoring before or after initiation of Pravachol 10 mg

  18. Safety Considerations • Overdose • Pregnancy

  19. Pravachol Safety Considerations: Overdose • Doses of 160 mg/day appeared safe and well tolerated in a clinical trial of 6 weeks duration (n=48) • 4x highest prescription dose • 16x proposed OTC dose • 14 reported cases of overdose during Post Marketing Surveillance • 1 death • Attempted suicide with multiple CV drugs and suffered cardiac shock and arrest • 13 recovered without sequelae • 2 ingested > 1 gram (no laboratory abnormalities) • Proposed OTC label contains following warnings • Keep out of reach of children • In case of overdose get medical help or contact a poison control center right away

  20. Pravachol Safety Considerations: Pregnancy • Pre Clinical • Not teratogenic at doses with a 20 x (rabbits) or 240 x (rats) greater exposure than in humans (based on surface area and 40 mg dose) • No evidence of impaired organogenesis: offspring normal birth weight • Post Marketing Surveillance • 43 pregnancies reported • 29 cases with known outcome - no evidence of teratogenicity • Preclinical data and experience with exposure during pregnancy do not demonstrate increased risk of congenital malformation • Proposed OTC label contains following warning • If pregnant or breast feeding consult a health professional before use

  21. Conclusion Pravachol 10 mg is Appropriate for OTC Use • Drug interaction • Lack of significant drug interactions • Musculoskeletal • Serious musculoskeletal events similar to placebo in clinical trials; rarely reported in post marketing surveillance • Hepatobiliary • Hepatobiliary profile comparable to placebo supports elimination of LFT monitoring • Overdose • Safety of 16x OTC dose is demonstrated • Pregnancy • No evidence of reproductive risk if taken inadvertently by pregnant women

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