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

AA-7-2 Pravachol Safety

AA-7-3 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 to 160 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 than  22 million patient years of exposure

AA-7-4 Special Safety Considerations For OTC Use Drug interactions Musculoskeletal Hepatobiliary Overdose Pregnancy

AA-7-5 Safety Considerations Drug Interactions

AA-7-6 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 mg dose range No warning for drug interactions in proposed OTC label

AA-7-7 Lack of Drug Interactions with Pravastatin Pravastatin Increase in Statin AUC with Interacting Drug SimvastatinLovastatin 25x 20x 15x 10x 5x 0

AA-7-8 Safety Considerations Musculoskeletal

AA-7-9 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: Weiner SL: Pg Grenvik A. Textbook of Critical Care. WB Saunders. 2000:

AA-7-10 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* 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

AA-7-11 U.S. Post-Marketing Cases of Rhabdomyolysis Show No Apparent Relationship to Dose or Country Distribution by Country Cases Per Million Tablets Distributed JapanFranceOther  10 mg Distribution by Dose Cases Per Million Tablets Distributed* 20 mg 40 mg * Dose unknown in 18 cases n=13n=43n=4n=21n=43n=7n=3

AA-7-12 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

AA-7-13 Safety Considerations Hepatobiliary System

AA-7-14 Pravachol Liver Monitoring Label History: Reduction of Monitoring Requirements Over Time 1991: NDA Approval (Class Labeling) 900 treated patients 1994: Post Marketing Experience 7.5 million patient years 1996: West of Scotland Coronary Prevention Study (WOSCOPS) 3,302 treated patients 2000: PRAVA 3 CARE, LIPID, WOSCOPS 9,895 treated patients  50,000 patient years of exposure Baseline, Week 6, 12, 20, 28, 36,periodically or dose elevation Baseline,Week 6, 12,periodically or dose elevation Baseline, Week 12 or dose elevation Supports elimination of liver function monitoring

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

AA-7-16 No Statistically Significant Differences Between Pravastatin and Placebo in Abnormalities of ALT in Subjects with an Elevated Baseline Value Pravastatin 40 mg* (n=317) Placebo (n=262) ALT (%)  3x ULN,  5x ULN  5x ULN,  7 x ULN  7x ULN,  9 x ULN  9x ULN Post Baseline ALT Abnormalities Data from pooled analysis of WOSCOPS, CARE and LIPID * p=NS pravastatin vs. placebo for all comparisons

AA-7-17 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

AA-7-18 Safety Considerations Overdose Overdose Pregnancy Pregnancy

AA-7-19 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

AA-7-20 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

AA-7-21 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