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René Belder, MDRené Belder, MD

Executive DirectorClinical Development and Life Cycle Management

Cardiovascular / Metabolics

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Pravachol SafetyPravachol Safety

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Pravachol Extensive Worldwide Pravachol Extensive Worldwide Safety ExperienceSafety 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

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Special Safety Considerations For OTC UseSpecial Safety Considerations For OTC Use

Drug interactions

Musculoskeletal

Hepatobiliary

Overdose

Pregnancy

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Safety Considerations Safety Considerations Drug InteractionsDrug Interactions

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Pravachol: No Clinically Relevant Pravachol: No Clinically Relevant Pharmacokinetic Drug InteractionsPharmacokinetic 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

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Lack of Drug Interactions with PravastatinLack of Drug Interactions with Pravastatin

Cyclosporine

Verapamil

Itraconazole

Erythromycin

Clarithromycin

Grapefruit Juice

Diltiazem

Pravastatin

Increase in Statin AUC with

Interacting Drug

SimvastatinLovastatin

25x

20x

15x

10x

5x

0

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Safety Considerations Safety Considerations MusculoskeletalMusculoskeletal

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RhabdomyolysisRhabdomyolysis

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.

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Rhabdomyolysis Reported During Pravastatin UseRhabdomyolysis 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

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0.002

0.009

0.007 0.007

0.000

0.005

0.010

0.015

0.020

U.S.U.S.

Post-Marketing Cases of Rhabdomyolysis ShowPost-Marketing Cases of Rhabdomyolysis ShowNo Apparent Relationship to Dose or CountryNo Apparent Relationship to Dose or Country

Distribution by CountryCases Per Million Tablets Distributed

JapanJapan FranceFrance OtherOther

0.006

0.003

0.011

0.000

0.005

0.010

0.015

0.020

10 10 mgmg

Distribution by DoseCases Per Million Tablets Distributed*

20 mg20 mg 40 mg40 mg

* Dose unknown in 18 cases

n=13n=13n=43n=43 n=4n=4 n=21n=21 n=43n=43 n=7n=7 n=3n=3

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Rhabdomyolysis SummaryRhabdomyolysis 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

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Safety Considerations Safety Considerations Hepatobiliary SystemHepatobiliary System

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Pravachol Liver Monitoring Label History:Pravachol Liver Monitoring Label History:Reduction of Monitoring Requirements Over TimeReduction of Monitoring Requirements Over Time

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 patients50,000 patient yearsof exposure

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

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No Statistically Significant Differences Between No Statistically Significant Differences Between Pravastatin and Placebo in Abnormalities of ALTPravastatin and Placebo in Abnormalities of ALT

Pravastatin 40 mg*(n=9,185)

Placebo(n=9,152)ALT

0.3 0.2

0.1 0.1

0.2 0.1

5 x ULN, 7 x ULN

7 x ULN, 9 x ULN

9 x ULN

0.93 x ULN, 5 x ULN 1.0

(%)(%)

Post Baseline ALT Abnormalities

Data from pooled analysis of WOSCOPS, CARE and LIPID

* p=NS pravastatin vs. placebo for all comparisons

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No Statistically Significant Differences Between No Statistically Significant Differences Between Pravastatin and Placebo in Abnormalities of ALT Pravastatin and Placebo in Abnormalities of ALT

in Subjects with an Elevated Baseline Valuein Subjects with an Elevated Baseline Value

Pravastatin 40 mg*(n=317)

Placebo(n=262)ALT

3.5 6.1

1.3 0.8

0 0

0.3 0.4

(%) (%)

3 x ULN, 5 x ULN

5 x ULN, 7 x ULN

7 x ULN, 9 x ULN

9 x ULN

Post Baseline ALT Abnormalities

Data from pooled analysis of WOSCOPS, CARE and LIPID

* p=NS pravastatin vs. placebo for all comparisons

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Pravachol Hepatobiliary SafetyPravachol 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

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Safety ConsiderationsSafety Considerations

OverdoseOverdose

PregnancyPregnancy

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Pravachol Safety Considerations: OverdosePravachol 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

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Pravachol Safety Considerations: PregnancyPravachol 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

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ConclusionConclusion Pravachol 10 mg is Appropriate for OTC Use 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