1 Bayer Corporation Consumer Care Division September 20, 2002 Allen H. Heller, MD Vice President, Global Research & Development Consumer Care NDAC Hearing September 20, 2002

2 Bayer OTC Analgesic Products Aspirin -Bayer  Aspirin (81, 325, 500 mg) -Alka-Seltzer  Naproxen Sodium - Aleve  - Aleve  Cold & Sinus Ibuprofen -Midol  Cramp Acetaminophen Combination Products -Alka-Seltzer Plus  - Midol  - Vanquish  NDAC Hearing September 20, 2002

3 Bayer Position Each OTC ingredient requires labeling appropriate for that ingredient and use OTC analgesic ingredients are safe & effective and there are no meaningful safety differences No credible data that switch from APAP to other OTC analgesics would increase risk Adverse events are well known, rare, and adequately labeled for safe use NDAC Hearing September 20, 2002

4 Aspirin and NSAID Safety Aspirin and NSAIDs used short term (OTC) -low risk -current labeling is adequate and sufficient Aspirin CV prophylaxis -favorable benefit/risk relationship NDAC Hearing September 20, 2002

5 Agenda Overview of safety assessment -- Construct for evaluating analgesic safety -Gerald A. Faich MD, MPH, Safety and Epidemiology Consultant Comparative safety of OTC analgesics -James F. Fries MD, Professor, Stanford University Aspirin cardiovascular benefits and risks -Charles H. Hennekens, MD, DrPH, Visiting Professor, University of Miami Conclusions -- Regulatory implications -Allen H. Heller, MD NDAC Hearing September 20, 2002

6 Construct for Evaluating OTC Analgesic Safety Gerald A. Faich MD, MPH Safety and Epidemiology Consultant

7 Points to Consider Risk is a function of the treated population, indication and pattern of use (who, why, when, how long) -Susceptibility -Indication (selection bias and underlying risk) -Dose and duration Evaluation requires adequate data on patients, exposure, outcomes (especially if not randomized trials) -Trial data at OTC doses are limited -Observational studies may lack good exposure and risk factor data (esp severity) -Spontaneous reports often not representative Cross study comparisons must be made cautiously RCTs > Observational > Spontaneous

8 RCT of ASA, Ibuprofen and APAP for Short Term Analgesia (PAIN) Moore N, et al. Clin Drug Invest 1999;18(2): ,108 GPs in France Up to 7 days for common painful conditions (musculoskeletal pain, sore throat, cold and flu) Blinded randomization of 8,677 adults Ibuprofen (up to 1.2g/day) or APAP or ASA (up to 3g/day) Total GI events 4.0%, 5.3%, 7.1% 6 nonserious GI bleeds - 4 APAP, 2 ASA

9 OTC Naproxen Metaanalysis DeArmond Clin Therapeutics 1995; 17(4): RCTs studies with naproxen mg per dose vs. placebo Dental pain, dysmenorrhea, cold/sore throat, musculoskeletal pain, other pain indications 45% single dose, 55% multiple dose Naproxen Placebo (n=4,138) (n=2,423) Dyspepsia 1.2%1.5% Nausea3.4%3.1% Vomiting1.0%1.0% No pairwise differences between ibuprofen, acetaminophen or naproxen

10 Observational Data Cohort -Limited for OTC analgesic doses -Valid comparisons with acetaminophen needed Case control with acetaminophen comparisons -GPRD (Garcia Rodriguez, 2001) -ARAMIS (Fries, et al., 2002) -Lewis and Strom - U Penn Caveats -Rx doses and long term vs OTC use -Risk factors -Residual confounding -Selection bias -Secular trends in GI bleeding

11 Risk of UGI Complications Among Users of Acetaminophen and NSAIDs Garcia Rodriguez LA, Hernandez-Diaz S. Epidemiology 2001; 12: Nested case control study in GPRD, year olds 2,105 cases of UGI Complications (PUBs) 11,500 controls Adjusted for age, sex, calendar year, smoking, prior UGI disease, use of steroids, anticoagulants, H 2 receptor antagonists, omeprazole, misoprostol and ASA

12 Risk of UGI Complications Among Users of Acetaminophen and NSAIDs Garcia Rodriguez LA, Hernandez-Diaz S. Epidemiology 2001; 12: High dose NSAIDs Low-medium dose NSAIDs APAP >2g/d 0.6 to to 1.9APAP <2g/d vs non-users 95% CIRRExposure

13 Risk of UGI Complications Among Users of Acetaminophen and NSAIDs Garcia Rodriguez LA, Hernandez-Diaz S. Epidemiology 2001; 12: Only study that analyzes APAP by dose Cannot rule out selection bias (high risk patients treated preferentially with APAP) even though attempt made to adjust for risk factors

14 FDA ASA GI Spontaneous SAE Reports ( ) 541 cases of GI hemorrhage, ulceration, or perforation; 29 deaths Risk factors in approximately 90% -- over 65 years, prior GI ulcer, multiple NSAIDs, concomitant steroids, anticoagulants, alcohol use Mean age 69.3 years Mean duration 42 days Majority vascular indicators (68.9% of cases)

15 Naproxen FDA Gastrointestinal Spontaneous SAE Reports ( ) 89 cases, with 73 where naproxen is primary suspect drug; 5 deaths but only one where naproxen is primary suspect drug Risk factors in 60 (67%) -- GI, severe illness, alcohol, meds, high dose, age over 65 years Mean age 62 years Duration half more than 7d, half less than 7d; median time to onset of bleed was 7d Half of reports were consumer reports

16 Summary of Safety Evidence Existent trial data don’t provide information on rare serious risks Observational studies are limited but suggest little difference in serious GI risks at OTC doses Spontaneous reports do not allow for comparative risk assessments

17 Comparative Safety of OTC Analgesics James F. Fries, MD Stanford University School of Medicine

18 ARAMIS Post-Marketing Surveillance Program Rates of serious GI events associated with low dose use of acetysaliscylic acid, acetaminophen, and ibuprofen in osteoarthritis (OA) and rheumataid arthritis (RA) patients (2002) Prospective, protocol-driven surveillance with Health Assessment Questionnaire (HAQ) 27,000 patient years of exposure (RA) 19,000 patient years of exposure (OA) Serious GI events (requiring hospitalizations) - perforations -ulcers - bleeds

19 Rates of Serious GI Events Per 1,000 Patient Years by Drug Use, Irrespective of Dose

20 Risk of Serious GI Events GI Risk Scores (OA)

21 Risk of Serious GI Events Rate as a Function of GI Risk Score (OA*)

22 Comparative OTC Analgesic Safety Conclusions OTC analgesics are well tolerated at OTC dose levels and durations Safety is comparable between ingredients Serious GI events are related more to underlying GI risk and comorbid factors than to specific OTC analgesic ingredient

23 Cardiovascular Disease: Benefits and Risks of Aspirin Charles H. Hennekens, MD, DrPH Visiting Professor of Medicine & Epidemiology and Public Health University of Miami School of Medicine

24 Introduction 199 Randomized trials of over 267,000 subjects (about 200,000 in 194 secondary prevention trials and 67,000 in 5 primary prevention trials) 3-5 years of treatment with predominantly aspirin or other antiplatelet drugs Doses from 30 mg to >1800 mg

25 Secondary Prevention and Acute MI Patients Aspirin is approved by FDA to decrease MI (by 33%), stroke (by 25%) and cardiovascular death (by 15%) All secondary prevention patients with prior MI, unstable/stable angina, PCI, CABG, occlusive stroke, and TIA (of which % are being treated) All acute MI patients (of which % are being treated)

26 Primary Prevention Patients Recommended to decrease risk of first MI (by 32%) by the American Heart Association for all men and women whose 10 year risk is > 10% US Preventive Services Task Force for all men and women whose 10 year risk is > 6%

27 CVD Risks of Aspirin Relative (and absolute) risks are low GI distress: 1.2 (4 -14%) GI bleed: 1.6 (1 - 4%) Cerebral hemorrhage: 1.6 ( %) Randomized trial data are necessary to provide reliable evidence for small to moderate benefits or risks due to inherent biases and uncontrollable confounding in observational epidemiological studies

28 CVD Risks of Aspirin UK TIA Trial 2435 patients enrolled in randomized, double-blind, placebo- controlled trial Average duration of treatment and follow-up of 4 years Doses compared: 300 mg and 1200 mg aspirin daily Placebo300 mg1200 mg GI Discomfort 25.0% 29.0% 39.0% Bleeding 1.6% 2.6% 4.9%

29 Summary In randomized trials of secondary prevention and acute MI (10 year risks > 20%) the CVD benefits of aspirin outweigh risks (FDA approved) In randomized trials of primary prevention (10 year risks > %) the CVD benefits of aspirin outweigh risks Daily doses demonstrating benefits ranged from 75mg to > 1800mg Observational epidemiological studies have inherent biases and uncontrollable confounding in attempting to evaluate benefits and risks of aspirin in CVD There is underutilization and mis-medication with aspirin in CVD The more widespread and appropriate use of aspirin could avoid over 10,000 premature deaths in secondary prevention and over 100,000 first MI’s in primary prevention in the US each year

30 Regulatory Implications Allen H. Heller, MD Vice President, Global Research & Development NDAC Hearing September 20, 2002

31 Regulatory Implications Regulatory decisions must be based on substantial evidence OTC analgesics are well tolerated and their overall safety is comparable ASA and NSAID OTC labeling is accurate and appropriate NDAC Hearing September 20, 2002