Bayer Corporation Consumer Care Division September 20, 2002 Allen H. Heller, MD Vice President, Glob

1
Bayer CorporationConsumer Care
DivisionSeptember 20, 2002Allen H. Heller,
MDVice President, Global Research Development
Consumer Care
NDAC Hearing September 20, 2002
2
NDAC Hearing September 20, 2002
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?

3
NDAC Hearing September 20, 2002
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

4
NDAC Hearing September 20, 2002
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

5
NDAC Hearing September 20, 2002
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

6
Construct for Evaluating OTCAnalgesic
SafetyGerald 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
199918(2)89-98

• 1,108 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 MetaanalysisDeArmond Clin
Therapeutics 1995 17(4)587-601

• 48 RCTs studies with naproxen 200-400mg per dose
  vs. placebo
• Dental pain, dysmenorrhea, cold/sore throat,
  musculoskeletal pain, other pain indications
• 45 single dose, 55 multiple dose
• Naproxen Placebo
  (n4,138)
  (n2,423)
• Dyspepsia 1.2 1.5
• Nausea 3.4 3.1
• Vomiting 1.0 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 NSAIDsGarcia Rodriguez LA,
Hernandez-Diaz S. Epidemiology 2001 12570-576

• Nested case control study in GPRD, 40-79 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, H2 receptor antagonists,
  omeprazole, misoprostol and ASA

12
Risk of UGI Complications Among Users of
Acetaminophen and NSAIDsGarcia Rodriguez LA,
Hernandez-Diaz S. Epidemiology 2001 12570-576
13
Risk of UGI Complications Among Users of
Acetaminophen and NSAIDsGarcia Rodriguez LA,
Hernandez-Diaz S. Epidemiology 2001 12570-576

• 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 (1998 - 2001)

• 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
NaproxenFDA Gastrointestinal Spontaneous SAE
Reports (1998-2001)

• 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 dont 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 AnalgesicsJames F.
Fries, MDStanford University School of Medicine
18
ARAMIS Post-Marketing Surveillance ProgramRates
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 EventsGI Risk Scores (OA)
21
Risk of Serious GI EventsRate 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
AspirinCharles H. Hennekens, MD, DrPHVisiting
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 50 - 80 are being
  treated)
• All acute MI patients (of which 40 - 70 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 (0.1 -0.2)
• 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
• Placebo 300 mg 1200 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 6 - 10) 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
  MIs in primary prevention in the US each year

30
Regulatory ImplicationsAllen H. Heller,
MDVice President, Global Research Development
NDAC Hearing September 20, 2002
31
NDAC Hearing September 20, 2002
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