1 bayer corporation consumer care division september 20, 2002 allen h. heller, md vice president,...

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Bayer CorporationBayer CorporationConsumer Care DivisionConsumer Care Division

September 20, 2002September 20, 2002

Allen H. Heller, MDAllen H. Heller, MDVice President, Global Research & Vice President, Global Research &

DevelopmentDevelopment

Consumer Care

NDAC HearingSeptember 20, 2002

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Bayer OTC Analgesic ProductsBayer 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


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Bayer PositionBayer 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


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Aspirin and NSAID SafetyAspirin 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


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AgendaAgenda

• 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


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Construct for Evaluating OTCConstruct for Evaluating OTCAnalgesic SafetyAnalgesic Safety

Gerald A. Faich MD, MPHGerald A. Faich MD, MPH Safety and Epidemiology ConsultantSafety and Epidemiology Consultant

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Points to ConsiderPoints 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

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RCT of ASA, Ibuprofen and APAP for Short Term RCT of ASA, Ibuprofen and APAP for Short Term Analgesia (PAIN)Analgesia (PAIN)

Moore N, et al. Clin Drug Invest 1999;18(2):89-98Moore N, et al. Clin Drug Invest 1999;18(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

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OTC Naproxen MetaanalysisOTC Naproxen MetaanalysisDeArmond Clin Therapeutics 1995; 17(4):587-601DeArmond 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 (n=4,138) (n=2,423)

Dyspepsia 1.2% 1.5%Nausea 3.4% 3.1%Vomiting 1.0% 1.0%

No pairwise differences between ibuprofen, acetaminophen or naproxen

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Observational DataObservational 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

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Risk of UGI Complications Among Users of Risk of UGI Complications Among Users of Acetaminophen and NSAIDsAcetaminophen and NSAIDs

Garcia Rodriguez LA, Hernandez-Diaz S. Epidemiology 2001; 12:570-576Garcia Rodriguez LA, Hernandez-Diaz S. Epidemiology 2001; 12:570-576

• 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

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4.1 - 5.84.9High dose NSAIDs

1.9 - 3.12.4Low-medium dose NSAIDs

2.6 - 5.13.6APAP >2g/d

0.6 to 2.60.8 to 1.9APAP <2g/d vs non-users

95% CIRRExposure

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• 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

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FDA ASA GI Spontaneous SAE Reports (1998 - 2001)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)

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NaproxenNaproxenFDA Gastrointestinal Spontaneous SAE Reports FDA Gastrointestinal Spontaneous SAE Reports

(1998-2001)(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

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Summary of Safety EvidenceSummary 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

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Comparative Safety of OTC Comparative Safety of OTC AnalgesicsAnalgesics

James F. Fries, MDJames F. Fries, MDStanford University School of MedicineStanford University School of Medicine

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ARAMIS Post-Marketing Surveillance ProgramARAMIS Post-Marketing Surveillance ProgramRates of serious GI events associated with low dose use of Rates of serious GI events associated with low dose use of

acetysaliscylic acid, acetaminophen, and ibuprofen in osteoarthritis (OA) acetysaliscylic acid, acetaminophen, and ibuprofen in osteoarthritis (OA) and rheumataid arthritis (RA) patients (2002)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

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

OA RA

Pt Yrs Rate Pt Yrs Rate

ASA

Alone 1396 2.9 2752 4.0

Plus Concurrent Rx† 3177 4.7 7668 8.7

APAP

Alone 489 2.1 390 2.6

Plus Concurrent Rx 3215 12* 5192 15*

IBU

Alone 823 2.4 974 3.1

Plus Concurrent Rx 2056 5.4 2799 6.1 *Significantly different (p<0.05) from the rates for the other two study analgesics in the same category.†Concurrent therapy includes prednisone, or NSAID, or another of the study analgesics.

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Risk of Serious GI EventsRisk of Serious GI Events

GI Risk Scores (OA)GI Risk Scores (OA)

RiskScore

% Low Risk(GI Score <10)

ASA

Alone 11.9 26

Plus Concurrent Rx 12.1 23

APAP

Alone 12.0 26


IBU

Alone 11.4 38


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Risk of Serious GI EventsRisk of Serious GI Events

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

Low Risk(GI Score <10)

Increased Risk(GI Score >10)

PtYears Rate

PtYears Rate

ASA

Alone 283 3.5 827 3.6

Plus Concurrent Rx 550 1.8 1838 7.6

APAP

Alone 89 0 256 3.7


IBU

Alone 234 4.3 386 0


*RA findings are comparable

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Comparative OTC Analgesic Safety ConclusionsComparative 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

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Cardiovascular Disease: Cardiovascular Disease: Benefits and Risks of AspirinBenefits and Risks of Aspirin

Charles H. Hennekens, MD, DrPHCharles H. Hennekens, MD, DrPHVisiting Professor of Medicine & Visiting Professor of Medicine & Epidemiology and Public Health Epidemiology and Public Health

University of Miami School of MedicineUniversity of Miami School of Medicine

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IntroductionIntroduction

• 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

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Secondary Prevention and Acute MI PatientsSecondary 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)

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Primary Prevention PatientsPrimary 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%

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CVD Risks of AspirinCVD 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

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CVD Risks of Aspirin CVD Risks of Aspirin UK TIA TrialUK 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 mgGI Discomfort 25.0% 29.0% 39.0%Bleeding 1.6% 2.6% 4.9%

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SummarySummary

• 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 MI’s in primary prevention in the US each year

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Regulatory ImplicationsRegulatory Implications

Allen H. Heller, MDAllen H. Heller, MDVice President, Global Research & Vice President, Global Research &

DevelopmentDevelopment


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Regulatory ImplicationsRegulatory 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


1 bayer corporation consumer care division september 20, 2002 allen h. heller, md vice president,...

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