1. Regulatory History of Aspirin Cardiovascular and Renal Drugs Advisory Committee Meeting Michelle M. Jackson, Ph.D. Division of Over-The-Counter Drug Products Cardiovascular and Renal Drugs Advisory Committee Meeting Michelle M. Jackson, Ph.D. Division of Over-The-Counter Drug Products Cardiovascular and Renal Drugs AC Meeting December 8, 2003

2. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 2 ContentContent The OTC Drug Monograph Process Regulatory History of Aspirin 1989 & 1997 Advisory Committee Discussions Professional Labeling for Aspirin The OTC Drug Monograph Process Regulatory History of Aspirin 1989 & 1997 Advisory Committee Discussions Professional Labeling for Aspirin

3. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 3 OTC Drug Monograph Process 1.Advisory Review Panels Panels submit reports to FDA 2.Advance Notice of Proposed Rulemaking (ANPR) Public comment period 3.Tentative Final Monograph (TFM) Public comment period 4.Final Monograph (FM) 1.Advisory Review Panels Panels submit reports to FDA 2.Advance Notice of Proposed Rulemaking (ANPR) Public comment period 3.Tentative Final Monograph (TFM) Public comment period 4.Final Monograph (FM)

4. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 4 OTC Drug Review Citizen Petition (21 CFR 10.30) Right of citizens to petition the government Used to issue, amend, or revoke a regulation Used to take or refrain from taking certain actions Citizen Petition (21 CFR 10.30) Right of citizens to petition the government Used to issue, amend, or revoke a regulation Used to take or refrain from taking certain actions

5. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 5 OTC Drug Review (con’t) OTC Drug Labeling – -OTC drug labeling provided for consumers - Consumers are able to safely self medicate Professional Drug Labeling – -OTC drug labeling provided for healthcare professionals (not for the general public) -Advice of a healthcare professional is needed for the safe and effective use of the drug product OTC Drug Labeling – -OTC drug labeling provided for consumers - Consumers are able to safely self medicate Professional Drug Labeling – -OTC drug labeling provided for healthcare professionals (not for the general public) -Advice of a healthcare professional is needed for the safe and effective use of the drug product

6. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 6 Regulatory History of Aspirin July 21, 1972Review of OTC internal analgesic ingredients Advisory Review Panel July 8, 1977ANPR - Publication of OTC internal analgesic panel report Public Comment Period November 16, 1988TFM - Public Comment Period May 8, 1989Comment: Sterling Drug Inc. Claim for aspirin for the prevention of primary heart attack October 6, 1989Advisory Committee Meeting July 21, 1972Review of OTC internal analgesic ingredients Advisory Review Panel July 8, 1977ANPR - Publication of OTC internal analgesic panel report Public Comment Period November 16, 1988TFM - Public Comment Period May 8, 1989Comment: Sterling Drug Inc. Claim for aspirin for the prevention of primary heart attack October 6, 1989Advisory Committee Meeting

7. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 7 Regulatory History of Aspirin (con’t) October 15, 1992Aspirin Foundation (CP9): Claim for treating acute MI December 21, 1992Aspirin Strategy Group (CP10): Claim for treating acute MI June 6, 1994Aspirin Strategy Group (CP12): Claim for anyone at risk for MI and stroke June 13, 1996Amendment to the TFM January 23, 1997Advisory Committee Meeting October 23, 1998Final Monograph: Professional Labeling October 15, 1992Aspirin Foundation (CP9): Claim for treating acute MI December 21, 1992Aspirin Strategy Group (CP10): Claim for treating acute MI June 6, 1994Aspirin Strategy Group (CP12): Claim for anyone at risk for MI and stroke June 13, 1996Amendment to the TFM January 23, 1997Advisory Committee Meeting October 23, 1998Final Monograph: Professional Labeling

8. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 8 ANPR – July 8, 1977 Panel’s Report: ANPR – July 8, 1977 Panel’s Report: Anti-platelet effects of aspirin Increased bleeding time Warnings against use in people with GI or bleeding problems, or during pregnancy No mention of CV claims Anti-platelet effects of aspirin Increased bleeding time Warnings against use in people with GI or bleeding problems, or during pregnancy No mention of CV claims

9. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 9 TFM – November 16, 1988 TFM – November 16, 1988 Proposed professional labeling for use of aspirin: - reducing the risk of recurrent TIAs or stroke in men - reducing the risk of death and/or nonfatal MI - rheumatologic diseases Proposed professional labeling for use of aspirin: - reducing the risk of recurrent TIAs or stroke in men - reducing the risk of death and/or nonfatal MI - rheumatologic diseases

10. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 10 Comments to the TFM Professional Labeling for Aspirin: Use for primary prevention of MI Reduce the dose for TIA and stroke from 1,300 mg to 300 mg a day Include labeling for both men and women Professional Labeling for Aspirin: Use for primary prevention of MI Reduce the dose for TIA and stroke from 1,300 mg to 300 mg a day Include labeling for both men and women

11. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 11 1989 Advisory Committee Meeting (PHS: Labeling claim for primary prevention of MI) No effect on total cardiovascular mortality No data on routine use in men w/o risk factors and in women Concerns about use in healthy people or inappropriate patient populations No effect on total cardiovascular mortality No data on routine use in men w/o risk factors and in women Concerns about use in healthy people or inappropriate patient populations

12. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 12 Amendment to the TFM June 13, 1996 In response to 2 CPs requesting: an indication for use of aspirin in treating acute MI: initial dose of 160 mg to 162.5 mg continued daily for at least 30 days In response to 2 CPs requesting: an indication for use of aspirin in treating acute MI: initial dose of 160 mg to 162.5 mg continued daily for at least 30 days

13. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 13 1997 Advisory Committee Meeting CP requested an amendment to the professional labeling for aspirin in secondary prevention of CV events in patients: 1997 Advisory Committee Meeting CP requested an amendment to the professional labeling for aspirin in secondary prevention of CV events in patients: undergoing coronary, cerebral, or peripheral arterial revascularization procedures with chronic non-valvular atrial fibrillation requiring hemodialysis access with fistula or shunt with elevated risk due to some form of vascular disease undergoing coronary, cerebral, or peripheral arterial revascularization procedures with chronic non-valvular atrial fibrillation requiring hemodialysis access with fistula or shunt with elevated risk due to some form of vascular disease

14. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 14 1997 Advisory Committee Meeting Recommendations Low-dose aspirin in patients with stable angina Low-dose aspirin in patients with arterial revascularization procedures Not indicated in patients with peripheral vascular disease Low-dose aspirin in patients with stable angina Low-dose aspirin in patients with arterial revascularization procedures Not indicated in patients with peripheral vascular disease

15. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 15 1998 Final Monograph FDA’s Evaluation of the PHS Reasons why the claim for primary prevention of MI was not included in the FM : 1998 Final Monograph FDA’s Evaluation of the PHS Reasons why the claim for primary prevention of MI was not included in the FM : Some subjects had prior MI 8% who suffered a nonfatal MI also had evidence of a previous MI No statistically significant effects of aspirin when fatal / nonfatal MI and stroke were combined Some subjects had prior MI 8% who suffered a nonfatal MI also had evidence of a previous MI No statistically significant effects of aspirin when fatal / nonfatal MI and stroke were combined

16. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 16 1998 Final Monograph FDA’s Evaluation of the PHS (con’t) 1998 Final Monograph FDA’s Evaluation of the PHS (con’t) Reduction in the incidence of fatal and non-fatal MI was accompanied by an increase in: - hemorrhagic stroke - sudden death - other CV deaths BDT does not support the use of aspirin to prevent initial MI Reduction in the incidence of fatal and non-fatal MI was accompanied by an increase in: - hemorrhagic stroke - sudden death - other CV deaths BDT does not support the use of aspirin to prevent initial MI

17. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 17 Professional Labeling Information does not appear on the OTC label Labeling is provided to healthcare professionals by manufacturers Prescribing information for: vascular indications revascularization procedures rheumatologic diseases Information does not appear on the OTC label Labeling is provided to healthcare professionals by manufacturers Prescribing information for: vascular indications revascularization procedures rheumatologic diseases

18. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 18 Professional Labeling (cont.) Professional Labeling of Aspirin Components of Professional Labeling Warnings Precautions Adverse Reactions Overdosage Dosage & Administration Contraindications Indications

19. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 19 Professional Labeling (cont.) Vascular Indications Indications Recommended Daily Dose (mg) Ischemic Strokes / TIA 50 - 325 Suspected Acute MI 160 - 162.5 Prevention of Recurrent MI 75 - 325 Unstable Angina Pectoris 75 - 325 Chronic Stable Angina Pectoris 75 - 325

20. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 20 Professional Labeling (cont.) Revascularization Procedures IndicationsRecommended Daily Dose (mg) Coronary Artery 325 Bypass Graft Percutaneous Transluminal Presurgery: 325 Coronary Artery Postsurgery: 160 - 325 Carotid Endarterectomy 80 - 650

21. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 21 Bayer Healthcare’s Request Professional labeling for the use of aspirin regimen (75-325 mg) for primary prevention of MI in patients at risk for a CHD

22. Cardiovascular and Renal Drugs AC Meeting December 8, 2003 22

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