1. Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting November 29, 2006 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia, and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Overview of Presentation Cardiovascular findings from COX-2 development FDA conclusions about CV Risk and NSAIDs

3. 3 Vioxx May 20, 1999 Approval of New Drug Application for Vioxx (rofecoxib) for the treatment of acute pain in adults, dysmenorrhea and osteoarthritis ~ 5000 subjects ~ 5000 subjects 700+ at least 1 year (12.5 and 25 mg) 700+ at least 1 year (12.5 and 25 mg) No cardiovascular signal – small number of events, no dose response No cardiovascular signal – small number of events, no dose response

4. 4 Vioxx - VIGOR Rofecoxib 50 mg daily vs. naproxen 500 mg BID Rofecoxib 50 mg daily vs. naproxen 500 mg BID 8,000 RA patients, no ASA 8,000 RA patients, no ASA Median exposure - 9 months Median exposure - 9 months Endpoints Endpoints –serious GI events –serious CV/thrombotic events

5. 5 Vioxx - VIGOR Cardiovascular risk identified for rofecoxib vs. naproxen  All CV events - RR 2.37  MI - RR 5.0 (20 vs. 4)  Incidence increased over time  Results taken to AC February, 2001

6. 6 Vioxx - Alzheimer’s Disease To slow progression or prevent onset To slow progression or prevent onset 3 placebo-controlled, double-blind, multicenter studies 3 placebo-controlled, double-blind, multicenter studies Rofecoxib 25 mg vs. placebo Rofecoxib 25 mg vs. placebo 15-24 months 15-24 months No consistent cardiovascular signal No consistent cardiovascular signal

7. 7 Vioxx - APPROVe Reduce incidence of adenomatous polyps in patients with history of colorectal adenomas Reduce incidence of adenomatous polyps in patients with history of colorectal adenomas Randomized, placebo-controlled, double-blind, 3 years + 1 year Randomized, placebo-controlled, double-blind, 3 years + 1 year Rofecoxib 25 mg vs. placebo Rofecoxib 25 mg vs. placebo 2586 patients 2586 patients

8. 8 Vioxx - APPROVe September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. placebo in APPROVe  All CV events – RR 1.8  MI – RR 2.5  Ischemic CVA – RR 1.8 September 30, 2004 – Merck withdraws Vioxx from the market

9. 9 Celebrex December 31, 1998 Approval of New Drug Application for Celebrex (celecoxib) for the signs and symptoms of osteoarthritis and rheumatoid arthritis No CV signal with initial application No CV signal with initial application

10. 10 Celebrex - CLASS CLASS Double-blind, active-controlled, 1 year Double-blind, active-controlled, 1 year ~ 8,000 patients with OA or RA, ASA if indicated ~ 8,000 patients with OA or RA, ASA if indicated Celecoxib 400 mg twice daily Celecoxib 400 mg twice daily Endpoint – serious GI events Endpoint – serious GI events No cardiovascular signal vs. ibuprofen 800 mg TID or diclofenac 75 mg BID No cardiovascular signal vs. ibuprofen 800 mg TID or diclofenac 75 mg BID

11. 11 Celebrex - APC APC (Prevention of Sporadic Colorectal Adenomas with Celecoxib) Double-blind, placebo-controlled, 3 years, over 1900 patients Double-blind, placebo-controlled, 3 years, over 1900 patients –Celebrex 400 mg twice daily –Celebrex 200 mg twice daily –Placebo

12. 12 Celebrex - APC December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebo December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebo Death from CV causes, MI, or stroke – –celecoxib 200 mg bid vs. placebo RR 2.5 – –celecoxib 400 mg bid vs. placebo RR 3.4

13. 13 Celebrex - APC Solomon SD, et al: N Engl J Med 352, 2005 *In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure 671

14. 14 Celebrex - ADAPT Alzheimer’s prevention study December 17, 2004 – ADAPT trial halted December 17, 2004 – ADAPT trial halted Cardiovascular risk not found for celecoxib vs. placebo in this data set, while a risk for naproxen compared to placebo is suggested.

15. 15 February 2005 Joint advisory committee meeting with the arthritis and drug safety committees Data presented on rofecoxib, celecoxib and other products not approved in the U.S. Presentations on GI risk, CV risk, possible mechanisms of CV risk

16. 16 Epidemiological Studies Consistent risk associated with high dose rofecoxib Variable findings of risk associated with other selective and nonselective NSAIDs – –In particular, some studies show CV risk associated with celecoxib while others show no CV with celecoxib

17. 17 FDA Conclusions April 6, 2005 Decisional Memorandum: “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk” April 6, 2005 Decisional Memorandum: “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk” http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf http://www.fda.gov/cder/drug/infopag e/COX2/NSAIDdecisionMemo.pdf

18. 18 FDA Conclusions “The three approved COX-2 selective NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are associated with an increased risk of serious adverse CV events compared to placebo. The available data do not permit a rank ordering of these drugs with regard to CV risk.”

19. 19 FDA Conclusions “Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs. ”

20. 20 FDA Conclusions In addition: Long-term, placebo-controlled clinical trial data are not available for the non-selective NSAIDs Pending additional clinical trial data, interpret findings as consistent with a class effect of an increased risk of serious adverse CV events for COX-2 selective and non- selective NSAIDs.

21. 21 FDA Regulatory Actions April 7, 2005 Boxed warning all Rx NSAIDs Boxed warning all Rx NSAIDs – Potential increased risk serious CV events – May be higher with prior history of CV disease/risk – Added GI warnings to box – Contraindication perioperative CABG

22. 22 FDA Regulatory Actions Class Medication Guide for all Rx NSAIDs Class Medication Guide for all Rx NSAIDs Revised warnings for OTC NSAIDs Revised warnings for OTC NSAIDs

23. 23 Information Request Review of all clinical trial data from controlled studies Review of all clinical trial data from controlled studies Unable to draw conclusions Unable to draw conclusions –Small sample size, even with pooling –Very small number of CV events –Short duration of treatment

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