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COX-2 CV Safety valdecoxib-parecoxib

COX-2 CV Safety valdecoxib-parecoxib. James Witter MD, PhD DAAODP/ODE V February 16, 2005. Bextra (valdecoxib). Original NDA (January 15, 2001) 60 studies Phase 1-2: 31 studies Arthritis (OA/RA): 10 studies Included open-label exposure Post-surgical analgesia: 19 studies CABG 035

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COX-2 CV Safety valdecoxib-parecoxib

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  1. COX-2 CV Safetyvaldecoxib-parecoxib James Witter MD, PhD DAAODP/ODE V February 16, 2005

  2. Bextra (valdecoxib) • Original NDA (January 15, 2001) • 60 studies • Phase 1-2: 31 studies • Arthritis (OA/RA): 10 studies • Included open-label exposure • Post-surgical analgesia: 19 studies • CABG 035 • Original approval did not contain sulfonamide warning • Addressed by subsequent label changes and DHCP letters

  3. Valdecoxib - OA and RA Exposure (pt-yrs) From Medical Officer review: November 7, 2001

  4. Valdecoxib - Deaths • Total of 22 deaths in NDA • 17 occurred during double-blind studies • 4 in CABG trials (discussed in parecoxib data) • 2 were CV related • 8 in patients receiving valdecoxib • 4 were CV related • 3 in patients receiving NSAIDs • 2 were CV related • 2 non-CV deaths occurred in cancer pain trial • 5 during open-label studies • 3 were CV related

  5. Valdecoxib - CV Mortality

  6. Valdecoxib - CV SafetySpecial Analysis Rates of Serious Thromboembolic CV Adverse Events Calculated for High- and At-risk Patients: • High-risk patients: - angina, myocardial infarction, coronary artery disease and cerebrovascular accident • At-risk patients: - hypertension, hyperlipidemia or smoking • FDA-defined endpoints: - MI, myocardial ischemia, unstable angina, cardiac arrest, sudden cardiac death, CVA/TIA, PE, venous thrombosis, embolism, peripheral gangrene and peripheral ischemia

  7. Valdecoxib - CV safetyHigh Risk Patients From Medical Officer review (Nov. 7, 2001) All valdecoxib groups: incidence = 1.3%; events/100 pt-yrs = 4.6%

  8. Valdecoxib - CV safetyAt Risk Patients From Medical Officer review (Nov. 7, 2001) All valdecoxib groups: incidence = 0.4%; events/100 pt-yrs = 1.2%

  9. CV Adverse Events - Study 0476-month (OA/RA) • Table 2.3b.2 and 7.0.1: 6/25/01 consult. Labeled doses for OA/RA = 10 mg QD. • P < 0.05

  10. Parecoxib IV/IM

  11. Toradol IV/IM Label - PDR

  12. Parecoxib • Parenteral precursor to valdecoxib • T1/2 = 15-30 minutes • Allows exposure to different patient population with different risk factors • Intended to address the issues • multi-modal analgesia • COX-2 role in pain • pre-emptive analgesia • opioid sparing • Certain studies conducted with valdecoxib • CABG studies

  13. Parecoxib • Original NDA (September 11, 2000) • 36 studies • Phase 1-2: 14 studies • GI-renal-platelet: 7 studies • Post-surgical analgesia: 8 studies • Pre-operative analgesia: 4 studies • Opioid-sparing analgesia: 2 studies • CABG-035 • Long-term safety (with valdecoxib): 1 study

  14. Parecoxib - CABG I (035) • First time via median sternotomy • 2:1 randomization • 311 parecoxib • 151 placebo (standard-of-care; PCA/opioids) • Study with 2 phases • parecoxib IV/IM 40 mg q12 hrs for 72 hours • valdecoxib 40 mg orally q 12 hrs to day 14 • ASA (≤ 325 mg) during study

  15. Safety Assessment-CABG I Complex (patients, procedures, co-meds) Blinded committees established to: verify AE meet criteria established addressed date and attribution to include: CRAEs (clinically relevant adverse events) No active controls in CABG trials Are NSAIDs appropriate?

  16. CABG (035) - Exposure Data from Medical Officer review (December 1, 2000)

  17. CRAEs - CABG (035) • Death • All cause death following randomization within 30 days of last dose of study drug • Cardiovascular Events • myocardial infarction. • severe myocardial ischemia • cerebrovascular accident (CVA, TIA, or hemorrhage) • peripheral arterial occlusion • deep vein thrombosis • pulmonary embolism • Pericarditis • Congestive Heart Failure (new onset or exacerbation) • Renal Failure/Dysfunction • Gastrointestinal Event • Major non-GI bleed (requiring transfusion) • Infection (requiring institution of antibiotics) • Pulmonary complications (non-infectious)

  18. Myocardial Infarction - CRAE (035)diagnosed by 2 of following criteria • Prolonged (>20 min) typical chest pain not relieved by rest and/or nitrates • Enzyme level elevation, either by: • CK-MB >5% of total CPK • CK greater than 2x normal • LDH subtype 1>LDH subtype 2 • troponin >0.2 micrograms/ml • New wall motion abnormalities • Serial ECG (at least two) showing changes from baseline or serially in ST-T and/or Q waves that are 0.03 seconds in width and/or > or + one third of the total QRS complex in two or more contiguous leads

  19. CRAEs - 035 * P = 0.012 (Fischer’s)

  20. MI - CABG (035) • Of 13 possible MI, 11 sent to committee: • 9 events (parecoxib) • 2 events (placebo) • Of these, 2 MIs believed met CRAE definition • 1 parecoxib • 1 placebo • One rejected event in parecoxib group resulted in death (probable MI) of patient • Difficulty of adjudication • Timing of drug vs. event

  21. Parecoxib - Deaths • 58 y/o male- 4 doses (IV): • died on day 15 of duodenal ulcer • 69 y/o female-20 doses (IV/PO): • died on day 19 of probable MI • 67 y/o male-12 doses (IV/PO): • died day 12 septicemia, pneumonia • 62 y/o male-7 doses (IV): • died day 5 of infarct-left cerebellum

  22. CABG II(Study 071) • 50% dose reduction • dosing on day 1 • timing of events (IV vs. PO)

  23. CRAEs - 071 (entire study) * p < 0.05; information included in valdecoxib label

  24. Deaths - 071 • Placebo • Intestinal perforation • Placebo/valdecoxib • Cardiac arrest • Pneumonia • Cardiac failure • Parecoxib/valdecoxib • Cardiac arrest • PE • MI • VF

  25. General Surgery (study 069) -40 mg LD, then 20 mg BID -General Surgery Patients including orthopedic, GI, GYN, thoracic, other

  26. CRAEs - 069 (Entire Study) Data included in valdecoxib label

  27. Deaths - 069 • Placebo • Cardiac failure • Carcinoma • Mesenteric vein thrombosis • Cardiac arrest • Parecoxib/valdecoxib • GI hemorrhage • MI • PE

  28. Is Safety Related to COX selectivity? GI CV COX-2 COX-1

  29. Safety: Selectivity or Drug ? Celecoxib NSAID Diclofenac COX-2

  30. Endoscopic UlcerationRA (6 month) * p < 0.001 (CMH); included in original label.

  31. CLASS - GI outcomes • Compared to diclofenac, celecoxib did not demonstrate statistical superiority for any prospectively defined, adjudicated endpoint including: • Primary endpoint (complicated ulcers) • Including non-ASA users • Expanded endpoint of complicated and symptomatic ulcers • Including non-ASA users

  32. CLASS - Hepatic Events * p < 0.05

  33. Safety Data - NSAIDs vs COX-2 • Think about the data we have • Worry about the data we don’t have • Absence of evidence, is not evidence of absence

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