Cox 2 cv safety valdecoxib parecoxib
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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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Cox 2 cv safety valdecoxib parecoxib

COX-2 CV Safetyvaldecoxib-parecoxib

James Witter MD, PhD

DAAODP/ODE V

February 16, 2005


Bextra valdecoxib

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


Valdecoxib oa and ra exposure pt yrs

Valdecoxib - OA and RA Exposure (pt-yrs)

From Medical Officer review: November 7, 2001


Valdecoxib deaths

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


Valdecoxib cv mortality

Valdecoxib - CV Mortality


Valdecoxib cv safety special analysis

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


Valdecoxib cv safety high risk patients

Valdecoxib - CV safetyHigh Risk Patients

From Medical Officer review (Nov. 7, 2001)

All valdecoxib groups: incidence = 1.3%; events/100 pt-yrs = 4.6%


Valdecoxib cv safety at risk patients

Valdecoxib - CV safetyAt Risk Patients

From Medical Officer review (Nov. 7, 2001)

All valdecoxib groups: incidence = 0.4%; events/100 pt-yrs = 1.2%


Cv adverse events study 047 6 month oa ra

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


Cox 2 cv safety valdecoxib parecoxib

Parecoxib

IV/IM


Toradol iv im label pdr

Toradol IV/IM Label - PDR


Parecoxib

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


Parecoxib1

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


Parecoxib cabg i 035

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


  • Safety assessment cabg i

    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?


    Cox 2 cv safety valdecoxib parecoxib

    CABG (035) - Exposure

    Data from Medical Officer review (December 1, 2000)


    Craes cabg 035

    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)


    Myocardial infarction crae 035 diagnosed by 2 of following criteria

    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


  • Craes 035

    CRAEs - 035

    * P = 0.012 (Fischer’s)


    Mi cabg 035

    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


  • Parecoxib deaths

    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


    Cox 2 cv safety valdecoxib parecoxib

    • CABG II(Study 071)

      • 50% dose reduction

      • dosing on day 1

      • timing of events (IV vs. PO)


    Craes 071 entire study

    CRAEs - 071 (entire study)

    * p < 0.05; information included in valdecoxib label


    Dea ths 071

    Deaths - 071

    • Placebo

      • Intestinal perforation

    • Placebo/valdecoxib

      • Cardiac arrest

      • Pneumonia

      • Cardiac failure

    • Parecoxib/valdecoxib

      • Cardiac arrest

      • PE

      • MI

      • VF


    Cox 2 cv safety valdecoxib parecoxib

    General Surgery (study 069)

    -40 mg LD, then 20 mg BID

    -General Surgery Patients including orthopedic, GI, GYN, thoracic, other


    Craes 069 entire study

    CRAEs - 069 (Entire Study)

    Data included in valdecoxib label


    Deaths 069

    Deaths - 069

    • Placebo

      • Cardiac failure

      • Carcinoma

      • Mesenteric vein thrombosis

      • Cardiac arrest

    • Parecoxib/valdecoxib

      • GI hemorrhage

      • MI

      • PE


    Cox 2 cv safety valdecoxib parecoxib

    Is Safety Related to COX selectivity?

    GI

    CV

    COX-2

    COX-1


    Cox 2 cv safety valdecoxib parecoxib

    Safety: Selectivity or Drug ?

    Celecoxib NSAID

    Diclofenac COX-2


    Endoscopic ulceration ra 6 month

    Endoscopic UlcerationRA (6 month)

    * p < 0.001 (CMH); included in original label.


    Class gi outcomes

    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


    Class hepatic events

    CLASS - Hepatic Events

    * p < 0.05


    Safety data nsaids vs cox 2

    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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