An Update on NSAID Labeling and Data Review DSaRM Advisory Committee February 10, 2006 Sharon Hertz, M.D. Deputy Director Division of Anesthesia, Analgesia, and Rheumatology Products

September February 2006 September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. placebo in APPROVe September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. placebo in APPROVe September 30, 2004 – Merck withdraws Vioxx (rofecoxib) from the market September 30, 2004 – Merck withdraws Vioxx (rofecoxib) from the market 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 December 17, 2004 – ADAPT trial halted (celecoxib and naproxen) December 17, 2004 – ADAPT trial halted (celecoxib and naproxen)

September February 2006 February 16-18, 2005 Joint Advisory Meeting Arthritis and Drug Safety and Risk Management Committees February 16-18, 2005 Joint Advisory Meeting Arthritis and Drug Safety and Risk Management Committees April 6, 2005 – FDA Memo on CV risk and NSAIDs April 6, 2005 – FDA Memo on CV risk and NSAIDs April 7, 2005 – Information request letter April 7, 2005 – Information request letter June 14, 2005 – Labeling supplement request letter June 14, 2005 – Labeling supplement request letter

NSAID Labeling New Boxed Warning Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).

NSAID Labeling New Boxed Warning Cardiovascular Risk, continued TRADENAME is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). TRADENAME is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

NSAID Labeling Box continued: Gastrointestinal Risk NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS). NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

NSAID Labeling INDICATIONS AND USAGE Carefully consider the potential benefits and risks of TRADENAME and other treatment options before deciding to use TRADENAME. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Carefully consider the potential benefits and risks of TRADENAME and other treatment options before deciding to use TRADENAME. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

NSAID Labeling CONTRAINDICATIONS TRADENAME is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). TRADENAME is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

NSAID Labeling WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.

NSAID Labeling Cardiovascular Thrombotic Events, continued All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. Use the lowest dose for the shortest period. Use the lowest dose for the shortest period.

NSAID Labeling Cardiovascular Thrombotic Events, continued There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serous GI events The concurrent use of aspirin and an NSAID does increase the risk of serous GI events CABG-associated risk CABG-associated risk

NSAID Labeling New WARNINGS continued: Hypertension Hypertension Congestive Heart Failure and Edema Congestive Heart Failure and Edema Renal Effects (from PRECAUTIONS) Renal Effects (from PRECAUTIONS) Advanced Renal Disease Advanced Renal Disease Anaphylactoid Reactions Anaphylactoid Reactions Skin Reactions Skin Reactions Pregnancy Pregnancy

NSAID Labeling Existing WARNING Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation

NSAID Labeling Information for Patients Serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death.

NSAID Labeling Information for Patients Promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity Patients should be informed of the warning signs and symptoms of hepatotoxicity Signs of an anaphylactoid reaction Signs of an anaphylactoid reaction Avoided in late pregnancy Avoided in late pregnancy

NSAID Labeling DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks Carefully consider the potential benefits and risks Use the lowest effective dose for the shortest duration Use the lowest effective dose for the shortest duration The dose and frequency should be adjusted to suit an individual patient's needs The dose and frequency should be adjusted to suit an individual patient's needs

Information Request Perform a review of all clinical trial data available Perform a review of all clinical trial data available Include data from studies longer than one month duration and which are controlled by a placebo, dose-response, or active control. Include data from studies longer than one month duration and which are controlled by a placebo, dose-response, or active control.

Information Request For each controlled clinical trial of one- month duration or longer, provide the following information by treatment group: For each controlled clinical trial of one- month duration or longer, provide the following information by treatment group: –CV deaths, MI, stroke, hospitalization for CHF where known –include definitions of events and descriptions of any clinical events committee. –Relevant baseline characteristics …

Information Request Information on CV events from any epidemiologic or other observational studies Information on CV events from any epidemiologic or other observational studies Information from controlled trials for the effects of your drug on blood pressure, including data from clinic and automated blood pressure machine (ABPM) measurements, relation of medication effects to dose, and interaction with antihypertensive medications. Information from controlled trials for the effects of your drug on blood pressure, including data from clinic and automated blood pressure machine (ABPM) measurements, relation of medication effects to dose, and interaction with antihypertensive medications.

Information Request Provide any information describing the cardiovascular effects of concomitant use of aspirin and your drug. Provide any information describing the cardiovascular effects of concomitant use of aspirin and your drug. Provide any new data regarding the lowest effective dose necessary for the approved indications of your drug. Provide any new data regarding the lowest effective dose necessary for the approved indications of your drug.

Review of CV data Working group with representatives from the Office of New Drugs review division, Office of Drug Safety, Office of Non- Prescription Drugs and Office of Biostatistics Working group with representatives from the Office of New Drugs review division, Office of Drug Safety, Office of Non- Prescription Drugs and Office of Biostatistics Reviewed and reanalyzed the data for the prescription and nonprescription products Reviewed and reanalyzed the data for the prescription and nonprescription products

Sample Response, Prescription NSAIDs Meta-analysis performed for individual products Placebo- and active-controlled RCTs Placebo- and active-controlled RCTs Planned duration of treatment ≥ 1 month Planned duration of treatment ≥ 1 month Clinical Study Report (CSR) or other appropriate documentation with safety assessment Clinical Study Report (CSR) or other appropriate documentation with safety assessment The cut-off date of database searching was April 7, 2005 The cut-off date of database searching was April 7, 2005

NSAID CV Data

Conclusion The data can not support the presence or absence of an association between these NSAIDs and CV adverse events The data can not support the presence or absence of an association between these NSAIDs and CV adverse events Small sample size, even with pooling Small sample size, even with pooling Very small number of CV events Very small number of CV events Short duration of treatment Short duration of treatment High heterogeneity and substantial variability from trials to trials High heterogeneity and substantial variability from trials to trials Trials were not originally designed for the CV safety Trials were not originally designed for the CV safety

Nonprescription NSAIDs Data submitted from original prescription applications and over-the-counter applications Data submitted from original prescription applications and over-the-counter applications Similar findings as the previous data found Similar findings as the previous data found –Rx studies small, short in duration, few events, not designed for safety outcome –OTC studies even smaller and shorter

Next Steps New NSAIDs under development New NSAIDs under development –Medical outcomes studies to evaluate cardiovascular outcomes Celecoxib cardiovascular outcomes study Celecoxib cardiovascular outcomes study –Have not come to agreement with sponsor –Have discussed concerns about the proposed protocol with the sponsor