An Update on NSAID Labeling and Data Review DSaRM Advisory Committee February 10, 2006 Sharon Hertz,...

An Update on NSAID An Update on NSAID Labeling and Data Labeling and Data

Review Review

DSaRM Advisory CommitteeDSaRM Advisory CommitteeFebruary 10, 2006February 10, 2006Sharon Hertz, M.D.Sharon Hertz, M.D.

Deputy DirectorDeputy DirectorDivision of Anesthesia, Analgesia, and Division of Anesthesia, Analgesia, and

Rheumatology ProductsRheumatology Products

September 2004-September 2004-February 2006February 2006

September 27, 2004 – Merck informs September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. FDA of CV signal for rofecoxib vs. placebo in APPROVeplacebo in APPROVe

September 30, 2004 – Merck withdraws September 30, 2004 – Merck withdraws Vioxx (rofecoxib) from the marketVioxx (rofecoxib) from the market

December 16, 2004 – APC study halted December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebodue to CV signal for celecoxib vs. placebo

December 17, 2004 – ADAPT trial halted December 17, 2004 – ADAPT trial halted (celecoxib and naproxen)(celecoxib and naproxen)

September 2004-September 2004-February 2006February 2006

February 16-18, 2005 Joint Advisory February 16-18, 2005 Joint Advisory Meeting Arthritis and Drug Safety and Meeting Arthritis and Drug Safety and Risk Management CommitteesRisk Management Committees

April 6, 2005 – FDA Memo on CV risk April 6, 2005 – FDA Memo on CV risk and NSAIDsand NSAIDs

April 7, 2005 – Information request April 7, 2005 – Information request letterletter

June 14, 2005 – Labeling supplement June 14, 2005 – Labeling supplement request letterrequest letter

NSAID LabelingNSAID Labeling

New Boxed WarningNew Boxed WarningCardiovascular Risk Cardiovascular Risk NSAIDs may cause an increased risk of NSAIDs may cause an increased risk of

serious cardiovascular thrombotic serious cardiovascular thrombotic events, myocardial infarction, and events, myocardial infarction, and stroke, which can be fatal. This risk may stroke, which can be fatal. This risk may increase with duration of use. Patients increase with duration of use. Patients with cardiovascular disease or risk with cardiovascular disease or risk factors for cardiovascular disease may factors for cardiovascular disease may be at greater risk (see WARNINGS). be at greater risk (see WARNINGS).


New Boxed WarningNew Boxed Warning

Cardiovascular Risk, continuedCardiovascular Risk, continued TRADENAME is contraindicated TRADENAME is contraindicated

for the treatment of peri-for the treatment of peri-operative pain in the setting of operative pain in the setting of coronary artery bypass graft coronary artery bypass graft (CABG) surgery (see WARNINGS).(CABG) surgery (see WARNINGS).


Box continued:Box continued:Gastrointestinal Risk Gastrointestinal Risk NSAIDs cause an increased risk of NSAIDs cause an increased risk of

serious gastrointestinal adverse events serious gastrointestinal adverse events including bleeding, ulceration, and including bleeding, ulceration, and perforation of the stomach or intestines, perforation of the stomach or intestines, which can be fatal. These events can which can be fatal. These events can occur at any time during use and occur at any time during use and without warning symptoms. Elderly without warning symptoms. Elderly patients are at greater risk for serious patients are at greater risk for serious gastrointestinal events (see gastrointestinal events (see WARNINGS). WARNINGS).


INDICATIONS AND USAGE INDICATIONS AND USAGE Carefully consider the potential Carefully consider the potential

benefits and risks of TRADENAME and benefits and risks of TRADENAME and other treatment options before other treatment options before deciding to use TRADENAME. Use the deciding to use TRADENAME. Use the lowest effective dose for the shortest lowest effective dose for the shortest duration consistent with individual duration consistent with individual patient treatment goals (see patient treatment goals (see WARNINGS). WARNINGS).


CONTRAINDICATIONSCONTRAINDICATIONS TRADENAME is contraindicated for the TRADENAME is contraindicated for the

treatment of peri-operative pain in the treatment of peri-operative pain in the setting of coronary artery bypass graft setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).(CABG) surgery (see WARNINGS).


WARNINGSWARNINGSCARDIOVASCULAR EFFECTSCARDIOVASCULAR EFFECTSCardiovascular Thrombotic EventsCardiovascular Thrombotic Events Clinical trials of several COX-2 Clinical trials of several COX-2

selective and nonselective NSAIDs of selective and nonselective NSAIDs of up to three years duration have shown up to three years duration have shown an increased risk of serious an increased risk of serious cardiovascular (CV) thrombotic events, cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, myocardial infarction, and stroke, which can be fatal. which can be fatal.


Cardiovascular Thrombotic Events,Cardiovascular Thrombotic Events, continuedcontinued

All NSAIDs, both COX-2 selective and All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. nonselective, may have a similar risk. Patients with known CV disease or risk Patients with known CV disease or risk factors for CV disease may be at factors for CV disease may be at greater risk. greater risk.

Use the lowest dose for the shortest Use the lowest dose for the shortest period.period.


Cardiovascular Thrombotic Events, Cardiovascular Thrombotic Events, continuedcontinued

There is no consistent evidence that There is no consistent evidence that concurrent use of aspirin mitigates the concurrent use of aspirin mitigates the increased risk of serious CV thrombotic increased risk of serious CV thrombotic events associated with NSAID use. events associated with NSAID use.

The concurrent use of aspirin and an The concurrent use of aspirin and an NSAID does increase the risk of serous NSAID does increase the risk of serous GI events GI events

CABG-associated risk CABG-associated risk


New WARNINGS continued:New WARNINGS continued: Hypertension Hypertension Congestive Heart Failure and EdemaCongestive 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


Existing WARNINGExisting WARNING Gastrointestinal Effects-Risk of Gastrointestinal Effects-Risk of

Ulceration, Bleeding, and Perforation Ulceration, Bleeding, and Perforation


Information for Patients Information for Patients Serious CV side effects, such as MI or Serious CV side effects, such as MI or

stroke, which may result in stroke, which may result in hospitalization and even death. hospitalization and even death.

GI discomfort and, rarely, serious GI side GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, effects, such as ulcers and bleeding, which may result in hospitalization and which may result in hospitalization and even death. even death.

Serious skin side effects such as Serious skin side effects such as exfoliative dermatitis, SJS, and TEN, exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and which may result in hospitalizations and even death. even death.


Information for Patients Information for Patients Promptly report signs or symptoms of Promptly report signs or symptoms of

unexplained weight gain or edema to unexplained weight gain or edema to their physicians. their physicians.

Patients should be informed of the Patients should be informed of the warning signs and symptoms of warning signs and symptoms of hepatotoxicity hepatotoxicity

Signs of an anaphylactoid reaction Signs of an anaphylactoid reaction Avoided in late pregnancyAvoided in late pregnancy


DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION Carefully consider the potential Carefully consider the potential

benefits and risksbenefits and risks Use the lowest effective dose for the Use the lowest effective dose for the

shortest duration shortest duration The dose and frequency should be The dose and frequency should be

adjusted to suit an individual patient's adjusted to suit an individual patient's needs needs

Information RequestInformation Request

Perform a review of all clinical trial Perform a review of all clinical trial data availabledata available

Include data from studies longer than Include data from studies longer than one month duration and which are one month duration and which are controlled by a placebo, dose-controlled by a placebo, dose-response, or active control. response, or active control.


For each controlled clinical trial of one-For each controlled clinical trial of one-month duration or longer, provide the month duration or longer, provide the following information by treatment following information by treatment group: group:

– CV deaths, MI, stroke, hospitalization CV deaths, MI, stroke, hospitalization for CHF where knownfor CHF where known

– include definitions of events and include definitions of events and descriptions of any clinical events descriptions of any clinical events committee. committee.

– Relevant baseline characteristics …Relevant baseline characteristics …


Information on CV events from any Information on CV events from any epidemiologic or other observational epidemiologic or other observational studies studies

Information from controlled trials for Information from controlled trials for the effects of your drug on blood the effects of your drug on blood pressure, including data from clinic pressure, including data from clinic and automated blood pressure and automated blood pressure machine (ABPM) measurements, machine (ABPM) measurements, relation of medication effects to relation of medication effects to dose, and interaction with dose, and interaction with antihypertensive medications. antihypertensive medications.


Provide any information describing Provide any information describing the cardiovascular effects of the cardiovascular effects of concomitant use of aspirin and your concomitant use of aspirin and your drug. drug.

Provide any new data regarding the Provide any new data regarding the lowest effective dose necessary for lowest effective dose necessary for the approved indications of your the approved indications of your drug. drug.

Review of CV dataReview of CV data

Working group with representatives Working group with representatives from the Office of New Drugs review from the Office of New Drugs review division, Office of Drug Safety, Office division, Office of Drug Safety, Office of Non-Prescription Drugs and Office of Non-Prescription Drugs and Office of Biostatisticsof Biostatistics

Reviewed and reanalyzed the data Reviewed and reanalyzed the data for the prescription and for the prescription and nonprescription productsnonprescription products

Sample Response, Sample Response, Prescription NSAIDsPrescription NSAIDs

Meta-analysis performed for individual Meta-analysis performed for individual productsproducts

Placebo- and active-controlled RCTs Placebo- and active-controlled RCTs Planned duration of treatment Planned duration of treatment ≥ ≥ 1 1

monthmonth Clinical Study Report (CSR) or other Clinical Study Report (CSR) or other

appropriate documentation with appropriate documentation with safety assessmentsafety assessment

The cut-off date of database The cut-off date of database searching was April 7, 2005searching was April 7, 2005

NSAID CV DataNSAID CV DataNSAIDs

Eligible RCT

Sample Size

MI Stroke All CV deaths

NSAID 1 Treatment 8 257 0 0 0 Placebo 232 0 0 0 Treatment 12 531 0 0 0 Other NSAIDs 538 1 1 1 Treatment 8 655 1 0 0 ASA 633 1 0 0 NSAID 2

Treatment 10 305 0 0 0 Placebo 147 0 0 0 Treatment 25 1056 3 0 3 Other NSAIDs 1413 1 0 1 Treatment 5 165 0 0 0 ASA 169 0 0 0

NSAID CV DataNSAID CV Data

NSAIDs Eligible

RCT Sample

Size MI Stroke

All CV deaths

NSAID 3 Treatment 6 664 1 1 1 Placebo 465 1 0 1 Treatment 20 856 2 0 0 Other NSAIDS 841 0 0 0 Treatment 11 904 2 1 1 ASA 664 0 0 0 NSAID 4

Treatment 3 572 0 1 0 Placebo 413 1 0 1 Treatment 2 250 0 0 0 Other NSAIDs 253 0 1 0

ConclusionConclusion

The The data can not support the presence data can not support the presence or absence of an association between or absence of an association between these NSAIDs and CV adverse eventsthese NSAIDs and CV adverse events

Small sample size, even with poolingSmall sample size, even with pooling Very small number of CV eventsVery small number of CV events Short duration of treatment Short duration of treatment High heterogeneity and substantial High heterogeneity and substantial

variability from trials to trialsvariability from trials to trials Trials were not originally designed for Trials were not originally designed for

the CV safetythe CV safety

Nonprescription Nonprescription NSAIDsNSAIDs

Data submitted from original Data submitted from original prescription applications and over-the-prescription applications and over-the-counter applications counter applications

Similar findings as the previous data Similar findings as the previous data found found – Rx studies small, short in duration, few Rx studies small, short in duration, few

events, not designed for safety events, not designed for safety outcomeoutcome

– OTC studies even smaller and shorterOTC studies even smaller and shorter

Next StepsNext Steps

New NSAIDs under developmentNew NSAIDs under development– Medical outcomes studies to evaluate Medical outcomes studies to evaluate

cardiovascular outcomescardiovascular outcomes

Celecoxib cardiovascular outcomes Celecoxib cardiovascular outcomes studystudy– Have not come to agreement with Have not come to agreement with

sponsorsponsor– Have discussed concerns about the Have discussed concerns about the

proposed protocol with the sponsorproposed protocol with the sponsor

An Update on NSAID Labeling and Data Review DSaRM Advisory Committee February 10, 2006 Sharon Hertz,...

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