An Update on NSAID Labeling and Data Review

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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

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September 2004-February 2006

• 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
• December 16, 2004 APC study halted due to CV
  signal for celecoxib vs. placebo
• December 17, 2004 ADAPT trial halted (celecoxib
  and naproxen)

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September 2004-February 2006

• 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 7, 2005 Information request letter
• June 14, 2005 Labeling supplement request letter

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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).

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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).

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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).

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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).

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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).

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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.

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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.
• Use the lowest dose for the shortest period.

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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.
• The concurrent use of aspirin and an NSAID does
  increase the risk of serous GI events
• CABG-associated risk

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NSAID Labeling

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

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NSAID Labeling

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

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NSAID Labeling

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

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NSAID Labeling

• Information for Patients
• 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
• Signs of an anaphylactoid reaction
• Avoided in late pregnancy

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NSAID Labeling

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

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Information Request

• 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.

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Information Request

• 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

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Information Request

• 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.

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Information Request

• 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.

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

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Sample Response, Prescription NSAIDs

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

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NSAID CV Data
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NSAID CV Data
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Conclusion

• 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
• Very small number of CV events
• Short duration of treatment
• High heterogeneity and substantial variability
  from trials to trials
• Trials were not originally designed for the CV
  safety

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Nonprescription NSAIDs

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

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Next Steps

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