Drugs

CDER Statement: FDA Approves Labeling Supplement for Celebrex (celecoxib)

June 28, 2018

The U.S. Food and Drug Administration today approved a labeling supplement for Celebrex (celecoxib), a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), to include results from a postmarketing cardiovascular outcomes trial that found that at the lowest dose, Celebrex was similar to moderate doses of naproxen and ibuprofen with regard to cardiovascular (CV) safety.

The concerns about the cardiovascular thrombotic risk of COX-2 selective NSAIDS emerged in the early 2000’s. Following an FDA Advisory Committee meeting held in 2005, in which data from large clinical outcome trials in a wide range of indications and epidemiology studies of several individual NSAIDs were considered, FDA concluded that the risk for cardiovascular thrombotic events was present for both COX-2 selective NSAIDs and nonselective NSAIDs.

The “Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen” (PRECISION) trial was conducted to address the remaining concerns about the relative cardiovascular safety of COX-2 selective NSAIDS and non-selective NSAIDs. PRECISION was a large, randomized, double-blind controlled trial that began in 2006. Ninety percent of the patients enrolled in the trial had osteoarthritis and the remaining 10% had rheumatoid arthritis.

The results of the PRECISION trial demonstrated that celecoxib at the lowest approved dose of 100 mg twice daily, is non-inferior to (or no worse than) ibuprofen dosed in the range of 600 mg - 800 mg three times daily or naproxen dosed in the range of 375 mg - 500 mg twice daily on a composite cardiovascular endpoint consisting of cardiovascular death, nonfatal myocardial infarction (“heart attack,” or MI), and nonfatal stroke.

In an ambulatory blood pressure monitoring study that was part of the larger PRECISION trial, celecoxib dosed at 100 mg twice daily showed little effect on average 24-hour systolic blood pressure (SBP), whereas ibuprofen dosed in the range of 600 mg - 800 mg three times daily and naproxen dosed in the range of 375 mg – 500 mg twice daily increased average 24-hour SBP by 3.7 mmHg and 1.6 mmHg, respectively.

Too few patients received higher doses of Celebrex to evaluate the risk of cardiovascular events or the effect on blood pressure for doses greater than 100 mg twice daily. The cardiovascular risks of the NSAID class are dose-dependent, therefore, the results for celecoxib 100 mg twice daily on the composite cardiovascular endpoint and the lack of effect on SBP cannot be extrapolated to dosing regimens using the higher strengths of celecoxib (200 mg or 400 mg). Patients with recent cardiovascular events such as acute MI, coronary revascularization, or coronary stent placement were not studied in the PRECISION trial. NSAID class labeling warns against the use of NSAIDs in such patients.

NSAIDs are effective treatments for pain, inflammation, and fever, yet should always be dosed at the lowest effective dose for the shortest duration necessary. Postmarketing safety studies such as the PRECISION trial can add valuable information to our understanding of drug safety issues that emerge in the postmarketing period, and we provide this information to give health care providers a better understanding of the NSAIDs’ drug safety profile. Patients should talk to their doctor if they have any questions or concerns about prescription or over-the-counter NSAIDs, and always inform the doctor about their complete medical history, including any history of cardiovascular disease or stomach ulcers.

Page Last Updated: 06/28/2018
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