FDA Adds Labeling Supplement for Celecoxib


The supplement included data from decade-long noninferiority PRECISION trial, which revealed safety data for using celecoxib in conjunction with aspirin.

The US Food and Drug Administration (FDA) has approved a labeling supplement for celecoxib (Celebrex), a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), to include the results of a cardiovascular outcomes trial—PRECISION.

The decade-long noninferiority trial showed that taking celecoxib (Celebrex, Pfizer) in combination with aspirin can lessen the cardiovascular safety profile of the therapy, however, the combination still offers a lower risk for gastrointestinal issues in comparison with naproxen (Naprosyn) and ibuprofen (Motrin), and fewer kidney problems than with ibuprofen.

PRECISION included data from more than 23,000 patients, of which 11,018 were also taking aspirin. Principle investigator Steve Nissen, MD, the chairman of Cardiovascular Medicine at Cleveland Clinic said in a statement at the time the results were announced that “past studies have reported conflicting results regarding using NSAIDs together with aspirin, but we know that many patients do combine the medications, so it was vital to understand the risks and differences among the drugs.”

Although NSAIDs are efficacious in their ability to treat pain, inflammation, and fever, the FDA warns that they should always be utilized at the lowest effective dose for the shortest duration necessary.

“[Post-marketing] safety studies such as the PRECISION trial can add valuable information to our understanding of drug safety issues that emerge in the [post-marketing] period, and we provide this information to give health care providers a better understanding of the NSAIDs’ drug safety profile,” the agency wrote in a statement. “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.”

In PRECISION, the use sans aspirin of naproxen (hazard ratio [HR], 1.52; 95% CI, 1.22 to 1.90; P <.001) or ibuprofen (HR, 1.81; 95% CI, 1.46 to 2.26; P <.001) was associated with a greater risk of major adverse cardiovascular events (MACE)—consisting of non-cardiovascular death, gastrointestinal or renal events&mdash;than celecoxib. Ibuprofen was associated with more MACE (P <.05) than celecoxib and both ibuprofen and naproxen were linked to more gastrointestinal (P <.001) and renal (P <.05) events.

Additionally, in combination with aspirin, ibuprofen was revealed to have a greater risk of MACE (HR, 1.27; 95% CI, 1.06 to 1.51; P <.01) than celecoxib, but naproxen did not have a significantly higher risk (HR, 1.18; 95% CI, 0.98 to 1.41; P = .08). MACE was similar among the 3 NSAIDs when taken with aspirin, although when compared with celecoxib, ibuprofen-related gastrointestinal (0.9% vs. 1.4%, respectively) and renal (0.6% vs. 1.2%) events were worse (P <.05). Gastrointestinal events were worse with naproxen (1.6%; P <.05).

Grant Reed, MD, an interventional cardiology fellow at Cleveland Clinic, and the study’s first author told MD Mag in April 2018 that "opposed to the overall PRECISION trial, an intent-to-treat analysis, we looked at on-treatment analysis, which is, I think, the more important analysis for cardiovascular and overall safety.” Reed noted that the analysis only accounted for patients that were taking medications, as those in pain will often switch medications consistently in order to achieve an analgesic effect.

Ultimately, Reed said at the time, the PRECISION data add more to the understanding of the interplay between COX-1 and COX-2 inhibition and overall safety, and could suggest that there is a real difference between NSAID options when it comes to safety.

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