FDA News

CV safety of celecoxib, other NSAIDs debated before FDA

In patients treated for arthritis, the timing and dose of celecoxib, ibuprofen or naproxen, when taken with aspirin, affects the degree of CV risk, according to presenters at a joint meeting of two FDA advisory committees.

The joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was prompted by a supplemental new drug application submitted by Pfizer requesting an update of CV safety information on the labeling of celecoxib (Celebrex); it continues on Tuesday, April 25.

Previous panel meetings on this topic resulted in updated labels indicating an increased risk for MI and stroke and recommended consultation with a doctor before use, especially in those with high BP, heart disease or a history of stroke, liver cirrhosis and kidney disease.

According to a briefing document written by FDA staff, all non-steroidal anti-inflammatory drugs must have labeling mentioning that MI or stroke risk can occur within the first weeks of NSAID use, which appears greater at higher doses; data are not sufficient to determine which NSAIDs confer the greatest CV risk; CVD risk conferred by NSAIDs can occur in people with or without heart disease or related risk factors, but the risk appears to be greatest in those with CHD or risk factors; patients taking NSAIDs within 1 year after MI are more likely to die than those who do not use NSAIDs after MI; and NSAIDs confer increased risk for HF. 

Pfizer is seeking modifications to the CV safety section of celecoxib’s labeling based on results from the PRECISION trial. The committees will also consider whether labeling for over-the-counter versions of ibuprofen and naproxen should be modified.

“Based on the available data, the FDA is considering additional or new labelling changes to OTC naproxen products to address this concern and a labelling of OTC ibuprofen products may be impacted,” Jenny Lee Kelty, MD, medical officer in the division of nonprescription drug products of the FDA, said in a presentation.

Some studies have shown that there is no relevant direct effect of celecoxib (Celebrex, Pfizer) on platelet function and its ability to impair the effect of aspirin on platelets, Jack Cook, PhD, vice president of clinical pharmacology at Pfizer, said in the presentation. Ibuprofen can also reduce the antiplatelet activity of aspirin, though the degree of its effects is dependent on the timing and sequence of the administration of both drugs.

“Specifically, the ibuprofen-aspirin interaction can be minimized by taking ibuprofen at least 8 hours before or 30 minutes after immediate-release aspirin,” Cook said.

In the Kontakt study, researchers assessed whether concurrent administration of naproxen resulted in a pharmacodynamic interaction when combined with chewable aspirin and whether the interval between the dosing of both drugs influenced this interaction. Researchers found that the interaction was minimized in patients who received aspirin 30 minutes before naproxen.

The joint meeting also included a discussion of the implications of results from the PRECISION trial.

As Cardiology Today previously reported, in the main results of PRECISION, celecoxib at moderate doses was noninferior to the nonselective nonsteroidal anti-inflammatory drugs ibuprofen and naproxen with regard to CV safety, but conferred fewer gastrointestinal and renal events. In a subsequent analysis from PRECISION, celecoxib had a better CV safety profile than ibuprofen and naproxen in patients not taking aspirin, and a similar CV safety profile in those taking aspirin.

“These findings challenge the widely-held view that naproxen provides superior cardiovascular safety,” Steven E. Nissen, MD, professor and chairman of cardiovascular medicine at Cleveland Clinic and Cardiology Today Editorial Board Member, said in a presentation.

Steven E. Nissen, MD
Steven E. Nissen

Celecoxib can also have a benefit regarding the treatment for arthritis.

“Based on the results of the PRECISION trial, in patients with osteoarthritis, treatment with celecoxib 200 mg daily can be expected to achieve clinically meaningful pain relief without an increase in cardiovascular risk and with the likelihood of less GI and renal toxicity when compared to the doses of ibuprofen and naproxen that were studied,” Stanley B. Cohen, MD, clinical professor of rheumatology at UT Southwestern Medical School in Dallas, said in a presentation.

A statistical assessment of the PRECISION trial also showed positive effects.

“At the doses studied, prespecified primary analysis results showed no evidence of excess CV risk associated with celecoxib compared to naproxen and ibuprofen,” Bo Li, PhD, statistical reviewer in the division of biometrics VII of the FDA, said in a presentation.

In a clinical assessment of the trial, Anjelina Pokrovnichka, MD, medical officer of the FDA, said that the CV risk related to celecoxib was no worse than the risk associated with naproxen or ibuprofen. The Division of Epidemiology performed a data review from December 4, 2012 to January 24, 2018 and determined that there is no new information that would support additional label changes.

Education is a critical component for consumers to understand how to read labels and to use over-the-counter NSAIDs correctly. Barbara A. Kochanowski, PhD, senior vice president of regulatory and scientific affairs of the Consumer Healthcare Products Association, said that the organization has previously made educational efforts and will continue to do so.

Edwin Kuffner, MD, chief medical officer of Johnson & Johnson Consumer, said in a presentation that the CV risk of over-the-counter ibuprofen is low when it is used according to the label.

“Adding a contraindication to the OTC label would be overly restrictive, potentially confusing and it could have unintended consequences,” Kuffner said. “Data suggest that taking immediate-release aspirin 30 minutes before a 400-mg dose of ibuprofen is likely to maintain aspirin’s cardioprotective benefit. This situation certainly does not meet the definition of a contraindication.”

A live webcast of the 2-day meeting will be available at https://collaboration.fda.gov/aac0418/ and will be archived.

The FDA is not required to follow the advice of its advisory panels, but it usually does. – by Darlene Dobkowski

Reference:

FDA Briefing Document. sNDA 020998/S-050.

Disclosures: One panel member reports her spouse holds equity in two health care sector mutual funds. The other panel members report no relevant financial disclosures.

In patients treated for arthritis, the timing and dose of celecoxib, ibuprofen or naproxen, when taken with aspirin, affects the degree of CV risk, according to presenters at a joint meeting of two FDA advisory committees.

The joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was prompted by a supplemental new drug application submitted by Pfizer requesting an update of CV safety information on the labeling of celecoxib (Celebrex); it continues on Tuesday, April 25.

Previous panel meetings on this topic resulted in updated labels indicating an increased risk for MI and stroke and recommended consultation with a doctor before use, especially in those with high BP, heart disease or a history of stroke, liver cirrhosis and kidney disease.

According to a briefing document written by FDA staff, all non-steroidal anti-inflammatory drugs must have labeling mentioning that MI or stroke risk can occur within the first weeks of NSAID use, which appears greater at higher doses; data are not sufficient to determine which NSAIDs confer the greatest CV risk; CVD risk conferred by NSAIDs can occur in people with or without heart disease or related risk factors, but the risk appears to be greatest in those with CHD or risk factors; patients taking NSAIDs within 1 year after MI are more likely to die than those who do not use NSAIDs after MI; and NSAIDs confer increased risk for HF. 

Pfizer is seeking modifications to the CV safety section of celecoxib’s labeling based on results from the PRECISION trial. The committees will also consider whether labeling for over-the-counter versions of ibuprofen and naproxen should be modified.

“Based on the available data, the FDA is considering additional or new labelling changes to OTC naproxen products to address this concern and a labelling of OTC ibuprofen products may be impacted,” Jenny Lee Kelty, MD, medical officer in the division of nonprescription drug products of the FDA, said in a presentation.

Some studies have shown that there is no relevant direct effect of celecoxib (Celebrex, Pfizer) on platelet function and its ability to impair the effect of aspirin on platelets, Jack Cook, PhD, vice president of clinical pharmacology at Pfizer, said in the presentation. Ibuprofen can also reduce the antiplatelet activity of aspirin, though the degree of its effects is dependent on the timing and sequence of the administration of both drugs.

“Specifically, the ibuprofen-aspirin interaction can be minimized by taking ibuprofen at least 8 hours before or 30 minutes after immediate-release aspirin,” Cook said.

In the Kontakt study, researchers assessed whether concurrent administration of naproxen resulted in a pharmacodynamic interaction when combined with chewable aspirin and whether the interval between the dosing of both drugs influenced this interaction. Researchers found that the interaction was minimized in patients who received aspirin 30 minutes before naproxen.

The joint meeting also included a discussion of the implications of results from the PRECISION trial.

As Cardiology Today previously reported, in the main results of PRECISION, celecoxib at moderate doses was noninferior to the nonselective nonsteroidal anti-inflammatory drugs ibuprofen and naproxen with regard to CV safety, but conferred fewer gastrointestinal and renal events. In a subsequent analysis from PRECISION, celecoxib had a better CV safety profile than ibuprofen and naproxen in patients not taking aspirin, and a similar CV safety profile in those taking aspirin.

“These findings challenge the widely-held view that naproxen provides superior cardiovascular safety,” Steven E. Nissen, MD, professor and chairman of cardiovascular medicine at Cleveland Clinic and Cardiology Today Editorial Board Member, said in a presentation.

Steven E. Nissen, MD
Steven E. Nissen

Celecoxib can also have a benefit regarding the treatment for arthritis.

“Based on the results of the PRECISION trial, in patients with osteoarthritis, treatment with celecoxib 200 mg daily can be expected to achieve clinically meaningful pain relief without an increase in cardiovascular risk and with the likelihood of less GI and renal toxicity when compared to the doses of ibuprofen and naproxen that were studied,” Stanley B. Cohen, MD, clinical professor of rheumatology at UT Southwestern Medical School in Dallas, said in a presentation.

A statistical assessment of the PRECISION trial also showed positive effects.

“At the doses studied, prespecified primary analysis results showed no evidence of excess CV risk associated with celecoxib compared to naproxen and ibuprofen,” Bo Li, PhD, statistical reviewer in the division of biometrics VII of the FDA, said in a presentation.

In a clinical assessment of the trial, Anjelina Pokrovnichka, MD, medical officer of the FDA, said that the CV risk related to celecoxib was no worse than the risk associated with naproxen or ibuprofen. The Division of Epidemiology performed a data review from December 4, 2012 to January 24, 2018 and determined that there is no new information that would support additional label changes.

Education is a critical component for consumers to understand how to read labels and to use over-the-counter NSAIDs correctly. Barbara A. Kochanowski, PhD, senior vice president of regulatory and scientific affairs of the Consumer Healthcare Products Association, said that the organization has previously made educational efforts and will continue to do so.

Edwin Kuffner, MD, chief medical officer of Johnson & Johnson Consumer, said in a presentation that the CV risk of over-the-counter ibuprofen is low when it is used according to the label.

“Adding a contraindication to the OTC label would be overly restrictive, potentially confusing and it could have unintended consequences,” Kuffner said. “Data suggest that taking immediate-release aspirin 30 minutes before a 400-mg dose of ibuprofen is likely to maintain aspirin’s cardioprotective benefit. This situation certainly does not meet the definition of a contraindication.”

A live webcast of the 2-day meeting will be available at https://collaboration.fda.gov/aac0418/ and will be archived.

The FDA is not required to follow the advice of its advisory panels, but it usually does. – by Darlene Dobkowski

Reference:

FDA Briefing Document. sNDA 020998/S-050.

Disclosures: One panel member reports her spouse holds equity in two health care sector mutual funds. The other panel members report no relevant financial disclosures.