FDA Advisory Panel Recommends Softening “Celebrex” Safety Labeling
A U.S. Food and Drug Administration (FDA) advisory panel concluded that prescription pain medication celecoxib (
Celebrex)
, marketed by Pfizer, is as safe as other common
nonsteroidal anti-inflammatory drugs (NSAIDs)
when it comes to cardiovascular (CV) risks. The panel recommended updating the medicine’s safety labeling to reflect that.
Celecoxib is a selective COX-2 inhibitor, which means it blocks production of an enzyme associated with inflammation. “Nonselective” NSAIDs, such as naproxen and ibuprofen, block both COX-1 and COX-2; by blocking COX-1, they give rise to gastrointestinal (GI) side effects. Celecoxib is often prescribed to patients with osteoarthritis (OA) or an inflammatory type of arthritis, such as rheumatoid arthritis (RA) , especially those who are at higher risk of GI side effects.
But its cardiovascular safety profile has been under a cloud of suspicion for more than a decade, after two other COX-2 inhibitors were pulled from the U.S. market. Rofecoxib ( Vioxx ) was removed in 2004 and valdecoxib ( Bextra) in 2005 over concerns they raised the risk of cardiovascular events, such as heart attack and stroke, to unacceptable levels. (All NSAIDs increase the risk of cardiovascular side effects ; risks rise with the dose and length of time used.)
Celecoxib was allowed to remain on the market; however, the wording on the label was strengthened to say it had increased risk of heart attacks and strokes. The FDA ordered Pfizer to conduct a post-market study of its safety.
That study, called PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen), compared cardiovascular outcomes of prescription doses of celecoxib, naproxen and ibuprofen in more than 24,000 patients with both arthritis and established cardiovascular disease or risk factors. It found rates of cardiovascular side effects were lowest with celecoxib (2.3 percent) compared to naproxen (2.5 percent) or ibuprofen (2.7 percent). (Critics of PRECISION say there were numerous problems with the study, including the facts that more than half of the participants had stopped taking their assigned drug by the end of the study, the allowed doses of the medications were not truly equivalent, and the use of low-dose aspirin, which could throw off the results, was not considered.)
After reviewing results of the study, the FDA Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee voted in a joint meeting in late April, by a vote of 15 to 5 (with one abstention), in favor of updating the safety labeling on Celebrex to reflect this data.
An FDA spokesperson says the matter is pending before the agency, adding that the committee “provided FDA with important perspectives on the topics discussed. FDA cannot speculate about any outcomes from the advisory committee meeting, including the timing of any possible changes.”
The FDA doesn’t have to follow the recommendations of its advisory committees, but it generally does.
A spokesperson for Pfizer, Inc., which had applied for the update, welcomed the vote. “The PRECISION study helped dispel misperceptions about the cardiovascular risk associated with long-term use of Celebrex . In fact, the totality of evidence supports the use of Celebrex to manage pain and inflammation in people with osteoarthritis or rheumatoid arthritis who also have or are at high risk for cardiovascular disease,” said Milton Pressler, MD, vice president and head of clinical affairs for Pfizer.
But Donald Miller, PharmD, professor of pharmacy practice at North Dakota State University, in Fargo, cautions that the dosages in the study may be lower than those that some patients take. The PRECISION trial compared 100 to 200 mg twice a day of celecoxib, 600 to 800 mg three times a day of ibuprofen, and 375 to 500 mg twice a day of naproxen.
“The cardiovascular risk with all NSAIDs is dose-related,” says Miller. “The big issue with the PRECISION study is they only allowed a dose of 200 mg of Celebrex, but it can also be used as a 400 mg dose [200 mg twice daily].”
If you have concerns, discuss your dosage with your doctor, Miller says.
The findings probably will not change how celecoxib is prescribed, he adds, in part because the PRECISION study results were published a year and a half ago.
“From a labeling point of view, this is probably important for Pfizer because it makes the medication less scary,” Miller says. “But rheumatologists are already familiar with this data because the findings of this study were published 18 months ago. So, this decision probably won’t have much effect on practice.”
Author: Jennifer Davis for the Arthritis Foundation
Celecoxib is a selective COX-2 inhibitor, which means it blocks production of an enzyme associated with inflammation. “Nonselective” NSAIDs, such as naproxen and ibuprofen, block both COX-1 and COX-2; by blocking COX-1, they give rise to gastrointestinal (GI) side effects. Celecoxib is often prescribed to patients with osteoarthritis (OA) or an inflammatory type of arthritis, such as rheumatoid arthritis (RA) , especially those who are at higher risk of GI side effects.
But its cardiovascular safety profile has been under a cloud of suspicion for more than a decade, after two other COX-2 inhibitors were pulled from the U.S. market. Rofecoxib ( Vioxx ) was removed in 2004 and valdecoxib ( Bextra) in 2005 over concerns they raised the risk of cardiovascular events, such as heart attack and stroke, to unacceptable levels. (All NSAIDs increase the risk of cardiovascular side effects ; risks rise with the dose and length of time used.)
Celecoxib was allowed to remain on the market; however, the wording on the label was strengthened to say it had increased risk of heart attacks and strokes. The FDA ordered Pfizer to conduct a post-market study of its safety.
That study, called PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen), compared cardiovascular outcomes of prescription doses of celecoxib, naproxen and ibuprofen in more than 24,000 patients with both arthritis and established cardiovascular disease or risk factors. It found rates of cardiovascular side effects were lowest with celecoxib (2.3 percent) compared to naproxen (2.5 percent) or ibuprofen (2.7 percent). (Critics of PRECISION say there were numerous problems with the study, including the facts that more than half of the participants had stopped taking their assigned drug by the end of the study, the allowed doses of the medications were not truly equivalent, and the use of low-dose aspirin, which could throw off the results, was not considered.)
After reviewing results of the study, the FDA Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee voted in a joint meeting in late April, by a vote of 15 to 5 (with one abstention), in favor of updating the safety labeling on Celebrex to reflect this data.
An FDA spokesperson says the matter is pending before the agency, adding that the committee “provided FDA with important perspectives on the topics discussed. FDA cannot speculate about any outcomes from the advisory committee meeting, including the timing of any possible changes.”
The FDA doesn’t have to follow the recommendations of its advisory committees, but it generally does.
A spokesperson for Pfizer, Inc., which had applied for the update, welcomed the vote. “The PRECISION study helped dispel misperceptions about the cardiovascular risk associated with long-term use of Celebrex . In fact, the totality of evidence supports the use of Celebrex to manage pain and inflammation in people with osteoarthritis or rheumatoid arthritis who also have or are at high risk for cardiovascular disease,” said Milton Pressler, MD, vice president and head of clinical affairs for Pfizer.
But Donald Miller, PharmD, professor of pharmacy practice at North Dakota State University, in Fargo, cautions that the dosages in the study may be lower than those that some patients take. The PRECISION trial compared 100 to 200 mg twice a day of celecoxib, 600 to 800 mg three times a day of ibuprofen, and 375 to 500 mg twice a day of naproxen.
“The cardiovascular risk with all NSAIDs is dose-related,” says Miller. “The big issue with the PRECISION study is they only allowed a dose of 200 mg of Celebrex, but it can also be used as a 400 mg dose [200 mg twice daily].”
If you have concerns, discuss your dosage with your doctor, Miller says.
The findings probably will not change how celecoxib is prescribed, he adds, in part because the PRECISION study results were published a year and a half ago.
“From a labeling point of view, this is probably important for Pfizer because it makes the medication less scary,” Miller says. “But rheumatologists are already familiar with this data because the findings of this study were published 18 months ago. So, this decision probably won’t have much effect on practice.”
Author: Jennifer Davis for the Arthritis Foundation
