Apr 7 2005
Despite an expert panel stating last month that the three COX-2 drugs Vioxx, Bextra and Celebrex were safe enough to be marketed, the U.S. Food and Drug Administration (FDA) has this week told drug manufacturer Pfizer to remove the drug Bextra from the market and a statement by Pfizer confirms that the European Union regulators have done the same.
Pfizer while disagreeing with the FDA will comply with the agency and remove Bextra from the market in the United States and Europe while further studies are done.
The withdrawal of Bextra, at the FDA's request, leaves only one of three blockbusters in the COX-2 class on the US market creating considerable controversy over safety which erupted in September when Merck withdrew their drug Vioxx. Any hope that Merck might return Vioxx to the market now seems dashed.
The ruling has taken the industry by surprise, but the vote in February by the panel on Bextra and Vioxx was tight.The FDA believes the entire class of COX-2 drugs causes heart risks and the few benefits did not outweigh its risks.
This intervention on the part of the FDA against Pfizer's Bextra and Celebrex ends any remaining notion that COX-2 pain inhibitors are wonder drugs.
This now leaves only one of three blockbusters in the COX-2 class on the US market - Celebrex - and the FDA is insisting Pfizer put a black box warning on the drug.
The labelling requirement will now put COX-2s on an equal footing with older, cheaper medications and could possibly make the approval of other experimental COX-2 drugs, such as Merck's Arcoxia, Novartis's Prexige, and a compound by GlaxoSmithKline much more difficult.
The black-box warning on all prescription Nsaids will advise of the “potential for increased risk of cardiovascular events and the well-described, serious, and potentially life-threatening gastrointestinal bleeding associated with these drugs”.
This mandatory warning will also apply to other prescription anti-inflammatory pain drugs, including Boehringer Ingelheim's Mobic. and reflects a collapse in confidence in COX-2 drugs following the Vioxx withdrawal that is both sudden and unexpected.
At their launch in 1999 COX-2 inhibitors were hailed as super-aspirin painkillers. Aggressive marketing ensured the products reached sales of $1bn a year, mainly because of the promise that they were safer than existing chronic pain medicines and they reduced the risk of stomach ulcers.
This latest decision by the FDA puts Celebrex ,which must now carry the strongest warning possible in its labelling, in the category of a non-steroidal anti-inflammatory drugs, or Nsaids. The FDA also recommended that Celebrex be used at the lowest effective dose, for the shortest duration. It has asked for a long-term safety study on Celebrex.
The black-box warning on all prescription NSAIDS will advise of the “potential for increased risk of cardiovascular events and the well-described, serious, and potentially life-threatening gastrointestinal bleeding associated with these drugs”.
Many critics have said the drugs were over-prescribed, overpriced and alleviated pain no better than cheaper, over-the-counter products, such as ibuprofen.
In order to give consumers some guidelines manufacturers of other prescription NSAIDs have been told to revise their labelling to include the same warning and manufacturers of non- prescription NSAIDs are being asked to include on their labels more specific information about potential side effects, which also include gastrointestinal bleeding and skin reactions.
The FDA based its decision on recommendations from its Arthritis and Drug Safety and Risk Management Advisory Committee following a hearing in February. Investigations into COX-2 and other non-steroidal anti-inflammatory drugs began last fall when studies showed Merck's Vioxx doubled a patient's risk of cardiovascular events, including heart attacks, when taken longer than 18 months.
Pfizer views the FDA's decision as an opportunity to demonstrate that other, older pain drugs are untested and also pose heart risks and finds some consolation in the fact that other prescriptions drugs such as Mobic and Diclofenac must also carry the black box heart risk warning and that the FDA has said they should not be used for heart surgery patients. Pfizer says the FDA is acknowledging that there is inherent risks in the older NSAIDS.
Drugmakers do see a positive side to the FDA's request for new labelling about the safe use of ibuprofen and naproxen.
The FDA's current tough line appears to be intended to quash concerns that the FDA had been lax in its earlier monitoring on safety of COX-2 and other drugs.