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The FDA has asked Pfizer to withdraw valdecoxib (Bextra) from the market due to safety concerns. The request was part of a "Series of Changes to the Class of Marketed Non-Steroidal Anti-Inflammatory Drugs" released by the agency on April 7th. The report included a black box warning for Pfizer’s other COX-2 inhibitor, celecoxib (Celebrex). All other NSAIDs are also required to add boxed warnings to their labeling which highlight the potential for increased risk of cardiovascular (CV) events and gastrointestinal (GI) bleeding associated with their use. OTC NSAIDs such as Advil and Aleve will also be required to include labeling regarding CV events and GI bleeding risk, as well as the potential for serious skin reactions. Bextra is the second COX-2 inhibitor to be withdrawn from the market after rofecoxib (Vioxx) was withdrawn in September 2004. The move comes amid continued criticism of the FDA for its lack of action regarding the risks of COX-2 inhibitors. The FDA stated that Bextra is being withdrawn because "the overall risk versus benefit profile for the drug is unfavorable." The agency cited lack of adequate data on the cardiovascular safety of long-term use of valdecoxib, and noted that short-term use the drug in coronary artery bypass surgery patients has been associated with increased cardiovascular events. The drug has also been associated with reports of serious and potentially life-threatening skin reactions. The FDA also noted that there is no data to suggest that valdecoxib has any therapeutic advantages over other NSAIDs. The withdrawal comes as somewhat of a surprise, given that the FDA had previously ruled in February that all 3 approved coxibs—rofecoxib, celecoxib, and valdecoxib—were safe enough to be marketed. Many within the pharmaceutical industry were even predicting a return of rofecoxib to the market. Pfizer still may be the net winner in this scenario, with celecoxib’s survival as the only COX-2 drug left on the market, which may translate into an increase in its $3.3 billion sales from last year.
Is Holding NSAIDs Prior to Surgery Rational?
How long should NSAIDs be held prior to surgery? Non-selective NSAIDs, such as ibuprofen and naproxen, reversibly bind the COX-1 enzyme in platelets, which temporarily affects clotting, whereas aspirin irreversibly blocks platelets from clotting for the life of the platelet. Standard procedure is to hold aspirin, as well as other NSAIDs for 7 to 10 days prior to surgery. In a very simple study, 11 volunteers were tested after a 7-day course of ibuprofen 600 mg 3 times a day. Platelet function was assessed by platelet function analyzer exams on the last day of treatment and 24 hours after discontinuing the drug. Platelet dysfunction was apparent in 7 of the 11 participants on the last day of treatment, but all participants had normal platelet function 24 hours after the last dose of ibuprofen. The authors suggest that platelet function seems normalized 24 hours after cessation of ibuprofen, and that it may be appropriate to rethink the rationale for holding NSAIDs 1-week prior to surgery (Ann Int Med. 2005;142:506-509).
Low-Dose Aspirin: Men vs Women
Is there a difference in men and women with regard to the benefits of aspirin in primary prevention of cardiovascular disease? A large primary prevention trial of women suggests that low-dose aspirin lowers the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes. This is the opposite of previous findings in male patients. Results from 5 randomized trials in which the vast majority of subjects were men, showed that low-dose aspirin reduces the risk of myocardial infarction but not the risk of stroke. The new study was part of the Women’s Health Study, which enrolled nearly 40,000 women and followed them for a mean of 10 years. The study was designed to assess the effect of low-dose aspirin and vitamin E on cardiovascular end points, including non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes. The aspirin dose used was 100 mg every other day. The risk of stroke was reduced by 17% in the aspirin group, compared to placebo (RR, 0.83; 95%; CI, 0.80-1.03; P = 0.13). This was due to a 24% reduction in the risk of ischemic stroke and a nonsignificant increase in the risk of hemorrhagic stroke. Aspirin had no significant effect on the risk of fatal or non-fatal myocardial infarction (RR, 1.02) or deaths from cardiovascular causes (RR, 0.95). Interestingly, a subgroup analysis showed that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction among women 65 years of age or older. The authors have no explanation for the differences between men and women with regard to the cardiovascular benefits of aspirin, and suggest that more research is needed (N Engl J Med. 352:1293-1304).
FDA Actions
The FDA has approved Sepracor’s levalbuterol metered dose inhaler for the treatment of asthma and other chronic breathing disorders. Levalbuterol is approved for adults, adolescents, and children 4 years of age or older. The drug has been available since 2002 as a solution for use in nebulizers. The new metered dose form utilizes hydrofluroalkane (HFA) as the propellant in compliance with the FDA’s ban on chlorofluorocarbon (CFC) propellants. Sepracor will market levalbuterol as Xopenex HFA.
After a nearly 6-year delay, Schering-Plough has received approval to market a dry powder inhalation formulation of the corticosteroid mometasone furoate for the treatment of asthma. The drug, which was first considered for approval in 1998, is approved for prevention of asthma in patients age 12 and older. It is unique in that the drug is administered once a day via a Twisthaler—a device that is inhalation driven and does not employ a propellant. Schering-Plough will market mometasone as Asmanex, and the device as Asmanex Twisthaler.
The FDA has approved a new once a month bisphosphonate for the treatment and prevention of postmenopausal osteoporosis. Ibandronate has been available since 2003 in a 2.5 mg daily formulation. The new formulation, which contains 150 mg of ibandronate, was approved based on the Monthly Oral Ibandronate In Ladies (MOBILE) trial, which showed that the monthly formulation is at least as effective as the once a day formulation. Ibandronate 150 mg will be marketed by Roche and GlaxoSmithKline as Boniva. An IV formulation of the drug that can be given 4 times a year is also being studied.
Bristol-Myers has received approval to market entecavir tablets and oral solution for the treatment of chronic hepatitis B virus in adults. The drug is an oral nucleoside analogue, which is indicated for patients with evidence of active viral replication and either evidence of persistent elevations in serum transaminase levels or histologically active disease. The approval was based on 3 studies in which entecavir was compared to lamivudine, and was found superior in terms of reducing viral load and normalizing transaminase levels in both e-antigen positive and e-antigen negative patients. Entecavir will be marketed by Bristol-Myers Squibb as Baraclude.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: [email protected].
The FDA has asked Pfizer to withdraw valdecoxib (Bextra) from the market due to safety concerns.
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