FDA, Manufacturers Advise Physicians of Actions Involving Various Drugs

Family physicians should be aware that the FDA and various pharmaceutical manufacturers recently issued notifications about a number of products, including the anticonvulsant valproate sodium and related drugs; the weight-loss drug sibutramine; the osteoarthritis product diclofenac topical gel; and the protease inhibitor fosamprenavir calcium.

An expanding list of indications has prompted the FDA to remind physicians about the increased risk of neural tube defects and other major birth defects in infants exposed to valproate sodium (Depacon) and related products, such as valproic acid (Depakene and Stavzor) and divalproex sodium (Depakote, Depakote CP and Depakote ER), in utero.

The agency approved valproic acid for the treatment of epilepsy more than 30 years ago, but it more recently approved valproate for the treatment of bipolar disorder and migraine headaches.

In information it released for physicians, the FDA said women of childbearing potential should use valproate only if it is essential to managing their medical condition and added that those who are not planning a pregnancy should use contraception while taking the drug. Agency officials also said physicians should inform patients about the risks associated with the drug and consider alternative therapies, especially if using valproate to treat conditions that are not considered life-threatening.

The FDA cautioned that untreated or inadequately treated epilepsy or bipolar disorder during pregnancy increases the risk of complications in both the pregnant woman and her infant. The agency also said physicians should inform patients that taking folic acid before and during the first trimester of pregnancy can decrease the risk of neural tube defects.

The FDA said it is working with the manufacturers of valproate sodium and related products to address labeling changes that reflect the increased risk of birth defects.

Pregnant women using valproate or other antiepileptic drugs are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry, which gathers information about the effects of these medications during pregnancy.

The FDA has notified physicians that it is reviewing preliminary data from a study that suggests patients using sibutramine hydrochloride, which is marketed as Meridia, have a higher number of cardiovascular events than patients using a placebo.

FDA officials said analysis of the data is ongoing, and the agency has reached no conclusions about the prescription weight-management drug. However, the FDA said preliminary study findings reinforce the importance of avoiding the use of sibutramine in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke, as recommended in sibutramine's labeling.

Manufacturers Endo Pharmaceuticals and Novartis Pharmaceuticals Corp. have, at the FDA's request, notified physicians (2-page PDF; About PDFs) about revisions to the prescribing information for all products containing the nonsteroidal anti-inflammatory drug diclofenac sodium -- including diclofenac sodium topical gel, which is marketed as Voltaren Gel. The revisions add new warnings and precautions about the potential for elevation in liver function tests.

The manufacturers said severe hepatic reactions -- including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure -- have been reported. Some cases have resulted in liver transplantation or death.

The FDA and pharmaceutical manufacturer GlaxoSmithKline, or GSK, have notified physicians (3-page PDF; About PDFs) of a potential association between the antiretroviral agent fosamprenavir calcium, which is marketed as Lexiva, and myocardial infarction and hypercholesterolemia in adults with HIV infection.

GSK said it has modified the warnings and precautions section of its prescribing information to note that increases in cholesterol have occurred with fosamprenavir treatment. According to the manufacturer, this statement highlights the importance of ongoing lipids management in patients using this drug by recommending that triglyceride and cholesterol testing be performed before initiating treatment and at periodic intervals during therapy.

Physicians are encouraged to report adverse reactions associated with any of the aforementioned products to the FDA's MedWatch program.