FDA Warnings Dominate Pharmaceutical News

Pharmacology Watch

In this issue: FDA warnings for existing drugs dominate pharmaceutical news this month. The FDA and its advisory committees have issued warnings on erythropoiesis-stimulating agents, oseltamivir (Tamiflu) and zanamivir (Relenza) for the treatment of influenza, rosiglitazone (Avandia) for the treatment of type 2 diabetes, varenicline (Chantix) to help stop smoking, the beta agonist salmeterol (Serevent), and modafinil (Provigil) for use in children. The FDA has also asked for marketing suspension of Bayer's aprotinin (Trasylol). These warnings represent a new push by the FDA to regulate existing drugs for safety after they have been approved for marketing. It also comes at a time when the FDA is cleaning up its advisory committee processes, especially with regard to limiting potential conflict of interest by advisory committee members. A summary of the new committee processes can be found at www.FDA.gov.

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Erythropoiesis-stimulating agents (ESAs) are the subject of new warnings from the FDA. The drugs, Aranesp, Epogen, and Procrit are used to treat anemia associated with cancer chemotherapy and chronic kidney failure. For cancer patients, several studies have shown that the drugs promote tumor growth and decrease survival rates in patients with advanced breast, head neck, lymphoid, and non-small cell lung cancer when given in doses that achieve a hemoglobin level of 12 g/dl or greater—the target in clinical practice. There is currently no evidence to know whether the ESA's promote tumor growth or shorten survival in patients who achieve hemoglobin levels less than 12 g/dl. The warning also specifically states that ESA's should only be used in cancer patients to treat chemotherapy-related anemia, not other causes of anemia associated with cancer and stress, and that the drug should be discontinued once chemotherapy is discontinued. For patients with chronic kidney failure, the new warnings states that ESA's should be used to maintain hemoglobin levels between 10 to 12g/dl. Higher hemoglobin levels increase risk for death and serious cardiovascular events such as stroke, heart attack, or heart failure. Finally, the new labeling emphasizes that there is no data that demonstrates that ESA's improve symptoms associated with anemia such as quality of life, fatigue, or patient well-being for patients with cancer or for patients with HIV undergoing AZT therapy.

An FDA panel is recommending new warnings on the flu drugs oseltamivir (Tamiflu-Roche) and zanamivir (Relenza-Glaxo) regarding abnormal psychiatric behavior associated with the drugs. This issue came up last year with a number of reports from Japan of erratic behavior including jumping from buildings resulting in deaths in patients taking the drugs. Many of the cases involved children. Japan has already taken the step of warning prescribers not to use the drugs in those aged 10 to 19. The panel reports 700 cases of psychiatric adverse events associated with both drugs, and 25 potential deaths in patients taking Tamiflu. No fatalities have been reported with Relenza. Both companies insist their drugs are safe and suggest that it is difficult to know if symptoms are caused by influenza or by medications. In the meantime Roche has agreed to stronger warnings for Tamiflu. Both medications reduce the symptoms of influenza and reduce the duration by approximately one-and-a-half days.

The manufacturers of rosiglitazone (Avandia-GlaxoSmithKline) have agreed to add new information to the existing black box warning regarding the potential increased risk of heart attacks associated with drug. The FDA's press release states that "People with type 2 diabetes who have underlying heart disease or who are at high risk of heart attack should talk with their health-care provider about the revised warning as they evaluate treatment options. FDA advises health-care providers to closely monitor patients who take Avandia for cardiovascular risks." Rosiglitazone is approved for treatment of type 2 diabetes as single therapy or in combination therapy with metformin, sulfonylureas or other oral anti-diabetes treatments. GSK has been asked by the FDA to conduct a long-term study to evaluate the potential cardiovascular risks of rosiglitazone.

The FDA has issued an "Early Communication" regarding varenicline (Chantix), Pfizer's prescription medication to help adults stop smoking. Pfizer has received reports describing suicidal ideation and erratic behavior in some patients taking the drug which have been submitted to the FDA. The Agency is soliciting any additional similar cases from Pfizer and will complete analysis when more data is available and then communicate conclusions and recommendations. In the meantime the FDA recommends health-care providers monitor patients taking Chantix for behavior and mood changes.

An expert panel of the FDA is also recommending a new warning for the long acting beta agonist salmeterol (Serevent-GlaxoSmithKline) regarding use in children. Nine new adverse event reports including five deaths in children using the drug had been reported in the last year as well as reports of increased hospitalizations and asthma-related deaths in children. Before a final recommendation is made by the FDA, review of other long-acting beta agonists will also be included, including formoterol (Foradil), Novartis' long-acting beta agonist and GlaxoSmithKline's Advair which is a combination inhaler of salmeterol and fluticasone. There is some evidence that steroid inhalers mitigate the risk of asthma-related deaths in patients taking long-acting beta agonists.

An FDA panel is recommending stronger warnings for use of modafinil (Provigil) in children. The drug is approved to treat certain sleep disorders in adults, and is not approved for use in children, but is occasionally used off label for the treatment of attention deficit hyperactivity disorder. The drug's labeling was recently updated to warn of serious skin reactions and psychological problems such as hallucinations and suicidal ideation.

Bayer Pharmaceuticals is complying with the FDA's request for a marketing suspension of aprotinin (Trasylol). The drug, which is used to control bleeding during heart surgery, is the subject of a large Canadian study, the preliminary results of which have shown an increased risk of death associate with the drug.

FDA Actions

The FDA has approved over-the-counter sales of cetirizine 5 mg plus pseudoephedrine HCL 120 mg (Zyrtec-D) for adults and children aged 12 years and older. The product has been available as a prescription drug since 2001 for the treatment of upper respiratory allergies.

The FDA has approved several new generics for marketing. Oxcarbazepine (Trileptal) will soon be available as a generic in 150, 300, and 600 mg strengths the treatment of partial seizures in adults and children. Hydrocodone/ibuprofen (Vicoprofen) is also approved as a new generic. The drug is approved for short-term treatment of acute pain. Rivastigmine (Exelon) will be available in generic 1.5, 3, 4 .5, and 6 mg strengths for the treatment of mild to moderate dementia of the Alzheimer's type and mild to moderate dementia assisted with Parkinson's disease.


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) 262-5413. E-mail: iris.young@ahcmedia.com.