1. Aschenbrenner, Diane S. MS, APRN, BC

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Postmarketing case reports of adverse effects of an approved drug and the findings of more recent clinical research can prompt the Food and Drug Administration (FDA) to perform a "safety review" of all such information received by the product manufacturer and the agency. Additionally, the FDA might ask the manufacturer to review all of its clinical trial data pertaining to a particular adverse effect of a drug.


A complete safety review can take as long as nine months, after which the FDA concludes either that there is no demonstrated association between the drug and a reported possible adverse effect or that there is such an association; in such cases revision of the product labeling-or withdrawal of the product from the market-might be required. Recently, the FDA issued an "early communication" stating that safety reviews of several drugs are under way.


The first drug of concern is montelukast (Singulair), a leukotriene-receptor antagonist used to treat asthma and allergic rhinitis. Postmarketing case reports indicating changes in behavior or mood, suicidality (suicidal ideation and behavior), and suicide possibly associated with the use of montelukast have been received by the manufacturer and the FDA. In 2007, prior to the recent call for a safety review, the manufacturer revised the drug's labeling, citing postmarketing reports of suicidality. Now the FDA is collaborating with the manufacturer to further evaluate the possible association between the use of the drug and the reported serious adverse effects. The FDA is also investigating other leukotriene-modifying agents. Although the incidence of the reported adverse effects would seem minimal, the best action for providers to take while the FDA completes the safety review would be to carefully monitor patients for changes in behavior or mood and suicidality. At present, the FDA isn't recommending that the drug no longer be prescribed; indeed, the FDA says that patients should not stop taking it without consulting their prescribers; any further recommendations concerning the use of montelukast would be made after completion of the safety review.


Another respiratory drug undergoing an ongoing FDA safety review is tiotropium bromide inhalation powder (the Spiriva HandiHaler), an anticholinergic bronchodilator used in the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). An analysis of pooled data conducted by the manufacturer revealed a higher risk of stroke with the use of Spiriva, preliminarily estimated at eight cases per 1,000 patients treated for one year, compared with six cases per 1,000 patients taking a placebo for one year. In addition, a large clinical trial conducted by the manufacturer to further assess the risk of stroke and other adverse effects associated with the use of Spiriva is in progress; results of that trial were expected to be submitted to the FDA in June (after we went to press). At present, the FDA doesn't recommend discontinuing treatment with Spiriva without consultation with the prescriber.


Another ongoing safety review announced by the FDA concerns the antiretroviral HIV drugs abacavir (Ziagen) and didanosine (also known as ddl [Videx]), both nucleoside reverse-transcriptase inhibitors. At the 15th Conference on Retroviruses and Opportunistic Infections, held in February, findings of the seven-year analyses of the Data Collection on Adverse Events of Anti-HIV Drugs study (D:A:D) were presented, revealing that the risk of myocardial infarction (MI) increased by 90% with the use of abacavir and by 49% with the use of didanosine, although the overall incidence of MI was slight (192 events in patients taking abacavir and 124 in those taking didanosine, out of more than 33,000 total subjects). The greatest risk was in patients at high risk for cardiovascular disease at the beginning of the trial. The heightened risk of MI was not seen in patients who had discontinued therapy with either abacavir or didanosine for at least six months. In analyses of their own clinical trial data, the manufacturers of abacavir and didanosine didn't find that use of the products increased the risk of MI, findings that the FDA considers inconclusive. At this time, the FDA also considers the analyses of the D:A:D study data incomplete.


It is recommended that patients consult their prescribers to determine whether modification of their HIV drug regimen is appropriate. To help patients lower their risk of MI, nurses should emphasize the importance of quitting smoking, decreasing the intake of fats and cholesterol, and controlling diabetes and hypertension.


Finally, another drug undergoing an ongoing FDA safety review is becaplermin (Regranex), a topical medication used in patients with diabetes to promote the healing of ulcers in the lower extremities that extend into the subcuta-neous tissue or deeper, in the presence of sufficient blood supply. Because becaplermin promotes rapid cell division, the manufacturer continued to monitor ongoing clinical studies (begun before approval of the drug in 1997) for evidence of a greater incidence of cancer in patients using the drug, and the product labeling indicates that the drug shouldn't be used if there is neoplasm at the site(s) of application.


Recently, the FDA received information indicating that there were more deaths attributable to cancer among study patients who'd been given three or more prescriptions for becaplermin than among those who didn't use the drug. No single type of cancer was identified, nor did the research yield information sufficient to determine whether the use of becaplermin increased the incidence of new cases of cancer.


In patients with diabetes, untreated leg and foot ulcers pose a number of serious risks, including infection and the need for amputation. The quality of the lives of such patients is also adversely affected. Therefore, in each case any risk that might be incurred in the use of becaplermin must be weighed against the expected benefits. Prior to the initiation of treatment with becaplermin, nurses should confirm the absence of any type of cancer at the site of the ulcer; they should also teach patients how to use the drug properly, according to the manufacturer's detailed instructions. Further, a patient's need for more than one course of becaplermin therapy should be discussed by the health care team to determine whether the expected benefits outweigh any risks that might be incurred.


Nurses and other health care providers can report serious suspected adverse effects of all of the drugs discussed above, as well as of any other drug, to the FDA's MedWatch program at For additional safety information released by the MedWatch program, see (the site is updated continually).




* In response to postmarketing case reports of adverse effects and ongoing clinical trial data, the FDA has begun safety reviews of five drugs:


[white circle] montelukast (Singulair) and tiotropium bromide inhalation powder (Spiriva), used in chronic respiratory disorders


[white circle] abacavir (Ziagen) and didanosine (Videx), two HIV drugs


[white circle] becaplermin (Regranex), a topical drug used to treat ulcers in patients with diabetes


* Nurses should report any suspected adverse effects of these drugs to the FDA MedWatch program.