1. Aschenbrenner, Diane S. MS, RN, CS

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Concerns with safety prompt further revisions.

On March 2, the U.S. Food and Drug Administration (FDA) announced that it is requiring revisions in the labeling of all products that contain salmeterol, a long-acting [beta]2-agonist used as a maintenance drug in the treatment of severe asthma and an active component in both Serevent Diskus and Advair Diskus. (The changes will also be made to the label of Foradil Aerolizer [formoterol], another long-acting [beta]2-agonist). The warnings section, including the black box warning, and the clinical pharmacology section of the label must be revised, and additionally, a medication guide for patients must be distributed with each salmeterol prescription. The new labels and the medication guide are available on the FDA's Web site at


From 2003 to 2005 the drug manufacturer further analyzed existing data and submitted findings to the FDA indicating that, during the 28 weeks of an earlier trial, death related to asthma was more likely to occur among patients taking salmeterol, in comparison with those taking the placebo (13 deaths among 13,176 patients, and three deaths among 13,179 patients, respectively). Subgroup analysis showed, too, that although the relative risks among whites and blacks of asthma-related death with the use of salmeterol (versus placebo) were comparable, there was a higher rate of estimated "excess deaths" among black patients than among white patients. (In other words, had 10,000 patients in each subgroup been given salmeterol for 28 days, it would be expected that 27 black patients would have died as a result of salmeterol use, versus only six white patients.)


While the drug manufacturer performed the additional data analysis, the FDA continued to receive and review case reports describing the deaths of patients taking salmeterol (201 were reported in the year after the drug was approved in 1994). Because of all findings, it was determined that a stronger and more detailed warning was necessary to alert providers and patients.


A November 18, 2005, public health advisory offered the following recommendations for the prescription of salmeterol and other long-acting [beta]2-agonists.


* Do not use the drugs as initial therapy.


* Use the drugs as adjunctive therapy only in patients in whom asthma has not been controlled with inhaled corticosteroids or other drugs that provide long-term relief of asthma. An inhaled corticosteroid is the drug recommended first in the National Heart, Lung, and Blood Institute and World Health Organization guidelines for controlling chronic asthma.


* Do not use the drugs as mono-therapy; they should be adjuncts to other therapy to provide long-term relief of asthma.


* Instruct patients to seek medical attention immediately if asthma worsens.



The recommendations, which apply strictly to patients with chronic asthma, always have appeared on salmeterol product labeling, but they are now being emphasized to avoid inappropriate prescription of the medication. Patients with asthma induced by exercise or chronic obstructive pulmonary disease also can take salmeterol, but whether they would be subject to a greater risk of bronchospasm is not yet known.


Black patients warrant closer monitoring because reevaluation of the trial data indicates that they may be at greater risk for life-threatening bronchospasm while taking salmeterol. Patients should be taught that long-acting [beta]2-agonists decrease the incidence of asthma attacks but that when one does occur during drug use, it tends to be more severe, possibly causing acute or life-threatening bronchospasm (as evidenced by wheezing).


Patients should be informed also that they will receive a medication guide with the drug and that the information it provides is intended to help them monitor themselves while taking it and to know when to seek medical attention. Patients should not stop taking salmeterol in the absence of the provider's recommendation to do so. Nurses should confirm that patients have a short-acting [beta]2-agonist inhaler to be used as the "rescue" drug in the event of an acute asthma attack, which a long-acting [beta]2-agonist will not resolve. Patients should be made fully aware of the differences between the two types of medication and of the appropriate use of each.


Seymour S, Sullivan E. Medical officer review: Serevent Inhalation Aerosol, Serevent Diskus, Advair Diskus. 2004 Sep 20., U.S. Food and Drug Administration. FDA public health advisory: Serevent Diskus (salmeterol xinafoate inhalation powder), Advair Diskus (fluticasone propionate and salmeterol inhalation powder), Foradil Aerolizer (formoterol fumarate inhalation powder). 2005 Nov 18.



Information on safety and efficacy is now on the labeling of 100 drugs.

The U.S. Food and Drug Administration (FDA) announced in December of 2005 that 100 drug labels had been revised to include information specific to pediatric use. Historically, few drug labels have had information on safety, efficacy, dosing, or risks specific to children because clinical drug trials in that population pose unique ethical and legal concerns to the manufacturers and therefore have not often been performed. Consequently, drug trial data usually pertaining only to adults were available for submission to the FDA for its approval. Many drug labels therefore bear a disclaimer asserting that the drug's safety and efficacy in children have not been established. Because it is not considered appropriate to deny children medications that might possibly cure or control a chronic illness, some drugs have been prescribed off-label, a practice that, while legal, presents its own set of problems.


Parents and prescribers of drugs for children have expressed both dissatisfaction with this practice and a desire for pertinent information on drug labeling. In response, two federal laws to promote pediatric clinical drug studies have been passed, the Food and Drug Administration Modernization Act of 1997 and the Best Pharmaceuticals for Children Act of 2002, both of which amended part of the Federal Food, Drug, and Cosmetic Act. They offer a financial incentive to drug manufacturers that conduct pediatric clinical trials of their products by extending the period of exclusivity, meaning that they have an additional six months to sell a product before a generic version can be offered competitively, allowing them to recoup the cost of a trial and to generate additional profit. Manufacturers seeking approval of new drugs were thereby encouraged to conduct pediatric clinical trials and submit the findings to the FDA.


The results of the legislative initiative have been substantial. In the eight years since the first law was enacted, there has been a 20-fold increase in the number of drug studies conducted in children (250 studies involving 125 products), in comparison with those conducted during the approximately equal time period prior to the enactment (11 studies of 114 - products). The Best Pharmaceuticals for Children Act will be in effect until October 2007, at which time further legislation would have to be passed to extend the incentive offered to manufacturers. To view a list of the drugs (there are now 103) and the revised labels, please go to the FDA Web site at


Hunt A. Congressional Budget Office pay-as-you-go estimate: S. 830 The Food and Drug Administration Modernization Act of 1997. 1997.; Christensen J. Congressional Budget Office pay-as-you-go estimate: S. 1789 Best Pharmaceuticals for Children Act. 2002 Jan 14.; U.S. Food and Drug Administration. FDA news: FDA joins children's health groups to mark historic milestone for pediatric drugs. 2005 Dec 19.



Additional risk of adverse effects is possible.

The labeling of the Ortho Evra contraceptive patch (norelgestromin, ethinyl estradiol transdermal system) is being revised to indicate that the product exposes patients to continuous levels ("steady-state concentrations") of estrogen higher than those associated with typical oral contraceptives containing 35 micrograms of estrogen. Ortho Evra, the only contraceptive patch available, is changed once weekly and has unique pharmacokinetic properties attributable to the transdermal delivery system, which produces consistent levels of estrogen in the blood with a peak concentration that is 25% lower than the peak and trough characteristic of oral contraceptives.


But patients who use the Ortho Evra patch are exposed to about 60% more total estrogen over the course of the week than they would be in taking an oral contraceptive, and because greater exposure to estrogen generally is associated with a higher risk of thrombotic events, such patients may be at risk, although that has not yet been documented. While there are high-dose birth control pills containing 50 micrograms of estrogen, there are no data concerning how the steady-state and peak concentrations of such formulations compare with the pharmacokinetics of Ortho Evra.


U.S. Food and Drug Administration. FDA news: FDA updates labeling for Ortho Evra contraceptive patch. 2005 Nov 10.



Adverse hematologic effects are noted.

The labels of the erythropoietin products darbepoetin alfa (Aranesp) and epoetin alfa (Epogen, Procrit) are being revised to indicate that the drugs increase one's risk of developing pure red cell aplasia and severe anemia (changes in other blood cell counts may also be present) associated with neutralizing antibodies to erythropoietin (indicating that an immune response to erythropoietin has occurred). These effects occur predominantly in patients taking an erythropoietin product for chronic renal failure, not in those receiving it to treat adverse effects of chemotherapy. The revised label indicates that patients with chronic renal failure should receive the drug intravenously rather than by subcutaneous injection. Nurses should monitor patients taking the products for continuity of the response to the drug--if that response suddenly falters and there is severe anemia and a low reticulocyte count, an evaluation of the cause of the unresponsiveness is warranted. If antierythropoietin antibody-associated anemia is suspected, the drug should be discontinued and the manufacturer contacted for the performance of assays for binding and neutralizing antibodies. Patients with confirmed antierythropoietin antibody-associated anemia should not resume therapy with any erythropoietin product.


Amgen Inc. Dear health care professional [letter: darbepoetin alfa (Aranesp)]. 2005 Nov., Amgen Inc. Dear health care professional [letter: epoetin alfa (Epogen)]. 2005 Nov.; Ortho Biotech. Dear health care professional [letter: epoetin alfa (Procrit)]. 2005 Nov.



A risk of thrombotic events in some.

The labeling of coagulation factor VIIa (recombinant) (NovoSeven) has been revised to include new warnings and information on its adverse effects.


While there is a risk, considered quite low, of thrombotic events occurring when the drug is used to treat hemophilia, new findings of clinical trials in patients without hemophilia and postmarketing reports have raised concern about its use. As a result, a new warning states that all patients with disseminated intravascular coagulation, advanced atherosclerotic disease, crush injury, or septicemia, and those receiving concomitant treatment with activated or nonactivated prothrombin complex concentrate may have a higher risk of thromboembolic adverse events such as myocardial ischemia or infarction, cerebral ischemia or infarction, or both; thrombophlebitis; arterial thrombosis; and deep venous thrombosis and related pulmonary embolism. One study conducted in elderly, nonhemophilic adults with intracerebral hemorrhage indicated a possible risk of arterial thromboembolic events associated with the use of NovoSeven. While a causal relationship has not been established, caution should be exercised in the administration of the drug and nurses should monitor patients closely for evidence of thrombotic events and intervene appropriately if the occurrence of one is suspected.


Novo Nordisk. Dear healthcare professional [letter: NovoSeven Coagulation Factor VIIa (Recombinant)]. 2005 Nov 23.