THE FDA APPROVES TWO NEW DRUGS, EACH THE FIRST OF ITS KIND
* Romiplostim (Nplate), administered in weekly subcutaneous injections, is a thrombopoietin receptor agonist that directly stimulates the bone marrow to produce platelets in patients with chronic immune thrombocytopenic purpura.
* Tetrabenazine (Xenazine) reversibly depletes monoamine neurotransmitters as it reversibly binds to a specific monoamine transporter, decreasing dopamine levels and diminishing the chorea of Huntington's disease. Possible adverse effects of the drug include severe depression.
Romiplostim (Nplate) is a thrombopoietin receptor agonist that increases the production of platelets by a mechanism similar to that in endogenous thrombopoietin activity. It has been approved as the first drug that directly stimulates the bone marrow in patients who have responded inadequately to corticosteroids, immunoglobulins, or a splenectomy in the treatment of chronic immune thrombocytopenic purpura, a rare blood disorder that can cause serious, life-threatening bleeding. Nurses administering the drug should note the precise, detailed directions for its reconstitution in the product labeling, administer it weekly by subcutaneous injection, and monitor the patient's complete blood count with platelet count and peripheral blood smear weekly until it is stable, that is, at least 50 × 109/L for at least four weeks at the same dose, after which it can be monitored monthly. To achieve the desired platelet level, the dose of romiplostim should be titrated up to the maximum weekly dose of 10 micrograms per kilogram. Although the purpose of the drug therapy is to raise the platelet count enough to prevent severe bleeding, no attempt should be made to return it to within the normal range. The therapy should be discontinued if the platelet count doesn't rise to a level sufficient to avert clinically significant bleeding after four weeks of administration at the maximum weekly dose.
Because of serious concerns that have arisen concerning the use of romiplostim, including the risks of bone marrow fibrosis with cytopenias; worsened thrombocytopenia upon discontinuation of therapy; serious, possibly fatal thrombotic– thromboembolic events; and the worsening of hematologic malignancies, the drug is available only through the restrictive Nplate NEXUS Program ( 675-2831), in which only registered prescribers can prescribe and administer the product and only registered patients can receive it.
Tetrabenazine (Xenazine) is the first drug to be approved in the United States to treat the chorea of Huntington's disease, a rare genetic disorder characterized by jerky, involuntary movements of the limbs and facial muscles. The medication depletes the monoamine neurotransmitters (dopamine, serotonin, norepinephrine, and histamine) from neural synapses as it reversibly binds to a specific monoamine transporter. The result of this binding decreases the uptake of monoamines in the synaptic spaces and depletes the amount stored there. Because chorea in Huntington's disease is attributable to excessive dopamine activity in the brain, the depletion of dopamine at brain synapses decreases the incidence of chorea. Since tetrabenazine also depletes stores of other monoamine neurotransmitters, including serotonin, adverse effects are possible—the most serious being the risk of depression and suicidality that already is heightened in patients with Huntington's disease. In two open-label studies of tetrabenazine, one of which lasted as long as 80 weeks, depression or worsened depression was noted in 35% of patients, and the product labeling bears a black box warning indicating that the risk of depression and suicidality can be heightened in patients taking the drug. Therefore its use is contraindicated in those who are actively suicidal and in those with either untreated or inadequately treated depression. Further, as with most dopamine antagonists, tetrabenazine can produce the possibly fatal neuroleptic malignant syndrome (manifested clinically by hyperpyrexia, muscle rigidity, altered mental status, cardiovascular changes and other symptoms of autonomic instability, irregular pulse or labile blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia), tardive dyskinesia, and other extrapyramidal disorders (parkinsonism and akathisia), and it also can prolong the QT interval. Possible adverse effects thought to be attributable to the disruption of norepinephrine activity include hypotension, dizziness, sedation and somnolence, and additive effects when tetrabenazine is taken concurrently with alcohol. Nurses should educate patients and their families about the risk of depression or worsened depression, the occurrence of which should be communicated to the prescriber of as soon as possible, and instruct them to carefully read the medication guide that accompanies the initial tetrabenazine prescription and each subsequent one for new information on possible adverse effects of the drug.
Amgen, Inc. Nplate (romiplostim) for subcutaneous injection. 2008. http://www.fda.gov/cder/foi/label/2008/125268lbl.pdf; Prestwick Pharmaceuticals. Xenazine (tetrabenazine) tablets. 2008. http://www.fda.gov/cder/foi/label/2008/021894lbl.pdf; FDA approves first bone marrow stimulator to treat immune-related low platelet counts [press release]. FDA News 2008 Aug 22. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01876.html; FDA approves first drug for treatment of chorea in Huntington's disease [press release]. FDA News 2008 Aug 15. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01874.html.
THE FDA URGES GREATER PRECAUTION IN THE USE OF THREE DRUGS
* Exenatide (Byetta), an antidiabetes drug, has been associated with cases of either hemorrhagic or necrotizing pancreatitis.
* Naltrexone (Vivitrol), a drug used in the treatment of alcohol dependence, has been associated with serious injection site reactions that can necessitate surgical intervention.
* Natalizumab (Tysabri), a drug used in the treatment of relapsing multiple sclerosis and Crohn's disease, has been associated with progressive multifocal leukoencephalopathy.
Nurses should be aware that the Food and Drug Administration (FDA) received case reports of either hemorrhagic or necrotizing pancreatitis in six patients taking the antidiabetes drug exenatide (Byetta), two of whom died. The cases occurred after a cautionary statement had been added to the labeling in October 2007 in response to 30 postmarketing case reports of acute pancreatitis in patients taking the medication (see Drug Watch, February). Because of the more recent reports of hemorrhagic or necrotizing pancreatitis, the label warning will be revised with stronger wording and placed more prominently. Nurses should carefully assess for inexplicable persistent and severe abdominal pain with or without vomiting in patients taking exenatide. Patients with these symptoms should be instructed to contact their provider as soon as possible. If pancreatitis is confirmed, exenatide should be permanently discontinued unless another cause is identified.
The FDA issued an alert to inform health care professionals of the occurrence of serious injection site reactions in patients receiving intramuscular injections of naltrexone (Vivitrol), an opioid receptor antagonist used to treat alcohol dependence. Since naltrexone was approved for marketing in 2007, 196 cases of injection site reactions, including cellulitis, induration, hematoma, abscess, sterile abscess, and necrosis have been reported, 16 of which required surgical intervention ranging from incision and drainage to extensive surgical debridement. The adverse effect of the drug is not new—one patient in a clinical trial developed necrotic tissue at the injection site that required surgery. Nurses should be aware that improper administration might contribute to adverse effects and they should follow the instructions given in the naltrexone package insert—the short (0.5-inch, 20-gauge) needle provided in the product package should be used only to draw up the diluent, and the reconstituted drug should be administered with the other (1.5-inch, 20-gauge) needle provided, and only by deep intramuscular injection into gluteal muscle, alternating buttocks each time. Naltrexone should not be administered intravenously, subcutaneously, or into fatty tissue, or with a standard needle of longer length. Patients should be instructed to monitor the injection site for pain, swelling, tenderness, induration, bruising, pruritus, or redness that either doesn't improve or worsens within two weeks, and to contact their provider if any of these reactions develop. Further, the depth of subcutaneous tissue can vary according to sex and weight, and alternate treatment should be considered in patients who have a greater thickness of gluteal fat.
The FDA announced that the manufacturer of natalizumab (Tysabri) has received two reports of progressive multifocal leukoencephalopathy (PML), an almost exclusively opportunistic and usually fatal or severely disabling viral infection of the brain, in European patients receiving monotherapeutic injections of the drug. Natalizumab is used in the United States only in patients with relapsing multiple sclerosis or moderate-to-severe Crohn's disease under a stringently restrictive prescribing program (see Drug Watch, May). Although natalizumab had already been noted to increase the risk of PML when used in combination with other immunosuppressants, these are the first reports of it occurring in monotherapy. The FDA stated that it will request a revision of the product labeling. Nurses should closely monitor patients taking the drug for the gradually emerging but rapidly worsening symptoms associated with PML—progressive weakness or clumsiness on one side of the body (difficulty walking, for example); disturbance or loss of vision; difficulty with speech; partial blindness; and changes in thinking, memory, and orientation (dementia) leading to confusion and alterations of personality. (Seizure can occur, but rarely.) The progression of the neurologic deficits occurs within days to weeks, usually leading to death or severe disability within weeks to months. If PML is suspected, the administration of natalizumab should be suspended until a clinical evaluation has been performed.
Center for Drug Evaluation and Research. FDA alert: exenatide (marketed as Byetta). Rockville, MD: U.S. Food and Drug Administration; 2008 Aug 18. http://www.fda.gov/cder/drug/InfoSheets/HCP/exenatide2008HCP.htm; Center for Drug Evaluation and Research. FDA alert: naltrexone injection site reactions [naltrexone for extended-release injectable suspension (marketed as Vivitrol)]. Rockville, MD: U.S. Food and Drug Administration; 2008 Aug 12. http://www.fda.gov/cder/drug/InfoSheets/HCP/naltrexoneHCP.htm; Center for Drug Evaluation and Research. FDA alert: natalizumab injection for intravenous use (marketed as Tysabri). Rockville, MD: U.S. Food and Drug Administration; 2008 Aug. http://www.fda.gov/cder/drug/InfoSheets/HCP/natalizumab2008HCP.htm.
DO STATINS CAUSE CANCER?
* An early FDA communication indicates a possible association.
The Food and Drug Administration (FDA) is evaluating preliminary findings of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial that indicate a possible association between use of the combination antihyperlipidemic agent (marketed as Vytorin) and the incidence of cancer. (The trial was conducted to determine whether the risk of major cardiovascular events in patients with aortic stenosis can be decreased by lowering LDL cholesterol levels through the use of simvastatin– ezetimibe.) An association between statin use and the incidence of cancer also has been described in recent literature. A 2007 metaanalysis of 23 treatment arms in 17 clinical trials involving 75,317 patients who took statin drugs at various dosages revealed a statiscically significant inverse relationship between lowered LDL cholesterol levels achieved with statin use and the rate of newly diagnosed cases of cancer (P = 0.009). Alsheikh-Ali and colleagues note that although the findings are not conclusive, they do warrant investigation.
The present findings (the SEAS trial preliminary data and the results of the metaanalysis) stand in contradiction to other published clinical trial findings, such as those of the 2002 Heart Protection Study, a randomized statin trial involving approximately 20,000 patients, in which the incidence of new cases of cancer was comparable among subjects taking a statin drug and those taking a placebo. The FDA also reports that interim data from two other statin clinical trials, the Study of Heart and Renal Protection and the Improved Reduction in High-Risk Subjects Presenting with Acute Coronary Syndrome, don't indicate any increase in the incidence of cancer associated with the use of simvastatin–ezetimibe. (The trials are expected to conclude in 2010 and 2012, respectively.) At present the FDA is not recommending any changes in the use of simvastatin–ezetimibe to treat high LDL cholesterol levels. When the SEAS trial data have been analyzed completely the FDA will review its present findings and, if warranted, issue further conclusions and recommendations, most likely in March 2009. At present, nurses should encourage patients to continue taking simvastatin– ezetimibe or other prescribed statin therapy.
Center for Drug Evaluation and Research. Early communication about an ongoing safety review of ezetimibe/simvastatin (marketed as Vytorin), simvastatin (marketed as Zocor) and ezetimibe (marketed as Zetia). FDA investigates a report from the SEAS trial. Rockville, MD: U.S. Food and Drug Administration; 2008 Aug 21. http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin_SEAS.htm; Alsheikh-Ali AA, et al. J Am Coll Cardiol 2007;50(5):409–18; Heart Protection Study Collaborative Group. Lancet 2002; 360(9326):7–22.