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

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Postmarketing analysis raises further concern.

A recently published analysis has heightened concerns about the safety of the lipid-lowering drug, rosuvastatin (Crestor), the most potent of the drugs in the statin class, because its findings contradict a March 2005 U.S. Food and Drug Administration (FDA) news release in which the agency stated that the drug poses a risk of rhabdomyolysis that is only comparable to that posed by the others (see Drug Watch, July).


In the analysis, the reports of adverse events associated with rosuvastatin that had been made to the FDA between October 1, 2003, and September 30, 2004, the first year in which the drug was available for sale in the United States, were compared to those concerning the other commonly used statins, atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol), during the same time period. The researchers also looked at rates of adverse events associated with the other statins during each drug's first year on the market (that analysis included cerivastatin [Baycol], which was withdrawn from the market in 2001 because of an excessive incidence of adverse effects).


The adverse events that are recognized as the significant risks posed by statin use are rhabdomyolysis (a serious, potentially fatal muscle disease), proteinuria, nephropathy, and renal failure, and reports of them were especially closely tracked.


The analysis revealed that during the first period of time in question the rates of those serious adverse events were significantly higher with rosuvastatin use than with the use of atorvastatin, simvastatin, or pravastatin. And the comparison of reports made during the first year of the marketing of each of the drugs reveals that there was a significantly greater number of reports of adverse events associated with rosuvastatin, compared with atorvastatin and pravastatin, but not with simvastatin. (There were significantly fewer reports of adverse events associated with rosuvastatin, compared with reports concerning cerivastatin.)


Overall, the postmarketing analysis revealed a significantly greater number of reports of rhabdomyolysis, proteinuria, nephropathy, and renal failure associated with rosuvastatin use, as compared with the use of the other statins. Additional differences noted in rosuvastatin therapy, compared with other statin therapy, were the earlier onsets of rhabdomyolysis and renal toxicity (within the first 12 weeks, on average, rather than several months or years), the relatively younger age of the patients taking the drug, and the comparatively lower daily dosages (10 mg or less; the recommended therapeutic dosage is 20 mg/day).


The FDA is further at odds with the findings of the analysis in stating that it cannot confirm that statin use (in the absence of diabetes, hypertension, atherosclerosis, or heart failure, any of which can heighten the risk of renal failure in patients taking statins), causes or worsens renal failure. The FDA's position is based on its own review of the same reports of adverse events and findings of controlled, randomized drug trials. It can be argued that case reports cannot serve as a definitive source of information--certainly, controlled, randomized trials constitute the standard in research. Yet they are more likely to underrep-resent the occurrence of adverse events than to overstate them because they are made voluntarily and usually not until the health care provider recognizes that such events are related to drug therapy. Moreover, postmarketing case reports also reflect the use of a drug in the greater population, instead of in only a selected group of subjects participating in a clinical drug trial.


Nursing implications.

How then might nurses put the conflicting findings into perspective? First, they should be aware that, despite the greater incidence of adverse events reported in regard to rosuvastatin, the actual number of such events is very small and the drug is safely used in the majority of patients-most taking any statin, including rosuvastatin, are unlikely to suffer any grave complications of the therapy. Still, because, among the statin drugs, rosuvastatin does appear to pose the greatest risk of several serious adverse effects, nurse practitioners should be cautious when it comes to prescribing it, perhaps limiting its use to patients who have not attained lower low-density lipoprotein cholesterol levels with other drug therapies and who are not disposed toward myopathies or renal toxicities, and at initial dosages that are low, 5 to 10 mg daily.


Nurses who monitor patients taking rosuvastatin should be aware that rhabdomyolysis, proteinuria, nephropathy, and renal failure are possible adverse effects, and patients' renal function should be monitored closely, especially in the first three months. Patients who report otherwise inexplicable muscle pain should be considered to be experiencing a symptom of myopathy or rhabdomyolysis.


Finally, patients should be informed of the possibility of the occurrence of the serious adverse effects, which symptoms to look for, when to contact their providers, and the importance of returning for follow-up appointments and blood work.


Alsheikh-Ali AA, et al. Circulation 2005; 111(23):3051-7; U.S. Food and Drug Administration. FDA News. FDA provides updated patient and healthcare provider information concerning Crestor. 2005.



Black boxes and cautions.


Revisions reflecting concerns about cardiotoxicity and secondary acute myelogenous leukemia (AML) have been made to the boxed warnings and the warnings section on the labeling of mitoxantrone (Novantrone), an injection medication used to diminish neurologic disability and the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis. Cardiotoxicity (specifically, that resulting in congestive heart failure) is already recognized as an adverse effect of the drug, but because it has recently been revealed that it can occur early in the course of treatment, the revised black box warning states that a baseline evaluation of left ventricular ejection fraction (LVEF), accomplished either by echocardiography or multigated radionuclide angiography, should be performed and that it should be repeated prior to each dose of mitoxantrone. Patients with a baseline LVEF of less than 50% or those in whom the LVEF falls to less than 50% after administration of the drug should not receive mitoxantrone therapy.


The second boxed warning revision indicates that secondary AML consequent to mitoxantrone therapy recently has been reported both in patients with multiple sclerosis and those with cancer. Because the data were derived from case reports, the exact incidence of secondary AML and degree of risk of its development are not known, but health care providers should adhere strictly to the manufacturer's recommendations concerning the monitoring of the blood cell count, which call for complete counts, including platelets, prior to each dose of mitoxantrone and whenever there are signs or symptoms of infection. The drug should not be administered if the neutrophil count, specifically, is less than 1,500 cells/mm3.



The Food and Drug Administration (FDA) has updated its August 1998 recommendation regarding the administration of albumin to critically ill patients with hypovolemia, in which providers are advised to exercise caution in light of study findings indicating that such patients are more likely to die, compared with those receiving normal saline. The agency's change of position was prompted by the findings of a recent large randomized clinical trial (the Saline versus Albumin Fluid Evaluation [SAFE] study) involving 6,997 patients that indicate that those in the general ICU population who received either 4% albumin or normal saline for fluid resuscitation fare comparably. Mortality rates were found to be comparable, regardless of which treatment was received; rates were also comparable among subgroups of ICU patients: those with acute respiratory distress syndrome, severe sepsis, or trauma. However, there was a higher mortality rate among trauma patients receiving albumin in the presence of traumatic brain injury.


Conversely, there was a higher survival rate among patients with severe sepsis treated with albumin, but because the finding was not of statistical significance, its clinical significance is unknown. Although the FDA determined that the SAFE study findings serve to resolve the concerns raised earlier, it notes that the effect of albumin on patients with severe burns is unknown because that population was not included in the study. Moreover, the FDA also notes that further study is necessary to conclusively determine the effects of albumin on patients with traumatic brain injury and those in septic shock.



The FDA has granted its approval of a new indication for ropinirole (Requip), a dopamine receptor stimulant already approved for use in Parkinson disease--the treatment of severe restless legs syndrome. The known common adverse effects of the drug include nausea, headache, and vomiting. In addition, the labeling will now bear both the pre-cautionary statement that it has been associated with somnolence, presenting the possibility of the patient falling asleep while performing daily activities, including driving, and the warning that syncope and symptomatic hypotension can occur with its use, especially during the initiation of treatment or upon elevation of the dosage.


Scios Incorporated. Dear physician/patient advocate letter. Natrecor (nesiritide). 2005.; Serono Incorporated. Dear healthcare professional letter: Novantrone (mitoxantrone for injection concentrate). 2005.; U.S. Food and Drug Administration. Safety of albumin administration in critically ill patients. 2005.; U.S. Food and Drug Administration. F DA Talk Paper: FDA approves Requip for restless legs syndrome. 2005.