[2-28-2012] The U.S. Food and Drug Administration (FDA) has approved important safety label changes for the class of cholesterol-lowering drugs known as statins. These changes were made to provide the public with more information for the safe and effective use of statins and are based on FDA’s comprehensive review of the statin class of drugs (see below). The changes include the following:
Removal of routine monitoring of liver enzymes from drug labels
FDA reviewed current monitoring guidelines, including the National Lipid Association’s Liver Expert Panel and Statin Safety Task Force recommendations.1, 2 The Liver Expert Panel stated that the available scientific evidence does not support the routine monitoring of liver biochemistries in asymptomatic patients receiving statins. The Panel made this recommendation because (1) irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic in nature, and (2) no data exist to show that routine periodic monitoring of liver biochemistries is effective in identifying the very rare individual who may develop significant liver injury from ongoing statin therapy. The Panel believed that routine periodic monitoring will instead identify patients with isolated increased aminotransferase levels, which could motivate physicians to alter or discontinue statin therapy, thereby placing patients at increased risk for cardiovascular events.1 The National Lipid Association’s Statin Task Force also stated that routine monitoring of liver function tests is not supported by the available evidence.2
FDA reviewed post-marketing data to evaluate the risk of clinically serious hepatotoxicity associated with statins. FDA had conducted several post-marketing reviews of statins and hepatotoxicity between years 2000 and 2009 by searching the Agency’s Adverse Event Reporting System (AERS) database. Those reviews consistently noted that reporting of statin-associated serious liver injury to the AERS database was extremely low (reporting rate of ≤2 per one million patient-years). FDA’s updated review focused on cases of severe liver injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury Network (DILIN) liver injury severity scale, which were reported to AERS from marketing of each statin through 2009. Cases meeting those criteria were further assessed for causality. Seventy-five cases (27 cases with a severity score of 4, and 48 cases with a severity score of 5 (37 deaths and 11 liver transplants) were assessed for causality. Thirty of the 75 cases (14 deaths, 7 liver transplantations, and 9 severe liver injury) were assessed as possibly or probably associated with statin therapy. No cases were assessed as highly likely or definitely associated with statin therapy. FDA concluded that, despite a rising use of statins as a class since the late 1990s, there has not been a detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use.
FDA also reviewed cases from the DILIN and Acute Liver Failure Study Group (ALFSG), organizations that have been submitting reports to FDA of drug-associated liver injury in their liver injury outcome studies. As of January 1, 2011, DILIN had submitted 25 reports of statin-associated liver injury to FDA, 12 of which gave hospitalization as an outcome. A 2010 article from ALFSG included 133 prospectively identified cases of idiopathic drug-induced liver injury resulting in acute liver failure.3 Of these 133 patients, 15 were taking statins, and in six of these 15 individuals a statin was identified as the only potential drug to cause drug-induced liver injury.
Based on all available data, FDA has determined that all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury in association with statins.
Cognitive adverse events
FDA reviewed the AERS database, the published medical literature (case reports and observational studies),4-13 and randomized clinical trials to evaluate the effect of statins on cognition.14-17
The post-marketing adverse event reports generally described individuals over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy. Time to onset of the event was highly variable, ranging from one day to years after statin exposure. The cases did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease. The review did not reveal an association between the adverse event and the specific statin, the age of the individual, the statin dose, or concomitant medication use.
Data from the observational studies and clinical trials did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline.
Increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose
FDA’s review of the results from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients. High-dose atorvastatin had also been associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy.18
FDA also reviewed the published medical literature.19-26 A meta-analysis by Sattar et al.,19 which included 13 statin trials with 91,140 participants, reported that statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02-1.17), with little heterogeneity (I2=11%) between trials. A meta-analysis by Rajpathak et al.,20 which included 6 statin trials with 57,593 participants, also reported a small increase in diabetes risk (relative risk [RR] 1.13; 95% CI 1.03-1.23), with no evidence of heterogeneity across trials. A recent study by Culver et al.,26 using data from the Women’s Health Initiative, reported that statin use conveys an increased risk of new-onset diabetes in postmenopausal women, and noted that the effect appears to be a medication class effect, unrelated to potency or to individual statin.
Based on clinical trial meta-analyses and epidemiological data from the published literature, information concerning an effect of statins on incident diabetes and increases in HbA1c and/or fasting plasma glucose was added to statin labels.
Lovastatin drug-drug interactions
Information regarding drug-drug interactions and contraindications and dose limitations has been added to the lovastatin label. Subsequent to the June 2011 label revisions to the simvastatin-containing products, which were based largely on the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial,27 a review of drug-drug interactions with lovastatin was conducted because the physicochemical and pharmacokinetic properties of lovastatin are comparable to those of simvastatin.
Lovastatin is a sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrate. Strong CYP3A4 inhibitors are predicted to significantly increase lovastatin exposure. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold and the drug interaction appears to result in rhabdomyolysis.28 The effect of itraconazole on lovastatin exposure can therefore be extrapolated to other strong CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, human immunodeficiency virus (HIV) protease inhibitors, boceprevir, telaprevir, and nefazodone.