Pharmacy & Therapeutics - February 2009 - (Page 91)

Pharmaceutical Approval Update continued from page 88 monotherapy or TriLipix with statins as well as in patients receiving fenofibric acid. Elevated creatinine levels were generally stable over time, with no evidence of continued elevations after long-term therapy. Levels tended to return to baseline values after treatment was discontinued. The clinical significance of these observations is not clear. Renal monitoring should be considered for patients with renal impairment after they take TriLipix and for patients at risk for renal insufficiency, such as the elderly and those with diabetes. Liver function. When administered at a dose of 135 mg once daily as monotherapy or when given with low-to-moderate doses of statins, the capsule has been associated with increases in serum aspartate transaminase (AST) and alanine transaminase (ALT) levels. However, after discontinuation of treatment or during continued treatment, transaminase values usually returned to normal. Increases in ALT and AST were not accompanied by increases in bilirubin or clinically significant increases in alkaline phosphatase. Hepatocellular, chronic active, and cholestatic hepatitis, which have been noted with fenofibrate therapy, have been reported after exposures of weeks to several years. In rare cases, cirrhosis has been reported in association with chronic active hepatitis. Regular monitoring of liver function, including serum ALT, should be performed for the duration of therapy with TriLipix, and therapy should be discontinued if enzyme levels persist above three times the ULN. Cholelithiasis. Like fenofibrate (e.g., Tricor, Abbott), clofibrate (Atromid-S, Wyeth), and gemfibrozil (Lopid), TriLipix may increase cholesterol excretion into the bile, potentially leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. TriLipix therapy should be discontinued if gallstones are found. Concomitant oral anticoagulants. Caution should be exercised when TriLipix is given with oral anticoagulants, such as warfarin (Coumadin, Bristol-Myers Squibb). TriLipix may potentiate the anticoagulant effects of these agents, thereby prolonging the prothrombin time (PT) and the International Normalized Ratio (INR). Frequent monitoring of the PT and INR and dose adjustments of the oral anticoagulant are recommended until the PT and INR have stabilized in order to prevent bleeding complications. Pancreatitis. Pancreatitis has been reported in patients taking drugs of the fibrate class, including TriLipix. This event may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. Hypersensitivity reactions. In rare cases, acute hypersensitivity reactions, including severe skin rashes requiring hospitalization and steroid treatment, have occurred during fenofibrate therapy, including rare spontaneous reports of Stevens–Johnson syndrome and toxic epidermal necrolysis. Hematological changes. Mild-to-moderate decreases in hemoglobin, hematocrit, and white blood cells have been observed in patients receiving initial TriLipix and fenofibrate therapy. Rare spontaneous cases of thrombocytopenia and agranulocytosis have been reported in association with fenofibrate. Mortality and coronary heart disease. The effect of TriLipix on CHD morbidity and mortality rates and on noncardiovascular mortality rates has not been established. Because of similarities between TriLipix and the other fibrates— fenofibrate, clofibrate, and gemfibrozil—the findings in several clinical studies with these fibrate drugs may also apply to this new medication. The FIELD Study. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was a five-year randomized, placebo-controlled study of 9,795 patients with type-2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a nonsignificant 11% relative reduction in the primary outcome of CHD events and a significant 11% reduction in the secondary outcome of total cardiovascular disease events. There was a nonsignificant 11% increase in total and coronary heart disease mortality, respectively, with fenofibrate compared with placebo. The Coronary Drug Project. In a study of post–myocardial infarction patients treated for five years with clofibrate, there was no difference in mortality rates between clofibrate and placebo, but there was a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3% vs. 1.8%, respectively). The WHO Study. In a study conducted by the World Health Organization (WHO), 5,000 subjects without known coronary artery disease received placebo or clofibrate for five years and were observed for an additional year. There was a statistically significant, higher age-adjusted all-cause mortality rate in the clofibrate group compared with the placebo group. Excess mor tality was a result of a 33% increase in non cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. The Helsinki Heart Study. In a large study of 4,081 middleaged men without a history of coronary artery disease, subjects received either placebo or gemfibrozil for five years, with a 3.5-year open extension afterward. More men in the gemfibrozil group died, but this figure did not achieve statistical significance. Although more cancer deaths occurred with gemfibrozil, cancers (except basal cell carcinoma) were diagnosed with equal frequency in both study groups. Even with the large number of subjects included in the study, statistical significance was not achieved, and the relative risk of death from any cause did not differ from that seen in the nine-year followup data from the WHO study. A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men who had been excluded from the primary prevention study because of known or suspected CHD. Subjects received gemfibrozil or placebo for five years. Although the number of cardiac deaths tended to be higher in the gemfibrozil group, this value was not statistically significant. Venothromboembolic disease. In the FIELD trial, pulmonary embolus (PE) and deep-vein thrombosis (DVT) were observed at higher rates with fenofibrate than with placebo. Of 9,795 patients enrolled in FIELD, 4,900 received placebo and 4,895 received fenofibrate. There were 48 DVT events (1%) in the placebo group and 67 (1%) in the fenofibrate group, and there were 32 PE events (0.7%) in the placebo group and 53 continued on page 94 Vol. 34 No. 2 • February 2009 • P&T® 91

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - February 2009

Pharmacy & Therapeutics - February 2009 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Pushing an Expanded Role for Pharmacists Better Asthma Management with Advanced Technology Pharmaceutical Approval Update 58th Annual Meeting, American Society of Human Genetics, 2008 American Society of Hematology, 50th Annual Meeting and Exposition 2008 San Antonio Breast Cancer Symposium Stahl’s Essential Psychopharmacology, 3rd Edition Author Guidelines

Pharmacy & Therapeutics - February 2009

For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.