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| __NOTOC__
| | #REDIRECT [[Fenofibrate]] |
| {{Fenofibrate}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Warnings and Precautions==
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| ===Mortality and Coronary Heart Disease Morbidity===
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| The effect of Antara on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.
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| The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2[[diabetes mellitus]] on background [[statin]] therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus[[statin]] combination therapy showed a nonsignificant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal [[myocardial infarction]], nonfatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79- 1.08) (p=0.32) as compared to [[statin]] monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus [[statin]]monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus [[statin]] monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.
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| The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2[[diabetes mellitus]] treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.
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| Because of chemical, pharmacological, and clinical similarities between TRICOR (fenofibrate tablets), [[clofibrate]], and [[gemfibrozil]], the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Antara.
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| In the Coronary Drug Project, a large study of post [[myocardial infarction]] of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of [[cholelithiasis]] and[[cholecystitis]] requiring surgery between the two groups (3.0% vs. 1.8%).
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| In a study conducted by the World Health Organization (WHO), 5000 subjects without known [[coronary artery disease]] were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p≤0.01). Excess mortality was due to 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.
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| The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of [[coronary artery disease]]. Subjects received either placebo or [[gemfibrozil]] for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the [[gemfibrozil]] randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the [[gemfibrozil]] group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR=1.29)
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| A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received [[gemfibrozil]] or placebo for 5 years. Although cardiac deaths trended higher in the [[gemfibrozil]]group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).
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| ===Skeletal Muscle===
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| Fibrates increase the risk for myopathy, and have been associated with [[rhabdomyolysis]]. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with [[diabetes]],[[ renal failure]], or [[hypothyroidism]].
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| Data from observational studies suggest that the risk for [[rhabdomyolysis]] is increased when fibrates, in particularly [[gemfibrozil]], are co-administered with an HMG-CoA reductase inhibitor ([[statin]]). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3)].
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| Myopathy should be considered in any patient with diffuse [[myalgias]], muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels.
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| Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Antara therapy should be discontinued if markedly elevated CPK levels occur or[[myopathy]]/[[myositis]] is suspected or diagnosed.
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| Cases of [[myopathy]], including [[rhabdomyolysis]], have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with [[colchicine]] [see Drug Interactions (7.4)]
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| ===Liver Function===
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| Fenofibrate at doses equivalent to 90 mg Antara per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].
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| In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases levels related to fenofibrate therapy appears to be dose related.
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| Hepatocellular, chronic active and cholestatic [[hepatitis]] associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, [[cirrhosis]] has been reported in association with chronic active [[hepatitis]].
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| Baseline and regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Antara, and therapy discontinued if enzyme levels persist above three times the normal limit.
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| ===Serum Creatinine===
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| Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Antara. Renal monitoring should also be considered for patients taking Antara at risk for [[renal insufficiency]] such as the elderly and patients with diabetes.
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| ===Cholelithiasis===
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| Fenofibrate, like clofibrate and [[gemfibrozil]], may increase cholesterol excretion into the bile, leading to [[cholelithiasis]]. If [[cholelithiasis]]is suspected, gallbladder studies are indicated. Antara therapy should be discontinued if gallstones are found.
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| ===Coumarin Anticoagulants===
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| Caution should be exercised when anticoagulants are given in conjunction with Antara because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin time/International Normalized Ratio (INR/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)].
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| ===Pancreatitis===
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| [[Pancreatitis]] has been reported in patients taking fenofibrate, [[gemfibrozil]], and [[clofibrate]]. This occurrence 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.
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| ===Hematologic Changes===
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| Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. [[Thrombocytopenia]] and [[agranulocytosis]] have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Antara administration.
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| ===Hypersensitivity Reactions===
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| Acute [[hypersensitivity]] reactions such as [[Stevens-Johnson syndrome]] and toxic necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials.
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| ===Venothromboembolic Disease===
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| In the FIELD trial, [[pulmonary embolus ]]([[PE]]) and [[deep vein thrombosis]] ([[DVT]]) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9795 patients enrolled in FIELD, there were 4900 in the placebo group and 4895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).
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| In the Coronary Drug Project, a higher proportion of the [[clofibrate]] group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).
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| ===Paradoxical Decreases in HDL Cholesterol Levels===
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| There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = TRIGLIDE (FENOFIBRATE) TABLET [SHIONOGI INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=94a4a99b-24df-4e81-b409-5325d36647d2#nlm34067-9 | publisher = | date = | accessdate = 12 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| {{Lipid modifying agents}}
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| {{Antigout preparations}}
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| [[Category:Fibrates]]
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| [[Category:Prodrugs]]
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| [[Category:Organochlorides]]
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| [[Category:Benzophenones]]
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| [[Category:Phenol ethers]]
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| [[Category:Carboxylate esters]]
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