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Fenofibrate
Introduction
C20H21ClO4
Fenofibrate, a fibric acid derivative, is an antilipemic agent.
Uses
Dyslipidemias
Fenofibrate is used as an adjunct to dietary therapy in the management of primary hypercholesterolemia and mixed dyslipidemia. Fenofibrate also is used in the management of hypertriglyceridemia. Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of saturated fat and cholesterol intake, addition of plant stanol/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated. The effect of fenofibrate on cardiovascular morbidity and mortality or noncardiovascular mortality has not been established.
Primary Hypercholesterolemia and Mixed Dyslipidemia
Fenofibrate is used as an adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol, triglyceride, and apo B concentrations and to increase HDL-cholesterol concentrations in the management of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia.
Efficacy and safety of fenofibrate in the management of hypercholesterolemia were established in randomized, double-blind, placebo-controlled studies of 3-6 months' duration in patients with primary hypercholesterolemia or mixed dyslipidemia. In these studies, patients who received fenofibrate in dosages equivalent to 160 mg (as micronized, microcoated tablets) or 200 mg (as micronized capsules) daily had mean reductions of about 17-22% in total cholesterol, 20-31% in LDL-cholesterol, 24-36% in triglyceride, and (in a subset of patients) 25% in apo B concentrations; mean increases of 10-15% in HDL-cholesterol concentrations also were reported.
While few studies are available on the comparative efficacy of fenofibrate and other antilipemic agents, limited data suggest that fenofibrate may have more favorable effects on serum total cholesterol and LDL-cholesterol concentrations than gemfibrozil. Fenofibrate appears to be more effective than hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in lowering triglyceride and increasing HDL-cholesterol concentrations but generally is less effective in reducing LDL-cholesterol concentrations.
Hypertriglyceridemia
Fenofibrate also is used as an adjunct to dietary therapy in the management of patients with elevated serum triglyceride concentrations. Efficacy of the drug in reducing the risk of pancreatitis in patients with marked elevations in triglyceride concentrations (i.e., greater than 2000 mg/dL) has not been established. Fenofibrate is not indicated for use in the management of patients with chylomicronemia.
Efficacy and safety of fenofibrate in the management of hypertriglyceridemia were established in randomized, double-blind, placebo-controlled studies of 8 weeks' duration in patients with type IV or V hyperlipoproteinemia. In these studies, patients who received fenofibrate dosages equivalent to 160 mg (as micronized, microcoated tablets) or 200 mg (as micronized capsules) daily had mean reductions of 46-55 and 45-49% in triglyceride and VLDL-cholesterol concentrations, respectively; mean increases of 20-23% in HDL-cholesterol concentrations also were reported.
Treatment of patients with type IV hyperlipoproteinemia and elevated triglycerides with fenofibrate often is associated with increases in LDL-cholesterol concentrations. In clinical studies with fenofibrate, LDL-cholesterol concentrations were increased by 15 or 45% in patients with baseline triglyceride concentrations of 350-499 or 500-1500 mg/dL, respectively.
For additional information on the role of antilipemic therapy in the treatment of lipoprotein disorders, prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement
Dosage and Administration
General
Fenofibrate is administered orally once daily, preferably with meals to maximize GI absorption of the drug. The manufacturer states that the patient should be placed on a standard cholesterol-lowering diet before initiation of fenofibrate therapy and should remain on this diet during treatment with the drug. The National Cholesterol Education Program (NCEP) treatment guidelines should be consulted for details on dietary therapy.
Dosage of fenofibrate must be carefully adjusted according to individual requirements and response. Serum lipoprotein concentrations should be determined periodically during fenofibrate therapy. Reduction of fenofibrate dosage should be considered in patients whose serum cholesterol concentrations fall below the desired target range.
Fenofibrate micronized, microcoated tablets and micronized capsules are not bioequivalent on a mg-for-mg basis; the difference in bioequivalence should be considered when a patient is switched from one formulation to another. In general, a fenofibrate dosage of 67 or 200 mg daily as micronized capsules is bioequivalent to a dosage of 54 or 160 mg daily, respectively, as micronized, microcoated tablets.
Dyslipidemias
The recommended initial dosage of fenofibrate for the management of primary hypercholesterolemia or mixed dyslipidemia is 160 mg daily (as micronized, microcoated tablets).
The recommended initial dosage of fenofibrate for the management of elevated serum triglyceride concentrations in adults is 54-160 mg daily (as micronized, microcoated tablets) or 67 mg daily (as micronized capsules).
Dosage should be adjusted at intervals of 4-8 weeks until the desired effect on lipoprotein concentrations is observed or a maximum dosage of 160 mg daily (as micronized, microcoated tablets) or 200 mg daily (as micronized capsules) is reached. Fenofibrate should be discontinued in patients who fail to achieve an adequate response after 2-3 months of therapy with the maximum recommended dosage of 160 mg daily (as micronized, microcoated tablets) or 200 mg daily (as micronized capsules).
Special Populations
The recommended initial dosage of fenofibrate for the management of hyperlipoproteinemia in patients 65 years of age or older and in those with renal impairment (creatinine clearance less than 50 mL/minute) is 54 mg daily (as micronized, microcoated tablets) or 67 mg daily (as micronized capsules). Dosage should be adjusted only after evaluating therapeutic response and the effects of the drug on renal function.
Cautions
Contraindications
Severe hepatic impairment, including primary biliary cirrhosis and unexplained and persistent liver function abnormality; severe renal impairment; or preexisting gallbladder disease.
Known hypersensitivity to fenofibrate or any ingredient in the formulation.
Warnings/Precautions
Hepatic Effects Elevations in serum aminotransferase (transaminase) concentrations (i.e., AST [SGOT], ALT [SGPT]) exceeding 3 times the upper limit of normal were reported in approximately 5% of patients receiving fenofibrate in clinical studies.These increases appear to be dose-related and reportedly occurred in 13% of patients receiving fenofibrate in dosages equivalent to 107-160 mg (as micronized, microcoated tablets) or 134-200 mg (as micronized capsules) and in 0% of those receiving dosages equivalent to 54 mg or less (as micronized, microcoated tablets) or 34-67 mg (as micronized capsules). Serum aminotransferase concentrations usually return slowly to pretreatment values during continued therapy or following discontinuance of fenofibrate.
Chronic active hepatitis and cholestatic hepatitis have occurred as early as several weeks and as late as several years after initiation of fenofibrate therapy; cirrhosis associated with chronic active hepatitis has been reported rarely with fenofibrate.
Liver function tests should be performed periodically (i.e., every 3 months) during the first 12 months of therapy. If serum aminotransferase concentrations of 3 times the upper limit of normal or higher persist, fenofibrate therapy should be discontinued.
Cholelithiasis Fenofibrate, like other fibric acid derivatives (e.g., gemfibrozil), may increase cholesterol excretion in bile, resulting in cholelithiasis. If gallbladder studies indicate the presence of gallstones, fenofibrate should be discontinued.
Musculoskeletal Effects Myositis, myopathy, and/or rhabdomyolysis have been reported in patients (usually those with impaired renal function) receiving fenofibrate or other fibric acid derivatives in clinical studies. Rhabdomyolysis and other complications also have been reported in patients receiving fenofibrate concomitantly with certain other antilipemic agents. Patients receiving fenofibrate should be advised to report promptly any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Creatine kinase (CK, creatine phosphokinase, CPK) concentrations should be monitored periodically in patients reporting these adverse effects. Fenofibrate therapy should be discontinued if serum CK concentrations become markedly elevated or if myositis/myopathy is suspected or diagnosed.
Sensitivity Reactions
Severe rashes requiring hospitalization and corticosteroid therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely with fenofibrate in clinical studies. Urticaria and rash also have been reported in approximately 1% of patients receiving fenofibrate therapy in controlled trials.
Major Toxicities
Pancreatitis Pancreatitis has occurred in patients treated with fenofibrate and other fibric acid derivatives.
Hematologic Effects Mild to moderate decreases in hemoglobin, hematocrit, and leukocyte counts have occurred in patients receiving fenofibrate; these counts usually normalize during long-term therapy. Thrombocytopenia and agranulocytosis have been reported rarely during postmarketing surveillance. Blood cell counts should be monitored periodically during the first 12 months of fenofibrate therapy.
General Precautions
Effect on Morbidity and Mortality The effect of fenofibrate on cardiovascular or noncardiovascular morbidity and mortality has not been established. However, because fenofibrate is chemically, pharmacologically, and clinically similar to other fibric acid derivatives, some adverse effects of clofibrate (no longer commercially available in the US) and gemfibrozil such as increased incidence of cholelithiasis, cholecystitis requiring surgery, postcholecystectomy complications, malignancy, pancreatitis, appendectomy, gallbladder disease, and increased overall mortality may also apply to fenofibrate, and the usual precautions associated with fibrate therapy should be observed.4For additional information, see Cautions: Precautions and Contraindications, in Gemfibrozil.
Carcinogenicity Carcinogenicity (e.g., hepatic, pancreatic tumors) demonstrated in animals.
Specific Populations
Pregnancy Category C. (See Users Guide.) Teratogenicity and embryolethality demonstrated in animals.No adequate and well-controlled studies to date in pregnant women. Use during pregnancy only when the potential benefits justify the possible risks to the fetus.
Lactation Because of the potential for serious effects in nursing infants, fenofibrate should not be used in nursing women; discontinue nursing or the drug.
Pediatric Use Safety and efficacy not established in children younger than 18 years of age.
Geriatric Use Dosage reduction recommended for patients 65 years of age or older because of potentially decreased renal function in these patients. (See Dosage and Administration: Special Populations.)
Renal Impairment Dosage reduction recommended for patients with creatinine clearance less than 50 mL/min. (See Dosage and Administration: Special Populations.)
Common Adverse Effects
Adverse effects occurring in 2% or more of patients receiving fenofibrate include abnormal liver function tests (e.g., increased ALT, AST), respiratory disorder, abdominal pain, back pain, headache, increased CK concentrations,1, 14 diarrhea, nausea, rhinitis, constipation, asthenia, and flu syndrome.
Drug Interactions
Oral Anticoagulants
Potential pharmacologic interaction (prolongation of prothrombin time [PT]/international normalized ratio [INR]). Reduce anticoagulant dosage (e.g., by approximately one-third initially with subsequent dosage adjustment as necessary) and monitor PT/INR periodically until stabilized.
HMG-CoA Reductase Inhibitors (Statins)
Increased risk of adverse musculoskeletal effects (i.e., increased CK, myoglobinuria, rhabdomyolysis). Avoid concomitant use unless potential benefit outweighs risk. For additional information, see Drug Interactions in Gemfibrozil
Bile Acid Sequestrants
Potential pharmacokinetic interaction (decreased absorption of fenofibrate). Fenofibrate should be administered 1 hour before or 4-6 hours after a bile acid sequestrant.
Cyclosporine
Increased risk of cyclosporine-induced nephrotoxicity (i.e., deterioration in renal function). Use with caution.
Drugs Metabolized by Cytochrome P-450 (CYP) Isoenzymes
Potential pharmacokinetic interaction (increased or decreased metabolism of concomitant drugs metabolized by CYP2C9, CYP2A6, or CYP2C19). Data from in vitro studies indicate that fenofibrate and fenofibric acid are mild to moderate inhibitors of CYP2C9 and weak inhibitors of CYP2A6 and CYP2C19.
Description
Fenofibrate, a halogenated phenoxyisobutyric acid derivative, is an antilipemic agent. The drug is structurally and pharmacologically related to clofibrate (no longer commercially available in the US) and gemfibrozil. Clofibrate, fenofibrate, and gemfibrozil have been referred to as fibric acid derivatives.
Fenofibrate is a prodrug and has no antilipemic activity until it is hydrolyzed by tissue and plasma esterases in vivo to fenofibric acid; no unchanged fenofibrate is detectable in plasma after administration. Fenofibric acid decreases serum concentrations of total cholesterol, low-density lipoprotein (LDL)-cholesterol, apolipoprotein B (apo B), very low-density lipoprotein (VLDL)-cholesterol, and triglycerides. Fenofibric acid also increases serum concentrations of high-density lipoprotein (HDL)-cholesterol, apolipoprotein A-I (apo A-I), and apolipoprotein A-II (apo A-II).
The antilipemic effects of fenofibrate appear to be related to the drug's effects on clearance of triglyceride-rich particles. Data from in vitro and in vivo studies indicate that fenofibric acid activates lipoprotein lipase and reduces production of apolipoprotein C-III (apo C-III), an inhibitor of lipoprotein lipase activity, thereby increasing lipolysis and clearance of triglyceride-rich particles. The reduction in triglyceride concentrations via this mechanism alters the size and composition of LDL-cholesterol from small, dense particles to larger, more buoyant particles that are less atherogenic and more rapidly catabolized. Fenofibric acid also appears to activate a receptor (peroxisome proliferator activated receptor a) that induces the synthesis of HDL-cholesterol, apo A-I, and apo A-II. Limited data in patients with type diabetes mellitus indicate that fenofibrate may slow the progression of coronary atherosclerosis.
Fenofibrate has been shown to reduce serum uric acid concentrations in healthy and hyperuricemic individuals by increasing the urinary excretion of uric acid.
Fenofibrate is commercially available as micronized drug in capsules (Lofibra®) and micronized, microcoated drug in tablets (TriCor®). Fenofibrate capsules contain micronized fenofibrate particles that disperse and aggregate randomly to excipients, while fenofibrate tablets contain micronized fenofibrate particles that coat an inert excipient core (i.e., micronized, microcoated tablets). The micronized, microcoated tablet formulation of fenofibrate has higher bioavailability on a mg-for-mg basis compared with micronized fenofibrate capsules. Pharmacokinetic data indicate that plasma concentrations of fenofibric acid achieved following administration of the 54- or 160-mg micronized, microcoated tablets are equivalent under fed conditions to those achieved with the 67- or 200-mg micronized capsules, respectively. A nonmicronized formulation of fenofibrate has been available in countries outside the US. Pharmacokinetic data from single-dose studies in healthy individuals indicate that 100 mg of nonmicronized fenofibrate (not commercially available in the US) is bioequivalent to 67 mg of micronized fenofibrate (as capsules).
Absorption of fenofibrate (as micronized capsules or micronized, microcoated tablets) is increased (by 35%) when the drug is administered with food. Since fenofibrate is excreted principally in urine (about 60% of a dose), the drug may accumulate in patients with diminished renal function. Limited data in patients with severe renal impairment (creatinine clearance less than 50 mL/minute) indicate that clearance of fenofibrate is substantially reduced and drug accumulation occurs during repeated dosing. (See Dosage and Administration: Special Populations.)
Advice to Patients
Importance of patients informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.
Preparations
Fenofibrate
Oral
Capsules 67 mg Lofibra®,
Gate
134 mg Lofibra®,
Gate
200 mg Lofibra®,
Gate
Tablets
54 mg TriCor®, (with povidone)
Abbott
160 mg TriCor®, (with povidone)
Abbott
References
1. Abbott Laboratories. TriCor® (fenofibrate) tablets prescribing information. North Chicago, IL; 2001 Aug
2. Adkins JC, Faulds D: Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia, Drugs 1997 54: 615-33
3. Goldberg AC, Schonfeld G, Feldman EB: Fenofibrate for the treatment of type IV and V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study, Clin Ther 1989 11: 69-83
4. Anon: Fenofibrate for hypertriglyceridemia, Med Lett Drugs Ther 1998 40: 68-9
5. Diabetes Atherosclerosis Intervention Study (DAIS) Investigators: Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study, Lancet 2001 357: 905-10
6. Ooi TC, Heinonen T, Alaupovic P: Efficacy and safety of a new hydroxymethylglutaryl-coenzyme A reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate, Arterioscler Thromb Vasc Biol 1997 17: 1793-9
7. Guay DRP: Micronized fenofibrate: a new fibric acid hypolipidemic agent, Ann Pharmacother 1999 33: 1083-103
8. Jen SL, Chen JW, Lee WL: Efficacy and safety of fenofibrate or gemfibrozil on serum lipid profiles in Chinese patients with type IIb hyperlipidemia: a single-blind, randomized, and cross-over study, Chung Hua I Hsueh Tsa Chih (Taipei) 1997 59: 217-24
9. Perova N, Kalinina A, Paramanova I: Effects of two pharmaceutical forms of fenofibrate on plasma lipoproteins in Moscow residents, Atherosclerosis 1995 115: Suppl S56
10. Abbott Laboratories, North Chicago, IL: Personal communication.
11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, MD: National Institutes of Health. (NIH publication No. 01-3670.)
12. Abbott Laboratories. TriCor® (fenofibrate, micronized) capsules prescribing information. North Chicago, IL; 2000 Apr.
13. Anon. TriCor® fenofibrate tablets: convert to tablets. From TriCor® website 2002 Apr 11.
14. Gate Pharmaceuticals. Lofibra® (fenofibrate) capsules (micronized) prescribing information. Sellersville, PA; 2002 Jul.
15. Guichard JP, Blouquin P, Qing Y: A new formulation of fenofibrate: suprabioavailable tablets, Curr Med Res Opin 2000 16: 134-8
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