Pharmacology Update
Fenofibrate: New Antilipemic Agent
By William T. Elliott, MD, and James Chan, PharmD, PhD
The fda has granted abbott laboratories and Groupe Fournier approval to market fenofibrate (Tricor), a new antilipemic agent. Fenofibrate is the prodrug of the active metabolite fenofibric acid, a fibrate that is chemically similar to clofibrate and gemfibrozil. It is being produced in a micronized form to facilitate bioavailability. The drug was developed by Groupe Fournier in France and will be marketed in this country by Abbott under the terms of a 1997 licensing agreement. Fenofibrate is available in 77 countries worldwide and has been used in France since 1975.
Fenofibrate is a lipid-modifying drug that reduces plasma triglyceride, low density lipoprotein (LDL) cholesterol, and total cholesterol and increases high density lipoprotein (HDL) cholesterol.1-3 Its mechanisms of action are believed to result from modification of LDL subfraction distribution and promotion of LDL catabolism.2
Although fenofibrate has been available in Europe for years, the micronized formulation is new. The smaller particle size increases drug dissolution, rate of absorption, and bioavailability by about 35% compared to the standard formulation.2-4
Indications
Fenofibrate is indicated as adjunctive therapy to diet for treatment of adult patients with very high elevations of serum triglyceride levels (types IV and V hyperlipidemia) who are at risk of pancreatitis and who do not respond adequately to a determined dietary effect.3 These patients generally have serum triglyceride levels higher than 2000 mg/dL and have elevations of VLDL-cholesterol as well as fasting chylomicrons (type V hyperlipidemia). Patients with a history of pancreatitis and recurrent abdominal pain typical of pancreatitis and serum triglyceride levels between 1000 mg/dL and 2000 mg/dL may be considered for treatment.3
Dosing Information
Fenofibrate is available as 67 mg capsules. The initial dose is generally 67 mg/d. The dose should be titrated according to patient response at four- to eight-week intervals up to 201 mg (3 capsules per day).3 Fenofibrate should be taken with a meal since food increases absorption by about 35%.3
Fenofibrate should be taken one hour before or 4-6 hours after a bile-sequestering agent. The effect of warfarin may be increased by fenofibrate. For patients on warfarin therapy, the dose of warfarin should be reduced by about one-third and adjusted based on prothrombin determinations.2,3 Fenofibrate may also potentiate the nephrotoxicity of cyclosporine.3
Due to the potential risk of severe myopathy, rhabdomyolysis, and acute renal failure, the manufacturer does not recommend combining fenofibrate with a statin.3
Potential Advantages
Fenofibrate has an elimination half life of 20 hours, which permits dosing once daily. Limited comparative data suggest that fenofibrate may have a more favorable effect on LDL-cholesterol compared to gemfibrozil.4 Fenofibrate has also been reported to reduce uric acid levels by about 25%.5
Potential Disadvantages
Fenofibrate has been associated with significant increases in serum transaminases. Regular periodic monitoring of liver function tests should be performed, and, if levels are greater than three times the upper limit of normal, the drug should be discontinued. Transaminase increases have been reported in 8-10% of patients during controlled clinical trials.3 Fenofibrate may also increase the risk of cholelithiasis.3
As with other fibric acid derivatives, myositis, myopathy, and rhabdomyolysis may be associated with fenofibrate. Increased serum creatinine levels have been reported.4 The most common side effect of fenofibrate, associated with discontinuation of drug treatment, was skin rash (2%).3
Comments
Fenofibrate is a fibric acid derivative that has lipid-modifying effects similar to gemfibrozil. Its mechanism of action is believed to be mediated through activation of the peroxisome proliferator activated receptors (PPARs). These receptors apparently control transcription of genes involved in lipoprotein metabolism such as apolipoprotein C-III which inhibits lipolysis and the clearance of triglyceride-rich lipoproteins.1,2 In type IV and type V patients, fenofibrate has been reported to reduce triglyceride by 46-55%, with greater reduction in patients with baseline triglyceride levels of 500-1500 mg/dL vs. those with levels of 350-499 mg/dL.3,6 In type II patients, fenofibrate has been reported to be similar to or less effective than simvastatin 20 mg or pravastatin 20 mg in lowering total and LDL-cholesterol but more effective in reducing triglyceride levels and raising HDL-cholesterol levels.2,4,5 In contrast to HMGCoA reductase inhibitors (i.e., statins), fenofibrate reduces lipoprotein (a), uric acid, and fibrinogen.2
Clinical Implications
Fenofibrate provides an alternative to gemfibrozil for the reduction of very high triglyceride levels. For patients with moderately elevated triglycerides, or even "normal" levels, treatment has been controversial. Two recent studies suggest that high levels or "normal" levels of fasting triglycerides were risk factors for ischemic heart disease and new coronary artery disease, respectively.7,8 This atherogenic effect may be mediated by high triglyceride levels driving the formation of smaller and denser LDL and HDL particles and formation of cholesterol-rich VLDL or chyomicron remnants.9 The lipid-modifying effects of fibric acid derivatives may also be suited for dyslipidemia in type 2 diabetics, as the most common lipid pattern in these patients is elevated triglycerides and decreased HDL-cholesterol.
A recent study reported that diabetic patients without previous myocardial infarction had a similar hazard ratio for myocardial infarctions compared to patients with prior myocardial infarction.10 The authors suggested that diabetic patients should be treated as aggressively as nondiabetic patients with prior myocardial infarction.
Currently, fenofibrate is the only agent approved by the FDA for the treatment of adult patients with very high elevations of serum triglyceride levels (types IV and V hyperlipidemia) who are at risk of pancreatitis and who do not respond adequately to a determined dietary effect. The effect of fenofibrate on cardiovascular mortality and morbidity and non-cardiovascular mortality has not been established. Data from other fibrates (clofibrate, gemfibrozil) in placebo-controlled studies (e.g., Coronary Drug Project, WHO study, Helsinki Heart Studies) suggest an increased risk of non-cardiovascular and cardiovascular mortality and morbidity compared to placebo.3 Two long-term studies have been initiated to assess the effect of fenofibrate on coronary heart disease in type 2 diabetic patients. These are the Diabetes Atherosclerosis Intervention Study (DAIS) and the Fenofibrate Intervention and Event Lowering in Diabetes Study (FIELD).
Fenofibrate is more expensive than gemfibrozil, which is available generically. The average wholesale cost of 201 mg (3 ´ 67 mg) is about $2.00 per day, which is about nine times the cost of gemfibrozil (600 mg bid).
References
1. Packard CJ. Eur Heart J 1998;SupplA:A62-65.
2. Adkins JC, Faulds D. Drugs 1997;54(4):615-633.
3. TriCor Product Information. Abbott Laboratories, Inc. February 1998.
4. Anonymous. Med Lett 1998;40:68-69.
5. Steinmetz A, et al. J Cardiovasc Pharmacol 1996;27:563-570.
6. Goldberg AC, et al. Clin Thera 1989;11:69-82.
7. Jeppesen J, et al. Circulation 1998;97:1029-1036.
8. Miller M, et al. J Am Coll Cardiol 1998;31:1252-1257.
9. Packarad CJ. Curr Med Res Opin 1996;13:379-390.
10. Haffner SM, et al. N Engl J Med 1998;339:229-234.
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