Fenofibrate

Summary

Synopsis

Fenoflbrate is a lipid-regulating drug which is structurally related to other flbric acid derivatives, such as cloflbrate. At the recommended dosage of 200 to 400mg daily, it producessubstantial reductions in plasma triglyceride levels in hypertriglyceridaemic patients and in plasma total cholesterol levels in hypercholesterolaemic patients. High density lipoprotein (HDL)-cholesterol levels are generally increased in patients with low pretreatment values. Fenoflbrate appears to be equally effective in diabetic patients with hyperlipoproteinaemia without adversely affecting glycaemic control. The influence of fenoflbrate on the plasma lipid profile is sustained during long term (2 to 7 years) treatment.

Comparative studies conducted to date have involved only small groups of patients — in overall terms fenoflbrate was at least as effective as other fibrates, but larger comparative studies are needed before valid conclusions on its relative efficacy compared with nonfibrate lipid-lowering drugs can be drawn. The influence of fenoflbrate on morbidity and mortality from cardiovascular disease has not been studied.

Clinical adverse reactions to fenoflbrate have mainly consisted of gastrointestinal disturbances, headache and muscle cramps. Transient elevations in transaminase and creatine phosphokinase levels commonly occur. Isolated cases of hepatitis with substantially elevated transaminase levels have been reported. Fenoflbrate induces hepatomegaly, peroxisome proliferation and hepatic carcinomas in rodents, but this type of hepatotoxicity has not been observed in humans. The biliary lithogenic index is increased by fenoflbrate, but this has not been shown to have increased the incidence of gallstones in treated patients.

Thus, fenoflbrate offers an effective and well tolerated alternative to cloflbrate or other flbric acid derivatives, but its relative efficacy and tolerability compared with other types of lipid-lowering drugs, and its effect on cardiovascular morbidity and mortality, remain to be clarified.

Pharmacodynamic Properties

Fenofibrate is a lipid-regulating agent which reduces plasma levels of total cholesterol and triglycérides in healthy subjects and patients with hyperlipoproteinaemia.

In hyperlipoproteinaemic patients substantial reductions occur in the atherogenic very low density lipoprotein (VLDL) fraction, while levels of low density lipoprotein (LDL) are consistently decreased in those with elevated baseline levels and HDL consistently increased when baseline levels are low (see Therapeutic Use, below). Changes in apolipoproteins appear to reflect changes in the relevant lipoprotein fractions; levels of apolipoproteins AI and All are increased while those of apolipoproteins CII, CIII and E are decreased. Levels of apolipoprotein B are generally decreased when baseline LDL-cholesterol levels are elevated, but may be increased in patients with lcw pretreatment LDL-cholesterol levels.

The underlying mechanisms by which fenofibrate influences lipid and lipoprotein patterns are not fully established. The drug has a wide range of effects on cholesterol and triglyceride metabolism, but it is not clear which are primary and which are secondary effects. However, the major effect of fenofibrate is to enhance triglyceride-rich lipoprotein catabolism by increasing lipoprotein lipase activity. In addition, fenofibrate appears to decrease cholesterol biosynthesis, which may in turn enhance LDL clearance by increased hepatic LDL receptor activity. Mobilisation of cholesterol deposited in peripheral tissues (including arterial walls) may occur: regression of xanthomas and xanthelasmas has been observed following fenofibrate treatment in clinical studies, and preliminary studies have reported evidence of regression of atherosclerosis following administration of fenofibrate and nicotinic acid. Platelet hyperaggregability and platelet-derived growth factor activity may be decreased, and esterification of cholesterol in plasma increased; all of these actions could contribute to inhibition of atherogenesis.

In common with other fibrates. fenofibrate increases the lithogenic index of the bile by increasing cholesterol and decreasing bile acid concentrations. However, there is no clear link between fenofibrate administration and the occurrence of gallstones.

Fenofibrate decreases serum uric acid levels in both healthy volunteers and in hyperlipoproteinaemic patients. This effect may be particularly beneficial in hyperuricaemic type IV patients, since elevated serum uric acid concentrations are considered a risk factor for cardiovascular disease.

In rodent species fenofibrate induces hepatomegaly and peroxisome proliferation, with eventual hepatic tumour induction at very high doses, but these effects have not been observed in humans or other primates.

Pharmacokinetic Properties

Fenofibrate is a prodrug which immediately after absorption is hydrolysed by tissue and plasma esterases to its active major metabolite, fenofibric acid. Peak plasma concentrations of around 6 to 9.5 mg/L are attained approximately 4 to 6 hours following a single 300mg dose of the commercially available dosage form in healthy fasting volunteers. Steady-state concentrations of approximately 10 mg/L were reached after 120 hours in healthy subjects given 300mg daily in 2 divided doses, although much lower steadystate values have also been reported.

Fenofibric acid is more than 99% bound to plasma proteins and the volume of distribution has been reported as 0.89 L/kg in healthy subjects. The drug is eliminated mainly in the urine, in metabolised form, with some in the faeces, in varying proportions depending on the extent of absorption. The elimination patterns in animal species differ, a factor that may be important in interpreting toxicological findings. Mean elimination half-life values of 19.6 to 26.6 hours have been reported in healthy subjects.

In patients with renal failure, the plasma half-life of fenofibric acid was considerably prolonged, with no correlation between the elimination half-life and serum creatinine level or creatinine clearance. Fenofibric acid is not removed by haemodialysis. The use of fenofibrate is therefore not recommended in patients with chronic renal failure, since marked accumulation of the drug is likely to occur, even at reduced dosage levels.

Therapeutic Use

The lipid-regulating effects of fenofibrate have been evaluated in noncomparative and comparative studies, including some long term open trials of several years duration. These studies have mainly involved patients with the most commonly diagnosed forms of hyperlipoproteinaemia — types Ha, IIb and IV — although patients with type III or V disease have been included in a few trials, and a small number of children have been studied. Fenofibrate, at a dosage of 200 to 400mg daily (usually 100mg 3 times daily), has significantly reduced elevated total plasma cholesterol and triglyceride concentrations in such patients. Total plasma triglycerides are generally reduced by around 30 to 60% in type IIb patients, with substantial reductions also having been achieved in type III, IV and V patients. Total cholesterol levels are usually reduced by approximately 20 to 30% in type Ha and 13 to 32% in type IIb patients, with substantial decreases in the small number of type III patients studied. LDL-cholesterol levels (a major risk factor in coronary heart disease) are, decreased in patients with high pretreatment levels, but may be increased in those with hypertriglyceridaemia, who often have abnormally low LDL levels. HDL-cholesterol is generally increased by fenofibrate, particularly in patients with low pretreatment levels, but may be decreased in some individuals.

In small comparative studies, fenofibrate was approximately comparable overall with other lipid-lowering drugs such as ciprofibrate or bezafibrate although the effect on individual lipoprotein fractions varied among the drugs compared. Fenofibrate appeared to be more effective than clofibrate overall, but less effective than simvastatin in reducing plasma total and LDL-cholesterol in hypercholesterolaemic patients, but was more effective in decreasing triglyceride levels. However, further comparative studies in larger patient groups are needed before the relative efficacy of fenofibrate can be clearly described. The effects of fenofibrate on lipid and lipoprotein patterns are generally apparent after 1 month and have been sustained in small numbers of patients treated for several years. No studies on the long term effects of fenofibrate on morbidity and mortality from cardiovascular disease have been reported.

Additive effects on some lipid and lipoprotein parameters have been observed in dyslipidaemic patients when fenofibrate treatment was combined with other lipid-regulating agents with different mechanisms of action, such as nicotinic acid (niacin) and the bile acid sequestrants colestipol and cholestyramine. Combination therapy of this type, may be particularly beneficial in patients in whom single-agent therapy does not sufficiently reduce plasma lipid levels.

The influence of fenofibrate treatment on lipid and lipoprotein profiles in diabetic patients with hyperlipoproteinaemia is similar to that in nondiabetic patients; in patients receiving insulin or oral hypoglycaemic drugs, glycaemic control was maintained during fenofibrate therapy without the need for adjustment of antidiabetic medication.

Adverse Effects

Adverse reactions attributable to fenofibrate appear to occur with an overall incidence of about 6% in short term studies and 11% in longer term trials. The most frequently reported adverse reactions have been gastrointestinal disturbances, accounting for approximately one-half of adverse effects observed in long and short term clinical trials. Other relatively common reactions include headache, muscle pains and rash.

Hepatitis associated with markedly elevated transaminase levels has occasionally been reported, but appears generally to have slowly resolved after withdrawal of fenofibrate. Nonsymptomatic sporadic increases in alanine and/or aspartate aminotransferase have been reported in a number of studies. Elevations in plasma creatinine and urea are also frequently reported, as are increased creatine phosphokinase levels, which are sometimes associated with muscle cramps. Although fenofibrate increases the cholesterol saturation of bile, it has not been shown to be associated with an increased incidence of gallstones. A decrease in serum uric acid levels also generally occurs, which may be beneficiai in hyperuricaemic patients.

Dosage and Administration

As with other lipid-regulating drugs, fenofibrate therapy should only be instituted after dietary restrictions and other nonpharmacological interventions have proved inadequate for controlling lipid abnormalities. The recommended initial dosage of fenofibrate in adult patients with hyperlipoproteinaemia is 300mg daily in divided doses with meals. Patients with renal dysfunction require dosage reduction.

The response to therapy should be determined by serum lipid monitoring and dosage adjusted where necessary within the range of 200 to 400mg daily. If an adequate response is not achieved within 3 months fenofibrate should be discontinued.

Fenofibrate is contraindicated in severe hepatic or renal dysfunction or in gallbladder disease. Serum transaminases should be monitored during the first year of therapy and fenofibrate should be discontinued if ALT levels increase to more than 100 U/L.

The dosage of concomitantly prescribed oral anticoagulants should be decreased by approximately one-third at the start of fenofibrate treatment and adjusted as required according to prothrombin time.