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Pharmacotherapeutic Group: Serum Lipid Reducing Agents/Cholesterol and Triglycerides Reducers/Fibrates. ATC Code: C10 AB 05.
Pharmacology: Pharmacodynamics: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARa).
Through activation of PPARa, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII.
Activation of PPARa also induces an increase in the synthesis of apoproteins AI and AII.
The previously mentioned stated effects of fenofibrate on lipoproteins lead to a reduction in very low and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
During clinical trials with fenofibrate, a total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effects on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or Apo AI, all of which are markers of atherogenic risk.
Because of its significant effect on LDL cholesterol and triglycerides, treatment with fenofibrate should be beneficial in hypercholesterolaemic patients with or without hypertriglyceridaemia, including secondary hyperlipoproteinaemia such as type 2 diabetes mellitus.
At the present time, no results of long-term controlled trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated fenofibrate therapy.
Patients raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of Lp(a). Other inflammatory markers such as C-Reactive Protein are reduced with fenofibrate treatment.
The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.
Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.
Pharmacokinetics: FENOGAL 160 mg is a capsule containing 160 mg of fenofibrate and is suprabioavailable (larger bioavailability) compared to the previous formulations.
Absorption: Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
The absorption of fenofibrate is increased when administered with food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Plasma Half-Life: The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Metabolism and Excretion: No unchanged fenofibrate can be detected in the plasma where the principal metabolite is fenofibric acid. The drug is excreted mainly in the urine.
Practically all the drug is eliminated within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by haemodialysis.
Toxicology: Preclinical Safety Data: Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man.
Studies in mice, rats and rabbits did not reveal any teratogenic effect.
Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.
