Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: SUN PHARMA UK LIMITED, 6-9 The Square, Stockley Park, Uxbridge, UB11 1FW, United Kingdom
Pharmacotherapeutic group: Serum Lipid Reducing Agents/Cholesterol and Triglyceride Reducers/Fibrates.
ATC code: C10AB05
Fenofibrate 200 mg Capsules are a formulation containing 200 mg of micronized fenofibrate; the administration of this product results in effective plasma concentrations identical to those obtained with 3 capsules of 67 mg of micronized fenofibrate.
Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type α (PPARα). Through activation of PPARα, fenofibrate increases lipolysis and elimination of atherogenic triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of Apoprotein C-III. Activation of PPARα also induces an increase in the synthesis of Apoproteins A-I and A-II.
Epidemiological studies have demonstrated a positive correlation between abnormally increased serum lipid levels and an increased risk of coronary heart disease. The control of such dyslipidaemia forms the rationale for treatment with Fenofibrate Micro 200. However the possible beneficial and adverse long term consequences of drugs used in the management of dyslipidaemia are still the subject of scientific discussion. Therefore the presumptive beneficial effect of Fenofibrate Micro 200 on cardiovascular morbidity and mortality is as yet unproven.
There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all cause mortality in the primary or secondary prevention of cardiovascular disease.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p=0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (≤34 mg/dl or 0.88 mmol/L) and highest tertile of TG (≥204 mg/dl or 2.3 mmol/L) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI 0.49-0.97, p=0.03; absolute risk reduction: 4.95%). Another prespecified subgroup analysis identified a statistically significant treatment-by-gender interaction (p=0.01) indicating a possible treatment benefit of combination therapy in men (p=0.037) but a potentially higher risk for the primary outcome in women treated with combination therapy compared to simvastatin monotherapy (p=0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
Studies with fenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol. HDL cholesterol levels are frequently increased. LDL and VLDL triglycerides are reduced. The overall effect is a decrease in the ratio of low and very low density lipoproteins to high density lipoproteins, which epidemiological studies have correlated with a decrease in atherogenic risk. Apolipoprotein-A and apolipoprotein-B levels are altered in parallel with HDL and LDL and VLDL levels respectively.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic patients, particularly in those with type IV disease.
Patients with 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.
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.
Fenofibric acid is strongly bound to plasma albumin (more than 99%). It can displace antivitamin K compounds from the protein binding sites and may potentiate their anti-coagulant effect.
After oral administration, fenofibrate is rapidly hydrolised by esterases to the active metabolite fenofibric acid.
No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP 3A4. No hepatic microsomal metabolism is involved.
The drug is excreted mainly in the urine; 70% in 24 hours and 88% in 6 days, at which time the total excretion in urine and faeces reaches 93%. Practically all the drug is eliminated within 6 days. Fenofibrate is mainly excreted as fenofibric acid and its derived glucuroconjugate.
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 during haemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
In a three-month oral nonclinical study in the rat species with fenofibric acid, the active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those rich in type I slow oxidative myofibres) and cardiac degeneration, anaemia and decreased body weight were seen. No skeletal toxicity was noted at doses up to 30 mg/kg (approximately 17-time the exposure at the human maximum recommended dose (MRHD). No signs of cardiomyotoxicity were noted at an exposure about 3 times the exposure at MRHD. Reversible ulcers and erosions in the gastro-intestinal tract occurred in dogs treated for 3 months. No gastro-intestinal lesions were noted in that study at an exposure approximately 5 times the exposure at the MRHD.
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.
Reversible hypospermia and testicular vacuolation and immaturity of the ovaries were observed in a repeat-dose toxicity study with fenofibric acid in young dogs. However no effects on fertility were detected in non-clinical reproductive toxicity studies conducted with fenofibrate.
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