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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 (PPARα).
Through activation of PPARα, 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 PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The previously 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, total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
In hypercholesterolemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or Apo B to Apo AI, or a decrease if the levels of non-HDL cholesterol all of which are markers of atherogenic risk.
Lipanthyl NT 145 mg: Only for countries where is already approved: Results of the Diabetes Atherosclerosis Intervention Study (DAIS) showed that fenofibrate significantly reduces the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes and hyperlipoproteinemia. DAIS was a double-blind, randomized, placebo-controlled study in 418 patients with type 2 diabetes and hyperlipoproteinemia (mean total cholesterol 5.57 mmol/L, triglycerides 2.54 mmol/L, LDL cholesterol 3.37 mmol/L, HDL cholesterol 1.03 mmol/L). Treatment with fenofibrate for an average of 38 months resulted in a significant reduction of the progression of the focal coronary artery lesions assessed by quantitative coronary angiography by 40%.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
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 dyslipidemic 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.
Effects of fenofibrate on the reduction of the progression of microvascular complications in patients with type 2 of diabetes mellitus have been proven in international randomized placebo-controlled trials.
In the ACCORD trial (in a subgroup of 1593 patients, ACCORD-eye substudy) the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale was 6.5% with fenofibrate and simvastatin combined dyslipidemia therapy, versus 10.2% with simvastatin and placebo therapy (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006).
Fenofibrate therapy was also associated with lower frequency of laser treatment required for retinopathy (5.2% vs 3.6%, p=0,0003) in the FIELD study.
Lipanthyl 67 mg: Limited pediatric data are available. The effects of fenofibrate in dyslipidemic children have been studied in two small clinical trials and in an open long-term surveillance registry with 76 hypercholesterolemic children aged 3 to 18 years receiving fenofibrate for 1 to 11 years. However, due to limited data and methodological insufficiencies, no definitive conclusion can be drawn on the use of fenofibrate in dyslipidemic children.
Adverse events similar to those observed in adults have been reported in children: leucopenia, liver function test abnormal, renal failure, hepatitis, jaundice, myositis and rhabdomyolysis.
Overall, the safety and efficacy of fenofibrate in children and adolescents have yet not been established (see Dosage & Administration).
Pharmacokinetics: Absorption: Lipanthyl NT 145 mg: Fenofibrate (Lipanthyl NT) 145 mg, film-coated tablets contains 145 mg of fenofibrate nanoparticles.
Maximum plasma concentrations (Cmax) occur within 2 to 4 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
Contrarily to previous fenofibrate formulations, the maximum plasma concentration and overall exposure of the nanoparticle formulation is independent from food intake. Therefore, Fenofibrate (Lipanthyl NT) 145 mg may be taken without regard to meals.
A food-effect study involving administration of the new 145 mg tablet formulation of fenofibrate to healthy male and female subjects under fasting conditions and with a high fat meal indicated that exposure (AUC and Cmax) to fenofibric acid is not affected by food.
Lipanthyl Supra 160 mg: Fenofibrate (Lipanthyl Supra) 160 mg is a film-coated tablet containing 160 mg of micronized fenofibrate and is suprabioavailable (larger bioavailability) compared to the previous formulations.
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.
Lipanthyl 67 mg: 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%).
Metabolism and excretion: After oral administration, fenofibrate is rapidly hydrolyzed 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. 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 hemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Toxicology: Preclinical Safety Data: Acute toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
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 - myofibers) and cardiac degeneration, anemia and decreased body weight were seen at exposure levels ≥50-fold the human exposure for the skeletal toxicity and >15-fold for the cardiomyotoxicity. Reversible ulcers and erosions in the gastro-intestinal tract occurred in dogs treated during 3 months at exposures approximately 7-fold the clinical AUC.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumors 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 effects on fertility were detected in non-clinical reproductive toxicity studies conducted with fenofibrate. However reversible hypospermia and testicular vacuolation and immaturity of the ovaries were observed in a repeat-dose toxicity study with fenofibric acid in young dogs.
