Review of European clinical experience with fenofibrate.

Since the introduction of fenofibrate to European clinical practice in 1975, some 6.5 million patient-years of experience in the treatment of hyperlipidemia have been accumulated. A review of results of clinical trials shows fenofibrate to have a broad spectrum of lipid-lowering activity, reducing the total cholesterol level by 20-25% in type IIa patients and triglycerides by 40-60% in type IIb and IV patients. High levels of low-density lipoprotein cholesterol are reduced and, where low at baseline, high-density lipoprotein levels are increased. An associated activity is a 10-28% reduction in serum uric acid levels. Adverse reactions in the mostly open clinical trials ranged from 2-15%; mild gastrointestinal problems dominated, and occurred with much the same frequency in the placebo-treated groups of controlled trials. There are also reports of fatigue, headache, loss of libido, dizziness, and insomnia. Some excess of skin rash emerged as the only statistically significant unwanted clinical effect in one placebo-controlled trial. Biochemically, there are occasional fluctuations in serum transaminase values, while gamma-glucuronyl transferase and alkaline phosphatase are often decreased, all without apparent clinical significance. Lithogenicity of the bile is often increased above pretreatment levels, but there is no evidence from trials or postmarketing surveillance that the use of fenofibrate is associated with an increase of gallstone formation.

Comparative toxicity and safety profile of fenofibrate and other fibric acid derivatives.

It is estimated that there are approximately six million patient-years of clinical experience with fenofibrate among physicians outside of the United States. A review of the European literature and unpublished studies supplied by the manufacturer (Laboratoires Fournier, Dijon, France) has been compiled with the data recently reported from a double-blind, placebo-controlled study completed in the United States. In general, fenofibrate has been found to reduce serum triglyceride levels by 30 to 60 percent in patients with type II B and IV hyperlipoproteinemia. Serum cholesterol levels were also reduced by 20 to 25 percent in this group of hypertriglyceridemic patients. A similar reduction in serum cholesterol levels was also found in type II A patients (normal triglyceride levels). Low-density lipoprotein levels were usually reduced in those patients with elevated levels and high-density lipoprotein levels increased when baseline levels were low. Fenofibrate also produced a 10 to 28 percent reduction in uric acid that was sustained for years. The incidence of unwanted effects ranged from 2 to 15 percent in the open trials lasting from a few months up to six years. Gastrointestinal problems (abdominal discomfort, diarrhea, and constipation) are most common, occurring in approximately 5 percent of patients. Reports including fatigue, headache, loss of libido, impotence, dizziness, and insomnia were grouped as neurologic and occurred with a total incidence of 3 to 4 percent. In about 1 percent of patients, muscle tenderness developed, often accompanied by elevated creatine phosphokinase levels. These and the gastrointestinal problems occurred with a similar frequency in the placebo-treated cohort in controlled studies. In approximately 2 percent of patients, a skin rash developed, an incidence that appears significantly higher than that of placebo control groups. Liver changes in rodents have included marked peroxisome proliferation and increased hepatic carcinomas with very high doses. In humans, only a small increase in incidence of elevated levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase seems to be present and is not clearly different from that of the control groups. Alkaline phosphatase, gamma-glutamyl transferase, and bilirubin levels are often decreased with no known undesirable effects. Investigations into the lithogenicity of bile indicated a significant increase in five studies. However, there has been no evidence of a significant rise in the incidence of cholelithiasis in the clinical trials completed to date.

Time and dose study on the response of rats to the hypolipidaemic drug fenofibrate.

Groups of male Wistar albino rats were administered diets containing sufficient fenofibrate to ensure intakes of either 200, 60 or 13 mg/kg/day or sufficient clofibrate to ensure an intake of 400 mg/kg/day. Four rats from each experimental group and 6 control rats were killed, 3, 7, 14 and 28 days, 8, 12 and 20 weeks and 6, 9, 12 and 18 months after commencement of treatment. At all time points livers were subjected to histological, electron microscopic and biochemical examination, the other major abdominal organs were removed for histological examination. A more extensive necropsy was carried out on rats killed after 12 and 18 months. The major alterations were observed in the liver, although there were also morphological changes in the thyroid, pancreas and kidney after prolonged treatment. The hepatic changes followed a distinct time course. Within 24 h of offering diets containing the compounds to the rats there was accumulation of small droplets of lipid, induction of peroxisomal enzymes and of the specific cytochrome P-450 catalysing omega-hydroxylation of fatty acids and an increase in the number of mitotic figures. More slowly developing changes were loss from the centrilobular zone of fat, glycogen and of glucose 6-phosphatase activity. Here maximal changes were observed after 14 days of treatment. A still more slowly developing change was accumulation of enlarged lipid-loaded lysosomes, which was maximal at 26 weeks, accompanied by the development of lipofuscin bodies. Finally, in animals treated for 12 months or more there was evidence for increasing cell turnover as indicated by an increased number of mitotic figures, more dark cells and induction of serum alanine transaminase. The last 2 groups of changes were not observed in rats treated with 13 mg/kg/day of fenofibrate. In general the degree of change in rats treated with 400 mg/kg/day of clofibrate was similar to those found in rats treated with 60 mg/kg/day of fenofibrate.

Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients.

The administration of lipid-lowering drugs to rodents, notably those related to clofibrate, rapidly provokes a hepatic response characterized by hepatomegaly, proliferation of smooth endoplasmic reticulum and proliferation of peroxisomes in hepatocytes. In some studies hepatocellular carcinoma has been found in rats or mice exposed for their entire life-span to high dose levels of various fibrates. In the present study liver biopsy samples were obtained from 38 hyperlipidemic patients, 28 of whom had been receiving fenofibrate for between 2 months and approximately 3 years (mean values: males 1.79, females 1.98 years). The remaining 10 patients had never been treated with a lipid-lowering drug. Examination of the biopsy samples by a variety of optical techniques and by electron microscopy failed to reveal any difference between the groups. Peroxisomes were relatively rare, there being no evidence of the clear proliferation seen in rodent studies. Other microscopic features of interest were some variation of nuclear size, mitochondria containing paracrystalline inclusions, dilated endoplasmic reticulum associated with reduced amounts of rough endoplasmic reticulum, and the presence of lipid droplets in the liver cells. However, these variations from normal were in general not much more apparent in samples from the fenofibrate-treated patients than in the untreated group. Light- and electron-microscopic observations did not suggest liver intoxication or a carcinogenic pattern.

[Fenofibrate: animal toxicology in relation to side-effects in man (author's transl)]. / Fénofibrate: études de toxicologie animale en rapport avec les effets secondaires chez les malades.

Chronic toxicity studies of fenofibrate were carried out in rats (3 months), dogs (7 et 24 months) and Rhesus monkeys (12 months). The results in the last named species (78 animals) were of particular interest, since the treated monkeys had normal size liver without histological abnormalities. Electron microscopy showed no increase in the number of hepatic peroxisomes. Long-term toxicity studies in rats failed to show any increase in the incidence of altered hepatocytes or of neoplastic tumours in treated animals. However, a few peroxisomes were found in animals receiving the highest doses of fenofibrate. In reproduction studies there was no evidence of teratogenic effects in rats with doses 45 times higher than the human dose, nor in rabbits with doses of 300 mg/kg/day. In mutagenicity studies fenofibrate proved unable to bind with DNA and could not, therefore, have any effect on genes. The side-effects encountered in clinical practice (e.g. digestive disorders, sexual fatigue, myalgia, alopecia) were rare and obliged to discontinue treatment in very few cases. Long-term clinical trials failed to demonstrate any fenofibrate-induced pathology, such as malignant or benign tumours, or biliary or urinary lithiasis. Serum transaminases were increased in 10 to 20% of the patients, but the rise was transient and never reached pathological levels. Electron microscope study of liver biopsies from patients treated with fenofibrate showed no proliferation of peroxisomes.