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PubMed1990

Safety, tolerability, and efficacy of simvastatin and fenofibrate--a multicenter study. Simvastatin-Fenofibrate Study Group.

Five centers participated in a double-blind, randomized, active-drug controlled study. The selected patients had a diagnosis of primary hypercholesterolemia (phenotype IIa or IIb, total cholesterol [TC] greater than 300 mg/dl, low-density lipoprotein [LDL] cholesterol greater than 195 mg/dl, triglycerides [TG] less than 350 mg/dl). Throughout the study the patients observed a lipid-lowering diet (American Heart Association). After a baseline placebo period (4 weeks), the patients were randomly assigned to simvastatin 20 mg q.p.m. or fenofibrate 200 mg b.i.d. If after 6 weeks of treatment the LDL cholesterol level remained over 140 mg/dl the dose of simvastatin was doubled. The total duration of treatment was 10 weeks. One hundred eighty-four patients completed the study; age ranged from 17 to 72 years (mean 46; 129 men, 55 women). Seventy-nine patients had ischemic heart diseases. Simvastatin significantly reduces TC, LDL, and apolipoprotein (apo) B (30%, 35%, and 27%, respectively). These effects are larger than those of fenofibrate (19%, 22%, and 14%, respectively). Fenofibrate decreased very-low-density lipoprotein and TG, and increased high-density lipoprotein and apo A1, to a larger extent than simvastatin. However, the difference reached statistical significance only for TG (29% versus 17%). Both drugs were well tolerated. Clinical adverse experiences occurred with a low frequency, and few of these were considered drug related (6 and 8% in the simvastatin and fenofibrate groups, respectively). Only two patients had serious laboratory adverse experiences considered drug related or possibly drug related (one in each treatment group with increased SGPT, gamma-GT, and/or creatine phosphokinase).

Adolescent↗

PubMed1980

[Metabolism of fenofibrate and fenofibric acid in vivo and in cultures of liver epithelial cells (author's transl)].

In vitro and in vivo studies using capillary column gas chromatography alone or coupled with mass spectrometry resulted in the identification of several metabolites of fenofibrate (LF 178). Fenofibric acid (LF 153) was omnipresent, being found in rats after acute, subacute and chronic administration, in human urine during chronic treatment, and in cultures of rat and human liver cells. Other metabolites were LF 433 (LF 153 benzhydrol), which increases in rats with the duration of treatment while LF 153 decreases, and LF - phenol" found in human urine. In hepatocyte cultures, fenofibric acid was predominant, but fenofibrate itself and LF 321 (LF 178 benzhydrol) were also present in addition to the above-mentioned metabolites. LF 321, however, was only found in human liver cell cultures.

Animals↗

PubMed1989

The biochemical pharmacology of fenofibrate.

Fenofibrate is metabolized in several stages. First, the carboxyl ester moiety is cleaved by hydrolysis, resulting in fenofibric acid, the main pharmacologically active compound. Fenofibric acid, in turn, undergoes carbonyl reduction, resulting in a pharmacologically active metabolite referred to as reduced fenofibric acid. Both fenofibric acid and reduced fenofibric acid may be conjugated to form glucuronides. There are important species differences in the metabolism and elimination patterns of fenofibrate. In the rat and dog, fenofibric acid and reduced fenofibric acid are the principal metabolites. In humans, the glucuronide of fenofibric acid is predominant. In the rat and dog, approximately 70-80% of fenofibrate and its metabolites are recovered in the feces, whereas in humans approximately 65% of the dose is excreted in the urine. Several mechanisms contribute to fenofibrate's hypolipidemic action, including inhibition of fatty acid synthesis, stimulation of fatty acid beta-oxidation, inhibition of triglyceride synthesis, and enhancement of lipoprotein lipase activity. Fenofibrate's hypocholesterolemic action is a result of both decreased biosynthesis of cholesterol through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and increased low-density lipoprotein (LDL) clearance via modulation of hepatic LDL receptors. Fenofibrate also has three other actions that may result in the prevention or at least slowing of atherogenesis, namely inhibition of cholesterol esterification, platelet aggregation, and platelet-derived growth factor. The native acyl glucuronide of fenofibric acid is very stable, and is unlikely to have any toxic potential. Although the elimination half-life of fenofibrate is prolonged in the elderly and in patients with impaired hepatic function, the area under the curve and its clearance are not altered because of compensatory changes in the volume of distribution.

Cholesterol↗

PubMed1995

Fenofibrate: metabolism and species differences for peroxisome proliferation in cultured hepatocytes.

The hypolipidemic agent fenofibrate, which is a peroxisome proliferator in some rodents in vivo, was studied in cultured hepatocytes for its metabolism and effects on enzymatic induction related to peroxisome proliferation so as to lead to a better understanding of the mechanisms involved in peroxisome proliferation. [14C]-Fenofibrate was completely metabolized within 24 hr by primary cultures of rat hepatocytes and the metabolic pattern corresponded to that found in vivo. The main products were fenofibric acid and its glucuronidated form. Carbonyl reduction of fenofibric acid also occurred. The metabolic pattern of [14C]fenofibric acid was nearly the same as that of fenofibrate. Fenofibrate, fenofibric acid, and its reduced metabolite all induced peroxisomal (cyanide-insensitive) palmitoyl-CoA oxidation activity (PCOA) in rat hepatocytes, whereas derivatives lacking the carboxyl group were nearly inactive. The known species differences with respect to sensitivity to peroxisome proliferators in vivo was mirrored in cultured cells because fenofibric acid did not induce peroxisomal PCOA in primary culture of guinea pig hepatocytes nor in the human hepatoma cell line HepG2. The mechanistic association between the induction of CYP4A1-catalyzed lauric acid omega-hydroxylase (LAH) activity and peroxisomal PCOA induction was investigated. Fenofibric acid concomitantly induced LAH activity and peroxisomal PCOA in rat hepatocytes. Specific inhibition of LAH activity (-52%) by 10-undecynoic acid partially prevented induction of peroxisomal PCOA (-32%). The putative role of dicarboxylic acids, the oxidation product of omega-hydroxymonocarboxylic acids, in PCOA induction was further substantiated by the observed induction of peroxisomal PCOA by 1-12-dodecanedioic acid. We conclude that (1) fenofibric acid is the possible proximate peroxisome proliferator of fenofibrate in rat hepatocytes, (2) cultured hepatocytes reflect in vivo sensitivity to fenofibrate with respect to peroxisome proliferation, and (3) there is some evidence that the catalytic activity of the CYP4A1 enzyme mediates, at least in part, peroxisomal PCOA induction.

Animals↗

PubMed1981

Plasma lipid concentrations and lecithin:cholesterol acyltransferase activity in normolipidemic subjects given fenofibrate and colestipol.

Plasma lipids and lipoprotein cholesterol concentrations and lecithin:cholesterol acyltransferase activity were measured in 7 normolipidemic subjects before, and 7 days after, the administration of fenofibrate (300 mg daily) and colestipol (15 g daily) taken separately or simultaneously. Fenofibrate provoked a significant decrease in the mean plasma triglycerides (26%) and cholesterol (10%) concentration; only plasma cholesterol concentrations were significantly lowered by colestipol (26%). The cholesterol lowering effects of the two drugs were additive as was observed when colestipol was added to fenofibrate. The mean plasma high density lipoprotein cholesterol (HDL-C) concentration was significantly increased by fenofibrate (10%) and when colestipol was added to fenofibrate (15%), but not by colestipol alone. Both fenofibrate and colestipol caused significant reduction of the mean plasma low density lipoprotein cholesterol (LDL-C) concentration and the mean plasma LDL-C/HDL-C ratio (13% and 18%, respectively, with fenofibrate, 44% and 52% with colestipol, and 53% and 62% with colestipol added to fenofibrate). The mean plasma fractional esterification rate was significantly increased by 25% and 12%, respectively, with fenofibrate and colestipol when taken separately, and still more (91%) when colestipol was added to fenofibrate. The mean plasma molar esterification rate was significantly lowered by colestipol, but remained unchanged with the other drug regimens. This study shows that fenofibrate and colestipol given to normolipidemic subjects can induce in a very short period of time (7 days) marked changes in lipoprotein metabolism. Interpretations of the findings in relation to lipoprotein metabolism are discussed.

Adult↗

PubMed1994

Growth inhibition of human vascular smooth muscle cells by fenofibrate: a possible therapy for restenosis.

OBJECTIVE: The aim was to assess the growth inhibitory effect of fibrates on human vascular smooth muscle cells. Restenosis is the most important factor limiting the long term success of invasive vascular interventions and there is as yet no effective preventive treatment. Platelet derived growth factor (PDGF) is considered to be an important growth promoting agent for vascular smooth muscle cells (VSMC) and fenofibric acid (a hypolipidaemic drug) has been reported to be a PDGF antagonist. METHODS: The effect of the fibrate drugs fenofibrate, clofibrate, bezafibrate, and gemfibrozil were examined on the proliferation of cultured human vascular smooth muscle cells derived from saphenous vein (n = 20) and graft stenoses (n = 7). RESULTS: Fenofibrate (100 microM) produced potent inhibition (48%) of VSMC proliferation at a concentration equivalent to that of its circulating metabolite fenofibric acid, but none of the other drugs produced any significant effect on growth. VSMC derived from graft stenoses were equally sensitive to inhibition as saphenous vein derived controls, in contrast to our previous work which reported that graft stenosis derived VSMC were resistant to growth inhibition by the physiological inhibitor heparin. The antiproliferative effect of fenofibrate was independent of inhibition of cellular cholesterol synthesis or toxicity. Fenofibrate inhibited VSMC growth induced by 15% fetal calf serum, PDGF, and basic fibroblast growth factor to a similar degree, indicating that it is not a specific PDGF antagonist. CONCLUSIONS: Fenofibrate is not a specific PDGF antagonist. Fenofibric acid, one of the principal metabolites of fenofibrate, did not produce any inhibition of growth, suggesting that oral administration of fenofibrate would not be efficacious. Fenofibrate is the first potent inhibitor to be described for VSMC derived from human myo-intimal hyperplastic lesions.

Bezafibrate↗

PubMed1980

Lack of pharmacokinetic interaction of colestipol and fenofibrate in volunteers.

The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 microgram/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs.

Adult↗

PubMed1992

Modulation of lipoprotein production in Hep G2 cells by fenofibrate and clofibrate.

Fenofibrate and other fibrate derivatives are commonly used to treat hyperlipidemia. It is not yet clear how they exert their modulatory effects on plasma lipoproteins. To investigate whether these drugs act on the liver to primarily inhibit very low density lipoprotein production, we utilized the highly differentiated human hepatoma cell line, Hep G2. At concentrations greater than 15 micrograms/mL, fenofibrate caused a 30% decrease in secreted apolipoprotein B (apo B) after 4 days of treatment. Pulse-chase studies demonstrated that this was not due to inhibition of apo B synthesis. Triglyceride synthesis by fenofibrate-treated Hep G2 cells was decreased by 30%, and the amount secreted into the medium was reduced by 50%. At a low concentration of drug (5 micrograms/mL), triglyceride secretion was reduced markedly while apo B secretion remained unchanged. Thus, apo B secretion is less sensitive to fenofibrate than the synthesis and secretion of triglyceride, and may be secondary to changes in the latter. Fenofibrate has also been shown to raise plasma high density lipoprotein concentrations. We found that low concentrations of fenofibrate caused a 20-101% increase in secreted apolipoprotein AI (apo AI), and pulse-chase immunoprecipitation studies showed that this was due to an increase in apo AI synthesis. Fenofibrate was compared to clofibrate to investigate whether their relative effects on lipoprotein production in Hep G2 cells were comparable to their relative effects on plasma lipoproteins. Both fibrates decreased the secretion of apo B to the same extent, but only fenofibrate increased apo AI secretion. Fenofibrate was more effective than clofibrate in inhibiting the secretion of lipids by these cells. Thus, the known effects of fenofibrate on plasma lipoproteins can be attributed to its direct modulation of lipoprotein synthesis in the liver cell. Hep G2 cells may thus be useful in testing the relative efficacy of fibric acid derivatives in vitro.

Apolipoproteins A↗

PubMed1995

[Anti-atheromatous effects of fenofibrate, a hypolipidemic drug. I: Anti-atheromatous effects are independent of its hypolipidemic effect in cholesterol-fed rabbits].

Anti-atheromatous effects of fenofibrate were studied in cholesterol-fed rabbits. Rabbits in the control group (HCD) and fenofibrate group (F-HCD) were fed the 0.5% cholesterol diet and the 0.5% cholesterol plus 0.11% fenofibrate diet (corresponding to ca. 30 mg/kg/day), respectively, for 2, 4 or 10 weeks. Fenofibrate did not change serum levels of total cholesterol, HDL-cholesterol and triglyceride during the feeding period. The percentage of plaque area (PPA) formation in the thoracic aorta was time-dependently increased. PPA values were reduced in the rabbits treated with fenofibrate for 2 and 4 weeks, but not in those treated for 10 weeks. Fenofibrate had no effect on the plaque thickness. The percentage of circulating free platelets in the HCD group was reduced at the 4th week of feeding, but that in the F-HCD group was not. The anti-platelet effect of fenofibrate might cause the anti-atheromatous effect. Fenofibric acid, an active metabolite of fenofibrate, had no inhibitory effect on LDL peroxidation in vitro. From these results, we conclude that fenofibrate manifests an anti-atheromatous effect independent of the hypolipidemic effect in cholesterol-fed rabbits and that it may inhibit an early event in the atherogenesis.

Animals↗

PubMed1989

Effects of simvastatin and fenofibrate on serum lipoproteins and apolipoproteins in primary hypercholesterolaemia.

Sixteen patients with primary hypercholesterolaemia received double-blind either fenofibrate (n = 8; 200 mg bid) or the HMG-CoA reductase inhibitor simvastatin (n = 8; 20 mg q.p.m. [corrected] or 40 mg q.p.m. [corrected] if LDL-cholesterol did not fall below 3.6 mmol.l-1 after 4 weeks of treatment). Simvastatin reduced total cholesterol from 9.7 to 7.0 mmol.l-1 after 10 weeks (-28%), and fenofibrate reduced it from 9.2 to 7.7 mmol.l-1 (-15%). The decrease was less during fenofibrate than during simvastatin treatment (time x drug: p = 0.02). Serum LDL-cholesterol fell from 8.3 to 5.3 mmol.l-1 (-36%) during simvastatin and from 7.2 to 6.0 mmol.l-1 (-16%) during fenofibrate administration. Again, the effect of simvastatin was more pronounced than that of fenofibrate (time x drug: p = 0.03). HDL-cholesterol increased significantly from 1.1 to 1.2 mmol.l-1 (+13%) during fenofibrate administration and it did not change significantly during simvastatin. Serum triglycerides fell from 1.3 to 1.1 mmol.l-1 (-16%) during simvastatin, and even more significantly from 2.2 to 1.1 mmol.l-1 (-51%) during fenofibrate (time x drug: p = 0.002). Apolipoprotein B fell on simvastatin from 1.9 to 1.4 g.l-1 (-24%) and from 1.8 to 1.4 g.l-1 (-22%) during fenofibrate. Both drugs were well tolerated and had no significant adverse effects. Simvastatin lowered total and LDL-cholesterol concentrations more than fenofibrate, while the latter had more effect on triglycerides, suggesting specific indications for the two drugs in the treatment of hyperlipoproteinaemias.

Adult↗

PubMed1987

Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia.

To investigate the lipoprotein effect of fenofibrate in hypercholesterolemia or combined hyperlipidemia (types II A and II B hyperlipidemias, respectively), 240 patients were recruited and 227 randomized to a double-blind randomized trial lasting 24 weeks and 192 patients continued to participate in an open-label phase for another 24 weeks. A 100-mg dose of fenofibrate or a matching placebo was given three times daily. Fenofibrate side effects in excess of placebo affected 6 percent of fenofibrate users and were confined almost entirely to skin rashes. In 180 hypercholesterolemic patients randomly assigned to receive fenofibrate versus placebo, triglyceride and very low-density lipoprotein cholesterol levels decreased 38 percent, total cholesterol levels decreased 17.5 percent, and low-density lipoprotein cholesterol levels decreased 20.3 percent with fenofibrate treatment. High-density lipoprotein cholesterol levels increased 11.1 percent with a decrease in the low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio of 27 percent. All differences were statistically significant (p less than 0.01). In combined hyperlipidemic (type II B) patients, triglyceride levels decreased by 45 percent, very low-density lipoprotein cholesterol levels decreased 52.7 percent, total cholesterol levels decreased 16 percent, low-density lipoprotein cholesterol levels decreased 6 percent, and high-density lipoprotein levels increased 15.3 percent for a low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio decrease of 13 percent. All differences were again statistically significant (p less than 0.01). In both groups of patients, the onset of the drug effect was generally rapid, with maximal total and low-density lipoprotein cholesterol level lowering achieved within four weeks in hypercholesterolemic patients and maximal triglyceride and cholesterol level lowering in hypertriglyceridemic patients achieved in two weeks. Maximum high-density lipoprotein increases occurred after four weeks in type II A patients and 12 to 16 weeks in type II B patients. Fenofibrate is a well-tolerated drug in the fibric acid series and has putatively beneficial effects on triglyceride, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations in both type II A and type II B hyperlipidemic patients. If the lipid hypothesis of atherosclerosis applies to the lipoprotein changes induced by fenofibrate, reductions in cardiovascular disease risk in both type II A and II B hyperlipidemic patients should result from fenofibrate treatment.

Adult↗

PubMed1991

Lipoprotein particle analysis comparing simvastatin and fenofibrate.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.

Adolescent↗

PubMed1994

Photosensitization by fenofibrate. II. In vitro phototoxicity of the major metabolites.

Fenofibric acid, the major metabolite of fenofibrate, was found to be photolabile. Its irradiation in aqueous solution gave rise to two photoproducts, whose formation involves photodecarboxylation of the dissociated acid to an aryloxy-substituted carbanion, which is directly protonated or, alternatively, undergoes a Wittig rearrangement. A comparative in vitro phototoxicity study has been carried out on the anti-hyperlipoproteinemic drug fenofibrate, its metabolites and the photoproducts of fenofibric acid. Fenofibrate, fenofibric acid and its two photoproducts were found to be active when examined by the photohemolysis test and were able to photosensitize peroxidation of linoleic acid, as evidenced by the UV monitoring of dienic hydroperoxides. In summary, the major metabolite of fenofibrate (fenofibric acid), as well as its photoproducts, are phototoxic in vitro. This behavior can be attributed to the fact that the four compounds retain the benzophenone chromophore present in fenofibrate and is indicative of free radical-mediated photosensitization. In agreement with this rationalization, the metabolites with a reduced ketone functionality exhibit no detectable in vitro phototoxicity.

Fenofibrate↗

PubMed1990

Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia.

Fenofibrate is a lipid-regulating drug which is structurally related to other fibric acid derivatives, such as clofibrate. At the recommended dosage of 200 to 400 mg daily, it produces substantial 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. Fenofibrate appears to be equally effective in diabetic patients with hyperlipoproteinaemia without adversely affecting glycaemic control. The influence of fenofibrate 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 fenofibrate 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 fenofibrate on morbidity and mortality from cardiovascular disease has not been studied. Clinical adverse reactions to fenofibrate 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. Fenofibrate 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 fenofibrate, but this has not been shown to have increased the incidence of gallstones in treated patients. Thus, fenofibrate offers an effective and well tolerated alternative to clofibrate or other fibric 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.

Clinical Trials as Topic↗

PubMed1992

Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation. Lack of interaction with the lipid-lowering agent, fenofibrate.

Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng.ml-1), Cmax (812 ng.ml-1 by RIA and 757 ng.ml-1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); tmax (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h). The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.

Adult↗

PubMed1989

Safety of fenofibrate--US and worldwide experience.

Fenofibrate is a fibric acid derivative with enhanced potency and specificity of action on lipids. Preclinical toxicology reveals minimal toxic effects; dose-related changes occurred seldom, with only hepatic effects in rodents (mainly enzyme changes), some renal effects in dogs, and no reactions in monkeys. Teratogenicity tests were negative, and mutagenicity was not associated with fenofibrate. Carcinogenicity was evident in rodents with liver carcinoma at doses of 12 or 40 times the human dose, but cancer has not been associated with fenofibrate in over 10 years of clinical research and use. European experience with fenofibrate involved 7,145 patients in short- and long-term clinical trials, plus 10 years of marketing experience with a patient exposure of 6 million patient-years. Adverse effects were relatively low in frequency (6%) in the European clinical trials and manifested as gastrointestinal effects, muscle pain, skin problems, and sweating or dizziness. Short- and long-term fenofibrate studies revealed basically the same scope and frequency of adverse effects. Experience in US clinical trials mirrored the European experience; three types of adverse effects occurred more commonly in fenofibrate patients versus placebo: skin reactions, neurologic effects, and musculoskeletal reactions. Laboratory tests were mildly abnormal for liver function, leukocytes, and hemoglobin; these reactions were significant enough to be considered adverse drug experiences only occasionally. Hepatobiliary tests for lithogenicity showed an increase in cholesterol saturation, but gallstones seldom have been associated with fenofibrate. Postmarketing, open experiences in Europe over 10 years have been consistent with the study results. The rate of reactions has been low (about 115/year or a 0.3% incidence rate). The reactions noted in these spontaneous reports were hepatic, renal, gallstones, cutaneous, hematologic, sexual asthenia, and weight loss. In general, fenofibrate can be considered a safe and well-tolerated lipid-lowering drug that has been scrutinized extensively for safety in clinical research and during an already long marketing period in Europe.

Clinical Trials as Topic↗

PubMed1989

Review of clinical studies of fenofibrate in combination with currently approved lipid-lowering drugs.

Recent trials have investigated the usefulness of fenofibrate, alone and in combination with other lipid-lowering therapies, in the treatment of hyperlipidemia. Studies of fenofibrate + bile acid sequestrants demonstrate that these two therapies may have an additive effect in reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol and triglyceride levels in patients with hyperlipoproteinemia or familial hypercholesterolemia. These lipoprotein changes have been associated with a regression of tendon xanthoma. Pharmacokinetic studies have shown that bile acid sequestrants do not alter the absorption or the plasma levels of fenofibrate. The combined use of fenofibrate with bile acid sequestrants has been found to be comparably effective with the new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, synvinolin, with respect to the reduction of total cholesterol and LDL. Although synvinolin was more effective in lowering LDL, VLDL cholesterol and triglycerides were reduced to a greater extent with fenofibrate. Another notable difference was that fenofibrate + bile acids more markedly increased HDL levels. The combination of fenofibrate + nicotinic acid also appears to have a beneficial effect on lipoproteins. These preliminary results indicate that fenofibrate may be a useful addition to the present lipid-lowering drug armamentarium.

Anticholesteremic Agents↗

PubMed1982

Fenofibrate and cholestyramine in type II hyperlipoproteinaemia.

The effect of fenofibrate (300-600 mg daily) was compared with cholestyramine (12 g daily) in 13 patients with primary type II hyperlipoproteinaemia. Seven of the patients had monogenic familial hypercholesterolaemia. Both fenofibrate (21.0%) and cholestyramine (18.5%) decreased serum cholesterol level. Fenofibrate (22.7%) and cholestyramine (19.6%) had equally decreasing effects on LDL-cholesterol, but fenofibrate increased HDL-cholesterol (10.4%), although not significantly, whereas cholestyramine decreased the HDL-cholesterol (11.9%). Therefore the ratio of HDL-cholesterol to total cholesterol was higher after fenofibrate (0.17) than after cholestyramine (0.13). Serum triglyceride concentration decreased by 57.1 per cent during six months' treatment with fenofibrate, but returned to a higher level during 3 months' cholestyramine treatment. When the dose of fenofibrate was increased from 300 mg to 600 mg daily, serum cholesterol, LDL-cholesterol, and triglyceride values decreased, and HDL-cholesterol and the ratio of HDL-cholesterol to total cholesterol increased, but only in patients with non-familial hypercholesterolaemia. Fenofibrate is in addition to cholestyramine an useful hypolipidaemic drug in type II hyperlipoproteinaemia.

Adult↗