Summary
Synopsis
Micronised fenofibrate is a new formulation of the fibric acid derivative fenofibrate. It is indicated for the treatment of patients with type IIa, IIb, III or TV dyslipidaemia who have failed to respond to dietary control or other non-pharmacological interventions. Micronised fenofibrate has improved absorption characteristics compared with the standard preparation, allowing a lower daily dosage and once-daily administration.
The lipid-modifying profile of micronised fenofibrate is characterised by a decrease in low density lipoprotein (LDL) and total cholesterol levels, a marked reduction in elevated plasma triglyceride levels and an increase in high density lipoprotein (HDL) cholesterol levels.
Consistent with the standard formulation, which is administered as 300mg daily in divided doses, the micronised preparation has demonstrated efficacy in the treatment of type Ha, IIb and IV primary dyslipidaemias but at a lower daily dosage of 200mg once daily. Because of its significant triglyceride-lowering effect, micronised fenofibrate appears to be of greatest benefit in patients with hypertriglyceridaemia (with or without hypercholesterolaemia), including patients with type 2 (non-insulin-dependent) diabetes mellitus and dyslipidaemia.
In the comparisons available, micronised fenofibrate 200mg once daily was of similar efficacy to or less effective than the HMG-CoA reductase inhibitors simvastatin 20mg daily and pravastatin 20mg daily at reducing LDL and total cholesterol levels. However, micronised fenofibrate produced greater improvements in triglyceride and, generally, HDL cholesterol levels than both simvastatin and pravastatin.
Data on the long term tolerability of micronised fenofibrate are limited. However, data from a large short term (3-month) study have indicated that gastrointestinal disorders are the most frequent adverse events associated with therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate.
In conclusion, available data suggest that the more convenient lower once-daily dosage of micronised fenofibrate retains the beneficial lipid-modifying effects of the standard formulation. Further studies are required to determine whether the lipid changes achieved with micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.
Overview of Pharmacodynamic Properties
Fenofibrate substantially modifies the low density lipoprotein (LDL) subfraction distribution, to produce larger, less dense LDL particles with a high binding affinity for cellular LDL receptors. This results in the catabolism of LDL particles via the nonatherogenic LDL-receptor pathway (as opposed to the receptor-independent atherogenic pathway).
Recent data suggest that many of the other beneficial lipid-modifying effects of fenofibrate are mediated via peroxisome proliferator activated receptors (PPARs). Via this mechanism fenofibrate markedly reduces plasma triglyceride levels by increasing the lipolysis and clearance of triglyceride-rich lipoproteins from plasma via activation of the enzyme lipoprotein lipase and decreased production of apolipoprotein CIII. Activation of acyl coenzyme A synthetase expression and subsequent stimulation of fatty acid β-oxidation, decreased fatty acid and triglyceride synthesis, and decreased VLDL triglyceride production also contribute to the hypotriglyceridaemic effect of fenofibrate.
Levels of the apolipoproteins AI and AII, which are major protein constituents of HDL and integral to the process of reverse cholesterol transport, are moderately increased by fenofibrate, whereas levels of apolipoprotein B, a major component of LDL and triglyceride-rich lipoproteins, are reduced by the drug. PPAR-mediated control of the transcription of apo AI and apo AII genes appears to be partially responsible for the increase in HDL cholesterol levels reported with fenofibrate.
Beneficial effects on levels of lipoprotein(a) and fibrinogen, both implicated as important risk factors in coronary heart disease, have also been reported in patients receiving fenofibrate.
Pharmacokinetic Properties
Fenofibrate is a prodrug, which after absorption is hydrolysed by tissue and plasma esterases to its principal active metabolite, fenofibric acid. The micronised formulation of fenofibrate has improved absorption characteristics compared with the standard preparation. This confers an approximately 30% increase in the bioavailability of fenofibric acid. Similar peak plasma concentrations of 3.8 and 4.0 mg/L were attained in healthy volunteers within 4 hours of a single dose of micronised fenofibrate 67mg and standard fenofibrate 100mg, respectively.
Interpatient variability in fenofibric acid absorption from the gastrointestinal tract appears to be reduced and less dependent upon the fat content of recently ingested food with the micronised formulation compared with the standard formulation.
Fenofibrate is >99% plasma protein bound and both the micronised and standard formulations have a plasma elimination half-life of approximately 20 hours. Fenofibric acid is predominantly excreted in the urine.
Clinical Efficacy
In patients with type IIa, IIb or IV dyslipidaemia, micronised fenofibrate 200mg once daily produces an approximately 17 to 27% reduction in total cholesterol levels (14% reduction in patients with familial defective apolipoprotein B-100). LDL cholesterol levels are also reduced in patients with type IIa or IIb dyslipidaemia, generally by about 17 to 35%, but may remain unchanged or increase slightly in patients with type IV dyslipidaemia. Plasma triglyceride levels were typically reduced by 15 to 43% in patients with type IIa dyslipidaemia and to a greater extent (32 to 53%) in patients with hypertriglyceridaemia (type IIb or IV dyslipidaemia) receiving micronised fenofibrate 200mg once daily. The increase in HDL cholesterol levels was more variable; 1 to 26% in patients with type IIa dyslipidaemia, 2 to 34% in those with type IIb and 2 to 16% in those with type IV dyslipidaemia.
Micronised fenofibrate 200mg once daily also had a beneficial lipid-modifying effect in patients with diabetic dyslipidaemia. Total cholesterol, LDL cholesterol and triglyceride levels were reduced by 17, 22 and 44%, respectively, while HDL cholesterol levels were increased by 20%. In heart transplant patients with dyslipidaemia who were receiving concomitant cyclosporin therapy, the beneficial lipid-modifying effect of micronised fenofibrate was frequently associated with a significant increase in serum creatinine levels, necessitating the cessation of treatment.
Micronised fenofibrate 200mg once daily appeared to be generally more effective than simvastatin 20mg daily or pravastatin 20mg daily in reducing plasma triglyceride levels and increasing HDL cholesterol levels in patients with type II dyslipidaemia. In reducing LDL and total cholesterol levels, micronised fenofibrate was of similar efficacy to or less effective than simvastatin or pravastatin.
An additive effect on LDL and total cholesterol and triglyceride levels was reported when micronised fenofibrate therapy was combined with fluvastatin treatment.
Pharmacoeconomic Considerations
In a retrospective pharmacoeconomic analysis of direct costs, the cost per successfully treated patient (based on 1994 to 1995 costs) was considerably lower with micronised fenofibrate 200mg once daily than with simvastatin 20mg daily (DM768 vs DM2080) in type IIb dyslipidaemia in the short term (12 weeks). In patients with type IIa dyslipidaemia, micronised fenofibrate was only marginally more cost effective (DM450 vs DM517 per responder). These results were in accordance with those of an earlier cost-effectiveness analysis of micronised fenofibrate which used similar efficacy data.
Tolerability
Short term (3-month) tolerability data from a large post-marketing surveillance programme suggest that the tolerability profile of micronised fenofibrate is comparable to that of the standard formulation. Adverse events associated with the micronised formulation occurred with an overall incidence of 4%. The most frequently reported adverse events were associated with the digestive system (2% of patients), followed by adverse events associated with the skin and appendages (0.7%), nervous system (0.5%) or body system as a whole (0.5%). 10% of all adverse events were classified as serious, 3 of which (2 cases of cholelithiasis and 1 case of jaundice) were considered to be possibly or probably related to the administration of micronised fenofibrate.
Elevated serum concentrations of creatine phosphokinase and transaminases have been reported in a small number of patients treated with micronised fenofibrate.
Limited data from comparative studies suggest that the tolerability profile of micronised fenofibrate is comparable to that of simvastatin.
Dosage and Administration
Micronised fenofibrate is indicated for the treatment of adults with type IIa, IIb, III or IV dyslipidaemia in conjunction with dietary management. The recommended daily dosage is one 200mg capsule taken during a main meal. In France, where 67mg micronised fenofibrate capsules are available, the drug may be prescribed to children aged ≥10 years with severe dyslipidaemia at a dosage of one 67mg capsule per 20kg bodyweight.
In patients with mild or moderate renal disease, dosage reduction is necessary according to serum creatinine levels. Fenofibrate is contraindicated in patients with severe renal disease, pre-existing gallbladder disease or severe hepatic impairment; monitoring of serum transaminase levels is recommended every 3 months during the first 12 months of treatment with micronised fenofibrate. For patients receiving concomitant micronised fenofibrate and warfarin therapy, the recommended dosage of warfarin should be reduced by approximately one-third and the prothrombin time should be monitored closely.
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Various sections of the manuscript reviewed by: M. Caslake, Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, Scotland; J-P. Desager, Pharmacotherapy Laboratory, Catholic University of Louvain, Brussels, Belgium; J.A. Farmer, Section of Cardiology, Ben Taub General Hospital, Houston, Texas, USA; M.D. Feher, Diabetes Unit, Chelsea and Westminster Hospital, London, UK; R.J. Havel, School of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California, USA; W. März, Department of Clinical Chemistry, University of Freiburg, Freiburg, Germany; V.S. Moisseyev, Department of Internal Medicine, Russian Peoples Friendship University, Moscow, Russia; K. Rašlová, Department of Lipid and Glucose Metabolism, Institute of Preventive and Clinical Medicine, Limbová, Bratislava, Slovak Republic; R.S. Rosenson, Preventive Cardiology Center, Rush-Presbyterian-St Luke’s Medical Center, Chicago, Illinois, USA; K. Schoonjans, Department of Atherosclerosis, Institut Pasteur de Lille, Lille, France
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Adkins, J.C., Faulds, D. Micronised Fenofibrate. Drugs 54, 615–633 (1997). https://doi.org/10.2165/00003495-199754040-00007
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DOI: https://doi.org/10.2165/00003495-199754040-00007