Drugs

, Volume 62, Issue 13, pp 1909–1944 | Cite as

Micronised Fenofibrate

An Updated Review of its Clinical Efficacy in the Management of Dyslipidaemia
Adis Drug Evaluation

Summary

Abstract

Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule.

The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipo-protein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels.

Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl co-enzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients.

Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [≥3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo.

Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation.

Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate.

In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with ≈10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.

Pharmacodynamic Properties

Fenofibrate reduces plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and very-low-density lipoprotein (VLDL) cholesterol levels, and increases high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) AI and ApoAII levels in patients with dyslipidaemia. The lipid-modifying effects of fenofibrate are mediated via the activation of the peroxisome proliferator-activated receptors (PPARs). Fenofibrate activates PP-ARα which regulates a number of genes involved in lipid metabolism (e.g. those encoding for ApoCIII, ApoAI, ApoAII and lipoprotein lipase). Fenofibrate also promotes the β-oxidation of fatty acids in liver cells, and reduces the production of small, dense LDL particles in favour of larger, more buoyant LDL particles with a higher affinity for cellular LDL receptors. In addition, PPARα activators, including fenofibrate, up-regulate the synthesis of cholesterol transporters.

Increased levels of fibrinogen or plasminogen activator inhibitor (PAI-1) are associated with an increased risk of atherosclerosis and coronary heart disease (CHD). Fenofibrate reduces plasma fibrinogen levels in both normolipidaemic individuals and those with dyslipidaemia, and was significantly more effective than simvastatin, atorvastatin or pravastatin. In one study, atorvastatin treatment resulted in a significant increase in fibrinogen, while fenofibrate had no significant effect. Thirty days of treatment with fenofibrate or ciprofibrate produced similar reductions in fibrinogen in patients with type IIb dyslipidaemia; however, only fenofibrate significantly reduced PAI-1 levels in this study.

The inflammatory marker C-reactive protein (CRP) has been implicated in the pathogenesis of atherosclerosis and CHD. Fenofibrate has an inhibitory effect on CRP in hyperlipidaemic individuals. In one study, micronised fenofibrate 200 mg/day (capsule) was significantly more effective than atorvastatin 10 mg/day in reducing plasma levels of CRP. The production of interleukin-6, another inflammatory marker, was also significantly reduced in hyperlipidaemic patients treated with fenofibrate.

Both atorvastatin 10 mg/day and micronised fenofibrate 200 mg/day (capsule) were associated with a significant increase in peak blood flow over baseline in hyperlipidaemic men; however, flow-mediated dilation was not significantly affected by either drug.

Hyperuricaemia is common in patients with dyslipidaemia and has been implicated as a possible risk factor for CHD. Fenofibrate has demonstrated beneficial effects on uric acid levels in patients with dyslipidaemia.

Pharmacokinetic Properties

In the tablet formulation, micronised fenofibrate is coated directly onto an inert excipient core and in vitro dissolution is increased by 46% over the non-microcoated micronised capsule form of the drug. Bioavailability is also increased; fenofibrate 160mg microcoated tablets are bioequivalent to micronised fenofibrate 200mg capsules. The interindividual variation in maximum plasma concentration (Cmax) and the variation in the area under the plasma concentration-time curve associated with food intake were reduced with the microcoated tablet compared with the capsule formulation.

The Cmax of fenofibric acid occurs within 6 to 8 hours after fenofibrate administration and the absorption of fenofibrate is increased when administered with food. With the microcoated tablets, the extent of absorption is increased by approximately 35% under fed compared with fasting conditions. The fat content of a meal eaten at the time of fenofibrate administration does not have a marked effect on pharmacokinetics.

Steady-state plasma concentrations of fenofibric acid are achieved after 5 days and the drug does not accumulate over time with repeated administration. At steady-state, the mean Cmax of fenofibric acid was 23 mg/L, and was reported approximately 5.4 hours after administration of micronised fenofibrate 200mg (capsule) to six healthy volunteers. Serum protein binding (mainly to albumin) exceeds 99% and is concentration-independent over the therapeutic dose range.

The half-life of fenofibric acid is 20 hours, allowing for once-daily administration. Fenofibrate is excreted mainly in the urine (≈60%), but faecal excretion also occurs to a variable extent depending on the rate of absorption. Under steady-state conditions the total body clearance of micronised fenofibrate was 0.01 L/h/kg.

The clearance of fenofibrate is greatly reduced in patients with renal dysfunction and the dosage should be reduced in this group. No pharmacokinetic studies of fenofibrate have been carried out in patients with hepatic impairment.

Fenofibrate has low potential for drug-drug interactions. In vivo data suggest that fenofibrate and fenofibric acid do not undergo significant oxidative metabolism by cytochrome P450 (CYP450) and do not inhibit CYP450 isoforms CYP3A4, CYP2D6, CYP2E1 or CYP1A2, but weakly inhibit CYP2C19 and CYP2A6. They are mild to moderate inhibitors of CYP2C9 at therapeutic levels. Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time. Fenofibrate should be taken at least 1 hour before or 4 to 6 hours after bile acid binding resins, so as not to impede the absorption of fenofibrate.

Interaction between fenofibrate and cyclosporin after long-term use has been reported. Whereas whole-blood levels of cyclosporin were significantly reduced in heart transplant patients, serum creatinine levels were significantly increased. Caution is therefore advised when administering fenofibrate with cyclosporin or other potentially nephrotoxic agents.

Clinical Efficacy

In clinical trials, patients received the capsule formulation of micronised fenofibrate unless stated otherwise. In patients with type IIa, IIb or IV dyslipidaemia who received micronised fenofibrate 160mg (tablet) or 200mg once daily, reductions from baseline in TC levels ranged from about 12 to 30%. LDL-C levels were decreased in patients with type IIa or IIb dyslipidaemia by about 13 to 35%, but underwent minimal change in patients with type IV dyslipidaemia (type IV dyslipidaemia is characterised by elevated TG levels, with normal or elevated TC levels). Greater reductions in TG levels tended to be seen in patients with type IIb or IV dyslipidaemia (−32 to −53%) than in patients with type IIa dyslipidaemia (−15 to −43%). Increases in HDL-C levels of up to 27% in patients with type IIa dyslipidaemia, of up to 34% in those with type IIb dyslipidaemia and of up to 22% in those with type IV dyslipidaemia were achieved.

Greater reductions in TG levels were seen in patients with dyslipidaemia who received micronised fenofibrate 200mg once daily (−26 to −53.2%) than in recipients of atorvastatin 10 or 40 mg/day, simvastatin 10 or 20 mg/day or pravastatin 20 mg/day (−32.2 to +24.7%). HDL-C levels also tended to increase to a greater extent in micronised fenofibrate than in hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor recipients (+1.3 to +33.6% vs −0.8 to +16.5%). Improvements in TC (−12.1 to −27.3%) and LDL-C (−7.7 to −33.5%) levels were seen in micronised fenofibrate recipients, although reductions were usually greater in HMG-CoA reductase inhibitor recipients (reductions of −15.0 to −35.3% for TC and −17.0 to −38.6% for LDL-C).

In a retrospective pharmacoeconomic analysis of direct costs, the cost per successfully treated patient (based on 1995 costs) was considerably lower with micronised fenofibrate 200mg once daily than with simvastatin 20 mg/day (DM768 vs DM2080) in patients with type IIb dyslipidaemia (12 weeks’ therapy). In patients with type IIa dyslipidaemia, micronised fenofibrate was only margin- ally more cost effective (DM450 vs DM517 per responder).

Limited data are available comparing micronised fenofibrate with other fibrates. Greater improvements in lipid levels tended to be seen after administration of micronised fenofibrate than after administration of gemfibrozil or bezafibrate.

Combination therapy with micronised fenofibrate 200mg once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions in TC, LDL-C and TG levels from baseline than micronised fenofibrate alone. Similar or greater changes in HDL-C levels were seen in combination therapy, compared with monotherapy, recipients.

Micronised fenofibrate 200mg once daily was associated with significantly greater improvements from baseline than placebo in TC, LDL-C, HDL-C and TG levels in patients with type 2 diabetes mellitus (n = 418) enrolled in the double- blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [≥3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo [changes in the average minimum lumen diameter of −0.06 vs −0.10mm (indicating 40% less progression; p = 0.029 vs placebo) and in the average percentage diameter stenosis of +2.11 vs +3.65% (indicating 42% less progression; p = 0.02 vs placebo)]. A smaller decrease in mean segment diameter was seen with micronised fenofibrate compared with placebo [change in mean segment diameter of −0.06 vs −0.08mm (indicating 25% less progression; p = 0.171 vs placebo)].

Twelve weeks’ therapy with micronised fenofibrate 200mg once daily was associated with significant improvements from baseline (p < 0.05) in mean TC, LDL-C, HDL-C, TG, fibrinogen and fasting serum insulin levels, factor VII activity, the insulin response during an oral glucose tolerance test, and blood pressure in a noncomparative study that enrolled 37 men with metabolic syndrome.

Treatment with micronised fenofibrate 200 to 268 mg/day was associated with reductions from baseline in TG levels in patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia in two small noncomparative studies.

Significant reductions from baseline (p < 0.05) in mean TC, LDL-C and TG levels were seen in 43 heart transplant recipients with dyslipidaemia who received micronised fenofibrate 200mg once daily for up to a year. A significant increase from baseline in serum creatinine levels was also seen, necessitating discontinuation of therapy in 14 patients.

Tolerability

Micronised fenofibrate is generally well tolerated. In a post-marketing surveillance programme in 9884 patients with type IIa, IIb or IV dyslipidaemia who received micronised fenofibrate 200mg once daily for 12 weeks, 380 patients (3.8%) reported adverse events. The most common adverse events affected the gastrointestinal system (1.9% of patients), skin and appendages (0.6%), the nervous system (0.4%), the cardiovascular system (0.3%) and the body as a whole (0.3%). Forty-three of 9884 patients (0.4%) experienced serious adverse events. Eight patients developed abnormal liver function tests and two patients experienced elevated creatine phosphokinase levels.

In two noncomparative trials (n = 177 and 198) examining the tablet formulation of micronised fenofibrate 160mg, adverse events were experienced by 24 and 40% of patients. However, none of the eight serious adverse events in these studies were considered drug-related. In both studies, few patients (n ≤ 3) devel- oped creatine phosphokinase levels that were 4 to 5 or >5 times the upper limit of normal (ULN), or AST or ALT levels that were >3 times ULN.

There were no significant differences between micronised fenofibrate 200mg (capsule) once daily (n = 207) and placebo (n = 211) recipients in the frequency of serious adverse events in the DAIS study (cancer, gall bladder symptoms and/or cholecystectomy, hepatic events, abdominal pain, diarrhoea, dizziness, musculoskeletal system events or events affecting the joints occurred in <3.5% of patients in each treatment group).

Data on the comparative tolerability of micronised fenofibrate and other lipid-modifying drugs are limited. In trials comparing micronised fenofibrate 200 mg/day (capsule) with simvastatin 20 mg/day, atorvastatin 10 or 40 mg/day or pravastatin 20 mg/day, both drugs were generally well tolerated. In a 24-week, double-blind study comparing micronised fenofibrate 200mg once daily (n = 116) with gemfibrozil 1200mg once daily (n = 118), 3.4 and 4.2% of patients in the corresponding treatment groups withdrew from the study because of adverse events.

In a 16-week, double-blind study, patients received micronised fenofibrate 200 mg/day (capsule) [n = 33], micronised fenofibrate 200 mg/day plus fluvastatin 20 mg/day (n = 35) or micronised fenofibrate 200 mg/day plus fluvastatin 40 mg/day (n = 34). Musculoskeletal adverse events (e.g. myalgia) occurred in 24, 17 and 15% of patients in the corresponding treatment groups, gastrointestinal adverse events occurred in 26, 6 and 24%, respectively, and respiratory adverse events occurred in 15, 11 and 24%, respectively. No significant between-group differences in the percentage changes in laboratory values (i.e. creatinine, AST, ALP, alkaline phosphatase, creatine phosphokinase or myoglobin levels) were seen.

Dosage and Administration

Micronised fenofibrate is indicated, as an adjunct to diet, for the treatment of patients with type IIa, IIb, IV or V dyslipidaemia; in Europe, the drug is also indicated for use in type III dyslipidaemia.

For adults, the recommended initial daily dosage is one 160mg tablet, taken during a main meal. For adults with hypertriglyceridaemia, US labelling recommends initiating treatment at a dosage of 54 to 160 mg/day and adjusting the dosage according to patient response. The 160 mg/day dosage is not recommended in patients with renal impairment or in children. A lower dosage is recommended in elderly patients and patients with renal impairment in the US (54mg tablets), and in children and patients with renal impairment in Europe.

Fenofibrate is contraindicated in patients with severe renal disease or pre-existing gall bladder disease; the drug is also contraindicated in patients with hepatic dysfunction in the US and in patients with severe hepatic dysfunction in Europe. Fenofibrate should generally not be used in pregnant women (US labelling states that fenofibrate should only be administered to pregnant women if the potential risk is justified by the potential benefit) or in breast-feeding women. Patients receiving micronised fenofibrate should undergo regular monitoring of their liver function.

In patients receiving concomitant therapy with a coumarin anticoagulant, the dosage of the anticoagulant should be reduced and adjusted as necessary according to the prothrombin time or international normalised ratio (these parameters should be monitored until they have stabilised). Combination therapy with micronised fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the potential benefit outweighs the potential risk. Micronised fenofibrate should be administered ≥1 hour before or ≥4 to 6 hours after bile acid sequestrants. The potential benefits and risks of administering micronised fenofibrate with immunosuppressants such as cyclosporin and other nephrotoxic agents should be carefully considered.

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© Adis International Limited 2002

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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