, Volume 51, Issue 3, pp 433-459

Fluvastatin

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Abstract

Synopsis

Fluvastatin, a member of the group of drugs known as HMG-CoA reductase inhibitors, is used in the treatment of patients with hypercholesterolemia. In clinical trials in patients with primary hypercholesterolemia, fluvastatin 20 or 40 mg/day achieved marked reductions from baseline in serum levels of low density lipoprotein (LDL)-cholesterol (19 to 31%) and total cholesterol (15 to 21%), along with modest declines in serum triglyceride levels (1 to 12%) and small increases in high density lipoprotein (HDL)-cholesterol levels (2 to 10%). These beneficial effects on the serum lipid profile were similar to those demonstrated with other HMG-CoA reductase inhibitors, although direct comparative trials are limited. Concomitant administration of fluvastatin plus another lipid-lowering agent, such as a bile acid sequestrant, a fibrate or nicotinic acid, usually reduced serum levels of total cholesterol and LDL-cholesterol by at least a further 5 to 10% from baseline compared with fluv astatin monotherapy.

Fluvastatin has a similar tolerability profile to that of other HMG-CoA reductase inhibitors. Gastrointestinal disturbances, which are usually mild and transient, were the most frequently reported adverse events with fluvastatin in clinical trials. Persistent elevation of serum transaminase levels occurred in approximately 1% of fluvastatin recipients, which is similar to the rate for other HMG-CoA reductase inhibitors. Unlike other HMG-CoA reductase inhibitors, which have been infrequently associated with myopathy and rarely with rhabdomyolysis, these events have not been associated with fluvastatin to date, although fluvastatin has not been used as extensively as agents such as lovastatin. HMG-CoA reductase inhibitors other than fluvastatin, when given in combination with drugs such as fibrates, nicotinic acid, cyclosporin or erythromycin, can increase the risk of these potentially serious adverse events. Thus far, myopathy or rhabdomyolysis have not been reported among patients receiving fluvastatin concomitantly with any of these drugs. Therefore, fluvastatin can be given with caution in combination with fibrates, nicotinic acid, cyclosporin or erythromycin.

In conclusion, fluvastatin has similar efficacy and tolerability profiles to other HMG-CoA reductase inhibitors, which are among the most effective agents available for treating patients with hypercholesterolemia. Pharmacoeconomic studies performed to date suggest an advantage for fluvastatin over other HMG-CoA reductase inhibitors, predominantly because of its relatively low acquisition costs (at least in those countries in which the evaluations were conducted). Thus, fluvastatin is effective and well tolerated in patients with hypercholesterolemia and appears to have an economic advantage over other HMG-CoA reductase inhibitors, primarily as a result of its relatively low acquisition costs.

Pharmacodynamic Properties

Fluvastatin is the first entirely synthetic inhibitor of HMG-CoA reductase and has a molecular structure distinct from that of other available HMG-CoA reductase inhibitors. Inhibition of HMG-CoA reductase in the liver markedly reduces cholesterol biosynthesis which, in turn, results in lower serum levels of total cholesterol and low density lipoprotein (LDL)-cholesterol. These effects lead to enhanced receptor-mediated LDL catabolism in the liver, which further reduces serum LDL-cholesterol levels. In vitro, fluvastatin 0.1 to 1.0 μmol/L significantly inhibited cholesterol biosynthesis in human liver-derived HepG2 cells and induced LDL receptor activity in a concentration-dependent manner. Fluvastatin appears to have a similar inhibitory effect on cholesterol synthesis in peripheral tissues to that in the liver; however, extensive first-pass metabolism and other pharmacokinetic properties result in low concentrations of unbound drug in the systemic circulation. In clinical trials, serum levels of apolipoprotein B were markedly reduced in parallel with LDL-cholesterol levels, and apolipoprotein A-I levels were increased to a similar degree to high density lipoprotein (HDL)-cholesterol levels. In vitro data and studies in animal models of intimai hyperplasia or atherosclerosis suggest that fluvastatin and some other HMG-CoA reductase inhibitors inhibit arterial myocyte proliferation and growth, possibly by reducing intracellular mevalonate production, thus providing an additional mechanism (aside from lowering serum cholesterol levels) for potentially inhibiting progression of atherosclerosis.

Pharmacokinetic Properties

Following oral administration, fluvastatin is well absorbed (98%) from the gastrointestinal tract and undergoes extensive first-pass metabolism. Absolute bioavailability is approximately 20 to 30%, but is somewhat increased at dosages above 20mg under fasting conditions. Concomitant administration of food slows the rate of absorption whereas the extent of bioavailability remains virtually unchanged, and these effects led to the same decrease in serum total cholesterol and LDL-cholesterol as administration without food. Fluvastatin is extensively bound to plasma proteins (≥99%) and has an elimination half-life of 1.2 hours (0.5 to 2.3 hours). Fluvastatin undergoes extensive metabolism and the major metabolite (TV-desisopropylpropionic acid) is pharmacologically inactive. Some other metabolites exhibit in vitro inhibitory activity towards HMG-CoA reductase, but elimination is rapid and plasma concentrations are low. Following administration of a radioactive dose of fluvastatin, unchanged fluvastatin accounted for less than 2% of total radioactivity excreted.

Therapeutic Efficacy

In noncomparative, placebo-controlled and dose-finding studies in patients with primary hypercholesterolaemia, fluvastatin 20 to 40 mg/day reduced serum levels of LDL-cholesterol by 19 to 31% and total cholesterol levels were decreased by 15 to 21% from baseline. Fluvastatin at this dosage also achieved modest reductions in serum triglyceride levels of 1 to 12% and increased serum HDL-cholesterol levels by 2 to 10%. Maximal effects on serum lipid profiles were usually achieved after 4 weeks of therapy and were maintained throughout treatment in long term studies of up to 156 weeks. Increasing fluvastatin dosage from 40 to 80 mg/day further reduced serum LDL-cholesterol levels by at least 6%.

In comparative trials in patients with primary hypercholesterolaemia, serum levels of total cholesterol and LDL-cholesterol were reduced to a similar extent by fluvastatin 20 mg/day and gemfibrozil 1200 mg/day for 8 weeks, and fluvastatin 40 mg/day for 12 weeks achieved more marked reductions in LDL-cholesterol levels than bezafibrate 400 mg/day. The fibrates achieved significantly greater reductions in serum triglyceride levels and more marked increases in serum HDL-cholesterol levels than fluvastatin. Fluvastatin 40 and 80 mg/day achieved at least equivalent reductions in serum levels of total cholesterol and LDL-cholesterol to pravastatin 20 and 40 mg/day, respectively. Likewise, fluvastatin was able to achieve similar serum cholesterol and LDL-cholesterol reductions to lovastatin when administered at approximately twice the total daily dosage of lovastatin, although bioequivalence between lovastatin formulations used in these trials and the marketed formulation was not demonstrated, and another randomised trial demonstrated equivalent lipid-lowering efficacy between fluvastatin 20mg/day and lovastatin 20 mg/day. Recent direct comparisons between fluvastatin and simvastatin indicate that simvastatin 5 mg/day achieved greater reductions in serum LDL-cholesterol than fluvastatin 20 mg/day and comparable reductions to fluvastatin 40 mg/day; however, indirect comparisons suggest that fluvastatin 40 mg/day has similar lipid-lowering efficacy to simvastatin 10 mg/day. Cholestyramine 16 g/day produced modestly greater reductions in serum total cholesterol and LDL-cholesterol levels than fluvastatin 40 mg/day for 12 weeks and these differences achieved statistical significance.

Combined treatment with fluvastatin 10 to 40 mg/day plus cholestyramine up to 16 g/day tended to achieve more marked reductions in serum levels of total cholesterol and LDL-cholesterol than fluvastatin monotherapy, and differences sometimes reached statistical significance. In general, reductions from baseline for serum LDL-cholesterol levels were approximately 5 to 10% greater with combined therapy than with fluvastatin alone. Similar effects were noted when fluvastatin 20 to 40 mg/day was used concomitantly with bezafibrate 400 mg/day and somewhat greater reductions of serum LDL-cholesterol levels were achieved when nicotinic acid up to 3 g/day was used concurrently with fluvastatin 20 mg/day. Thus, effects on serum total cholesterol and LDL-cholesterol levels with combined therapy appeared to be additive. In addition to providing greater reductions in serum levels of total cholesterol and LDL-cholesterol than fluvastatin monotherapy, combined treatment with either bezafibrate or nicotinic acid also tended to achieve larger reductions in serum triglyceride levels and more marked increases in serum HDL-cholesterol levels.

Currently in the US, the acquisition costs of fluvastatin 20 and 40mg are approximately 40 to 60% lower than those for lovastatin, simvastatin and pravastatin at dosages which are generally deemed to be therapeutically equivalent. Available pharmacoeconomic analyses suggest that fluvastatin is more cost-effective than other HMG-CoA reductase inhibitors when used to achieve moderate reductions in serum LDL-cholesterol levels in patients with hypercholesterolaemia. In addition, a Canadian pharmacoeconomic model showed that fluvastatin 40 mg/day was associated with a lower cost per life-year saved than simvastatin 10 mg/day, lovastatin 20 mg/day and pravastatin 20 mg/day in primary prevention of coronary heart disease (CHD) among middle-aged male smokers with hypercholesterolaemia.

Tolerability

Fluvastatin is generally well tolerated; most adverse events are mild and transient in nature. The most frequently reported adverse events associated with fluvastatin in patients with hypercholesterolaemia are gastrointestinal symptoms such as dyspepsia, nausea, flatulence and abdominal pain. Pooled data from controlled clinical trials showed that 13.9% of patients treated with fluvastatin and 8.8% of placebo recipients had adverse gastrointestinal events. Adverse events requiring discontinuation of therapy occurred in 3.5% of patients receiving fluvastatin monotherapy and 3.2% of patients receiving placebo.

Persistent elevation of serum transaminase levels ≥3 times the upper limit of normal occurred in approximately 1 % of patients receiving fluvastatin in clinical trials, which was similar to the incidence reported for other HMG-CoA reductase inhibitors. To date, drug-related myopathy (characterised by myalgias, muscle tenderness/weakness and elevation of creatine kinase levels ≥10 times the upper limit of normal) has not been reported with fluvastatin, although other HMG-CoA reductase inhibitors have infrequently (≤0.2%) been implicated. Asymptomatic creatine kinase elevations greater than 10 times the upper limit of normal occurred in 0.5% of fluvastatin and 0.4% of placebo recipients in clinical trials. Rhabdomyolysis has been reported rarely with other HMG-CoA reductase inhibitors, and the risk of developing rhabdomyolysis or myopathy is increased when this class of drug is used concomitantly with fibrates, nicotinic acid, cyclosporin or erythromycin. Fluvastatin has not been associated with these potentially serious adverse events, even when used concomitantly with fibrates, nicotinic acid or cyclosporin in short term studies; however, caution is advised if such combinations are used.

Dosage and Administration

Fluvastatin is administered orally starting at a dosage of 20mg once daily in the evening. Dosage may be increased to 40 mg/day after a minimum period of 4 weeks to allow for maximal effect. In patients with severe hypercholesterolaemia, the dosage may be further increased to 40mg twice daily. Concomitant administration with food does not have a clinically significant effect on the systemic exposure or efficacy of fluvastatin. Fluvastatin should be administered in the evening (at least 4 hours after a bile acid sequestrant if these drugs are used concomitantly).

Various sections of the manuscript reviewed by: J.D. Banga, Utrecht University Hospital, Utrecht, The Netherlands; F.U. Beil, Medizinische Kernklinic Universitatskrankenhaus Eppendorf, Hamburg, Germany; A. Breckenridge, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, England; A.M. Dart, Baker Medical Research Institute, Melbourne, Victoria, Australia; C.J. hearing, Ambulatory Care Division, Grady Health Systems, Atlanta, Georgia, USA; E. Hagen, Lipid Clinic, Medical Department A, National Hospital, Oslo, Norway; K. Hayashi, First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan; J.A. Herd, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; T.A. Jacobson, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; E. Eeitersdorf, Division of Medicine, Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah University Hospital, Jerusalem, Israel; L. Ose, Lipid Clinic, Medical Department A, National Hospital, Oslo, Norway; M.R. Soma, Institute of Pharmacological Sciences, University of Milan, Milan, Italy.