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At least 19 recordsLinked to original sources
PubMed1995

Efficacy of fluvastatin, a totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. FLUENT Study Group. Fluvastatin Long-Term Extension Trial.

The Fluvastatin Long-Term Extension Trial (FLUENT) was designed to assess the safety and efficacy of fluvastatin over a prolonged period of time. In this way, FLUENT represents a clinical scenario that is closer to office-based chronic treatment of hyperlipidemic patients. A total of 918 patients with severe primary hypercholesterolemia (mean baseline low density lipoprotein cholesterol [LDL-C], 227 mg/dL) were enrolled into the study and received open-label fluvastatin, 20 or 40 mg daily, depending on response. Results of the first year of treatment have been published previously and showed statistically significant changes in LDL-C (-30.7%), total cholesterol (-21.9%), and high density lipoprotein cholesterol (HDL-C; +3.5%). Of the original number of patients completing the 1-year study, 761 completed a second year of evaluation; the results are presented here. Any patient who did not achieve LDL-C levels of < or = 130 mg/dL could receive cholestyramine (usually 8 g/day) or fluvastatin up to 80 mg/day. At the end of the 2-year period there were significant changes in LDL-C with fluvastatin (20 mg/day, -25.4%; 40 mg/day, -30.6%; 80 mg/day, -33.7%; p < 0.001 vs baseline for all values). The combination of fluvastatin and cholestyramine changed LDL-C by -34.6%. Similar dose-response results were seen with reductions in total cholesterol and the LDL-C: HDL-C ratio. There were no unexpected or severe adverse events or laboratory abnormalities. In conclusion, fluvastatin offers a range of LDL-C reduction (25-34%) similar to other HMG-CoA reductase inhibitors, that conforms with guideline recommendations for over 90% of hypercholesterolemic patients.

Adult↗
PubMed1995

Comparison of fluvastatin versus pravastatin treatment of primary hypercholesterolemia. French Fluvastatin Study Group.

Following a 6-week placebo period, 134 patients with low density lipoprotein cholesterol (LDL-C) > or = 160 mg/dL and plasma triglyceride < or = 400 mg/dL, despite following a standard lipid-lowering diet, were randomized to double-blind, double-placebo treatment with fluvastatin (22 women, 46 men; age 21-71 years) or pravastatin (25 women, 41 men; age 19-76 years). Fluvastatin at 40 mg and pravastatin at 20 mg were given for the first 4 weeks, both once daily with the evening meal. For the following 12 weeks, fluvastatin at 40 mg twice daily and pravastatin at 40 mg once daily were given with the evening meal. Both drugs were equally effective in lowering LDL-C after 4 weeks of treatment (-24.0% with fluvastatin, -24.1% with pravastatin) but, after 16 weeks, LDL-C reduction was -30.4% with fluvastatin and -26.6% with pravastatin. This further lowering of LDL-C between week 4 and week 16 was significant (p < 0.001) for fluvastatin but not pravastatin. Adverse events were reported by 23 fluvastatin patients and 22 pravastatin patients: 3 patients in each group withdrew from the study because of these. No notable abnormalities in levels of alanine or aspartate aminotransferase values (defined as > 3 times the upper limit of normal on 2 consecutive occasions) or of creatine phosphokinase (defined as > 10 times the upper limit of normal on any occasion) were observed in either treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combination.

PURPOSE: Familial hypercholesterolemia (FH) carries a markedly increased risk for coronary artery disease (CAD). Reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs. The major objective of this study is to compare two different drug combinations for the treatment of heterozygous FH. PATIENTS AND METHODS: The current investigation is a short-term, double-blind study comparing the efficacy and safety of fluvastatin when combined with cholestyramine (group 1) or with bezafibrate (group 2) in 38 patients with heterozygous FH. RESULTS: After 6 weeks of combination treatment, in comparison to a drug-free baseline (patients receiving single-blind placebo during the lead-in period of an earlier study, ie, before ever receiving fluvastatin), the combination of 40 mg/d of fluvastatin with 400 mg/d of bezafibrate in group 2 reduced plasma LDL-C levels by 35% as compared with 32% in group 1, and reduced the LDL-C/high-density cholesterol (HDL-C) ratio by 46%, compared to 37% in group 1 (a non-significant difference for both comparisons). When compared to an intermittent 6-week open-label administration of 40 mg fluvastatin monotherapy, the addition of cholestyramine or bezafibrate each reduced LDL-C by an additional 13% (P < 0.01 for both regimens). CONCLUSIONS: Fluvastatin-bezafibrate is superior to a fluvastatin-cholestyramine combination for lowering serum triglycerides and elevating HDL-C serum levels in patients in conjunction with a significant lowering of LDL-C/HDL-C ratios, and may be an effective synergistic therapy for heterozygous FH. No episodes of myositis were seen in this short-term study, a finding that is in agreement with most of the reported studies on statin-fibrate combinations reviewed here.

Adult↗
PubMed1995

Changes in plasma apolipoprotein B-containing lipoparticle levels following therapy with fluvastatin and cholestyramine. European Fluvastatin Study Group.

Epidemiologic studies have demonstrated that apolipoprotein (apo) B-containing lipoparticles (LpE:B, LpC-III:B) are associated with the risk of coronary artery disease whereas apo A-1-containing lipoparticles (LpA-I) are protective against coronary artery disease. The effect on lipoparticle levels of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin, in combination with cholestyramine, was assessed in a double-blind randomized study. A total of 144 patients with primary hypercholesterolemia were recruited, who had successfully completed an original study comparing the effects of fluvastatin and cholestyramine on plasma lipoparticle levels. All subjects fulfilled the following inclusion criteria: plasma low density lipoprotein cholesterol (LDL-C) levels > 160 mg/dL, with premature coronary artery disease and 2 associated risk factors; or LDL-C > 190 mg/dL, no coronary artery disease, and triglycerides < 300 mg/dL, after a lipid-lowering diet. Patients were randomized to 1 of 3 combination therapy groups: fluvastatin 20 mg/day plus cholestyramine 4 g/day; fluvastatin 20 mg/day plus cholestyramine 8 g/day; and fluvastatin 20 mg/day plus cholestyramine 16 g/day. The study length was 6 weeks and patients were examined at 3-week intervals. Fluvastatin plus cholestyramine produced a significant (p < 0.001), dose-dependent reduction in levels of cholesterol (range, -29 to -34%), LDL-C (range, -30 to -44%), apo B (range, -23 to -34%), and apo E (range, -33 to -43%). LpE:B levels were also reduced (range, -19 to -26%), but not significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticholesteremic Agents↗
PubMed1994

Efficacy of a low dose-range of fluvastatin (XU 62-320) in the treatment of primary hypercholesterolaemia. A dose-response study in 431 patients. The French-Dutch Fluvastatin Study Group.

1. In this randomised, double-blind, placebo-controlled study, the efficacy of four dosages of fluvastatin (2.5, 5, 10 and 20 mg day-1) were assessed in 431 patients with primary hypercholesterolaemia recruited in 17 centres. 2. Following an 8-week dietary stabilisation phase and a 6-week placebo phase, the patients were randomised to receive placebo or fluvastatin 2.5, 5, 10 or 20 mg once daily at night for a period of 6 weeks. 3. Total cholesterol, beta-quant LDL-C, and the beta-quant LDL-C/HDL-C ratio were significantly reduced by all doses of fluvastatin, and HDL-C was significantly increased by the 10 mg and 20 mg doses. Fluvastatin 20 mg day-1 also significantly decreased TG and Lp(a):B levels. 4. Fluvastatin was well tolerated during the study, and relatively few biochemical or haematological abnormalities occurred. 5. Of the dosages tested, 20 mg fluvastatin day-1 is the optimal hypolipidaemic dose.

Adult↗
PubMed1994

Fluvastatin reduces levels of plasma apo B-containing particles and increases those of LpA-I. European Fluvastatin Study Group.

Epidemiologic studies have demonstrated an association between apolipoprotein (apo) B-containing particles (lipoprotein [Lp] E:B; LpC-III:B) and an inverse association between LpA-I and the risk of coronary artery disease (CAD). The effect of 6 weeks of treatment with fluvastatin (20 and 40 mg/day in the evening), a novel competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, on lipoparticle levels was studied in 423 patients with hypercholesterolemia after 14 weeks of standard dietary therapy. The combined data of the European double-blind controlled studies were used for the analysis. Two independent groups of hypercholesterolemic patients receiving fluvastatin (20 and 40 mg every evening) for 6 weeks were compared with a placebo group. For inclusion, patients had to fulfill the following criteria: plasma low-density lipoprotein (LDL) cholesterol levels > 160 mg/dL and premature CAD and/or two associated risk factors; LDL cholesterol > 190 mg/dL and no CAD; triglycerides < 300 mg/dL. All measurements were performed at the Pasteur Institute Central Laboratory, LpE:B and LpC-III:B were measured by double-site ELISA. Lipoprotein A-I and LpA-I:A-II were determined by differential electroimmunodiffusion. Treatment with 20 and 40 mg of fluvastatin was associated with reductions in plasma apo B (median change: -19.3% and -22.8%, respectively; p < 0.001), LpE:B (-12.5% and -22.6%, respectively; p < 0.001), and LpC-III:B (-3.6% and -36.8%, respectively; p < 0.001) particles compared with placebo. Significant increases in plasma apo A-I (1.7% and 4.8%, respectively; p < 0.001) and antiatherogenic LpA-I (2.3% and 6.9%, respectively; p < 0.001) were also observed. Levels of LpA-I:A-II were not affected by fluvastatin treatment. In conclusion, 6-week treatment with fluvastatin is associated with beneficial antiatherogenic changes in lipoparticle profiles in hypercholesterolemic patients.

Analysis of Variance↗
PubMed1994

Long-term treatment of hypercholesterolemia with fluvastatin: a 52-week multicenter safety and efficacy study. French-Dutch Fluvastatin Study Group.

In this long-term (52-week) open-label extension to an earlier randomized, multicenter, double-blind, placebo-controlled, dose-finding trial, 381 patients with primary hypercholesterolemia received fluvastatin at increasing doses of 10 to 40 mg/day to achieve plasma low-density lipoprotein (LDL) cholesterol normalization, according to the European Atherosclerosis Society guidelines. The aim of the extension study was to assess the long-term efficacy, safety, and tolerability of fluvastatin. After 52 weeks of therapy, 75% of patients were receiving fluvastatin at 40 mg/day (mean dose: 36 +/- 8 mg/day). The mean percent change in LDL-cholesterol levels from baseline was -24.8% (p < 0.001), and 82.6% of patients achieved an LDL-cholesterol reduction of > or = 15%. In patients in the lowest baseline quintile, high-density lipoprotein-cholesterol levels were significantly (p < 0.001) increased by 8.8% whereas, in the highest baseline quintile, triglycerides were significantly (p < 0.001) reduced by 15.3%. Plasma lipoparticle (a) [Lp(a)]:B levels were also significantly reduced (-38.6%; p < 0.001). Fluvastatin was considered to be well tolerated by the majority of patients by both patients and investigators. The most frequently reported adverse event was abdominal pain. Notable biochemical abnormalities were rare. In conclusion, the results of this extension study indicate that fluvastatin at dosages of 20-40 mg/day is effective and well tolerated in patients with primary hypercholesterolemia and is accompanied by no particular problems of safety.

Adult↗
PubMed1995

Long-term efficacy with fluvastatin as monotherapy and combined with cholestyramine (a 156-week multicenter study). French-Dutch Fluvastatin Study Group.

Fluvastatin monotherapy up to 40 mg/day over 52 weeks in patients with primary hypercholesterolemia decreased plasma low density lipoprotein cholesterol (LDL-C) by 28%, with varying decreases in plasma triglycerides and increases in high density lipoprotein cholesterol (HDL-C). Patients completing the 52-week study participated in a further trial to assess whether the efficacy of fluvastatin (20-40 mg/day), either as monotherapy or in combination with cholestyramine (CME; 4-16 g/day), taken at least 4 hours prior to fluvastatin, is sustained for up to 3 years. Patients were assessed every 12 weeks on average for safety and efficacy, the latter being calculated as a percent change from baseline of lipids or lipoproteins. During the second year (endpoint up to week 104), 147 patients received monotherapy (estimated mean dose, 30.2 mg/day) and 127 received additional CME (38.1 mg/day fluvastatin plus 10.1 g/day CME). During the third year (endpoint up to week 156), 140 patients received monotherapy (32.5 mg/day) and 67 received additional CME (39.3 mg/day fluvastatin plus 10.3 mg/day CME). Statistically significant reductions in mean total cholesterol and LDL-C and increases in mean HDL-C were achieved in both treatment groups and maintained throughout the study. A significant reduction in triglyceride levels was only observed at the second year endpoint in patients receiving monotherapy (-10.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Anticholesteremic Agents↗
PubMed1994

Effect of fluvastatin on plasma apolipoprotein-B-containing particles, including lipoprotein(a). European Fluvastatin Study Group.

Epidemiological studies have demonstrated an association between apolipoprotein-(apo)-B containing particles [lipoprotein (Lp) (a), LpE:B; LpC-III:B] and coronary heart disease (CHD). The effect of fluvastatin, a novel competitive inhibitor of HMG-CoA reductase, on these plasma lipoprotein levels was studied in patients with hypercholesterolaemia after 14 weeks of standard dietary therapy. The results of a placebo-controlled, dose-response study and of the combined data of the European double-blind, controlled studies on the effect of fluvastatin are presented. The patients were selected according to the following criteria of inclusion: plasma low-density-lipoprotein (LDL) cholesterol levels > 160 mg dL-1 and premature CHD and/or two associated risk factors, or LDL cholesterol > 190 mg dL-1 and no CHD, plus triglycerides < 300 mg dL-1. All measurements were performed at the Pasteur Institute Central Laboratory. Lp(a), LpE:B and LpC-III:B particles were measured by double-site ELISA. In the placebo-controlled, dose-response study, 429 subjects were randomly assigned to one of the following treatment groups: placebo, fluvastatin 2.5 mg q.p.m., 5 mg q.p.m., 10 mg q.p.m. and 20 mg q.p.m. Treatment with fluvastatin for 6 weeks was associated with a dose-dependent reduction of LDL cholesterol, apoB, LpE:B and LpCIII:B levels. In addition, treatment with fluvastatin 5 mg and 20 mg q.p.m. was associated with a significant reduction in median Lp(a) concentrations (3.2%, P < 0.05 and 6.4%, P < 0.05 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Fluvastatin for the prevention of restenosis after coronary balloon angioplasty: angiographic and methodological background of the fluvastatin angioplasty restenosis trial.

Luminal renarrowing (restenosis) is the major limitation of percutaneous transluminal coronary angioplasty (PTCA), and the search for a 'magic bullet' to prevent this apparent biological healing response to vessel injury has thus far been unsuccessful. Large clinical trials using serial quantitative coronary angiography have, however, provided some valuable insight into this area. In particular, the restenosis process may be measured as the loss in minimal luminal diameter from post-PTCA to follow-up angiography, and is essentially ubiquitous and normally distributed. The angiographic outcome of clinical trials can thus be appropriately evaluated using a continuous rather than a categorical approach, which also considerably reduces the number of patients required. Fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown experimentally to reduce the neointimal proliferative response after PTCA, independent of its lipid-lowering action. The FLuvastatin Angioplasty REstenosis trial was designed to evaluate whether fluvastatin 40 mg twice daily, commencing at least 2 weeks before planned PTCA, can reduce luminal loss by 30% from successful PTCA to follow-up angiography at 26 +/- 2 weeks in 730 evaluable patients.

Angioplasty, Balloon, Coronary↗
PubMed1996

Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia.

Fluvastatin, a member of the group of drugs known as HMG-CoA reductase inhibitors, is used in the treatment of patients with hypercholesterolaemia. In clinical trials in patients with primary hypercholesterolaemia, 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 fluvastatin 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 hypercholesterolaemia. 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 hypercholesterolaemia and appears to have an economic advantage over other HMG-CoA reductase inhibitors, primarily as a result of its relatively low acquisition costs.

Anticholesteremic Agents↗
PubMed1996

Development and pharmacology of fluvastatin.

Fluvastatin is the first synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor to be approved for clinical use, and has been studied extensively in humans since 1986. It is structurally distinct from the other currently available HMGCoA reductase inhibitors (lovastatin, simvastatin, and pravastatin), leading to unique biopharmaceutical properties relative to the other agents of this class. Absorption of fluvastatin is virtually complete across all species, including man, and is not affected by the presence of food. Systemic exposure is limited, as fluvastatin is subject to first-pass metabolism, and the plasma half-life of the drug is approximately 30 minutes. Some 95% of a single dosage of fluvastatin is excreted via the biliary route, with less than 2% of this being the parent compound. Additionally, there is no evidence of circulating active metabolites or accumulation during chronic dosing. Studies of the effect of food on the pharmacokinetics of fluvastatin have demonstrated marked reductions in the rate of bioavailability--from 40% to 60%; however, a comparison of fluvastatin administration with the evening meal or at bedtime has revealed no significant differences in the extent of bioavailability (area under the curve) of these two regimens. Furthermore, no significant difference in pharmacodynamic effect (reduction in low-density lipoprotein cholesterol levels) could be ascertained between mealtime dosing and bedtime dosing. The pharmacokinetics of fluvastatin have also been assessed in various demographic groups. Relative to the general population, plasma concentrations of fluvastatin do not vary as a function of either age or gender. In addition, administration to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both the rate and extent of bioavailability relative to controls. Also, although minimal alterations of fluvastatin clearance in patients with renal insufficiency are anticipated due to limited renal excretion (5%), a study in this patient group is currently underway to examine this further. Interaction studies have been performed with fluvastatin and several drugs with which it might be coadministered. Cholestyramine, an anionic-binding resin, has a considerable effect in lowering the rate and extent of fluvastatin bioavailability. Although this effect was noted even when cholestyramine was given 4 hours prior to fluvastatin, this regimen did not result in diminished efficacy. Further, no effects on either warfarin levels or prothrombin times were observed in a study involving concomitant administration of warfarin and fluvastatin. Moreover, additional interaction studies with niacin and propranolol have not demonstrated any effect on fluvastatin plasma levels, and administration to a patient population chronically receiving digoxin resulted in no difference in the extent of bioavailability of digoxin relative to control data. The results generated to date in clinical pharmacokinetic studies with fluvastatin thus support its use in a broad population of hypercholesterolaemic patients.

Adult↗
PubMed1994

Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients.

OBJECTIVE: To compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of low-dose combinations of cholestyramine and fluvastatin. DESIGN: Randomized, double-blind, parallel group, placebo-controlled trial with a 24-week double-blind treatment period divided into three phases. SETTING: Office-based clinics. PATIENTS: Hypercholesterolemic, with LDL cholesterol of 4.14 mmol/L or greater (> or = 160 mg/dL) and plasma triglycerides of 3.39 mmol/L or less (< or = 300 mg/dL). Four hundred sixty patients were screened; 224 patients were randomized into a double-blind treatment period; 203 completed the study; 6 dropped out because of adverse events. INTERVENTION: Patients were treated with 10 mg or 20 mg of fluvastatin alone, 8 g or 16 g of cholestyramine alone, or combinations of these fluvastatin and cholestyramine dosages (six treatment groups). MEASUREMENTS: Changes in lipid variables, particularly LDL cholesterol. RESULTS: The 10-mg and 20-mg fluvastatin monotherapy groups showed considerable reductions in LDL cholesterol initially (-20.1% [SD, 8.8%] and -20.2% [SD, 10.1%], respectively); these reductions were maintained. Reductions in LDL cholesterol that resulted from the addition of cholestyramine, 8 g/d, to 10 mg of fluvastatin and 20 mg of fluvastatin were greater than those observed with monotherapy (10-mg fluvastatin--[10-mg fluvastatin plus cholestyramine], 9.1%; 95% CI, 3.8% to 14.4%) and 20-mg fluvastatin--[20-mg fluvastatin plus cholestyramine], 11.6%; CI, 6.5% to 16.8%). The increase in cholestyramine dose to 16 g/d in the three combination groups provided only a modest additional response. CONCLUSIONS: Low-density lipoprotein cholesterol reductions of about 25% to 30% can be achieved with low-dose combination therapy with fluvastatin and cholestyramine. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the fluvastatin dosage. The low-dose combination treatment was highly successful in achieving the goals of the National Cholesterol Education Program guidelines.

Anticholesteremic Agents↗
PubMed1996

Fluvastatin in combination with other lipid-lowering agents.

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.

Anticholesteremic Agents↗
PubMed1993

Binding of fluvastatin to blood cells and plasma proteins.

The binding of fluvastatin, an inhibitor of hydroxymethylglutaryl coenzyme A reductase, to plasma proteins and red blood cells of rat, dog, and human in vitro was determined by ultrafiltration. Additionally, the stereospecificity of fluvastatin binding to proteins and the potential interaction between fluvastatin and the highly protein bound drugs warfarin, salicylic acid, and glyburide were investigated. Only a small fraction of fluvastatin in blood was taken up by the blood cells, amounting to 19-33% in the rat and < or = 15% in dog and humans. The plasma:blood fluvastatin ratio in these species at 37 degrees C was > or = 1.4. In human blood, this ratio was temperature independent. In the plasma concentration range 25-50,000 ng/mL, fluvastatin was > or = 98% bound to proteins. The binding was concentration dependent in the rat, but not in the dog and human. Both enantiomers of fluvastatin were > 99% bound in normal human plasma, the binding of each being unaffected by the presence of the other. A major fluvastatin-binding protein in human plasma was albumin, whereas binding to alpha 1-acid glycoprotein was relatively weak and concentration dependent. At therapeutic concentrations in normal human plasma, the protein binding of fluvastatin (0.1 microgram/mL) was unaffected by warfarin (1-10 micrograms/mL), salicylic acid (50-150 micrograms/mL), and glyburide (0.1-1 micrograms/mL). Similarly, fluvastatin had no influence on the binding of these compounds. In diluted human albumin solution (29 microM), bound fluvastatin was displaced by all three co-solutes tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

A review of current clinical findings with fluvastatin.

Fluvastatin, the newest member of the class of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, is structurally different from the fungal metabolites (lovastatin, pravastatin, and simvastatin) and is wholly synthetic. Fluvastatin has a distinct biopharmaceutical profile, including a short systemic exposure time (half-life of 1.2 hours) and virtually no active circulating metabolites. Fluvastatin is targeted to the liver, where it is rapidly metabolized; 98% of fluvastatin is protein bound. Double-blind, placebo-controlled studies have demonstrated that fluvastatin at daily dosages of 20-40 mg produces significant decreases from baseline in low-density lipoprotein (LDL) cholesterol on the order of 22-31% in patients with severe primary hypercholesterolemia (mean baseline LDL cholesterol 227 mg/dL) and decreases of 19-25% in patients with familial hypercholesterolemia (mean baseline LDL cholesterol 270 mg/dL). Interim results of a titrate-to-goal, 20-week study in patients with moderate hypercholesterolemia (LDL cholesterol >= 160 mg/dL and triglycerides <= 350 mg/dL) demonstrate that fluvastatin, 20 mg/day, lowers LDL cholesterol by 21% within 6 weeks. Long-term results indicate that the lipid-lowering effects of fluvastatin are sustained for 96 weeks. Further, 1 study has shown that the combination of low-dose fluvastatin plus niacin decreased LDL cholesterol levels 40% without untoward adverse events, suggesting that this combination is effective and safe for patients needing intensive lipid-lowering therapy. Asymptomatic, reversible increases in hepatic transaminase levels occur in fluvastatin-treated patients at a frequency comparable to that reported for other HMG-CoA reductase inhibitors. The 20-30% reduction in LDL cholesterol required by the majority of patients with hypercholesterolemia can be achieved with fluvastatin at 20 or 40 mg/day as well as with the other available HMG-CoA reductase inhibitors at their most commonly prescribed doses. Fluvastatin, priced 40% lower than other statins, provides the most cost-effective means of safely achieving goal LDL cholesterol levels in these patients.

Fatty Acids, Monounsaturated↗
PubMed1993

Safety and tolerability of fluvastatin with concomitant use of antihypertensive agents. An analysis of a clinical trial database.

The coexistence of hypercholesterolemia and hypertension often requires concomitant drug treatments. Thus, it is interesting to evaluate the efficacy, safety, and tolerability of the new lipid-lowering agent fluvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in patients receiving concomitant antihypertensive/cardiovascular drug treatments. A retrospective analysis was based on data from controlled clinical trials in which 1815 patients were treated with fluvastatin and 783 patients received placebo. The daily dose of fluvastatin was > or = 20 mg. At least one of the following drug treatments was taken by 445 of the fluvastatin-treated patients (24.5%) and 181 of those receiving placebo (23.1%): beta-adrenergic-receptor blockers (fluvastatin: n = 182; placebo: n = 84); diuretics (fluvastatin: n = 168; placebo: n = 72); calcium antagonists (fluvastatin: n = 161; placebo: n = 69); and angiotensin-converting enzyme (ACE) inhibitors (fluvastatin: n = 101; placebo: n = 30). The majority of patients received monotherapy with one of the above-mentioned antihypertensive agents (fluvastatin: 69%; placebo: 65%). The efficacy of fluvastatin in modifying low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol and triglyceride levels was not consistently different in patients taking a given antihypertensive compared with the overall group and the patients not taking the antihypertensive agent. In patients taking fluvastatin and antihypertensives, confirmed (measured at two consecutive occasions) increases more than three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) occurred in only two patients. One case involved the concomitant use of a beta-blocker (ASAT and ALAT) and the other a diuretic (ALAT).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1992

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (greater than 90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [3H]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗