Lack of Interaction between Modified-Release Fluvastatin and Amlodipine in Healthy Subjects.

OBJECTIVE: To investigate the potential for a pharmacokinetic interaction between fluvastatin modified-release 80mg tablet (Lescol((R)) XL; fluvastatin XL) and amlodipine 5mg tablet (Norvasc((R))) following multiple once-a-day doses for 2 weeks. DESIGN: This was a single-centre, six-sequence, three-period, randomised, crossover design study. Fluvastatin XL 80mg tablet and amlodipine 5mg tablet were administered once a day for 2 weeks either alone or in combination. Fluvastatin and amlodipine serum concentration profiles were characterised on day 14 for each treatment. The pharmacokinetic interaction between the two drugs was evaluated based on the p-values and 90% confidence intervals (CIs) for log-transformed highest observed concentration (C(max)), area under the plasma concentration-time curve calculated by the linear trapezoidal method up to 24 hours (AUC(24)), and apparent oral clearance at steady state (CL/F), using a single entity as the reference treatment and the combination as the test treatment. Adverse events (AEs), safety laboratory tests and physical examinations were evaluated for safety. STUDY PARTICIPANTS: Twenty-four healthy subjects were enrolled and 19 completed the study. The safety analysis was based on data from all 24 subjects who received at least one dose of a treatment, while the pharmacokinetic analysis was based on data from the 19 subjects who completed all treatments. RESULTS: The coadministration of fluvastatin XL and amlodipine resulted in no significant changes in the steady-state AUC (469 vs 454 mug . h/L), C(max) (96 vs 89 mug/L), and CL/F (197 vs 232 L/h) of fluvastatin when compared with fluvastatin XL alone. The p-values for these comparisons were between 0.172 and 0.238, and the 90% CIs for the geometric means were within 78% and 139%. A similar comparison for amlodipine showed no significant difference in the steady-state AUC (132 vs 140 mug . h/L), C(max) (7.1 vs 7.5 mug/L) and CL/F (41 vs 40 L/h) of amlodipine. The p-values for these comparisons were between 0.309 and 0.353, and the 90% CIs for the geometric means were within 90% and 111%. The majority of the AEs were mild in severity. There were no clinically relevant changes in clinical laboratory results, physical examinations or vital sign parameters. CONCLUSION: There were no significant differences in the steady-state pharmacokinetics of fluvastatin or amlodipine when they were administered together and the small differences observed were not clinically relevant. Therefore, no dose adjustment of either drug is necessary when fluvastatin and amlodipine are coadministered.

Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil).

This analysis was conducted to evaluate the effect of baseline triglyceride levels on lipid and lipoprotein changes after treatment with the combination of fluvastatin and fibrates. The analysis involved pooling data from 10 studies that included 1,018 patients with either mixed hyperlipidemia or primary hypercholesterolemia. Patients received a combination of fluvastatin and a fibrate (bezafibrate, fenofibrate, or gemfibrozil) from 16 to 108 weeks. The combination of fluvastatin and a fibrate improved lipid profiles, with reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol that were dependent on baseline triglyceride levels. The greatest triglyceride reductions were observed in patients with high baseline triglyceride levels (> or =400 mg/dl) (41%, p <0.0001). The greatest LDL cholesterol and non-HDL cholesterol reductions occurred in patients with normal baseline triglyceride levels (<150 mg/dl) (35% and 33%, respectively; p <0.0001). The combined fluvastatin-fibrate therapy was well tolerated. Two patients (0.2%) (1 patient on fluvastatin 80 mg + gemfibrozil 1,200 mg and 1 patient on fluvastatin 20 mg + fenofibrate 200 mg) had creatine kinase levels > or =10 times the upper limit of normal, 11 patients (1.1%) had an elevation in alanine transaminase >3 times the upper limit of normal, and 7 patients (0.7%) had elevations in aspartate transaminase >3 times the upper limit of normal. Combined fluvastatin-fibrate therapy takes advantage of the complementary effects of the 2 agents, with the extent of triglyceride, LDL cholesterol, and non-HDL cholesterol lowering dependent on baseline triglyceride levels. The combination of fluvastatin and fibrates was well tolerated with no major safety concerns.

Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia.

BACKGROUND: According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin. With the immediate-release (IR) formulation of fluvastatin, the maximal dose of 80 mg is recommended to be administered in divided doses (40 mg BID). An extended-release (ER) formulation of fluvastatin at a higher dose (fluvastatin ER 80 mg) was designed to provide greater LDL-C lowering with QD dosing. Use of this formulation should bring more patients into compliance with target LDL-C levels. OBJECTIVE: This analysis compared the efficacy and tolerability of fluvastatin ER 80 mg QD and fluvastatin IR 40 mg QD in lowering total cholesterol, LDL-C, triglyceride, and apolipoprotein (apo) B levels and raising high-density lipoprotein cholesterol (HDL-C) and apo A-I levels in patients with hypercholesterolemia over a 12-week treatment period. METHODS: This was a prospective, multicenter, double-blind, double-dummy, randomized, parallel-group, active-controlled study Patients with primary hypercholesterolemia who qualified for lipid-lowering drug therapy based on NCEP ATP II guidelines were randomized to fluvastatin ER 80 mg QD or fluvastatin IR 40 mg QD, and treated for 12 weeks. RESULTS: A total of 173 patients were randomized to treatment: 86 to the fluvastatin ER 80-mg group and 87 to the fluvastatin IR 40-mg group. Compared with fluvastatin IR 40 mg, fluvastatin ER 80 mg produced greater mean reductions in LDL-C (32% vs 22%, respectively; P < 0.001). For each of the 3 coronary heart disease (CHD) risk groups (defined by the NCEP), as well as for the total population studied, more patients from the fluvastatin ER 80-mg group than the IR 40 group achieved NCEP ATP II target LDL-C levels (79% vs 47%, respectively [P = NS], for patients with < 2 risk factors; 58% vs 15%, respectively [P < 0.001], for patients with > or = 2 risk factors; and 40% vs 14%, respectively [P = 0.012], for patients with CHD). The 80-mg ER dose of fluvastatin provided 9.1% greater LDL-C lowering than the 40-mg IR dose. The incidence of elevations in transaminase levels was low and similar for both doses, with 1 patient in each of the treatment groups being discontinued due to repeated elevation of transaminases > 3 x the upper limit of normal (ULN). Clinically relevant elevations in creatine kinase (ie, > or = 10x ULN) were not observed with either dose. Nine patients (5 in the fluvastatin ER group and 4 in the fluvastatin IR group) discontinued because of adverse events. CONCLUSIONS: Treatment with fluvastatin ER 80 mg resulted in greater reductions in LDL-C, total cholesterol, and apo B levels compared with fluvastatin IR 40 mg, with clinically equivalent reduction in triglyceride levels and elevation of HDL-C levels. Furthermore, there were few tolerability concerns of clinical relevance with either formulation and no clinically meaningful difference in the tolerability parameters between the 2 formulations. For patients with higher baseline LDL-C levels, and for patients who require greater LDL-C lowering, it may be appropriate to initiate therapy with fluvastatin ER 80 mg. Use of the higher starting dose likely would bring a greater proportion of high-risk patients into compliance with NCEP ATP II target LDL-C levels and would provide LDL-C lowering that is in the same range that has been proved in clinical trials to be associated with reductions in CHD event rates.