No significant (< 6%) renal excretion of fluvastatin occurs in humans.

Hepatic Insufficiency:

Fluvastatin is subject to saturable first-pass metabolism/sequestration by the liver and is eliminated primarily via the biliary route. Therefore, the potential exists for drug accumulation in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see WARNINGS).

Fluvastatin AUC and Cmax values increased by about 2.5- fold in hepatic insufficiency patients. This result was attributed to the decreased presystemic metabolism due to hepatic dysfunction. The enantiomer ratios of the two isomers of fluvastatin in hepatic insufficiency patients were comparable to those observed in healthy subjects.

Age:

Plasma levels of fluvastatin are not affected by age.

Gender:

Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations than men for the immediate- release capsule. This is most likely due to body weight differences, as adjusting for body weight decreases the magnitude of the differences seen. For Lescol XL, there are 67% and 77% increases in systemic availability for women over men under fasted and high- fat meal conditions.

Pediatric:

Pharmacokinetic data in the pediatric population are not available.

CLINICAL STUDIES

Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed Dyslipidemia

In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinemia, Lescol® (fluvastatin sodium) alone was administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration. After 24 weeks of treatment, daily doses of 20 mg, 40 mg, and 80 mg (40 mg twice daily) resulted in median LDL-C reductions of 22% (n=747), 25% (n=748) and 36% (n=257), respectively. Lescol treatment produced dose-related reductions in Apo B and in triglycerides and increases in HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) were +2 (-4,+10), +5 (-2,+12), and +4 (-3,+12), respectively. In a subgroup of patients with primary mixed dyslipidemia, defined as baseline TG levels ≥ 200 mg/dL, treatment with Lescol also produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) in this population were +4 (-2,+12), +8 (+1,+15), and +4 (-3,+13), respectively.

In a long-term open-label free titration study, after 96 weeks LDL-C decreases of 25% (20 mg, n=68), 31% (40 mg, n=298) and 34% (80 mg, n=209) were seen. No consistent effect on Lp(a) was observed.

Lescol® XL (fluvastatin sodium) Extended-Release Tablets have been studied in five controlled studies of patients with Type IIa or IIb hyperlipoproteinemia. Lescol XL was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these studies, Lescol XL given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and Apo B. Therapeutic response is well established within two weeks, and a maximum response is achieved within four weeks. After four weeks of therapy, the median decrease in LDL-C was 38% and at Week 24 endpoint the median LDL-C decrease was 35%. Significant increases in HDL-C were also observed. The median (25th and 75th percentile) percent changes from baseline in HDL-C for Lescol XL were +7(+0,+15) after 24 weeks of treatment.

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