Lescol (Fluvastatin Sodium) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin

(See WARNINGS: Skeletal Muscle).

      In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (~75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., ~5% and ~20%, respectively. If one pathway is inhibited in the elimination process of fluvastatin other pathways may compensate.

      In vivo drug interaction studies with CYP3A4 inhibitors/substrates such as cyclosporine, erythromycin, and itraconazole result in minimal changes in the pharmacokinetics of fluvastatin, confirming less involvement of CYP3A4 isozyme. Concomitant administration of fluvastatin and phenytoin increased the levels of phenytoin and fluvastatin, suggesting predominant involvement of CYP2C9 in fluvastatin metabolism.

Niacin/Propranolol:

Concomitant administration of immediate- release fluvastatin sodium with niacin or propranolol has no effect on the bioavailability of fluvastatin sodium.

Cholestyramine:

Administration of immediate- release fluvastatin sodium concomitantly with, or up to 4 hours after cholestyramine, results in fluvastatin decreases of more than 50% for AUC and 50%-80% for C_max. However, administration of immediate- release fluvastatin sodium 4 hours after cholestyramine resulted in a clinically significant additive effect compared with that achieved with either component drug.

Cyclosporine:

Plasma cyclosporine levels remain unchanged when fluvastatin (20 mg daily) was administered concurrently in renal transplant recipients on stable cyclosporine regimens. Fluvastatin AUC increased 1.9- fold, and C_max increased 1.3- fold compared to historical controls.

Digoxin:

In a crossover study involving 18 patients chronically receiving digoxin, a single 40 mg dose of immediate- release fluvastatin had no effect on digoxin AUC, but had an 11% increase in digoxin C_max and small increase in digoxin urinary clearance.

Erythromycin:

Erythromycin (500 mg, single dose) did not affect steady-state plasma levels of fluvastatin (40 mg daily).

Fluconazole:

Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of fluvastatin C_max (44%) and AUC (84%). Based on this data, caution should be exercised when fluvastatin is co-administered with fluconazole.

Itraconazole:

Concomitant administration of fluvastatin (40 mg) and itraconazole (100 mg daily x 4 days) does not affect plasma itraconazole or fluvastatin levels.

Gemfibrozil:

There is no change in either fluvastatin (20 mg twice daily) or gemfibrozil (600 mg twice daily) plasma levels when these drugs are co-administered.

Phenytoin:

Single morning dose administration of phenytoin (300 mg extended release) increased mean steady-state fluvastatin (40 mg) C_max by 27% and AUC by 40% whereas fluvastatin increased the mean phenytoin C_max by 5% and AUC by 20%. Patients on phenytoin should continue to be monitored appropriately when fluvastatin therapy is initiated or when the fluvastatin dosage is changed.

Diclofenac:

Concurrent administration of fluvastatin (40 mg) increased the mean C_max and AUC of diclofenac by 60% and 25% respectively.

Tolbutamide:

In healthy volunteers, concurrent administration of either single or multiple daily doses of fluvastatin sodium (40 mg) with tolbutamide (1 g) did not affect the plasma levels of either drug to a clinically significant extent.

Glibenclamide (Glyburide):

In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean C_max, AUC, and t_1/2 of glibenclamide approximately 50%, 69% and 121%, respectively. Glibenclamide (5-20 mg daily) increased the mean C_max and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin and C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 40 mg twice daily.

Losartan:

Concomitant administration of fluvastatin with losartan has no effect on the bioavailability of either losartan or its active metabolite.

Cimetidine/Ranitidine/Omeprazole:

Concomitant administration of immediate- release fluvastatin sodium with cimetidine, ranitidine and omeprazole results in a significant increase in the fluvastatin C_max (43%, 70% and 50%, respectively) and AUC (24%-33%), with an 18%-23% decrease in plasma clearance.

Rifampicin:

Administration of immediate- release fluvastatin sodium to subjects pretreated with rifampicin results in significant reduction in C_max (59%) and AUC (51%), with a large increase (95%) in plasma clearance.

Warfarin:

In vitro protein binding studies demonstrated no interaction at therapeutic concentrations. Concomitant administration of a single dose of warfarin (30 mg) in young healthy males receiving immediate- release fluvastatin sodium (40 mg/day x 8 days) resulted in no elevation of racemic warfarin concentration. There was also no effect on prothrombin complex activity when compared to concomitant administration of placebo and warfarin. However, bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

OVERDOSAGE

The approximate oral LD₅₀ is greater than 2 g/kg in mice and greater than 0.7 g/kg in rats.

      The maximum single oral dose of Lescol^® (fluvastatin sodium) capsules received by healthy volunteers was 80 mg. No clinically significant adverse experiences were seen at this dose. The maximum dose administered with an extended-release formulation was 640 mg for two weeks. This dose was not well tolerated and produced a variety of GI complaints and an increase in transaminase values (i.e., SGOT and SGPT).

      There has been a single report of 2 children, one 2 years old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems.

      Should an accidental overdose occur, treat symptomatically and institute supportive measures as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present.

      Information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference^®.*

CONTRAINDICATIONS

Hypersensitivity to any component of this medication. Lescol^® (fluvastatin sodium) and Lescol^® XL (fluvastatin sodium) are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases (see WARNINGS ).

Pregnancy and Lactation

Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. Fluvastatin sodium should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus.