In all clinical studies of Lescol® (fluvastatin sodium), 1.0% (32/2969) of fluvastatin-treated patients were discontinued due to adverse experiences attributed to study drug (mean exposure approximately 16 months ranging in duration from 1 to > 36 months). This results in an exposure adjusted rate of 0.8% (32/4051) per patient year in fluvastatin patients in controlled studies compared to an incidence of 1.1% (4/355) in placebo patients. Adverse reactions have usually been of mild to moderate severity.

In controlled clinical studies, 3.9% (36/912) of patients treated with Lescol® XL (fluvastatin sodium) 80 mg discontinued due to adverse events (causality not determined).

Clinically relevant adverse experiences occurring in the Lescol and Lescol XL controlled studies with a frequency > 2%, regardless of causality, include the following:

Table 5 Clinically Relevant Adverse Experiences Occurring in > 2% Patients in Lescol® and Lescol XL® Controlled Studies

The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with fluvastatin sodium therapy.

Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.

Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.

Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.

Reproductive: gynecomastia, loss of libido, erectile dysfunction.

Eye: progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

Pediatric Patients

In two open-label, uncontrolled studies, 114 patients (66 boys and 48 girls) with heterozygous familial hypercholesterolemia, 9-16 years of age, were treated for 2 years with fluvastatin sodium administered as Lescol capsules 20 mg- 40 mg bid or Lescol XL 80 mg extended-release tablets. The most common adverse events observed were influenza and infections. (See CLINICAL STUDIES: Heterozygous Familial Hyercholesterolemia in Pediatric Patients and PRECAUTIONS: Pediatric Use).

Concomitant Therapy

Fluvastatin sodium has been administered concurrently with cholestyramine and nicotinic acid. No adverse reactions unique to the combination or in addition to those previously reported for this class of drugs alone have been reported. Myopathy and rhabdomyolysis (with or without acute renal failure) have been reported when another HMG-CoA reductase inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase inhibitors and these agents is generally not recommended. (See WARNINGS: Skeletal Muscle.)

The below listed drug interaction information is derived from studies using immediate- release fluvastatin. Similar studies have not been conducted using the Lescol XL tablet.

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 Cmax. 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 Cmax 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 Cmax 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 Cmax (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) Cmax by 27% and AUC by 40% whereas fluvastatin increased the mean phenytoin Cmax 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 Cmax 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 Cmax, AUC, and t½ of glibenclamide approximately 50%, 69% and 121%, respectively. Glibenclamide (5-20 mg daily) increased the mean Cmax 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 Cmax (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 Cmax (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.

Endocrine Function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.

Fluvastatin exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by TSH. Small declines in total testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of fluvastatin upon female sex hormones may be made.

Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of fluvastatin at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p< 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of fluvastatin or placebo.

Patients treated with fluvastatin sodium who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.

CNS Toxicity

CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rat) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).

Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years.

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