WARNINGS
Liver Enzymes
Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents. Approximately 1.1% of patients treated with Lescol® (fluvastatin sodium) capsules in worldwide trials developed dose-related, persistent elevations of transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average fluvastatin exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which Lescol capsules were used, persistent transaminase elevations (>3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with 20, 40, and 80 mg (titrated to 40 mg twice daily) Lescol capsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8.
In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Lescol® XL (fluvastatin sodium) 80 mg, Lescol 40 mg and Lescol 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol XL the abnormality occurred within 12 weeks of initiation of treatment with Lescol XL 80 mg.
It is recommended that liver function tests be performed before the initiation of therapy and at 12 weeks following initiation of treatment or elevation in dose. Patients who develop transaminase elevations or signs and symptoms of liver disease should be monitored to confirm the finding and should be followed thereafter with frequent liver function tests until the levels return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist (found on two consecutive occasions) withdrawal of fluvastatin sodium therapy is recommended.
Active liver disease or unexplained transaminase elevations are contraindications to the use of Lescol and Lescol XL (see CONTRAINDICATIONS). Caution should be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism ). Such patients should be closely monitored.
Skeletal Muscle
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported with fluvastatin and with other drugs in this class. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, has been reported.
Myopathy should be considered in any patients with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Fluvastatin sodium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy and/or rhabdomyolysis during treatment with HMG-CoA reductase inhibitors has been reported to be increased if therapy with either cyclosporine, gemfibrozil, erythromycin, or niacin is administered concurrently. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of fluvastatin and colchicine. No information is available on the pharmacokinetic interaction between fluvastatin and colchicine. However, myotoxicity, including muscle pain and weakness and rhabdomyloysis, have been reported anecdotally with concomitant administration of colchicine.
Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with fluvastatin sodium together with niacin.
Uncomplicated myalgia has been observed infrequently in patients treated with Lescol at rates indistinguishable from placebo.
The use of fibrates alone may occasionally be associated with myopathy. The combined use of HMG-CoA reductase inhibitors and fibrates should generally be avoided.
PRECAUTIONS
General
Before instituting therapy with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin sodium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE).
The HMG-CoA reductase inhibitors may cause elevation of creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with fluvastatin sodium.
Homozygous Familial Hypercholesterolemia
HMG-CoA reductase inhibitors are reported to be less effective in patients with rare homozygous familial hypercholesterolemia, possibly because these patients have few functional LDL receptors.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Women should be informed that if they become pregnant while receiving Lescol or Lescol XL the drug should be discontinued immediately to avoid possible harmful effects on a developing fetus from a relative deficit of cholesterol and biological products derived from cholesterol. In addition, Lescol or Lescol XL should not be taken during nursing. (See CONTRAINDICATIONS.)
Drug Interactions
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 t1/2 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed.
The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.
In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.
Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 milligram human daily dose based on surface area, mg/m2). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 milligram daily dose).
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on Days 0 and 7 postpartum. Therefore, the maternal and neonatal lethality observed with fluvastatin sodium reflect its exaggerated pharmacologic effect during pregnancy. There are no data with fluvastatin sodium in pregnant women. However, rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took another HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first trimester of pregnancy. Lescol or Lescol XL should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking Lescol or Lescol XL, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus.
Nursing Mothers
Based on preclinical data, drug is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take Lescol or Lescol XL (see CONTRAINDICATIONS).
Pediatric Use
The safety and efficacy of Lescol and Lescol XL in children and adolescent patients 9-16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials of 2 years' duration. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL STUDIES: Heterozygous Familial Hypercholesterolemia in Pediatric Patients; ADVERSE REACTIONS: Pediatric Patients (9-16 years of age); and DOSAGE AND ADMINISTRATION: Heterozygous Familial Hypercholesterolemia in Pediatric Patients. Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin therapy ( see CONTRAINDICATIONS: Pregnancy and Lactation ) .
Geriatric Use
The effect of age on the pharmacokinetics of immediate- release fluvastatin sodium was evaluated. Results indicate that for the general patient population plasma concentrations of fluvastatin sodium do not vary as a function of age . (See also CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism.) Elderly patients (≥65 years of age) demonstrated a greater treatment response in respect to LDL-C, Total-C and LDL/HDL ratio than patients <65 years of age.
|
