warnings and cautions
5 WARNINGS AND PRECAUTIONS Risks increase with advanced age ( 65), uncontrolled hypothyroidism, renal impairment, and combination use with cyclosporine,or gemfibrozil. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue LESCOL/LESCOL XL if myopathy is diagnosed or suspected. ( , , ) Skeletal muscle effects (e.g. myopathy and rhabdomyolysis): > 5.1 8.5 8.7 Patients should be advised to report promptly any symptoms of myopathy. LESCOL/LESCOL XL therapy should be discontinued if myopathy is diagnosed or suspected ( ) 5.1 Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( ) Liver enzyme abnormalities: 5.2 5.1 Skeletal Muscle R habdomyolysis with acute renal failure secondary to myoglobinuria have been reported with LESCOL /LESCOL XL and other drugs in this class. LESCOL/LESCOL XL should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (>65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with LESCOL/LESCOL XL together with niacin. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of LESCOL/LESCOL XL and colchicine. No information is available on the pharmacokinetic interaction between LESCOL/LESCOL XL and colchicine. Uncomplicated myalgia has also been reported in LESCOL-treated patients [ ]. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with LESCOL at rates indistinguishable from placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was <0.1% in fluvastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. see Adverse Reactions (6) There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing LESCOL/LESCOL XL. LESCOL/LESCOL XL therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. LESCOL/LESCOL XL 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. 5.2 Liver Enzymes Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including LESCOL/LESCOL XL. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. Approximately 1.1% of patients treated with LESCOL capsules in worldwide trials developed dose-related, persistent elevations of serum 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 LESCOL 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 daily doses of 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 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 enzyme tests be performed prior to the initiation of LESCOL/LESCOL XL, and if signs or symptoms of liver injury occur. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LESCOL/LESCOL XL, promptly interrupt therapy. If an alternate etiology is not found do not restart LESCOL/LESCOL XL. In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of LESCOL and LESCOL XL [ ]. Caution should be exercised when LESCOL is administered to patients with a history of liver disease or heavy alcohol ingestion [ ]. Such patients should be closely monitored. 1 see Contraindications (4) and Warnings and Precautions (5.2) see Clinical Pharmacology (12.3) 5.3 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LESCOL/LESCOL XL. Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. LESCOL/LESCOL XL exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum 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 LESCOL/LESCOL XL 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 LESCOL 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 LESCOL or placebo. Patients treated with LESCOL/LESCOL XL who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones. 5.4 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 rats) 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 drug 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.