warnings and cautions
5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis) Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Altoprev®.Predisposing factors include advanced age (≥ 65), female gender, uncontrolled hypothyroidism, and renal impairment. Advise patients to report promptly to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness. Altoprev therapy should be discontinued immediately if myopathy is diagnosed or suspected. ( 5.1 ) Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.2 ) 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Altoprev ® . These risks can occur at any dose level, but increase in a dose-dependent manner. Predisposing factors for myopathy include advanced age (≥65 years), female gender, renal impairment, and inadequately treated hypothyroidism. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily. 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 starting therapy with Altoprev ® , or whose dose of Altoprev ® is being increased, should be advised of the risk of myopathy , including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Altoprev . Altoprev therapy should be discontinued immediately if myopathy is diagnosed or suspected. Altoprev ® therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Altoprev ® 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; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy. • Drug Interactions that can cause skeletal muscle effects Strong CYP3A Inhibitors: The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. Co-administration of these drugs with Altoprev is contraindicated. If treatment with strong CYP3A inhibitors is unavoidable, therapy with Altoprev should be suspended during the course of treatment (see Contraindications (4) ; Clinical Pharmacology (12.3) ; Drug Interactions (7.1) ]. Erythromycin: Co-administration of erythromycin with Altoprev is contraindicated. If treatment with erythromycin is unavoidable, therapy with Altoprev should be suspended during the course of treatment (see Contraindications (4) ; Drug Interactions (7.2) ] Gemfibrozil: Avoid the combined use of Altoprev with gemfibrozil. Other lipid-lowering drugs (other fibrates, or lipid-lowering doses (≥ 1 g/day) of niacin: Use caution when prescribing other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin with Altoprev, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered with Altoprev. Carefully weigh the expected benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin against the potential risks of these combinations [see Drug Interactions (7.3) ] . Cyclosporine: Avoid the combined use of Altoprev with cyclosporine [see Drug Interactions (7.4) ] . Danazol, diltiazem , dronedarone or verapamil with higher doses of lovastatin : Do not exceed 20 mg of Altoprev daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil. Weigh carefully the benefits of the use of Altoprev in patients receiving danazol, diltiazem, dronedarone or verapamil against the risks of these combinations [see Drug Interactions (7.6) ]. Amiodarone: Do not exceed 40 mg of Altoprev daily in patients receiving concomitant therapy with amiodarone . Avoid the combined use of Altoprev at doses exceeding 40 mg daily with amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy. The concomitant use of higher doses of a closely related member of the HMG-CoA reductase inhibitor class with amiodarone increased the risk of myopathy/rhabdomyolysis [see Drug Interactions (7.6) ] . Colchicine: There have been cases of myopathy, including rhabdomyolysis, reported in patients receiving lovastatin coadministered with colchicine. Use caution when prescribing Altoprev with colchicine [see Drug Interactions (7.9) ]. Ranolazine: Concomitant use of ranolazine and Altoprev may increase the risk of myopathy, including rhabdomyolysis. Consider dose adjustment of Altoprev if coadministering with ranolazine [see Drug Interactions (7.9) ]. Prescribing recommendations for interacting agents are summarized in Table 1. Table 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin Contraindicated with lovastatin Gemfibrozil Cyclosporine Avoid with lovastatin Danazol Diltiazem Dronedarone Verapamil Do not exceed 20 mg lovastatin daily Amiodarone Do not exceed 40 mg lovastatin daily Grapefruit juice Avoid grapefruit juice 5.2 Liver Enzyme Abnormalities Increases in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) have been reported with HMG-CoA reductase inhibitors, including Altoprev ® . Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials [see Adverse Reactions (6.1) ] . When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. It is recommended that liver enzyme tests be obtained prior to initiating therapy with Altoprev and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Altoprev, promptly interrupt therapy. If an alternate etiology is not found, do not restart Altoprev. The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of Altoprev ® . Altoprev ® In controlled clinical trials (467 patients treated with Altoprev ® and 329 patients treated with lovastatin immediate-release) no meaningful differences in transaminase elevations between the two treatments were observed. Lovastatin In the EXCEL study [see Clinical Studies (14) ], the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin immediate-release, symptomatic liver disease has been reported rarely at all dosages [ see Adverse Reactions (6.2) ] . In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301). 5.3 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.