warnings and cautions
5 WARNINGS AND PRECAUTIONS • 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 ) • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue Altoprev if IMNM is suspected. ( 5.2 ) • Hepatic Dysfunction : Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue Altoprev. ( 5.3 ) 5.1 Myopathy and Rhabdomyolysis Altoprev may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including Altoprev. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher Altoprev dosage [see Drug Interactions ( 7.1 )] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of strong CYP3A4 inhibitors with Altoprev is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend Altoprev during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of Altoprev with gemfibrozil or cyclosporine is not recommended [see Contraindications ( 4 ) and Drug Interactions ( 7.1 )] . Altoprev dosage modifications are recommended for patients taking amiodarone, danazol, diltiazem, dronedarone, and verapamil [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7.1 )] . Lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ranolazine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions ( 7.1 )] . Use of grapefruit juice is not recommended when taking Altoprev [see Drug Interactions ( 7.1 )] . Discontinue Altoprev if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if Altoprev is discontinued. Temporarily discontinue Altoprev in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Altoprev dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMGCoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue Altoprev if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have occurred with Altoprev [see Adverse Reactions ( 6.1 )] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the upper limit of normal (ULN) in serum transaminases have occurred in approximately 1.9% of patients receiving Altoprev in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with Altoprev. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Altoprev. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before Altoprev initiation and when clinically indicated thereafter. Altoprev is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue Altoprev. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Altoprev. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.