warnings and cautions
5 WARNINGS AND PRECAUTIONS • Myopathy and Rhabdomyolysis : Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs. Discontinue LESCOL XL if markedly elevated creatine kinase (CK) levels occur, or myopathy is diagnosed or suspected. Temporarily discontinue LESCOL XL in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing LESCOL XL dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 ) • Immune-Mediated Necrotizing Myopathy (IMNM) : Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue LESCOL XL 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 LESCOL XL ( 5.3 ) 5.1 Myopathy and Rhabdomyolysis LESCOL XL may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including LESCOL XL. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK, values to greater than 10 times the upper limit of normal (ULN) was < 0.1% in fluvastatin clinical trials [see Adverse Reactions (6.1)] . Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs (including other lipid-lowering therapies) [see Drug Interactions (7.1)] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Avoid concomitant use of LESCOL XL with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with LESCOL XL, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)] . Discontinue LESCOL XL if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if LESCOL XL is discontinued. Temporarily discontinue LESCOL XL 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 LESCOL XL. 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 CK, which persist despite discontinuation of statin treatment; positive anti-HMG CoA 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 LESCOL XL if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of LESCOL XL [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 ULN in serum transaminases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials. Marked persistent increases of hepatic transaminases have also occurred with fluvastatin. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LESCOL XL. 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 LESCOL XL initiation and thereafter, when clinically indicated. LESCOL XL 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 LESCOL XL. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LESCOL XL. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.