Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see DRUG INTERACTIONS (7.1)].
Concomitant use of cyclosporine, danazol or gemfibrozil [see DRUG INTERACTIONS (7.1)].
Acute liver failure or decompensated cirrhosis [see WARNINGS AND PRECAUTIONS (5.3)]
Hypersensitivity to simvastatin or any excipients in simvastatin tablets USP. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see ADVERSE REACTIONS (6.2)]
Simvastatin may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including simvastatin.
In clinical studies of 24,747 simvastatin -treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10xULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with simvastatin 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical study of 12,064 simvastatin -treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively. The incidences of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively [see ADVERSE REACTIONS (6.1)].
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 simvastatin dosage; Chinese patients on simvastatin may be at higher risk for myopathy [see CONTRAINDICATIONS (4), DRUG INTERACTIONS (7.1), AND USE IN SPECIFIC POPULATIONS (8.8)]. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking simvastatin 80 mg daily compared with patients taking lower simvastatin dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [see ADVERSE REACTIONS (6.1)].
Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
The concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend simvastatin during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of simvastatin with gemfibrozil, cyclosporine, or danazol is also contraindicated [see CONTRAINDICATIONS (4) AND DRUG INTERACTIONS (7.1)].
Simvastatin dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see DOSAGE AND ADMINISTRATION (2.5)]. Simvastatin use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis [see DRUG INTERACTIONS (7.1)].
Use the 80 mg daily dosage of simvastatin only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see DOSAGE AND ADMINISTRATION (2.1)]. If patients treated with simvastatin 80 mg are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [SEE DRUG INTERACTIONS (7.1)].
Discontinue simvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if simvastatin is discontinued. Temporarily discontinue simvastatin 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 simvastatin dosage and advise patients receiving simvastatin 80 mg of the increased risk of myopathy and rhabdomyolysis. 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-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue simvastatin if IMNM is suspected
5.3 Hepatic Dysfunction
Increases in serum transaminases have been reported with use of simvastatin [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 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with simvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin.
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 simvastatin initiation and when clinically indicated thereafter. Simvastatin 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 simvastatin.
5.4 Increases in HbA1c and Fasting Serum Glucose Levels
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.