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warnings and cautions
5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ezetimibe and simvastatin dosage. Chinese patients may be at higher risk for myopathy. Discontinue ezetimibe and simvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ezetimibe and simvastatin tablets 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 ezetimibe and simvastatin 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. Discontinue ezetimibe and simvastatin tablets 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 ezetimibe and simvastatin tablets. ( 5.3 ) 5.1 Myopathy and Rhabdomyolysis Ezetimibe and 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 ezetimibe and simvastatin. In clinical trials 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 (10 X ULN), 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 trial 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% an...
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adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] Hepatic Dysfunction [see Warnings and Precautions (5.3) ] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] Common (incidence ≥ 2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Ezetimibe and Simvastatin In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1,420 patients (age range 20 to 83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). The most common adverse reactions in the group treated with ezetimibe and simvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). Ezetimibe and simvastatin has been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in ≥ 2% of patients treated with ezetimibe and simvastatin (n = 1,420) and at an incidence greater than placebo from four placebo-controlled trials. Table 1 * : Adverse Reactions Reported ≥ 2% of Patients Treated with E zetimibe and Simvastatin at an Incidence Gr...
adverse reactions table
% Placebo N = 371 % Ezetimibe 10 mg N = 302 % Simvastatin† N = 1,234 % Ezetimibe and Simvastatin†N = 1,420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were co-administered and two placebo-controlled studies in which ezetimibe and simvastatin was administered. † All doses.