FDA label e9d5b283-094e-393f-e053-2995a90a930c

5.1 Use with Statins or Fenofibrate Concurrent administration of Ezetimibe Tablets with a specific statin or fenofibrate should be in accordance with the product labeling for that medication. 5.2 Liver Enzymes In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 x the upper limit of normal [ULN]) in hepatic transaminase levels was similar between Ezetimibe Tablets (0.5%) and placebo (0.3%). In controlled clinical combination studies of Ezetimibe Tablets initiated concurrently with a statin, the incidence of consecutive elevations (≥3 x ULN) in hepatic transaminase levels was 1.3% for patients treated with Ezetimibe Tablets administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When Ezetimibe Tablet is co-administered with a statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥3 x ULN persist, consider withdrawal of Ezetimibe Tablets and/or the statin. 5.3 Myopathy/Rhabdomyolysis In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetimibe Tablets compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 x ULN was 0.2% for Ezetimibe Tablets vs. 0.1% for placebo, and 0.1% for Ezetimibe Tablets co-administered with a statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. In post-marketing experience with Ezetimibe Tablets, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetimibe Tablets. However, rhabdomyolysis has been reported with Ezetimibe Tablets monotherapy and with the addition of Ezetimibe Tablets to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Ezetimibe Tablets and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 x the ULN indicates myopathy. 5.4 Hepatic Impairment Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, Ezetimibe Tablet is not recommended in these patients. [See Clinical Pharmacology (12.3 ).]

The following serious adverse reactions are discussed in greater detail in other sections of the label: Liver enzyme abnormalities [see Warnings and Precautions (5.2)] Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)] Monotherapy Studies: In the Ezetimibe Tablets controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Ezetimibe Tablets and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe Tablets that led to treatment discontinuation and occurred at a rate greater than placebo were: Arthralgia (0.3%) Dizziness (0.2%) Gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the Ezetimibe Tablets monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Co-Administration Studies: In the Ezetimibe Tablets + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Ezetimibe Tablets + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe Tablets + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: Alanine aminotransferase increased (0.6%) Myalgia (0.5%) Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the Ezetimibe Tablets + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%). 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Monotherapy In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9 to 86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe Tablets 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥2% of patients treated with Ezetimibe Tablets and at an incidence greater than placebo in placebo-controlled studies of Ezetimibe Tablets, regardless of causality assessment, are shown in Table 1. TABLE 1: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe Tablets and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Ezetimibe Tablets 10 mg (%) n = 2396 Placebo (%) n = 1159 Gastrointestinal disorders Diarrhea 4.1 3.7 General disorders and administration site conditions Fatigue 2.4 1.5 Infections and infestations Influenza 2.0 1.5 Sinusitis 2.8 2.2 Upper respiratory tract infection 4.3 2.5 Musculoskeletal and connective tissue disorders Arthralgia 3.0 2.2 Pain in extremity 2.7 2.5 The frequency of less common adverse reactions was comparable between Ezetimibe Tablets and placebo. Combination with a Statin In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10 to 93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with Ezetimibe Tablets 10 mg/day concurrently with or added to on-going statin therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks). The incidence of consecutive increased transaminases (≥3 x ULN) was higher in patients receiving Ezetimibe Tablets administered with statins (1.3%) than in patients treated with statins alone (0.4%). [See Warnings and Precautions (5.2).] Clinical adverse reactions reported in ≥2% of patients treated with Ezetimibe Tablets + statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2. TABLE 2: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe Tablets Co-Administered with a Statin and at an Incidence Greater than Statin, Regardless of Causality Body System/Organ Class Adverse Reaction All Statins* (%) n = 9361 Ezetimibe Tablets + All Statins* (%) n = 11,308 Gastrointestinal disorders Diarrhea 2.2 2.5 General disorders and administration site conditions Fatigue 1.6 2.0 Infections and infestations Influenza 2.1 2.2 Nasopharyngitis 3.3 3.7 Upper respiratory tract infection 2.8 2.9 Musculoskeletal and connective tissue disorders Arthralgia 2.4 2.6 Back pain 2.3 2.4 Myalgia 2.7 3.2 Pain in extremity 1.9 2.1 *All Statins = all doses of all statins Combination with Fenofibrate This clinical study involving 625 patients with mixed dyslipidemia (age range 20 to 76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated co-administration of Ezetimibe Tablets and fenofibrate. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (≥3 x ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy (n=188) and Ezetimibe Tablets co-administered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for fenofibrate monotherapy and Ezetimibe Tablets co-administered with fenofibrate, respectively [see Drug Interactions (7.3)].The numbers of patients exposed to co-administration therapy as well as fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. There were no CPK elevations >10 x ULN in any of the treatment groups. 6.2 Post-Marketing Experience Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during post-approval use of Ezetimibe Tablets: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis [see Warnings and Precautions (5.3)]; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.