Ezetimibe

5 WARNINGS AND PRECAUTIONS Ezetimibe is not recommended in patients with moderate or severe hepatic impairment. ( 5.4 , 8.7 , 12.3 ) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when ezetimibe is added to a statin. Therefore, when ezetimibe is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used. ( 5.2 ) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Cases of myopathy and rhabdomyolysis have been reported in patients treated with ezetimibe co-administered with a statin and with ezetimibe administered 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. ( 5.3 , 6.2 ) 5.1 Risks Associated with Combination Treatment with a Statin, Fenofibrate, or Other LDL-C Lowering Therapies If ezetimibe is administered with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for a description of their risks including, but not limited to, the warnings and precautions [see Contraindications (4)]. 5.2 Liver Enzymes Increases in serum transaminases have been reported with use of ezetimibe [see Adverse Reactions (6.1)]. In controlled clinical combination studies of ezetimibe 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 administered with statins and 0.4% for patients treated with statins alone. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe if increases in ALT or AST ≥ 3 X ULN persist. 5.3 Myopathy/Rhabdomyolysis Ezetimibe may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis [see Adverse Reactions (6.1)]. In post-marketing reports, most patients who developed rhabdomyolysis were taking a statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ezetimibe and other concomitant medications, as appropriate.

6 ADVERSE REACTIONS 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)] Common adverse reactions in clinical trials: ° Ezetimibe administered alone (incidence ≥ 2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1) ° Ezetimibe co-administered with a statin (incidence ≥ 2% and greater than statin alone): nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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, 2,396 patients with primary hyperlipidemia (age range 9 to 86 years; 50% female, 90% White, 5% Black or African American, 2% Asian, 3% other races; 3% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ezetimibe 10 mg daily for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥ 2% of patients treated with ezetimibe and at an incidence greater than placebo in placebo-controlled studies of ezetimibe is shown in Table 1. 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% female, 85% White, 7% Black or African American, 3% Asian, 5% other races; 4% identified as Hispanic or Latino ethnicity) and elevated LDL-C were treated with ezetimibe 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 administered with statins (1.3%) than in patients treated with statins alone (0.4%). Adverse reactions reported in ≥ 2% of patients treated with ezetimibe + statin and at an incidence greater than statin are shown in Table 2. Combination with Fenofibrate This clinical trial involving 625 patients with mixed dyslipidemia (age range 20 to 76 years; 44% female, 79% White, 1% Black or African American, 20% other races; 11% identified as Hispanic or Latino ethnicity) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated co-administration of ezetimibe and fenofibrate. Incidence rates for clinically important elevations (≥ 3 X ULN, consecutive) in hepatic transaminase levels were 4.5% and 2.7% for fenofibrate monotherapy (n=188) and ezetimibe co-administered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% and 1.7% for fenofibrate monotherapy and ezetimibe co-administered with fenofibrate, respectively [see Drug Interactions (7)]. 1 1 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: Blood Disorders : thrombocytopenia Gastrointestinal Disorders: abdominal pain; pancreatitis; nausea Hepatobiliary Disorders : elevations in liver transaminases, including elevations more than 5 X ULN; hepatitis; cholelithiasis; cholecystitis Immune System Disorders : Hypersensitivity reactions including: anaphylaxis, angioedema, rash, and urticaria Musculoskeletal Disorders : elevated creatine phosphokinase; myopathy/rhabdomyolysis Nervous System Disorders : dizziness; paresthesia; depression; headache Skin and Subcutaneous Tissue Disorders: erythema multiforme To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.