EZETIMIBE

Ezetimibe is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)- 3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C 24 H 21 F 2 NO 3 . Its molecular weight is 409.4 and its structural formula is: Ezetimibe, USP is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe, USP has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe tablets, USP are available as a tablet for oral administration containing 10 mg of ezetimibe, USP and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate. structure

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe tablets are an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet to: Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin) ( 1.1 ) Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate ( 1.1 ) Reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin ( 1.2 ) Reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) ( 1.3 ) Limitations of Use ( 1.4 ) The effect of ezetimibe tablets on cardiovascular morbidity and mortality has not been determined. Ezetimibe tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. 1.1 Primary Hyperlipidemia Monotherapy Ezetimibe tablets, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with HMG-CoA Reductase Inhibitors (Statins) Ezetimibe tablets, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with Fenofibrate Ezetimibe tablets, administered in combination with fenofibrate, are indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia. ​1.2 Homozygous Familial Hypercholesterolemia (HoFH) The combination of ezetimibe tablets and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Homozygous Sitosterolemia Ezetimibe tablets are indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. 1.4 Limitations of Use The effect of ezetimibe tablets on cardiovascular morbidity and mortality has not been determined. Ezetimibe tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

One 10-mg tablet once daily, with or without food ( 2.1 ) Dosing of ezetimibe tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ( 2.3 , 7.4 ) 2.1 General Dosing Information The recommended dose of ezetimibe tablets is 10 mg once daily. Ezetimibe tablets can be administered with or without food. 2.2 Concomitant Lipid-Lowering Therapy Ezetimibe tablets may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ezetimibe tablets may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications. 2.3 Co-Administration with Bile Acid Sequestrants Dosing of ezetimibe tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4) ] . 2.4 Patients with Hepatic Impairment No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.4) ] . 2.5 Patients with Renal Impairment No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3) ] . When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring [see Use in Specific Populations (8.6) ] . 2.6 Geriatric Patients No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3) ] .

Ezetimibe is contraindicated in the following conditions: The combination of ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy [see Use in Specific Populations (8.1) ]. Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ezetimibe treatment in combination with a statin should be advised not to nurse their infants [see Use in Specific Populations (8.3) ] . Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe [see Adverse Reactions (6.2) ] . Statin contraindications apply when ezetimibe is used with a statin: Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4, 5.2) Women who are pregnant or may become pregnant (4, 8.1) Nursing mothers (4, 8.3) Known hypersensitivity to product components (4, 6.2)

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 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 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 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 monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Co-Administration Studies: In the ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4% of patients on ezetimibe + 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 + 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 + 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%). Common adverse reactions in clinical trials: Ezetimibe co-administered with a statin (incidence ≥2% and greater than statin alone) nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea ( 6 ) Ezetimibe administered alone (incidence ≥2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremity ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993; email [email protected]; 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, 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 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 and at an incidence greater than placebo in placebo-controlled studies of ezetimibe, regardless of causality assessment, are shown in Table 1 . TABLE 1: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Ezetimibe 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 1.5 Sinusitis 2.8 2.2 Upper respiratory tract infection 4.3 2.5 Musculoskeletal and connective tissue disorders Arthralgia 3 2.2 Pain in extremity 2.7 2.5 The frequency of less common adverse reactions was comparable between ezetimibe 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 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%) [see Warnings and Precautions (5.2) ]. Clinical adverse reactions reported in ≥2% of patients treated with ezetimibe + 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 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 + All Statins * (%) n=11,308 Gastrointestinal disorders Diarrhea 2.2 2.5 General disorders and administration site conditions Fatigue 1.6 2 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 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 co-administered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0%, 3.1%) and 1.7% (95% CI: 0.6%, 4%) for fenofibrate monotherapy and ezetimibe 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: 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. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

[See Clinical Pharmacology (12.3) .] Cyclosporine: Combination increases exposure of ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe concomitantly. ( 7.1 , 12.3 ) Fenofibrate: Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. ( 6.1 , 7.3 ) Fibrates: Co-administration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. ( 7.2 ) Cholestyramine: Combination decreases exposure of ezetimibe. ( 2.3 , 7.4 , 12.3 ) 7.1 Cyclosporine Caution should be exercised when using ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ezetimibe and cyclosporine. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. 7.2 Fibrates The efficacy and safety of co-administration of ezetimibe with fibrates other than fenofibrate have not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology (13.2) ] . Co-administration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. 7.3 Fenofibrate If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see Adverse Reactions (6.1) and the product labeling for fenofibrate] . 7.4 Cholestyramine Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. 7.5 Coumarin Anticoagulants If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.