EZETIMIBE

Ezetimibe is a dietary cholesterol absorption inhibitor. 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 C24H21F2NO3. Its molecular weight is 409.42 and its structural formula is: Ezetimibe is a white to off white, crystalline powder that is freely soluble in methanol, and acetone, soluble in ethanol, and practically insoluble in water. Ezetimibe has a melting point of about 165.13°C and is stable at ambient temperature. Ezetimibe is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch (maize) and sodium lauryl sulfate. Structure

Ezetimibe tablets are indicated: In combination with a statin, or alone when additional low-density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). In combination with a statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH. In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia. In combination with a statin, and other LDL-C lowering therapies, to reduce elevated LDL-C levels in adults and in pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients 9 years of age and older with homozygous familial sitosterolemia. When ezetimibe tablets are used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use. Ezetimibe tablets are indicated ( 1 ): • In combination with a statin, or alone when additional low density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). • In combination with a statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH. • In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia. • In combination with a statin, and other LDL-C lowering therapies, to reduce elevated LDL-C levels in adults and in pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH). • As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients 9 years of age and older with homozygous familial sitosterolemia. When ezetimibe tablets are used in combination with a statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use ( 1 ).

The recommended dose of ezetimibe tablet is 10 mg orally once daily, administered with or without food. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe tablets. Administer ezetimibe tablets at least 2 hours before or 4 hours after administration of a bile acid sequestrant [ see Drug Interactions (7)]. 10 mg orally once daily, with or without food (2) Administer ezetimibe tablets either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. (2) Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe tablets. (2)

Ezetimibe tablets are contraindicated in patients with a known hypersensitivity to ezetimibe or any of the excipients in ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported [ see Adverse Reactions (6.2) ]. When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablets are contraindicated in patients for whom a statin, fenofibrate, or other LDLC lowering therapy are contraindicated. Refer to the Prescribing Information of these products for a list of their contraindications [see Warnings and Precautions (5.1)] • Hypersensitivity to ezetimibe or any excipient of ezetimibe tablets. (4) • When used in combination with a statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablets is contraindicated in patients for whom a statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for a list of their contraindications. (4)

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 tablets administered alone (incidence ≥2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza (6.1) Ezetimibe tablets coadministered 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 Ohm Laboratories Inc. at 1-800- 406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. [see Warnings and Precautions (5.2)] [see Warnings and Precautions (5.3)] 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 tablets 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 tablets and at an incidence greater than placebo in placebo-controlled studies of ezetimibe tablets are shown in Table 1. TABLE 1: Adverse Reactions Occurring in ≥ 2% and Greater than Placebo in ezetimibe tablets -treated Patients Adverse Reactions Placebo (%) n=1,159 Ezetimibe tablets 10mg (%) n=2,396 Upper respiratory tract infection 2.5 4.3 Diarrhea 3.7 4.1 Arthralgia 2.2 3.0 Sinusitis 2.2 2.8 Pain in extremity 2.5 2.7 Fatigue 1.5 2.4 1.5 2.0 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 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 times ULN) was higher in patients receiving ezetimibe tablets administered with statins (1.3%) than in patients treated with statins alone (0.4%). Adverse reactions reported in ≥2% of patients treated with ezetimibe tablets + statin and at an incidence greater than statin are shown in Table 2. TABLE 2: Adverse Reactions Occurring ≥2% in ezetimibe tablets -treated Patients Co-administered with a Statin and at an Incidence Greater than Statin Adverse Reaction All Statins* (%) n = 9,361 All Statins* (%) n = 9,361 Ezetimibe Tablets + All Statins* (%) n = 11,308 Nasopharyngitis 3.3 3.7 Myalgia 2.7 3.2 Upper respiratory tract infection 2.8 2.9 Arthralgia 2.4 2.6 Diarrhea 2.2 2.5 Back pain 2.3 2.4 Influenza 2.1 2.2 Pain in extremity 1.9 2.1 Fatigue 1.6 2.0 *All Statins = all doses of all statins 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 tablets 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 tablets 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 tablets co-administered with fenofibrate, respectively [see Drug Interactions (7) ]. 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: 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

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with ezetimibe and instructions for preventing or managing them. Table 3 Clinically Important Drug Interactions with Ezetimibe Tablets Cyclosporine Clinical Impact Concomitant use of ezetimibe tablets and cyclosporine increases ezetimibe and cyclosporine concentrations. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency [see Clinical Pharmacology ( 12.3 )] . Intervention Monitor cyclosporine concentrations in patients receiving ezetimibe tablets and cyclosporine. In patients treated with cyclosporine, weigh the potential effects of the increased exposure to ezetimibe from concomitant use against the benefits of alterations in lipid levels provided by ezetimibe tablets. Fibrates Clinical Impact Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. Co-administration of ezetimibe tablets with fibrates other than fenofibrate is not recommended [see Adverse Reactions ( 6.1 )] . Intervention If cholelithiasis is suspected in a patient receiving ezetimibe tablets and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. Bile Acid Sequestrants Clinical Impact Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe. This may result in a reduction of efficacy [see Clinical Pharmacology ( 12.3 )] . Intervention In patients taking a bile acid sequestrant, administer ezetimibe tablets at least 2 hours before or 4 hours after the bile acid sequestrant [see Dosage and Administration ( 2 )] . Cyclosporine: Combination increases exposure of ezetimibe tablets and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe tablets concomitantly. (7) Fibrates: Co-administration of ezetimibe tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. If cholelithiasis is suspected in a patient receiving ezetimibe tablets and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. (7) Bile Acid Sequestrants: Cholestyramine combination decreases exposure of ezetimibe tablets. (7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.