ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the label: oLiver enzyme abnormalities [see Warnings and Precautions (5.2)]o Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)]. oLiver enzyme abnormalities [see Warnings and Precautions (5.2)]. Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)]. oCommon adverse reactions in clinical trials: oEzetimibe Tablets administered alone (incidence >=2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1) oEzetimibe Tablets coadministered with 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 Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oCommon adverse reactions in clinical trials: oEzetimibe Tablets administered alone (incidence >=2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1) oEzetimibe Tablets coadministered with 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) 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of 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 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 median treatment duration of 12 weeks (range 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 >=2% and Greater than Placebo in Ezetimibe Tablets -treated Patients Adverse ReactionPlacebo(%)n 1,159Ezetimibe Tablets 10 mg(%)n 2,396Upper 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 Influenza 1.5 2.0 Combination with StatinIn 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 median treatment duration of weeks (range to 112 weeks). The incidence of consecutive increased transaminases (>=3 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 Coadministered with Statin and at an Incidence Greater than Statin Adverse ReactionAll Statins (%)n 9,361Ezetimibe Tablets All Statins (%)n 11,308Nasopharyngitis 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 statinsCombination 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 coadministration of ezetimibe tablets and fenofibrate. Incidence rates for clinically important elevations (>=3 ULN, consecutive) in hepatic transaminase levels were 4.5% and 2.7% for fenofibrate monotherapy (n=188) and ezetimibe tablets coadministered 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 coadministered with fenofibrate, respectively [see Drug Interactions (7)].. 6.2 Post-Marketing Experience. Because the reactions below are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish 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 X ULN; hepatitis; cholelithiasis; cholecystitisImmune 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1,500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.No evidence of mutagenicity was observed in vitro in microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1,000 mg/kg/day in male or female rats (~7 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to decrease in the delivery of intestinal cholesterol to the liver. This causes reduction of hepatic cholesterol stores and an increase in LDL receptors, resulting in clearance of cholesterol from the blood.. 12.2 Pharmacodynamics. Ezetimibe Tablet reduces total cholesterol (total-C), LDL-C, apolipoprotein (Apo) B, and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with hyperlipidemia. In 2-week clinical trial in 18 hypercholesterolemic patients, ezetimibe tablet inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe Tablet had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and (in trial of 113 patients) and did not impair adrenocortical steroid hormone production (in trial of 118 patients).. 12.3 Pharmacokinetics. Absorption After oral administration, ezetimibe is absorbed and extensively conjugated to pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After single 10-mg dose of ezetimibe tablets to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within to 12 hours (Tmax).Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between and hours (Tmax). There was no substantial deviation from dose proportionality between and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Effect of Food Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe tablets 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. Distribution Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. Elimination Metabolism Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Excretion Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. Specific Populations Geriatric Patients In multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (>=65 years) healthy subjects compared to younger subjects. However, the difference in plasma concentrations is not clinically meaningful. Gender In multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in females than in males. Race Based on meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and White subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in White subjects. Renal Impairment After single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl <=30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). Hepatic Impairment After single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3-to 4-fold and 5-to 6-fold, respectively, in patients with moderate (Child-Pugh score to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In 14-day, multiple-dose trial (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day and Day 14 compared to healthy subjects [see Use in Specific Populations (8.7)]. Drug Interactions Ezetimibe tablets had no significant effect on series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in cocktail trial of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.TABLE 4: Effect of Coadministered Drugs on Total EzetimibeCoadministered Drug and Dosing RegimenTotal Ezetimibe Change in AUCChange in Cmax Cyclosporine-stable dose required (75-150 mg BID)+, 240% 290% Fenofibrate, 200 mg QD,14 days 48% 64% Gemfibrozil, 600 mg BID, days 64% 91% Cholestyramine, 4g BID, 14 days 55% 4% Aluminum magnesium hydroxide combination antacid, single dose 4% 30% Cimetidine, 400 mg BID, days 6% 22% Glipizide,10 mg, single dose 4% 8% StatinsLovastatin 20 mg QD, days 9% 3% Pravastatin 20 mg QD,14 days 7% 23% Atorvastatin 10 mg QD,14 days 2% 12% Rosuvastatin10 mg QD,14 days 13% 18% Fluvastatin 20 mg QD, 14 days 19% 7% Based on 10-mg dose of ezetimibe.+ Post-renal transplant patients with mild impaired or normal renal function. In different trial, renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated 12-fold greater exposure to total ezetimibe compared to healthy subjects. See Drug Interactions (7). Supralox, 20 mL.TABLE 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other DrugsCoadministered Drug and its Dosage RegimenEzetimibe Dosage RegimenChange in AUCof Coadministered DrugChange in Cmax of Coadministered DrugWarfarin, 25-mg single dose on Day 10 mg QD, 11 days 2% (R-warfarin)4% (S-warfarin) 3% (R-warfarin)1% (S-warfarin) Digoxin, 0.5-mg single dose 10 mg QD, days 2% 7% Gemfibrozil, 600 mg BID, days 10 mg QD, days 1% 11% Ethinyl estradiol Levonorgestrel, QD, 21 days 10 mg QD, days 8-14of 21d oral contraceptive cycle Ethinyl estradiol0%Levonorgestrel0% Ethinyl estradiol9%Levonorgestrel5% Glipizide, 10 mg on Days 1and 10 mg QD, days 2-9 3% 5% Fenofibrate, 200 mg QD, 14 days 10 mg QD, 14 days 11% 7% Cyclosporine, 100-mg single dose Day 20 mg QD, days 15% 10% Statins Lovastatin 20 mg QD, days 10 mg QD, days 19% 3% Pravastatin 20 mg QD, 14 days 10 mg QD, 14 days 20% 24% Atorvastatin 10 mg QD, 14 days 10 mg QD, 14 days 4% 7% Rosuvastatin 10 mg QD, 14 days 10 mg QD, 14 days 19% 17% Fluvastatin 20 mg QD, 14 days 10 mg QD, 14 days 39% 27% See Drug Interactions (7).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Primary Hyperlipidemia in Adults Ezetimibe Tablet reduces total-C, LDL-C, Apo B, and non-HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within weeks and maintained during chronic therapy. Monotherapy In two multicenter, double-blind, placebo-controlled, 12-week trials in 1719 patients (age range 18 to 86 years, 52% females; 91% White, 5% Black or African American, 1% Asian, 3% other races mostly identified as Hispanic or Latino ethnicity) with primary hyperlipidemia, ezetimibe tablet significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to placebo (see Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.TABLE 6: Response to Ezetimibe Tablet in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline)TreatmentGroupNTotal-CLDL-CApo BNon-HDL-CTrial 1+Placebo 205 +1 +1 -1 +1 Ezetimibe 622 -12 -18 -15 -16 Trial 2+ Placebo 226 +1 +1 -1 +2 Ezetimibe 666 -12 -18 -16 -16 Pooled Data+ (Trials &2)Placebo 431 +1 -2 +1 Ezetimibe 1288 -13 -18 -16 -16 Baseline -on no lipid-lowering drug.+Ezetimibe Tablet significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to placebo.Combination with Statins: Ezetimibe Tablet Added to On-going Statin Therapy In multicenter, double-blind, placebo-controlled, 8-week trial, 769 patients (age range 22 to 85 years, 42% females; 90% White, 6% Black or African American, 1% Asian, 3% other races; and 2% identified as Hispanic or Latino ethnicity) with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy but who had not met their NCEP ATP II target LDL-C goal, were randomized to receive either ezetimibe tablet or placebo in addition to their on-going statin. Ezetimibe Tablet, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared with statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe Tablet were generally consistent across all statins. TABLE 7: Response to Addition of Ezetimibe Tablet to On-Going Statin Therapy in Patients with Hyperlipidemia (Mean Change from Treated Baseline+ Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-COn-going Statin Placebo 390 -2 -4 -3 -3 On-going Statin Ezetimibe Tablet 379 -17 -25 -19 -23 Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin).+ Baseline on statin alone. Ezetimibe Tablet statin significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to statin alone. Combination with Statins: Ezetimibe Tablet Initiated Concurrently with StatinIn four multicenter, double-blind, placebo-controlled, 12-week trials, in 2,382 patients (age range 18 to 87 years, 57% female; 88% White, 5% Black or African American, 2% Asian, 5% other races mostly identified as Hispanic or Latino) with hyperlipidemia, ezetimibe tablet or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.When all patients receiving ezetimibe tablet with statin were compared to all those receiving the corresponding statin alone, ezetimibe tablet significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to the statin administered alone. LDL-C reductions induced by ezetimibe tablet were generally consistent across all statins. (See footnote +, Tables to 11.) TABLE 8: Response to Ezetimibe Tablet and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline) Treatment(Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo 60+4 +4 +3 +4 Ezetimibe Tablet 65-14 -20 -15 -18 Atorvastatin 10 mg 60-26 -37 -28 -34 Ezetimibe Tablet Atorvastatin 10 mg 65-38 -53 -43 -49 Atorvastatin 20 mg 60-30 -42 -34 -39 Ezetimibe Tablet Atorvastatin 20 mg 62-39 -54 -44 -50 Atorvastatin 40 mg 66-32 -45 -37 -41 Ezetimibe Tablet Atorvastatin 40 mg 65-42 -56 -45 -52 Atorvastatin 80 mg 62-40 -54 -46 -51 Ezetimibe Tablet Atorvastatin 80 mg 63-46 -61 -50 -58 Pooled data (All Atorvastatin Doses)+ 248-32 -44 -36 -41 Pooled data (All Ezetimibe Tablet Atorvastatin Doses)+ 255-41 -56 -45 -52 Baseline on no lipid-lowering drug.+Ezetimibe Tablets all doses of atorvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of atorvastatin pooled (10-80 mg). TABLE 9: Response to Ezetimibe Tablet and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline) Treatment(Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo 70-1 -1 -1 Ezetimibe Tablet 61-13 -19 -14 -17 Simvastatin 10 mg 70-18 -27 -21 -25 Ezetimibe Tablet Simvastatin 10 mg 67-32 -46 -35 -42 Simvastatin 20 mg 61-26 -36 -29 -33 Ezetimibe Tablet Simvastatin 20 mg 69-33 -46 -36 -42 Simvastatin 40 mg 65-27 -38 -32 -35 Ezetimibe Tablet Simvastatin 40 mg 73-40 -56 -45 -51 Simvastatin 80 mg 67-32 -45 -37 -41 Ezetimibe Tablet Simvastatin 80 mg 65-41 -58 -47 -53 Pooled data (All Simvastatin Doses)+ 263-26 -36 -30 -34 Pooled data (All Ezetimibe Tablet +Simvastatin Doses)+ 274-37 -51 -41 -47 Baseline on no lipid-lowering drug.+ Ezetimibe Tablets all doses of simvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of simvastatin pooled (10-80 mg). TABLE 10: Response to Ezetimibe Tablet and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline) Treatment(Daily Dose)N Total-C LDL-C Apo Non-HDL-CPlacebo 650 -1 -2 Ezetimibe Tablet 64-13 -20 -15 -17 Pravastatin 10 mg 66-15 -21 -16 -20 Ezetimibe Tablet Pravastatin 10 mg 71-24 -34 -27 -32 Pravastatin 20 mg 69-15 -23 -18 -20 Ezetimibe Tablet Pravastatin 20 mg 66-27 -40 -31 -36 Pravastatin 40 mg 70-22 -31 -26 -28 Ezetimibe Tablet Pravastatin 40 mg 67-30 -42 -32 -39 Pooled data (All Pravastatin Doses)+ 205-17 -25 -20 -23 Pooled data (All Ezetimibe Tablet Pravastatin Doses)+ 204-27 -39 -30 -36 Baseline on no lipid-lowering drug.+ Ezetimibe Tablet all doses of pravastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and non- HDL-C compared to all doses of pravastatin pooled (10-40 mg).TABLE 11: Response to Ezetimibe Tablet and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline)Treatment(Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo 64+1 +1 +1 Ezetimibe Tablet 72-13 -19 -14 -16 Lovastatin 10 mg 73-15 -20 -17 -19 Ezetimibe Tablet Lovastatin 10 mg 65-24 -34 -27 -31 Lovastatin 20 mg 74-19 -26 -21 -24 Ezetimibe Tablet Lovastatin 20 mg 62-29 -41 -34 -39 Lovastatin 40 mg 73-21 -30 -25 -27 Ezetimibe Tablet Lovastatin 40 mg 65-33 -46 -38 -43 Pooled data (All Lovastatin Doses) 220-18 -25 -21 -23 Pooled data (All Ezetimibe Tablet Lovastatin Doses)+ 192-29 -40 -33 -38 Baseline on no lipid-lowering drug.+Ezetimibe Tablet all doses of lovastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of lovastatin pooled (10-40 mg).Combination with FenofibrateIn multicenter, double-blind, placebo-controlled, clinical trial in patients with mixed hyperlipidemia, 625 patients (age range 20 to 76 years, 44% female; 79% White, 1% Black or African American, 20% other races; and 11% identified as Hispanic or Latino ethnicity) were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe tablet alone, 160 mg fenofibrate alone, or ezetimibe tablet and 160 mg fenofibrate in the 12-week trial. After completing the 12-week trial, eligible patients were assigned to ezetimibe tablet coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.Ezetimibe Tablet coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone (see Table 12).TABLE 12: Response to Ezetimibe Tablet and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean Change from Untreated Baseline at 12 weeks)Treatment(Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo 63 0 -1 Ezetimibe Tablet 185 -12 -13 -11 -15 Fenofibrate 160 mg 188 -11 -6 -15 -16 Ezetimibe Tablet Fenofibrate 160 mg 183 -22 -20 -26 -30 Baseline on no lipid-lowering drug.The changes in lipid endpoints after an additional 48 weeks of treatment with ezetimibe tablet coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.HeFH in Pediatric PatientsThe effects of ezetimibe tablet coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in males and females with HeFH. In multicenter, double-blind, controlled trial followed by an open-label phase, 142 males and 106 postmenarchal females, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% White, 4% Asian, 2% Black or African American, 13% multi- racial; 14% identified as Hispanic or Latino ethnicity) with HeFH were randomized to receive either ezetimibe tablet coadministered with simvastatin or simvastatin monotherapy. Inclusion in the trial required 1) baseline LDL-C level between 160 and 400 mg/dL and 2) medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the ezetimibe tablet coadministered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered ezetimibe tablet and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for weeks, coadministered ezetimibe tablet and 40- mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe tablet and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.The results of the trial at Week are summarized in Table 13. Results at Week 33 were consistent with those at Week 6. TABLE 13: Mean Percent Difference at Week Between the Pooled Ezetimibe Tablet Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with HeFH Total-CLDL-C Apo Non-HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% 95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) HoFH in Adults and Pediatric PatientsA trial was conducted to assess the efficacy of ezetimibe tablet in the treatment of HoFH. This double-blind, randomized, 12-week trial enrolled 50 patients (age range 11 to 74 years, 58% female; 90% White, 2% Black or African American, 8% other races identified as Hispanic or Latino) with clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ezetimibe tablet administered with atorvastatin or simvastatin (40 mg), or ezetimibe tablet administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7)], ezetimibe was dosed at least hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ezetimibe tablet plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe tablet, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ezetimibe tablet plus 80-mg atorvastatin or with ezetimibe tablet plus 80-mg simvastatin, LDL-C was reduced by 27%.Homozygous Sitosterolemia (Phytosterolemia) in Adults and Pediatric PatientsA trial was conducted to assess the efficacy of ezetimibe tablet in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients (age range to 72 years, 65% females; 89% White, 3% Asian, 8% other races identified as Hispanic or Latino) with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive ezetimibe tablet (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7)], ezetimibe tablet was dosed at least hours before or hours after resins were administered. Excluding the one subject receiving LDL apheresis, ezetimibe tablet significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ezetimibe tablet, mean plasma levels of plant sterols were reduced progressively over the course of the trial. Reductions in sitosterol and campesterol were consistent between patients taking ezetimibe tablet concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Ezetimibe tablets is contraindicated in patients with 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 statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablets is contraindicated in patients for whom statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for list of their contraindications [see Warnings and Precautions (5.1)].. oHypersensitivity to ezetimibe or any excipient of ezetimibe tablets. (4) oWhen used in combination with statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablets is contraindicated in patients for whom statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for list of their contraindications. (4). oHypersensitivity to ezetimibe or any excipient of ezetimibe tablets. (4) oWhen used in combination with statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe tablets is contraindicated in patients for whom statin, fenofibrate, or other LDL-C lowering therapy are contraindicated. Refer to the Prescribing Information of these products for list of their contraindications. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Ezetimibe, USP is in class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe, USP 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 409.4 and its structural formula is: Ezetimibe, USP is white to off white, crystalline powder that is soluble in methanol. Ezetimibe, USP has melting point of about 163C and is stable at ambient temperature. Ezetimibe Tablet, USP is available as tablet for oral administration containing 10 mg of ezetimibe, USP and the following inactive ingredients: lactose monohydrate, croscarmellose sodium, Hypromellose, sodium lauryl sulfate, crospovidone, microcrystaline cellulose, and magnesium stearate.. ezetimibe-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oThe recommended dose of ezetimibe tablets is 10 mg orally once daily, administered with or without food. oIf as dose is missed, take the missed dose as soon as possible. Do not double the next dose.oAssess LDL-C when clinically appropriate, as early as weeks after initiating ezetimibe tablets. Administer ezetimibe tablets at least hours before or hours after administration of bile acid sequestrant [see Drug Interactions (7)]. oThe recommended dose of ezetimibe tablets is 10 mg orally once daily, administered with or without food. oIf as dose is missed, take the missed dose as soon as possible. Do not double the next dose.. oAssess LDL-C when clinically appropriate, as early as weeks after initiating ezetimibe tablets. o Administer ezetimibe tablets at least hours before or hours after administration of bile acid sequestrant [see Drug Interactions (7)]. o10-mg orally once daily, with or without food (2) oAdminister ezetimibe tablets either >=2 hours before or >=4 hours after administration of bile acid sequestrant. (2) oAssess LDL-C when clinically appropriate, as early as weeks after initiating ezetimibe tablets. (2). o10-mg orally once daily, with or without food (2) oAdminister ezetimibe tablets either >=2 hours before or >=4 hours after administration of bile acid sequestrant. (2) oAssess LDL-C when clinically appropriate, as early as weeks after initiating ezetimibe tablets. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 10-mg tablets are white to off white capsule shaped, flat faced, beveled edge tablets, debossed with A25 on one side and plain on other side. Tablets: 10 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes list of drugs with clinically important drug interactions when administered concomitantly with ezetimibe tablets and instructions for preventing or managing them.Table 3: Clinically Important Drug Interactions with Ezetimibe TabletsCyclosporineClinical 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. FibratesClinical 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 patient receiving ezetimibe tablets and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. Bile Acid SequestrantsClinical Impact:Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe. This may result in reduction of efficacy [see Clinical Pharmacology (12.3)]. Intervention:In patients taking bile acid sequestrant, administer ezetimibe tablets at least hours before or hours after the bile acid sequestrant [see Dosage and Administration (2)]. oCyclosporine: Combination increases exposure of ezetimibe tablets and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe tablets concomitantly. (7) oFibrates: Coadministration of ezetimibe tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. If cholelithiasis is suspected in patient receiving ezetimibe tablets and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. (7)oBile Acid Sequestrants: Cholestyramine combination decreases exposure of ezetimibe tablets. (7) oCyclosporine: Combination increases exposure of ezetimibe tablets and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe tablets concomitantly. (7) oFibrates: Coadministration of ezetimibe tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. If cholelithiasis is suspected in patient receiving ezetimibe tablets and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. (7). oBile Acid Sequestrants: Cholestyramine combination decreases exposure of ezetimibe tablets. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 2,396 patients who received ezetimibe tablets in clinical trials, 669 (28%) were 65 years of age and older, and 111 (5%) were 75 years of age and older. Of the 11,308 patients who received ezetimibe tablets in combination with statin in clinical trials, 3587 (32%) were 65 years of age and older, and 924 (8%) were 75 years of age and older [see Clinical Studies (14)]. No overall differences in safety or effectiveness of ezetimibe tablets have been observed between patients 65 years of age and older and younger patients. No clinically meaningful differences in the pharmacokinetics of ezetimibe were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Ezetimibe Tablets, USP 10 mg, are white to off white capsule shaped, flat faced, beveled edgetablets, debossed with A25 on one side and plain on other side. They are supplied as follows: Cartons of 20 tablets (10 tablets each blister pack 2), NDC 0904-7103-10 Cartons of 30 tablets (10 tablets each blister pack 3), NDC 0904-7103-04WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Storage Store at 25C (77F); excursions permitted between 15 to 30C (59 to 86F). [See USP Controlled Room Temperature.] Protect from moisture.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ezetimibe Tablets is indicated:oIn combination with 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). oIn combination with statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH. oIn combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia. oIn combination with 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). oAs an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients years of age and older with homozygous familial sitosterolemia.When ezetimibe tablets is used in combination with statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for information on the safe and effective use.. oIn combination with 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). oIn combination with statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH. oIn combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia. oIn combination with 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). oAs an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients years of age and older with homozygous familial sitosterolemia.. EZETIMIBE Tabletsis indicated (1):o In combination with 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).o In combination with statin as an adjunct to diet to reduce elevated LDL-C in pediatric patients 10 years of age and older with HeFH.o In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia.o In combination with 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).o As an adjunct to diet for the reduction of elevated sitosterol and campesterol levels in adults and in pediatric patients years of age and older with homozygous familial sitosterolemia.When ezetimibe tablets is used in combination with 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-Approved Patient Labeling (Patient Information).Inform patients that ezetimibe tablet may cause liver enzyme elevations [see Warnings and Precautions (5.2)].Muscle PainAdvise patients that ezetimibe tablet may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.3), and Drug Interactions (7)].PregnancyAdvise patients to inform their healthcare provider of known or suspected pregnancy to discuss if ezetimibe tablet should be discontinued [see Use in Specific Populations (8.1)].BreastfeedingAdvise patients who have lipid disorder and are breastfeeding to discuss the options with their healthcare provider [see Use in Specific Populations (8.2)].Missed DoseInstruct patients to take ezetimibe tablet only as prescribed. If dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose.For Patient Information, please visit:http://www.ascendlaboratories.com/pti/ezetimibetablets.pdfManufactured by: Alkem Laboratories Ltd., Mumbai 400 013, INDIA. Distributed by: Ascend Laboratories, LLC Bedminster, NJ 07921Packaged and Distributed by:MAJOR(R) PHARMACEUTICALSIndianapolis, IN 46268 USARefer to package label for Distributors NDC Number Revised: January 2025.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryThere is no information about the presence of ezetimibe in human milk. Ezetimibe is present in rat milk (see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information about the effects of ezetimibe on the breastfed infant or the effects of ezetimibe on milk production. Ezetimibe tablets should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.DataEzetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to decrease in the delivery of intestinal cholesterol to the liver. This causes reduction of hepatic cholesterol stores and an increase in LDL receptors, resulting in clearance of cholesterol from the blood.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1,500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.No evidence of mutagenicity was observed in vitro in microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1,000 mg/kg/day in male or female rats (~7 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of overdose, consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel MAJOR(R)NDC 0904-7103-10Unit DoseEzetimibeTablets, USP10 mg20 TABLETS (2 10)Rx only. 10mg carton label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ezetimibe tablets in combination with statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of ezetimibe tablets for this indication is based on double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)]. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females. The safety and effectiveness of ezetimibe tablets in combination with statin, and other LDL-C lowering therapies, to reduce LDL-C have been established in pediatric patients 10 years of age and older with HoFH. Use of ezetimibe tablets for this indication is based on 12-week double-blind, placebo-controlled clinical trial followed by an uncontrolled extension period in pediatric patients 11 years of age and older with HoFH [see Clinical Studies (14)].The safety and effectiveness of ezetimibe tablets as an adjunct to diet for the reduction of elevated sitosterol and campesterol levels have been established in adults and pediatric patients years of age and older with homozygous familial sitosterolemia. Use of ezetimibe tablets for this indication is based on an 8-week double-blind, placebo-controlled clinical trial in patients years of age and older with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) [see Clinical Studies (14)]. The safety and effectiveness of ezetimibe tablets have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, in pediatric patients younger than years of age with homozygous familial sitosterolemia, or in pediatric patients with other types of hyperlipidemia.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Ezetimibe Tablet reduces total cholesterol (total-C), LDL-C, apolipoprotein (Apo) B, and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with hyperlipidemia. In 2-week clinical trial in 18 hypercholesterolemic patients, ezetimibe tablet inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe Tablet had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and (in trial of 113 patients) and did not impair adrenocortical steroid hormone production (in trial of 118 patients).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption After oral administration, ezetimibe is absorbed and extensively conjugated to pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After single 10-mg dose of ezetimibe tablets to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within to 12 hours (Tmax).Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between and hours (Tmax). There was no substantial deviation from dose proportionality between and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Effect of Food Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe tablets 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. Distribution Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. Elimination Metabolism Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Excretion Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. Specific Populations Geriatric Patients In multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (>=65 years) healthy subjects compared to younger subjects. However, the difference in plasma concentrations is not clinically meaningful. Gender In multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in females than in males. Race Based on meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and White subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in White subjects. Renal Impairment After single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl <=30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). Hepatic Impairment After single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3-to 4-fold and 5-to 6-fold, respectively, in patients with moderate (Child-Pugh score to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In 14-day, multiple-dose trial (10 mg daily) in patients with moderate hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day and Day 14 compared to healthy subjects [see Use in Specific Populations (8.7)]. Drug Interactions Ezetimibe tablets had no significant effect on series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in cocktail trial of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.TABLE 4: Effect of Coadministered Drugs on Total EzetimibeCoadministered Drug and Dosing RegimenTotal Ezetimibe Change in AUCChange in Cmax Cyclosporine-stable dose required (75-150 mg BID)+, 240% 290% Fenofibrate, 200 mg QD,14 days 48% 64% Gemfibrozil, 600 mg BID, days 64% 91% Cholestyramine, 4g BID, 14 days 55% 4% Aluminum magnesium hydroxide combination antacid, single dose 4% 30% Cimetidine, 400 mg BID, days 6% 22% Glipizide,10 mg, single dose 4% 8% StatinsLovastatin 20 mg QD, days 9% 3% Pravastatin 20 mg QD,14 days 7% 23% Atorvastatin 10 mg QD,14 days 2% 12% Rosuvastatin10 mg QD,14 days 13% 18% Fluvastatin 20 mg QD, 14 days 19% 7% Based on 10-mg dose of ezetimibe.+ Post-renal transplant patients with mild impaired or normal renal function. In different trial, renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated 12-fold greater exposure to total ezetimibe compared to healthy subjects. See Drug Interactions (7). Supralox, 20 mL.TABLE 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other DrugsCoadministered Drug and its Dosage RegimenEzetimibe Dosage RegimenChange in AUCof Coadministered DrugChange in Cmax of Coadministered DrugWarfarin, 25-mg single dose on Day 10 mg QD, 11 days 2% (R-warfarin)4% (S-warfarin) 3% (R-warfarin)1% (S-warfarin) Digoxin, 0.5-mg single dose 10 mg QD, days 2% 7% Gemfibrozil, 600 mg BID, days 10 mg QD, days 1% 11% Ethinyl estradiol Levonorgestrel, QD, 21 days 10 mg QD, days 8-14of 21d oral contraceptive cycle Ethinyl estradiol0%Levonorgestrel0% Ethinyl estradiol9%Levonorgestrel5% Glipizide, 10 mg on Days 1and 10 mg QD, days 2-9 3% 5% Fenofibrate, 200 mg QD, 14 days 10 mg QD, 14 days 11% 7% Cyclosporine, 100-mg single dose Day 20 mg QD, days 15% 10% Statins Lovastatin 20 mg QD, days 10 mg QD, days 19% 3% Pravastatin 20 mg QD, 14 days 10 mg QD, 14 days 20% 24% Atorvastatin 10 mg QD, 14 days 10 mg QD, 14 days 4% 7% Rosuvastatin 10 mg QD, 14 days 10 mg QD, 14 days 19% 17% Fluvastatin 20 mg QD, 14 days 10 mg QD, 14 days 39% 27% See Drug Interactions (7).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are insufficient data on ezetimibe use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC (see Data). Ezetimibe tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe tablets is administered with statin, refer to the Prescribing Information for the statin.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal DataIn oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats (gestation days 6-15) and rabbits (gestation days 7-19), there was no evidence of maternal toxicity or embryolethal effects at the doses tested (250, 500, 1,000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1,000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1,000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using maternal dose of 1,000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1.5 for rats on gestation day 20 and 0.03 for rabbits on gestation day 22.The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1,000 mg/kg/day from gestation day through lactation day 21. No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures. Reproductive findings occurred at lower doses in combination therapy compared to monotherapy.

SPL UNCLASSIFIED SECTION.

5.1 Risks Associated with Combination Treatment with Statin, Fenofibrate, or Other LDL-C Lowering Therapies. If ezetimibe tablets is administered with statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for description of their risks including, but not limited to, the warnings and precautions [see Contraindications (4)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are insufficient data on ezetimibe use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC (see Data). Ezetimibe tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe tablets is administered with statin, refer to the Prescribing Information for the statin.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal DataIn oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats (gestation days 6-15) and rabbits (gestation days 7-19), there was no evidence of maternal toxicity or embryolethal effects at the doses tested (250, 500, 1,000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1,000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1,000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using maternal dose of 1,000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1.5 for rats on gestation day 20 and 0.03 for rabbits on gestation day 22.The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1,000 mg/kg/day from gestation day through lactation day 21. No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures. Reproductive findings occurred at lower doses in combination therapy compared to monotherapy.. 8.2 Lactation. Risk SummaryThere is no information about the presence of ezetimibe in human milk. Ezetimibe is present in rat milk (see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information about the effects of ezetimibe on the breastfed infant or the effects of ezetimibe on milk production. Ezetimibe tablets should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.DataEzetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12.. 8.4 Pediatric Use. The safety and effectiveness of ezetimibe tablets in combination with statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of ezetimibe tablets for this indication is based on double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)]. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the adolescent males or females, or on menstrual cycle length in females. The safety and effectiveness of ezetimibe tablets in combination with statin, and other LDL-C lowering therapies, to reduce LDL-C have been established in pediatric patients 10 years of age and older with HoFH. Use of ezetimibe tablets for this indication is based on 12-week double-blind, placebo-controlled clinical trial followed by an uncontrolled extension period in pediatric patients 11 years of age and older with HoFH [see Clinical Studies (14)].The safety and effectiveness of ezetimibe tablets as an adjunct to diet for the reduction of elevated sitosterol and campesterol levels have been established in adults and pediatric patients years of age and older with homozygous familial sitosterolemia. Use of ezetimibe tablets for this indication is based on an 8-week double-blind, placebo-controlled clinical trial in patients years of age and older with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) [see Clinical Studies (14)]. The safety and effectiveness of ezetimibe tablets have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, in pediatric patients younger than years of age with homozygous familial sitosterolemia, or in pediatric patients with other types of hyperlipidemia.. 8.5 Geriatric Use. Of the 2,396 patients who received ezetimibe tablets in clinical trials, 669 (28%) were 65 years of age and older, and 111 (5%) were 75 years of age and older. Of the 11,308 patients who received ezetimibe tablets in combination with statin in clinical trials, 3587 (32%) were 65 years of age and older, and 924 (8%) were 75 years of age and older [see Clinical Studies (14)]. No overall differences in safety or effectiveness of ezetimibe tablets have been observed between patients 65 years of age and older and younger patients. No clinically meaningful differences in the pharmacokinetics of ezetimibe were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment. No dosage adjustment of ezetimibe tablets is necessary in patients with renal impairment. 8.7 Hepatic Impairment. Ezetimibe tablets is not recommended for use in patients with moderate to severe hepatic impairment (Child-Pugh or C) due to the unknown effects of the increased exposure to ezetimibe [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oRisks Associated with Combination Treatment with Statin, Fenofibrate, or Other LDL-C Lowering Therapies: Refer to the Prescribing Information of these products for description of their risks including, but not limited to, the warnings and precautions. (5.1) oLiver Enzyme Abnormalities and Monitoring: Increases in serum transaminases have been reported with use of ezetimibe tablets. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe tablets if increases in ALT or AST >=3 ULN persist. (5.2) oSkeletal Muscle Effects (e.g., Myopathy and Rhabdomyolysis): ezetimibe tablets may cause myopathy and rhabdomyolysis. In post-marketing reports, most patients who developed rhabdomyolysis were taking statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ezetimibe tablets and other concomitant medications, as appropriate. (5.3) oRisks Associated with Combination Treatment with Statin, Fenofibrate, or Other LDL-C Lowering Therapies: Refer to the Prescribing Information of these products for description of their risks including, but not limited to, the warnings and precautions. (5.1) oLiver Enzyme Abnormalities and Monitoring: Increases in serum transaminases have been reported with use of ezetimibe tablets. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe tablets if increases in ALT or AST >=3 ULN persist. (5.2) oSkeletal Muscle Effects (e.g., Myopathy and Rhabdomyolysis): ezetimibe tablets may cause myopathy and rhabdomyolysis. In post-marketing reports, most patients who developed rhabdomyolysis were taking statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ezetimibe tablets and other concomitant medications, as appropriate. (5.3) 5.1 Risks Associated with Combination Treatment with Statin, Fenofibrate, or Other LDL-C Lowering Therapies. If ezetimibe tablets is administered with statin, fenofibrate, or other LDL-C lowering therapies, refer to the Prescribing Information of these products for 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 tablets [see Adverse Reactions (6.1)]. In controlled clinical combination studies of ezetimibe tablets initiated concurrently with statin, the incidence of consecutive elevations (>=3 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. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe tablets if increases in ALT or AST >=3 ULN persist. 5.3 Myopathy/Rhabdomyolysis. Ezetimibe tablets 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 statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ezetimibe tablets and other concomitant medications, as appropriate.