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. In 2-week clinical study in 18 hypercholesterolemic patients, Ezetimibe Tablets inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe Tablets had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and (in study of 113 patients), and did not impair adrenocortical steroid hormone production (in study of 118 patients). The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol. Ezetimibe has mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). 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 does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, 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 clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate [see Clinical Studies (14.1)]. 12.2 Pharmacodynamics. Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Ezetimibe Tablets reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe Tablets with statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe Tablets with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to statin or fenofibrate on cardiovascular morbidity and mortality have not been established. 12.3 Pharmacokinetics. AbsorptionAfter 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 ezetimibecannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.Effect of Food on Oral AbsorptionConcomitant 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. Ezetimibe Tablets can be administered with or without food.DistributionEzetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.Metabolism and ExcretionEzetimibe 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 majordrug-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.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 radio activity 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 PopulationsGeriatric Patients: In multiple-dose study 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.Pediatric Patients: [See Use in Specific Populations (8.4).]Gender: In multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.Race: Based on meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.HepaticImpairment: 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 study (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. Due to the unknown effects ofthe increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Ezetimibe Tablet is not recommended in these patients [see Warnings and Precautions (5.4)].Renal Impairment: After single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl <=30mL/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).Drug Interactions [See also Drug Interactions (7)]Ezetimibe Tablets had no significant effect on series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IVmidazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4)in cocktail study 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 Co-Administered Drugs on Total EzetimibeCo-Administered Drug and Dosing RegimenTotal Ezetimibe Change in AUC Change in Cmax Cyclosporine-stable dose required (75 to 150 mg BID)+, 240% 290% Fenofibrate, 200 mg QD, 14 days 48% 64% Gemfibrozil, 600 mg BID, days 64% 91% Cholestyramine, g 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% Statins Lovastatin 20 mg QD, days 9% 3% Pravastatin 20 mg QD, 14 days 7% 23% Atorvastatin 10 mg QD, 14 days 2% 12% Rosuvastatin 10 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 study, 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 Co-Administration on Systemic Exposure to Other DrugsCo-Administered Drug and its Dosage RegimenEzetimibe Dosage RegimenChange in AUC of Co-Administered DrugChange in Cmax of Co-Administered 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 to14 of 21d oral contraceptive cycle Ethinyl estradiol 0% Levonorgestrel 0% Ethinyl estradiol 9% Levonorgestrel 5% Glipizide, 10 mg on days and 10 mg QD, days to 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. 14.1 Primary Hyperlipidemia. Ezetimibe Tablets reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases 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 studies in 1719 patients with primary hyperlipidemia, Ezetimibe Tablets significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.TABLE 6: Response to Ezetimibe Tablets in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline+) Treatment Group Total-C LDL-C Apo Non-HDL-C TG HDL-C Study Placebo 205 +1 +1 -1 +1 -1 -1 Ezetimibe 622 -12 -18 -15 -16 -7 +1 Study Placebo 226 +1 +1 -1 +2 +2 -2 Ezetimibe 666 -12 -18 -16 -16 -9 +1 Pooled Data (Studies & 2) Placebo 431 +1 -2 +1 -2 Ezetimibe 1288 -13 -18 -16 -16 -8 +1 For triglycerides, median change from baseline Baseline on no lipid-lowering drug Ezetimibe Tablets significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.Combination with Statins Ezetimibe Tablets Added to On-going Statin Therapy In multicenter, double-blind, placebo-controlled, 8-week study, 769 patients 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 Tablets or placebo in addition to their on-going statin. Ezetimibe Tablets, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe Tablets were generally consistent across all statins.TABLE 7: Response to Addition of Ezetimibe Tablets to On-Going Statin Therapy in Patients with Hyperlipidemia (Mean+ Change from Treated Baseline)Treatment (Daily Dose) Total-C LDL-C Apo Non-HDL-C TG+ HDL-C On-going Statin Placebo 390 -2 -4 -3 -3 -3 +1 On-going Statin Ezetimibe Tablets 379 -17 -25 -19 -23 -14 +3 Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin) For triglycerides, median change from baseline Baseline on statin alone. Ezetimibe Tablets statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.Ezetimibe Tablets Initiated Concurrently with Statin In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe Tablets or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin. When all patients receiving Ezetimibe Tablets with statin were compared to all those receiving the corresponding statin alone, Ezetimibe Tablets significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by Ezetimibe Tablets were generally consistent across all statins. (See footnote Tables to 11.)TABLE 8: Response to Ezetimibe Tablets and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline+)Treatment (Daily Dose) Total-C LDL-C Apo Non-HDL-C TG HDL-C Placebo 60 +4 +4 +3 +4 -6 +4 Ezetimibe Tablets 65 -14 -20 -15 -18 -5 +4 Atorvastatin 10 mg 60 -26 -37 -28 -34 -21 +6 Ezetimibe Tablets Atorvastatin 10 mg 65 -38 -53 -43 -49 -31 +9 Atorvastatin 20 mg 60 -30 -42 -34 -39 -23 +4 Ezetimibe Tablets Atorvastatin 20 mg 62 -39 -54 -44 -50 -30 +9 Atorvastatin 40 mg 66 -32 -45 -37 -41 -24 +4 Ezetimibe Tablets Atorvastatin 40 mg 65 -42 -56 -45 -52 -34 +5 Atorvastatin 80 mg 62 -40 -54 -46 -51 -31 +3 Ezetimibe Tablets Atorvastatin 80 mg 63 -46 -61 -50 -58 -40 +7 Pooled data (All Atorvastatin Doses) 248 -32 -44 -36 -41 -24 +4 Pooled data (All Ezetimibe Tablets Atorvastatin Doses) 255 -41 -56 -45 -52 -33 +7 For triglycerides, median change from baseline Baseline on no lipid-lowering drug Ezetimibe Tablets all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg).TABLE 9: Response to Ezetimibe Tablets and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline+)Treatment (Daily Dose) Total-C LDL-C Apo Non-HDL-C TG HDL-C Placebo 70 -1 -1 -1 +2 +1 Ezetimibe Tablets 61 -13 -19 -14 -17 -11 +5 Simvastatin 10 mg 70 -18 -27 -21 -25 -14 +8 Ezetimibe Tablets Simvastatin 10 mg 67 -32 -46 -35 -42 -26 +9 Simvastatin 20 mg 61 -26 -36 -29 -33 -18 +6 Ezetimibe Tablets Simvastatin 20 mg 69 -33 -46 -36 -42 -25 +9 Simvastatin 40 mg 65 -27 -38 -32 -35 -24 +6 Ezetimibe Tablets Simvastatin 40 mg 73 -40 -56 -45 -51 -32 +11 Simvastatin 80 mg 67 -32 -45 -37 -41 -23 +8 Ezetimibe Tablets Simvastatin 80 mg 65 -41 -58 -47 -53 -31 +8 Pooled data (All Simvastatin Doses) 263 -26 -36 -30 -34 -20 +7 Pooled data (All Ezetimibe Tablets Simvastatin Doses) 274 -37 -51 -41 -47 -29 +9 For triglycerides, median change from baseline Baseline on no lipid-lowering drug Ezetimibe Tablets all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10 to 80 mg).TABLE 10: Response to Ezetimibe Tablets and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline+)Treatment (Daily Dose) Total-C LDL-C Apo Non-HDL-C TG HDL-C Placebo 65 -1 -2 -1 +2 Ezetimibe Tablets 64 -13 -20 -15 -17 -5 +4 Pravastatin 10 mg 66 -15 -21 -16 -20 -14 +6 Ezetimibe Tablets Pravastatin 10 mg 71 -24 -34 -27 -32 -23 +8 Pravastatin 20 mg 69 -15 -23 -18 -20 -8 +8 Ezetimibe Tablets Pravastatin 20 mg 66 -27 -40 -31 -36 -21 +8 Pravastatin 40 mg 70 -22 -31 -26 -28 -19 +6 Ezetimibe Tablets Pravastatin 40 mg 67 -30 -42 -32 -39 -21 +8 Pooled data (All Pravastatin Doses) 205 -17 -25 -20 -23 -14 +7 Pooled data (All Ezetimibe Tablets Pravastatin Doses) 204 -27 -39 -30 -36 -21 +8 For triglycerides, median change from baseline Baseline on no lipid-lowering drug Ezetimibe Tablets all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10 to 40 mg).TABLE 11: Response to Ezetimibe Tablets and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated Baseline+)Treatment (Daily Dose) Total-C LDL-C Apo Non-HDL-C TG HDL-C Placebo 64 +1 +1 +1 +6 Ezetimibe Tablets 72 -13 -19 -14 -16 -5 +3 Lovastatin 10 mg 73 -15 -20 -17 -19 -11 +5 Ezetimibe Tablets Lovastatin 10 mg 65 -24 -34 -27 -31 -19 +8 Lovastatin 20 mg 74 -19 -26 -21 -24 -12 +3 Ezetimibe Tablets Lovastatin 20 mg 62 -29 -41 -34 -39 -27 +9 Lovastatin 40 mg 73 -21 -30 -25 -27 -15 +5 Ezetimibe Tablets Lovastatin 40 mg 65 -33 -46 -38 -43 -27 +9 Pooled data (All Lovastatin Doses) 220 -18 -25 -21 -23 -12 +4 Pooled data (All Ezetimibe Tablets Lovastatin Doses) 192 -29 -40 -33 -38 -25 +9 For triglycerides, median change from baseline Baseline on no lipid-lowering drug Ezetimibe Tablets all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10 to 40 mg).Combination with Fenofibrate In multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe Tablets alone, 160 mg fenofibrate alone, or Ezetimibe Tablets and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe Tablets co-administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks. Ezetimibe Tablets co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe Tablets co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).TABLE 12: Response to Ezetimibe Tablets and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean Change from Untreated Baseline+ at 12 weeks)Treatment (Daily Dose) Total-C LDL-C Apo TG HDL-C Non-HDL-C Placebo 63 0 -1 -9 +3 Ezetimibe Tablets 185 -12 -13 -11 -11 +4 -15 Fenofibrate 160 mg 188 -11 -6 -15 -43 +19 -16 Ezetimibe Tablets Fenofibrate 160 mg 183 -22 -20 -26 -44 +19 -30 For triglycerides, median change from baseline Baseline on no lipid-lowering drugThe changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe Tablets co-administered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above. 14.2 Homozygous Familial Hypercholesterolemia (HoFH). study was conducted to assess the efficacy of Ezetimibe Tablets in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients 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 Tablets administered with atorvastatin or simvastatin (40 mg), or Ezetimibe Tablets administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], 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 Tablets plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe Tablets, 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 Tablets plus 80 mg atorvastatin or with Ezetimibe Tablets plus 80 mg simvastatin, LDL-C was reduced by 27%. 14.3 Homozygous Sitosterolemia (Phytosterolemia). study was conducted to assess the efficacy of Ezetimibe Tablets in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients 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 Tablets (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], ezetimibe was dosed at least hours before or hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe Tablets 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 Tablets, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established. Reductions in sitosterol and campesterol were consistent between patients taking Ezetimibe Tablets concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21). Limitations of Use The effect of Ezetimibe Tablets on cardiovascular morbidity and mortality has not been determined.

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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Ezetimibe Tablet is contraindicated in the following conditions: oThe combination of Ezetimibe Tablets with statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. oWomen 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 Tablets in combination with 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).] oNursing 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 Tablets treatment in combination with statin should be advised not to nurse their infants [see Use in Specific Populations (8.3)]. oPatients with known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with Ezetimibe Tablets [see Adverse Reactions (6.2)]. oThe combination of Ezetimibe Tablets with statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. oWomen 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 Tablets in combination with statin may cause fetal harm when administered to pregnant women. oNursing 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 Tablets treatment in combination with statin should be advised not to nurse their infants [see Use in Specific Populations (8.3)]. oPatients with known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with Ezetimibe Tablets [see Adverse Reactions (6.2)]. o Statin contraindications apply when Ezetimibe Tablet is used with statin: oActive liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4, 5.2) oWomen who are pregnant or may become pregnant (4, 8.1)oNursing mothers (4, 8.3) oKnown hypersensitivity to product components (4, 6.2) oActive liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4, 5.2) oWomen who are pregnant or may become pregnant (4, 8.1)oNursing mothers (4, 8.3) oKnown hypersensitivity to product components (4, 6.2) oNursing mothers (4, 8.3) oKnown hypersensitivity to product components (4, 6.2).

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)] oRhabdomyolysis and myopathy [see Warnings and Precautions (5.3)] Monotherapy Studies: In the Ezetimibe Tablets controlled clinical trials database (placebo-controlled) of 2396 patients with median treatment duration of 12 weeks (range to 39 weeks), 3.3% of patients on Ezetimibe Tablets and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe Tablets that led to treatment discontinuation and occurred at rate greater than placebo were: oArthralgia (0.3%) oDizziness (0.2%) oGamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence >=2% and greater than placebo) in the Ezetimibe Tablets monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Co-Administration Studies: In the Ezetimibe Tablets statin controlled clinical trials database of 11,308 patients with median treatment duration of weeks (range to 112 weeks), 4.0% of patients on Ezetimibe Tablets statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe Tablets statin that led to treatment discontinuation and occurred at rate greater than statin alone were: oAlanine aminotransferase increased (0.6%) oMyalgia (0.5%) oFatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence >=2% and greater than statin alone) in the Ezetimibe Tablets statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%). oLiver enzyme abnormalities [see Warnings and Precautions (5.2)] oRhabdomyolysis and myopathy [see Warnings and Precautions (5.3)] oArthralgia (0.3%) oDizziness (0.2%) oGamma-glutamyltransferase increased (0.2%) oAlanine aminotransferase increased (0.6%) oMyalgia (0.5%) oFatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) o Common adverse reactions in clinical trials: oEzetimibe Tablets co-administered with statin (incidence >=2% and greater than statin alone): onasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea (6) oEzetimibe Tablets 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 Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oEzetimibe Tablets co-administered with statin (incidence >=2% and greater than statin alone): onasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea (6) oEzetimibe Tablets administered alone (incidence >=2% and greater than placebo): oEzetimibe Tablets administered alone (incidence >=2% and greater than placebo): 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, 2396 patients with primary hyperlipidemia (age range to 86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe Tablets 10 mg/day for 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, regardless of causality assessment, are shown in Table 1. TABLE 1: Clinical Adverse Reactions Occurring in >=2% of Patients Treated with Ezetimibe Tablets and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse ReactionEzetimibe Tablets 10 mg (%) = 2396Placebo (%) = 1159Gastrointestinal disorders Diarrhea 4.1 3.7 General disorders and administration site conditions Fatigue 2.4 1.5 Infections and infestations Influenza 2.0 1.5 Sinusitis 2.8 2.2 Upper respiratory tract infection 4.3 2.5 Musculoskeletal and connective tissue disorders Arthralgia 3.0 2.2 Pain in extremity 2.7 2.5 The frequency of less common adverse reactions was comparable between Ezetimibe Tablets and placebo. Combination with Statin In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (age range 10 to 93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with Ezetimibe Tablets 10 mg/day concurrently with or added to on-going statin therapy for 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%). [See Warnings and Precautions (5.2).] Clinical adverse reactions reported in >=2% of patients treated with Ezetimibe Tablets statin and at an incidence greater than statin, regardless of causality assessment, are shown in Table 2.TABLE 2: Clinical Adverse Reactions Occurring in >=2% of Patients Treated with Ezetimibe Tablets Co-Administered with Statin and at an Incidence Greater than Statin, Regardless of Causality Body System/Organ Class Adverse Reaction All Statins (%) = 9361Ezetimibe Tablets All Statins (%) = 11,308Gastrointestinal disorders Diarrhea 2.2 2.5 General disorders and administration site conditions Fatigue 1.6 2.0 Infections and infestations Influenza 2.1 2.2 Nasopharyngitis 3.3 3.7 Upper respiratory tract infection 2.8 2.9 Musculoskeletal and connective tissue disorders Arthralgia 2.4 2.6 Back pain 2.3 2.4 Myalgia 2.7 3.2 Pain in extremity 1.9 2.1 All Statins all doses of all statinsCombination with Fenofibrate This clinical study involving 625 patients with mixed dyslipidemia (age range 20 to 76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated co-administration of Ezetimibe Tablets and fenofibrate. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>=3 ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy (n=188) and Ezetimibe Tablets co-administered with fenofibrate (n=183), respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for fenofibrate monotherapy and Ezetimibe Tablets co-administered with fenofibrate, respectively [see Drug Interactions (7.3)].The numbers of patients exposed to co-administration therapy as well as fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder disease risk. There were no CPK elevations >10 ULN in any of the treatment groups.. 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: 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Pharmacology OR Toxicology. The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 mcg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 mcg/kg/day, respectively. These results are consistent with Ezetimibe Tablets being potent cholesterol absorption inhibitor. In rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug. In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In 14-day study in mice given ezetimibe (0.3 to mg/kg/day) and fed low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. series of acute preclinical studies was performed to determine the selectivity of Ezetimibe Tablets for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins and D. In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

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 1500 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 1000 mg/kg/day in male or female rats (~7 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. oOne 10-mg tablet once daily, with or without food (2.1) oDosing of Ezetimibe Tablets should occur either >=2 hours before or >=4 hours after administration of bile acid sequestrant. (2.3, 7.4) oOne 10-mg tablet once daily, with or without food (2.1) oDosing of Ezetimibe Tablets should occur either >=2 hours before or >=4 hours after administration of 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 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 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 m2), 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS 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. o Tablets: 10 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. [See Clinical Pharmacology (12.3).] Cyclosporine: Combination increases exposure of Ezetimibe Tablets and cyclosporine. Cyclosporine concentrations should be monitored in patients taking Ezetimibe Tablets concomitantly. (7.1, 12.3) Fenofibrate: Combination increases exposure of Ezetimibe Tablets. If cholelithiasis is suspected in patient receiving Ezetimibe Tablets and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (6.1, 7.3) Fibrates: Co-administration of Ezetimibe Tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. (7.2) Cholestyramine: Combination decreases exposure of Ezetimibe Tablets. (2.3, 7.4, 12.3) Cyclosporine: Combination increases exposure of Ezetimibe Tablets and cyclosporine. Cyclosporine concentrations should be monitored in patients taking Ezetimibe Tablets concomitantly. (7.1, 12.3) Fenofibrate: Combination increases exposure of Ezetimibe Tablets. If cholelithiasis is suspected in patient receiving Ezetimibe Tablets and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (6.1, 7.3) Fibrates: Co-administration of Ezetimibe Tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. (7.2) Cholestyramine: Combination decreases exposure of Ezetimibe Tablets. (2.3, 7.4, 12.3) 7.1 Cyclosporine. Caution should be exercised when using Ezetimibe Tablets and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe Tablets 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 preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology (13.2)]. Co-administration of Ezetimibe Tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. 7.3 Fenofibrate. If cholelithiasis is suspected in patient receiving Ezetimibe Tablets 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, coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Monotherapy Studies Of the 2396 patients who received Ezetimibe Tablets in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. Statin Co-Administration Studies Of the 11,308 patients who received Ezetimibe Tablets statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [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: Carton of 30 Tablets (10 tablets per blister card 3), NDC 0904-7103-04 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 USAGE. 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 diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe Tablet is an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet to: oReduce 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)oReduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate (1.1)oReduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin (1.2)oReduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) (1.3)Limitations of Use (1.4)oThe effect of Ezetimibe Tablets on cardiovascular morbidity and mortality has not been determined. oEzetimibe Tablets has not been studied in Fredrickson Type I, III, IV, and dyslipidemias. oReduce 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). oReduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate (1.1). oReduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin (1.2). oReduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) (1.3). oThe effect of Ezetimibe Tablets on cardiovascular morbidity and mortality has not been determined. oEzetimibe Tablets has not been studied in Fredrickson Type I, III, IV, and 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 (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 3-hydroxy-3-methylglutaryl-coenzyme (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, is 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 Tablet is 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 has not been studied in Fredrickson Type I, III, IV, and dyslipidemias.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information).Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, regular exercise program, and periodic testing of fasting lipid panel. 17.1 Muscle Pain All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician.17.2 Liver Enzymes Liver tests should be performed when Ezetimibe Tablet is added to statin therapy and according to statin recommendations. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Ezetimibe Tablets added to statin therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination Ezetimibe Tablets and statin therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination Ezetimibe Tablets and statin therapy and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should be advised to not use Ezetimibe Tablets added to statin therapy. Patients who have lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals. Manufactured by: Alkem Laboratories Ltd. Mumbai 400 013, INDIADistributed by:Ascend Laboratories, LLCParsippany, NJ 07054Revised: March,2017 PT 2508-01.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In 2-week clinical study in 18 hypercholesterolemic patients, Ezetimibe Tablets inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe Tablets had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and (in study of 113 patients), and did not impair adrenocortical steroid hormone production (in study of 118 patients). The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol. Ezetimibe has mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). 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 does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, 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 clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate [see Clinical Studies (14.1)].

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 1500 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 1000 mg/kg/day in male or female rats (~7 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). 13.2 Animal Pharmacology OR Toxicology. The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 mcg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 mcg/kg/day, respectively. These results are consistent with Ezetimibe Tablets being potent cholesterol absorption inhibitor. In rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug. In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In 14-day study in mice given ezetimibe (0.3 to mg/kg/day) and fed low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. series of acute preclinical studies was performed to determine the selectivity of Ezetimibe Tablets for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins and D. In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe Tablet is administered to nursing woman. Ezetimibe Tablets should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In the event of an overdose, symptomatic and supportive measures should be employed.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel Ezetimibe Tablets, USP10 mg 30 Tablets. carton label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The effects of Ezetimibe Tablets co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe Tablets co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study 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 Tablets co-administered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered Ezetimibe Tablets and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for weeks, co-administered Ezetimibe Tablets and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered Ezetimibe Tablets and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.TABLE 3: Mean Percent Difference at Week Between the Pooled Ezetimibe Tablets Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia Total-C LDL-C Apo Non-HDL-C TG HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%,-9%) (-18%,-12%) (-15%, -9%) (-17%, -11%) (-9%, +4%) (-3%, +3%) For triglycerides, median change from baselineFrom the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in (6%) patients in the Ezetimibe Tablets co-administered with simvastatin group and in (2%) patients in the simvastatin monotherapy group.During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST >=3 ULN) occurred in four (3%) individuals in the Ezetimibe Tablets co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (>=10 ULN) occurred in two (2%) individuals in the Ezetimibe Tablets co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Co-administration of Ezetimibe Tablets with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe Tablets has not been studied in patients younger than 10 years of age or in pre-menarchal girls. Based on total ezetimibe (ezetimibe ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Ezetimibe Tablets reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe Tablets with statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe Tablets with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to statin or fenofibrate on cardiovascular morbidity and mortality have not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter 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 ezetimibecannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.Effect of Food on Oral AbsorptionConcomitant 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. Ezetimibe Tablets can be administered with or without food.DistributionEzetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.Metabolism and ExcretionEzetimibe 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 majordrug-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.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 radio activity 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 PopulationsGeriatric Patients: In multiple-dose study 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.Pediatric Patients: [See Use in Specific Populations (8.4).]Gender: In multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.Race: Based on meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.HepaticImpairment: 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 study (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. Due to the unknown effects ofthe increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Ezetimibe Tablet is not recommended in these patients [see Warnings and Precautions (5.4)].Renal Impairment: After single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl <=30mL/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).Drug Interactions [See also Drug Interactions (7)]Ezetimibe Tablets had no significant effect on series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IVmidazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4)in cocktail study 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 Co-Administered Drugs on Total EzetimibeCo-Administered Drug and Dosing RegimenTotal Ezetimibe Change in AUC Change in Cmax Cyclosporine-stable dose required (75 to 150 mg BID)+, 240% 290% Fenofibrate, 200 mg QD, 14 days 48% 64% Gemfibrozil, 600 mg BID, days 64% 91% Cholestyramine, g 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% Statins Lovastatin 20 mg QD, days 9% 3% Pravastatin 20 mg QD, 14 days 7% 23% Atorvastatin 10 mg QD, 14 days 2% 12% Rosuvastatin 10 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 study, 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 Co-Administration on Systemic Exposure to Other DrugsCo-Administered Drug and its Dosage RegimenEzetimibe Dosage RegimenChange in AUC of Co-Administered DrugChange in Cmax of Co-Administered 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 to14 of 21d oral contraceptive cycle Ethinyl estradiol 0% Levonorgestrel 0% Ethinyl estradiol 9% Levonorgestrel 5% Glipizide, 10 mg on days and 10 mg QD, days to 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. Pregnancy Category C: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 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 1000 mg/kg/day (~10 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 1000 mg/kg/day (150 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All statins are contraindicated in pregnant and nursing women. When Ezetimibe Tablet is administered with statin in woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4).].

SPL UNCLASSIFIED SECTION.

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 (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 3-hydroxy-3-methylglutaryl-coenzyme (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, is 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category C: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 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 1000 mg/kg/day (~10 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 1000 mg/kg/day (150 the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All statins are contraindicated in pregnant and nursing women. When Ezetimibe Tablet is administered with statin in woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4).] 8.3 Nursing Mothers. It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe Tablet is administered to nursing woman. Ezetimibe Tablets should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. 8.4 Pediatric Use. The effects of Ezetimibe Tablets co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe Tablets co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study 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 Tablets co-administered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered Ezetimibe Tablets and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for weeks, co-administered Ezetimibe Tablets and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered Ezetimibe Tablets and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.TABLE 3: Mean Percent Difference at Week Between the Pooled Ezetimibe Tablets Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia Total-C LDL-C Apo Non-HDL-C TG HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%,-9%) (-18%,-12%) (-15%, -9%) (-17%, -11%) (-9%, +4%) (-3%, +3%) For triglycerides, median change from baselineFrom the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in (6%) patients in the Ezetimibe Tablets co-administered with simvastatin group and in (2%) patients in the simvastatin monotherapy group.During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST >=3 ULN) occurred in four (3%) individuals in the Ezetimibe Tablets co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (>=10 ULN) occurred in two (2%) individuals in the Ezetimibe Tablets co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Co-administration of Ezetimibe Tablets with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe Tablets has not been studied in patients younger than 10 years of age or in pre-menarchal girls. Based on total ezetimibe (ezetimibe ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available. 8.5 Geriatric Use. Monotherapy Studies Of the 2396 patients who received Ezetimibe Tablets in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. Statin Co-Administration Studies Of the 11,308 patients who received Ezetimibe Tablets statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment. When used as monotherapy, no dosage adjustment of Ezetimibe Tablets is necessary.In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during median follow-up of 4.9 years. However, because renal impairment is risk factor for statin-associated myopathy, doses of simvastatin exceeding 20 mg should be used with caution andclose monitoring when administered concomitantly with Ezetimibe Tablets in patients with moderate to severe renal impairment.. 8.7 Hepatic Impairment. Ezetimibe Tablet is not recommended in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. Ezetimibe Tablets given concomitantly with statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4); Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oEzetimibe Tablet is not recommended in patients with moderate or severe hepatic impairment. (5.4, 8.7, 12.3) oLiver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when Ezetimibe Tablet is added to statin. Therefore, when Ezetimibe Tablet is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used. (5.2) oSkeletal muscle effects (e.g., myopathy and rhabdomyolysis): oCases of myopathy and rhabdomyolysis have been reported in patients treated with Ezetimibe Tablets co-administered with statin and with Ezetimibe Tablets administered alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. (5.3, 6.2) oEzetimibe Tablet is not recommended in patients with moderate or severe hepatic impairment. (5.4, 8.7, 12.3) oLiver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when Ezetimibe Tablet is added to statin. Therefore, when Ezetimibe Tablet is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used. (5.2) oSkeletal muscle effects (e.g., myopathy and rhabdomyolysis): oCases of myopathy and rhabdomyolysis have been reported in patients treated with Ezetimibe Tablets co-administered with statin and with Ezetimibe Tablets administered alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. (5.3, 6.2) 5.1 Use with Statins or Fenofibrate. Concurrent administration of Ezetimibe Tablets with specific statin or fenofibrate should be in accordance with the product labeling for that medication. 5.2 Liver Enzymes. In controlled clinical monotherapy studies, the incidence of consecutive elevations (>=3 the upper limit of normal [ULN]) in hepatic transaminase levels was similar between Ezetimibe Tablets (0.5%) and placebo (0.3%). In controlled clinical combination studies of Ezetimibe Tablets initiated concurrently with 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. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When Ezetimibe Tablet is co-administered with statin, liver tests should be performed at initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST >=3 ULN persist, consider withdrawal of Ezetimibe Tablets and/or the statin. 5.3 Myopathy/Rhabdomyolysis. In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetimibe Tablets compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 ULN was 0.2% for Ezetimibe Tablets vs. 0.1% for placebo, and 0.1% for Ezetimibe Tablets co-administered with statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. In post-marketing experience with Ezetimibe Tablets, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking statin prior to initiating Ezetimibe Tablets. However, rhabdomyolysis has been reported with Ezetimibe Tablets monotherapy and with the addition of Ezetimibe Tablets to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Ezetimibe Tablets and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and CPK level >10 the ULN indicates myopathy. 5.4 Hepatic Impairment. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe hepatic impairment, Ezetimibe Tablet is not recommended in these patients. [See Clinical Pharmacology (12.3 ).].