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 [seeWarnings and Precautions (5.3)]. oLiver enzyme abnormalities [see Warnings and Precautions (5.2)]. oRhabdomyolysis and myopathy [seeWarnings and Precautions (5.3)]. oCommon adverse reactions in clinical trials: oEzetimibe administered alone (incidence >=2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1)oEzetimibe co-administered 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 Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oCommon adverse reactions in clinical trials: oEzetimibe administered alone (incidence >=2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1)oEzetimibe co-administered 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). oEzetimibe administered alone (incidence >=2% and greater than placebo): upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1). oEzetimibe co-administered 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.MonotherapyIn 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 10 mg daily for median treatment duration of 12 weeks (range to 39 weeks).Adverse reactions reported in >=2% of patients treated with ezetimibe and at an incidence greater than placebo in placebo-controlled studies of ezetimibe are shown in Table 1.TABLE 1: Adverse Reactions Occurring >=2% and Greater than Placebo in Ezetimibe-treated PatientsAdverse ReactionPlacebo(%)n 1,159Ezetimibe 10 mg (%)n 2,396Upper respiratory tract infection2.54.3Diarrhea3.74.1Arthralgia2.23.0Sinusitis2.22.8Pain in extremity2.52.7Fatigue1.52.4Influenza1.52.0Combination 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 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 administered with statins (1.3%) than in patients treated with statins alone (0.4%).Adverse reactions reported in >=2% of patients treated with ezetimibe statin and at an incidence greater than statin are shown in Table 2.TABLE 2: Adverse Reactions Occurring >=2% in Ezetimibe-treated Patients Coadministered with Statin and at an Incidence Greater than StatinAdverse ReactionAll Statins All Statins all doses of all statins (%)n 9,361Ezetimibe All Statins (%)n 11,308Nasopharyngitis3.33.7Myalgia2.73.2Upper respiratory tract infection2.82.9Arthralgia2.42.6Diarrhea2.22.5Back pain2.32.4Influenza2.12.2Pain in extremity1.92.1Fatigue1.62.0Combination with FenofibrateThis 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 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 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 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:Blood Disorders: thrombocytopeniaGastrointestinal Disorders: abdominal pain; pancreatitis; nauseaHepatobiliary Disorders: elevations in liver transaminases; including elevations more than X ULN; hepatitis; cholelithiasis; cholecystitisImmune System Disorders: Hypersensitivity reactions including: anaphylaxis, angioedema, rash, and urticariaMusculoskeletal Disorders: elevated creatine phosphokinase; myopathy/rhabdomyolysisNervous System Disorders: dizziness; paresthesia; depression; headacheSkin and Subcutaneous Tissue Disorders: erythema multiforme.

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 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 inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe 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. AbsorptionAfter oral administration, ezetimibe is absorbed and extensively conjugated to pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After single 10-mg dose of ezetimibe 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 FoodConcomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. DistributionEzetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.EliminationMetabolismEzetimibe 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 PopulationsGeriatric 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. RaceBased 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 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 Ezetimibe Coadministered Drug and Dosing RegimenTotal Ezetimibe Based on 10-mg dose of ezetimibeChange in AUCChange in Cmax Cyclosporine-stable dose required (75-150 mg BID)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). 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 doseSupralox, 20 mL. 4%30%Cimetidine, 400 mg BID, days6%22%Glipizide, 10 mg, single dose4%8% Statins Lovastatin 20 mg QD, days9%3% Pravastatin 20 mg QD, 14 days7%23% Atorvastatin 10 mg QD, 14 days2%12% Rosuvastatin 10 mg QD, 14 days13%18% Fluvastatin 20 mg QD, 14 days19%7%TABLE 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs Coadministered Drug and its Dosage RegimenEzetimibe Dosage RegimenChange in AUC of Coadministered DrugChange in Cmax of Coadministered DrugWarfarin, 25-mg single dose on Day 10 mg QD, 11 days2% (R-warfarin) 4% (S-warfarin)3% (R-warfarin) 1% (S-warfarin)Digoxin, 0.5-mg single dose10 mg QD, days2%7%Gemfibrozil, 600 mg BID, daysSee Drug Interactions (7). 10 mg QD, days1%11%Ethinyl estradiol Levonorgestrel, QD, 21 days10 mg QD, days 8-14 of 21d oral contraceptive cycleEthinyl estradiol 0% Levonorgestrel 0%Ethinyl estradiol 9% Levonorgestrel 5%Glipizide, 10 mg on Days and 910 mg QD, days 2-93%5%Fenofibrate, 200 mg QD, 14 days 10 mg QD, 14 days11%7%Cyclosporine, 100-mg single dose Day 20 mg QD, days15%10%StatinsLovastatin 20 mg QD, days10 mg QD, days19%3%Pravastatin 20 mg QD, 14 days10 mg QD, 14 days20%24%Atorvastatin 10 mg QD, 14 days10 mg QD, 14 days4%7%Rosuvastatin 10 mg QD, 14 days10 mg QD, 14 days19%17%Fluvastatin 20 mg QD, 14 days10 mg QD, 14 days39%27%.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Primary Hyperlipidemia in Adults. Ezetimibe 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.MonotherapyIn 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 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 in Patients with Primary Hyperlipidemia (Mean Change from Untreated BaselineBaseline on no lipid-lowering drug) Treatment GroupNTotal-CLDL-CApo BNon-HDL-CTrial 1Ezetimibe significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to placebo.Placebo205+1+1-1+1Ezetimibe622-12-18-15-16Trial 2Placebo226+1+1-1+2Ezetimibe666-12-18-16-16Pooled Data (Trials1 2)Placebo4310+1-2+1Ezetimibe1288-13-18-16-16. Combination with Statins:Ezetimibe Added to On-going Statin TherapyIn 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 or placebo in addition to their on-going statin. Ezetimibe, 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 were generally consistent across all statins.TABLE 7: Response to Addition of Ezetimibe to On-Going Statin TherapyPatients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin) in Patients with Hyperlipidemia (Mean Change from Treated BaselineBaseline on statin alone.) Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-COn-going Statin PlaceboEzetimibe statin significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to statin alone. 390-2-4 -3-3On-going Statin Ezetimibe 379-17-25-19-23. Combination with Statins:Ezetimibe 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 or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.When all patients receiving ezetimibe with statin were compared to all those receiving the corresponding statin alone, ezetimibe significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to the statin administered alone. LDL-C reductions induced by ezetimibe were generally consistent across all statins. (See footnote, Tables to 11.)TABLE 8: Response to Ezetimibe and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated BaselineBaseline on no lipid-lowering drug) Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo60+4+4+3+4Ezetimibe65-14-20-15-18Atorvastatin 10 mg60-26-37-28-34Ezetimibe Atorvastatin 10 mg65-38-53-43-49Atorvastatin 20 mg60-30-42-34-39Ezetimibe Atorvastatin 20 mg62-39-54-44-50Atorvastatin 40 mg66-32-45-37-41Ezetimibe Atorvastatin 40 mg65-42-56-45-52Atorvastatin 80 mg62-40-54-46-51Ezetimibe Atorvastatin 80 mg63-46-61-50-58Pooled data (All Atorvastatin Doses)Ezetimibe all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg). 248-32-44-36-41Pooled data (All Ezetimibe Atorvastatin Doses) 255-41-56-45-52TABLE 9: Response to Ezetimibe and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated BaselineBaseline on no lipid-lowering drug) Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo70-1-10-1Ezetimibe61-13-19-14-17Simvastatin 10 mg70-18-27-21-25Ezetimibe Simvastatin 10 mg67-32-46-35-42Simvastatin 20 mg61-26-36-29-33Ezetimibe Simvastatin 20 mg 69-33-46-36-42Simvastatin 40 mg65-27-38-32-35Ezetimibe Simvastatin 40 mg73-40-56-45-51Simvastatin 80 mg67-32-45-37-41Ezetimibe Simvastatin 80 mg65-41-58-47-53Pooled data (All Simvastatin Doses)Ezetimibe all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of simvastatin pooled (10 to 80 mg). 263-26-36-30-34Pooled data (All Ezetimibe Simvastatin Doses) 274-37-51-41-47TABLE 10: Response to Ezetimibe and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean Change from Untreated BaselineBaseline on no lipid-lowering drug) Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo650-1-20Ezetimibe64-13-20-15-17Pravastatin 10 mg66-15-21-16-20Ezetimibe Pravastatin 10 mg71-24-34-27-32Pravastatin 20 mg69-15-23-18-20Ezetimibe Pravastatin 20 mg66-27-40-31-36Pravastatin 40 mg70-22-31-26-28Ezetimibe Pravastatin 40 mg67-30-42-32-39Pooled data (All Pravastatin Doses)Ezetimibe all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, and non-HDL-C compared to all doses of pravastatin pooled (10 to 40 mg). 205-17-25-20-23Pooled data (All Ezetimibe Pravastatin Doses) 204-27-39-30-36TABLE 11: Response to Ezetimibe and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean% Change from Untreated BaselineBaseline on no lipid-lowering drug) Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo64+10+1+1Ezetimibe72-13-19-14-16Lovastatin 10 mg73-15-20-17-19Ezetimibe Lovastatin 10 mg65-24-34-27-31Lovastatin 20 mg74-19-26-21-24Ezetimibe Lovastatin 20 mg62-29-41-34-39Lovastatin 40 mg73-21-30-25-27Ezetimibe Lovastatin 40 mg65-33-46-38-43Pooled data (All Lovastatin Doses)Ezetimibe all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, and non HDL-C compared to all doses of lovastatin pooled (10 to 40 mg). 220-18-25-21-23Pooled data (All Ezetimibe Lovastatin Doses) 192-29-40-33-38Combination 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 alone, 160 mg fenofibrate alone, or ezetimibe and 160 mg fenofibrate in the 12-week trial. After completing the 12-week trial, eligible patients were assigned to ezetimibe coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.Ezetimibe 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 and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean Change from Untreated BaselineBaseline on no lipid-lowering drug. at 12 weeks) Treatment (Daily Dose)NTotal-CLDL-CApo BNon-HDL-CPlacebo6300-10Ezetimibe185-12-13-11-15Fenofibrate 160 mg188-11-6-15-16Ezetimibe Fenofibrate 160 mg 183-22-20-26-30The changes in lipid endpoints after an additional 48 weeks of treatment with ezetimibe coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.HeFH in Pediatric Patients The effects of ezetimibe 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% multiracial; 14% identified as Hispanic or Latino ethnicity) with HeFH were randomized to receive either ezetimibe 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 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 and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for weeks, coadministered ezetimibe and 40mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe 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 Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with HeFHTotal-CLDL-CApo BNon-HDL-CMean percent differencebetween treatment groups-12%-15%-12%-14%95% Confidence Interval(-15%, -9%)(-18%, -12%)(-15%, -9%)(-17%, -11%)HoFH in Adults and Pediatric Patients trial was conducted to assess the efficacy of ezetimibe 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 administered with atorvastatin or simvastatin (40 mg), or ezetimibe 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 plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, 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 plus 80-mg atorvastatin or with ezetimibe plus 80-mg simvastatin, LDL-C was reduced by 27%.Homozygous Sitosterolemia (Phytosterolemia) in Adults and Pediatric Patients trial was conducted to assess the efficacy of ezetimibe 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 (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7)], ezetimibe was dosed at least hours before or hours after resins were administered. Excluding the one subject receiving LDL apheresis, ezetimibe significantlylowered 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, 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 concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes list of drugs with clinically important drug interactions when administered concomitantly with ezetimibe and instructions for preventing or managing them.Table 3: Clinically Important Drug Interactions with ezetimibeCyclosporineClinical Impact:Concomitant use of ezetimibe and cyclosporine increases ezetimibe and cyclosporineconcentrations. The degree of increase in ezetimibe exposure may be greater in patientswith severe renal insufficiency [see Clinical Pharmacology (12.3)].Intervention:Monitor cyclosporine concentrations in patients receiving ezetimibe and cyclosporine. Inpatients treated with cyclosporine, weigh the potential effects of the increased exposureto ezetimibe from concomitant use against the benefits of alterations in lipid levelsprovided by ezetimibe.FibratesClinical Impact:Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leadingto cholelithiasis. Co-administration of ezetimibe with fibrates other than fenofibrate is notrecommended [see Adverse Reactions (6.1)].Intervention:If cholelithiasis is suspected in patient receiving ezetimibe and fenofibrate, gallbladderstudies are indicated, and alternative lipid-lowering therapy should be considered.Bile Acid SequestrantsClinical Impact:Concomitant cholestyramine administration decreased the mean exposure of totalezetimibe. This may result in reduction of efficacy [see Clinical Pharmacology (12.3)].Intervention:In patients taking bile acid sequestrant, administer ezetimibe at least hours before or 4hours after the bile acid sequestrant [see Dosage and Administration (2)].. oCyclosporine: Combination increases exposure of ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe concomitantly. (7)oFibrates: Coadministration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. If cholelithiasis is suspected in patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. (7)oBile Acid Sequestrants: Cholestyramine combination decreases exposure of ezetimibe. (7). oCyclosporine: Combination increases exposure of ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients taking ezetimibe concomitantly. (7). oFibrates: Coadministration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. If cholelithiasis is suspected in patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered. (7). oBile Acid Sequestrants: Cholestyramine combination decreases exposure of ezetimibe. (7).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ezetimibe 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 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 is indicated (1):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 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).. 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 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 may cause liver enzyme elevations [see Warnings and Precautions (5.2)].Muscle Pain Advise patients that ezetimibe 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 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 only as prescribed. If dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose.Patient InformationEzetimibe Tablets, USP(ee-ZET-ah-mybe)Read this information carefully before you start taking ezetimibe and each time you get more ezetimibe. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ezetimibe, ask your doctor. Only your doctor can determine if ezetimibe is right for you.What is ezetimibe tabletEzetimibe is medicine used with cholesterol lowering diet:oand with other cholesterol medicines called statin, or alone (when additional cholesterol lowering treatments are not possible), to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia (too many fats in your blood), including heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol. oand with statin to lower LDL-C in adults and children 10 years of age and older with HeFH. oand with medicine called fenofibrate to lower elevated LDL-C in adults with mixed hyperlipidemia. oto lower elevated sitosterol and campesterol levels in adults and in children years of age and older with homozygous familial sitosterolemia (a rare inherited condition that prevents the body from getting rid of cholesterol from plants).Ezetimibe is also used:owith statin and other cholesterol lowering treatments to lower elevated LDL-C levels in adults and patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol.The safety and effectiveness of ezetimibe has not been established in children:oyounger than 10 years of age with HeFH or HoFH. oyounger than years of age with homozygous familial sitosterolemia. owith other types of hyperlipemia.Do not take ezetimibe tablets: oif you are allergic to ezetimibe or any of the ingredients in ezetimibe. See the end of this Patient Information leaflet for complete list of ingredients in ezetimibe. Stop using ezetimibe and get medical help right away if you have symptoms of serious allergic reaction including:oswelling of the face, tongue, or throat odifficulty breathing or swallowing ofainting or feeling dizzy overy fast heartbeat osevere skin rash, hives, and itching oflu-like symptoms including fever, sore throat, cough, tiredness, and joint pain owith certain statins, fenofibrate, or other LDL-C lowering medicines if your healthcare provider has told you not to take them.Before you take ezetimibe, tell your healthcare provider about all your medical conditions, including if you: ohave liver problems. Ezetimibe may not be right for you. oare pregnant or plan to become pregnant. It is not known if ezetimibe will harm your unborn baby. You and your healthcare provider should decide if you will take ezetimibe while you are pregnant. oare breastfeeding. It is not known if ezetimibe passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby if you take ezetimibe.Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines. Taking ezetimibe with certain other medicines may affect each other causing side effects. Ezetimibe may affect the way other medicines work, and other medicines may affect how ezetimibe works.Especially tell your healthcare provider if you take: ocyclosporine (a medicine for your immune system) ofibrates (medicine for lowering cholesterol) obile acid sequestrants (medicine for lowering LDL-C)Ask your healthcare provider or pharmacist for list of medicines if you are not sure. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take ezetimibe tabletsoTake ezetimibe 1-time each day, with or without food. It may be easier to remember to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. If you also take another medicine to reduce your cholesterol, ask your healthcare provider if you can take them at the same time. oIf you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take doses of ezetimibe at the same time.oWhile taking ezetimibe, continue to follow your cholesterol-lowering diet and to exercise as your healthcare provider told you to.oIf you take medicine called bile acid sequestrant, take ezetimibe at least hours before or hours after you take the bile acid sequestrant.oYour healthcare provider may do blood tests to check your LDL-C levels as early as weeks after starting treatment with ezetimibe.oIn case of an overdose, get medical help or contact live Poison Center expert right away at 1800-222-1222. Advice is also available online at poisonhelp.org.What are the possible side effects of ezetimibe tabletsEzetimibe may cause serious side effects including: oincreased liver enzymes. An increase in liver enzymes can happen in people taking ezetimibe alone or with statins. Your healthcare provider may do blood tests to check your liver before and during treatment. Your healthcare provider may need to change or stop your treatment with ezetimibe because of an increase in liver enzymes.omuscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown (rhabdomyolysis) can happen. Tell your healthcare provider right away if: oyou have unexplained muscle pain, tenderness, weakness, feel more tired than usual, or fever. oyou have muscle problems that do not go away even after your healthcare provider has advised you to stop taking ezetimibe. Your healthcare provider may do further tests to diagnose the cause of your muscle problems.Your chances of getting muscle problems are higher if you are also taking statins or fibrates.The most common side effects of ezetimibe taken alone include: oupper respiratory tract infectionojoint painopain in arms or legsoflu-like symptomsodiarrheaoinflammation of the sinusesofeeling tiredThe most common side effects of ezetimibe taken with statin include:orunny nose, sore throatojoint painoflu-like symptomsomuscle aches and painsodiarrheaopain in arms or legsoupper respiratory tract infectionoback painofeeling tiredTell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of ezetimibe. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.How should store ezetimibe tabletoStore ezetimibe at room temperature between 68oF to 77oF (20oC to 25oC). oProtect from moisture. Keep ezetimibe tablet and all medicines out of the reach of children.General information about safe and effective use of ezetimibe tablets. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ezetimibe for condition for which it was not prescribed. Do not give ezetimibe to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ezetimibe that is written for health professionals.What are the ingredients in ezetimibe tabletActive ingredient: ezetimibe.Inactive ingredients:Croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.Finished Drug Product Manufactured by Novartis Pharmaceutical Manufacturing LLC1000 Ljubljana, Slovenia forSandoz Inc., Princeton, NJ 08540Rev. January 2024. oand with other cholesterol medicines called statin, or alone (when additional cholesterol lowering treatments are not possible), to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia (too many fats in your blood), including heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol. oand with statin to lower LDL-C in adults and children 10 years of age and older with HeFH. oand with medicine called fenofibrate to lower elevated LDL-C in adults with mixed hyperlipidemia. oto lower elevated sitosterol and campesterol levels in adults and in children years of age and older with homozygous familial sitosterolemia (a rare inherited condition that prevents the body from getting rid of cholesterol from plants).. owith statin and other cholesterol lowering treatments to lower elevated LDL-C levels in adults and patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol.. oyounger than 10 years of age with HeFH or HoFH. oyounger than years of age with homozygous familial sitosterolemia. owith other types of hyperlipemia.. oif you are allergic to ezetimibe or any of the ingredients in ezetimibe. See the end of this Patient Information leaflet for complete list of ingredients in ezetimibe. Stop using ezetimibe and get medical help right away if you have symptoms of serious allergic reaction including:. oswelling of the face, tongue, or throat odifficulty breathing or swallowing ofainting or feeling dizzy overy fast heartbeat osevere skin rash, hives, and itching oflu-like symptoms including fever, sore throat, cough, tiredness, and joint pain owith certain statins, fenofibrate, or other LDL-C lowering medicines if your healthcare provider has told you not to take them.. ohave liver problems. Ezetimibe may not be right for you. oare pregnant or plan to become pregnant. It is not known if ezetimibe will harm your unborn baby. You and your healthcare provider should decide if you will take ezetimibe while you are pregnant. oare breastfeeding. It is not known if ezetimibe passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby if you take ezetimibe.. ocyclosporine (a medicine for your immune system) ofibrates (medicine for lowering cholesterol) obile acid sequestrants (medicine for lowering LDL-C). oTake ezetimibe 1-time each day, with or without food. It may be easier to remember to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. If you also take another medicine to reduce your cholesterol, ask your healthcare provider if you can take them at the same time. oIf you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take doses of ezetimibe at the same time.. oWhile taking ezetimibe, continue to follow your cholesterol-lowering diet and to exercise as your healthcare provider told you to.. oIf you take medicine called bile acid sequestrant, take ezetimibe at least hours before or hours after you take the bile acid sequestrant.. oYour healthcare provider may do blood tests to check your LDL-C levels as early as weeks after starting treatment with ezetimibe.. oIn case of an overdose, get medical help or contact live Poison Center expert right away at 1800-222-1222. Advice is also available online at poisonhelp.org.. oincreased liver enzymes. An increase in liver enzymes can happen in people taking ezetimibe alone or with statins. Your healthcare provider may do blood tests to check your liver before and during treatment. Your healthcare provider may need to change or stop your treatment with ezetimibe because of an increase in liver enzymes.. omuscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown (rhabdomyolysis) can happen. Tell your healthcare provider right away if: oyou have unexplained muscle pain, tenderness, weakness, feel more tired than usual, or fever. oyou have muscle problems that do not go away even after your healthcare provider has advised you to stop taking ezetimibe. Your healthcare provider may do further tests to diagnose the cause of your muscle problems.. oupper respiratory tract infection. ojoint pain. opain in arms or legs. oflu-like symptoms. odiarrhea. oinflammation of the sinuses. ofeeling tired. orunny nose, sore throat. ojoint pain. oflu-like symptoms. omuscle aches and pains. odiarrhea. opain in arms or legs. oupper respiratory tract infection. oback pain. ofeeling tired. oStore ezetimibe at room temperature between 68oF to 77oF (20oC to 25oC). oProtect from moisture.

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 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 FoodConcomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals. DistributionEzetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.EliminationMetabolismEzetimibe 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 PopulationsGeriatric 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. RaceBased 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 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 Ezetimibe Coadministered Drug and Dosing RegimenTotal Ezetimibe Based on 10-mg dose of ezetimibeChange in AUCChange in Cmax Cyclosporine-stable dose required (75-150 mg BID)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). 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 doseSupralox, 20 mL. 4%30%Cimetidine, 400 mg BID, days6%22%Glipizide, 10 mg, single dose4%8% Statins Lovastatin 20 mg QD, days9%3% Pravastatin 20 mg QD, 14 days7%23% Atorvastatin 10 mg QD, 14 days2%12% Rosuvastatin 10 mg QD, 14 days13%18% Fluvastatin 20 mg QD, 14 days19%7%TABLE 5: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs Coadministered Drug and its Dosage RegimenEzetimibe Dosage RegimenChange in AUC of Coadministered DrugChange in Cmax of Coadministered DrugWarfarin, 25-mg single dose on Day 10 mg QD, 11 days2% (R-warfarin) 4% (S-warfarin)3% (R-warfarin) 1% (S-warfarin)Digoxin, 0.5-mg single dose10 mg QD, days2%7%Gemfibrozil, 600 mg BID, daysSee Drug Interactions (7). 10 mg QD, days1%11%Ethinyl estradiol Levonorgestrel, QD, 21 days10 mg QD, days 8-14 of 21d oral contraceptive cycleEthinyl estradiol 0% Levonorgestrel 0%Ethinyl estradiol 9% Levonorgestrel 5%Glipizide, 10 mg on Days and 910 mg QD, days 2-93%5%Fenofibrate, 200 mg QD, 14 days 10 mg QD, 14 days11%7%Cyclosporine, 100-mg single dose Day 20 mg QD, days15%10%StatinsLovastatin 20 mg QD, days10 mg QD, days19%3%Pravastatin 20 mg QD, 14 days10 mg QD, 14 days20%24%Atorvastatin 10 mg QD, 14 days10 mg QD, 14 days4%7%Rosuvastatin 10 mg QD, 14 days10 mg QD, 14 days19%17%Fluvastatin 20 mg QD, 14 days10 mg QD, 14 days39%27%.

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe 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.

TERATOGENIC EFFECTS SECTION.

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe 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.

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe 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 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 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 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 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 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 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 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 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 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 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 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 is necessary in patients with renal impairment.. 8.7 Hepatic Impairment. Ezetimibe 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. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe if increases in ALT or AST >=3 ULN persist. (5.2)oSkeletal Muscle Effects (e.g., Myopathy and Rhabdomyolysis): Ezetimibe 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 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. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe if increases in ALT or AST >=3 ULN persist. (5.2). oSkeletal Muscle Effects (e.g., Myopathy and Rhabdomyolysis): Ezetimibe 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 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 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 [see Adverse Reactions 6.1)]. In controlled clinical combination studies of ezetimibe initiated concurrently with statin, the incidence of consecutive elevations (>=3 ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe administered with statins and 0.4% for patients treated with statins alone. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe if increases in ALT or AST >=3 ULN persist.. 5.3 Myopathy/Rhabdomyolysis. Ezetimibe may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis [see Adverse Reactions 6.1)]. In post-marketing reports, most patients who developed rhabdomyolysis were taking statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates. If myopathy is suspected, discontinue ezetimibe and other concomitant medications, as appropriate.