Ezetimibe

RECENT MAJOR CHANGES Indications and Usage ( 1 ) 07/2023 Dosage and Administration ( 2 ) 07/2023 Contraindications ( 4 ) 07/2023 Warnings and Precautions ( 5.1 , 5.2 , 5.3 ) 07/2023

1 INDICATIONS AND 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 a 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: 5. Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin) ( 1.1 ) 6. Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate ( 1.1 ) 7. Reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin ( 1.2 ) 8. Reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) ( 1.3 ) Limitations of Use ( 1.4 ) 3. The effect of ezetimibe tablets on cardiovascular morbidity and mortality has not been determined. 4. Ezetimibe tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. 1.1 Primary Hyperlipidemia Monotherapy Ezetimibe tablets, administered alone, are indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with HMG-CoA Reductase Inhibitors (Statins) Ezetimibe tablets, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), are indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with Fenofibrate Ezetimibe tablets, administered in combination with fenofibrate, are indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia. 1.2 Homozygous Familial Hypercholesterolemia (HoFH) The combination of ezetimibe and atorvastatin or simvastatin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Homozygous Sitosterolemia Ezetimibe tablets are indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. 1.4 Limitations of Use The effect of ezetimibe tablets on cardiovascular morbidity and mortality has not been determined. Ezetimibe tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

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

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

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

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Liver enzyme abnormalities [see Warnings and Precautions ( 5.2 )] • Rhabdomyolysis and myopathy [see Warnings and Precautions ( 5.3 )] Monotherapy Studies: In the Ezetimibe Tablets controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Ezetimibe 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 a rate greater than placebo were: • Arthralgia (0.3%) • Dizziness (0.2%) • Gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the Ezetimibe 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 a median treatment duration of 8 weeks (range 0 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 a rate greater than statin alone were: • Alanine aminotransferase increased (0.6%) • Myalgia (0.5%) • Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the Ezetimibe 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%). • Common adverse reactions in clinical trials: • Ezetimibe Tablets co-administered with a statin (incidence ≥2% and greater than statin alone): • nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea ( 6 ) • Ezetimibe 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. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Monotherapy In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9 to 86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe Tablets 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥2% of patients treated with Ezetimibe 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 Reaction Ezetimibe Tablets 10 mg (%) n = 2396 Placebo (%) n = 1159 Gastrointestinal disorders Diarrhea 4.1 3.7 General disorders and administration site conditions Fatigue 2.4 1.5 Infections and infestations Influenza 2.0 1.5 Sinusitis 2.8 2.2 Upper respiratory tract inf …

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 a 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 a 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 a 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, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC ( see Data ). Ezetimibe tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When ezetimibe tablets is administered with a 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 2 to 4% and 15 to 20%, respectively. Data Animal Data In 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 AUC 0-24hr 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 AUC 0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was 6 times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a 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 6 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 AUC 0-24hr 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 Summary There is no information about the presence of ezetimibe in human milk. Ezetimibe is present in rat milk (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information about the effects of ezetimibe on the breastfed infant or the effects of ezetimibe on milk production. Ezetimibe tablets should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Data Ezetimibe 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 a statin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of ezetimibe tablets for this indication is based on a 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 w …

12.1 Mechanism of Action Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 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 E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a 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 a 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 1 (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 a decrease in the delivery of intestinal cholesterol to the liver. This causes a 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 )] .

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

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ezetimibe Tablets USP, 10 mg are white to off-white, capsule-shape, flat-face, beveled edge, uncoated tablets debossed with '773' on one side and plain on other side and are supplied as follows: NDC 68382-773-06 in bottle of 30 tablets with child-resistant closure NDC 68382-773-16 in bottle of 90 tablets with child-resistant closure NDC 68382-773-01 in bottle of 100 tablets NDC 68382-773-05 in bottle of 500 tablets NDC 68382-773-10 in bottle of 1000 tablets NDC 68382-773-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tightly closed container.