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Ezetimibe and simvastatin tablets Ezetimibe and simvastatin tablets are a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.

Important Dosage and Administration Information: ( 2.1 ) Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food. Maximum recommended dosage is ezetimibe and simvastatin tablets 10 mg/40 mg once daily. Ezetimibe and simvastatin tablets 10 mg/80 mg daily dosage is restricted to patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 2 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary. Adults : Recommended dosage range of 10 mg/10 mg to 10 mg/40 mg once daily. ( 2.2 ) See full prescribing information for ezetimibe and simvastatin tablets dosage modifications due to drug interactions. ( 2.3 ) Patients with Renal Impairment: Doses exceeding 10 mg/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment. ( 2.4 )

Ezetimibe and simvastatin tablets are supplied as follows: Strength How Supplied NDC Tablet Description 10 mg/10 mg unit of use bottles of 30 45963-565-30 Light tan, slightly speckled, round, unscored, biconvex tablet debossed with 511 on one side and  on opposite side. unit of use bottles of 90 45963-565-08 10 mg/20 mg unit of use bottles of 30 45963-566-30 Light tan, slightly speckled, round, unscored, biconvex tablet debossed with 512 on one side and on opposite side. unit of use bottles of 90 45963-566-08 10 mg/40 mg unit of use bottles of 30 45963-567-30 Light tan, slightly speckled, round, unscored, biconvex tablet debossed with 513 on one side and on opposite side. unit of use bottles of 90 45963-567-08 10 mg/80 mg unit of use bottles of 30 45963-568-30 Light tan, slightly speckled, capsule shaped, unscored, biconvex tablet debossed with 515 on one side and on opposite side. unit of use bottles of 90 45963-568-08 Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed. Dispense in a tight, light-resistant container as defined in the USP.

Ezetimibe and simvastatin tablets are contraindicated in the following conditions: Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see Drug Interactions ( 7.1 )]. Concomitant use of cyclosporine, danazol, or danazol [see Drug Interactions ( 7.1 )]. Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )]. Hypersensitivity to simvastatin, ezetimibe, or any excipients in ezetimibe and simvastatin tablets. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome, have been reported [see Adverse Reactions ( 6.2 )].

Ezetimibe and simvastatin tablets contain ezetimibe USP, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin USP, an HMG-CoA reductase inhibitor. 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 molecular formula is C 24 H 21 F 2 NO 3 and its molecular weight is 409.4. Ezetimibe, USP is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is: Simvastatin, USP, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin, USP is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7β,8β(2 S *,4 S *),-8aβ]]. The molecular formula of simvastatin, USP is C 25 H 38 O 5 and its molecular weight is 418.57. Simvastatin, USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is: Ezetimibe and simvastatin is available for oral use as tablets containing 10 mg of ezetimibe USP, and 10 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/10 mg), 20 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/20 mg), 40 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/40 mg), or 80 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/80 mg). Each tablet contains the following inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric acid anhydrous, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate.

Ezetimibe and S imvastatin

Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that ezetimibe and simvastatin tablets may cause myopathy and rhabdomyolysis. Inform patients taking the 80 mg daily dose of simvastatin that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking ezetimibe and simvastatin tablets. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Drug Interactions ( 7.1 )]. Hepatic Dysfunction Inform patients that ezetimibe and simvastatin tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions ( 5.3 )]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with ezetimibe and simvastatin tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions ( 5.4 )]. Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if ezetimibe and simvastatin tablets should be discontinued [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that breastfeeding is not recommended during treatment with ezetimibe and simvastatin tablets [see Use in Specific Populations ( 8.2 )]. Missed Dose Instruct patients to take ezetimibe and simvastatin tablets only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose. Brands listed are the trademarks of their respective owners. Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Rev. E 4/2024

Risk Summary There is no information about the presence of ezetimibe or simvastatin in human breast milk, the effects of the drug on the breastfed infant or the effect of the drug on milk production. However, it has been shown that other statins pass into human milk. Statins, including ezetimibe and simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breast fed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with ezetimibe and simvastatin [see Use in Specific Populations ( 8.2 ) and Clinical Pharmacology ( 12.1 )]. Data Animal 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.

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 and simvastatin 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 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 and simvastatin have not been established in pediatric patients younger than 10 years of age with HeFH, or in pediatric patients with other types of hyperlipidemia.

Advanced age (≥65 years) is a risk factor for ezetimibe and simvastatin-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving ezetimibe and simvastatin for the increased risk of myopathy [see Warnings and Precautions ( 5.1 )]. Of the 10,189 patients who received ezetimibe and simvastatin in clinical studies, 3242 (32%) were 65 and older (this included 844 (8%) who were 75 and older). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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.

Ezetimibe and Simvastatin No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and simvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 600 mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test. Ezetimibe A 104-week dietary carcinogenicity trial with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). A 104-week dietary carcinogenicity trial with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (greater than 150 times the human exposure at 10 mg daily based on AUC 0-24hr 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 a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a 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 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Simvastatin In a 72-week carcinogenicity trial, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively, (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity trial in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year trial in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity trial with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80-mg daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation trial, an in vitro chromosome aberration trial in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility trial in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either trial. At 180 mg/kg/day (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )]

No specific antidotes for ezetimibe and simvastatin are known. In the event of an overdose with ezetimibe and simvastatin, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdosage management recommendations.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Ezetimibe and Simvastatin In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1420 patients (age range 20 to 83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). The most common adverse reactions in the group treated with ezetimibe and simvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). Ezetimibe and simvastatin have been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in greater than or equal to 2% of patients treated with ezetimibe and simvastatin (n=1420) and at an incidence greater than placebo from four placebo-controlled trials. Table 1*: Adverse Reactions Reported greater than or equal to 2% of Patients Treated with Ezetimibe and Simvastatin at an Incidence Greater than Placebo Regardless of Causality % Placebo N=371 % Ezetimibe 10 mg N=302 % Simvastatin † N=1234 % Ezetimibe and Simvastatin † N=1420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin was administered. †All doses. Study of Heart and Renal Protection In SHARP, 9270 patients were allocated to ezetimibe and simvastatin 10 mg/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued trial treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK greater than 10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (greater than 3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin and placebo, respectively. Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue. Simvastatin In a clinical outcome trial in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] greater than 10 times (1200 U/L) upper limit of normal [ULN] ) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%. The incidence of myopathy and rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported with simvastatin in placebo-controlled clinical trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and insomnia. Laboratory Tests Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions ( 5.3 )] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions ( 5.1 )] .

Ezetimibe and Simvastatin Risk Summary Discontinue ezetimibe and simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Ezetimibe and simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ezetimibe and simvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with ezetimibe and simvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m2). 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). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Ezetimibe 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. Simvastatin A Medicaid cohort linkage trial of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Trial limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Ezetimibe 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 embryolethality at any dose tested (250, 500, 1000 mg/kg/day) at exposure equivalent to 10 to 150 times the clinical exposure, based on AUC, in rats and rabbits. 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 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 1000 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 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 1000 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 1000 mg/kg/day (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 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. Simvastatin Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity, or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta.

Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food. The maximum recommended dosage is ezetimibe and simvastatin tablets 10 mg/40 mg once daily. The ezetimibe and simvastatin tablets 10 mg/80 mg daily dosage is restricted to adult patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity  [see Warnings and Precautions ( 5.1 )]. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary.

PATIENT INFORMATION Ezetimibe and Simvastatin ( e zet′  i mibe and sim′′  va stat′  in) Tablets, for oral use Read this Information carefully before you start taking ezetimibe and simvastatin tablets and each time you get ezetimibe and simvastatin tablets. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ezetimibe and simvastatin tablets, ask your healthcare provider. Only your healthcare provider can determine if ezetimibe and simvastatin tablets are right for you. What are ezetimibe and simvastatin tablets? Ezetimibe and simvastatin tablets are a prescription medicine that contains the cholesterol lowering medicines, simvastatin and ezetimibe. Ezetimibe and simvastatin tablets are used along with diet to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in: adults with primary hyperlipidemia (high level of fats in your blood). adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol. Ezetimibe and simvastatin tablets are also used with other cholesterol lowering treatments to lower elevated LDL-C levels in adults with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol. Simvastatin when used as a component of ezetimibe and simvastatin tablets are used to lower: the risk of death by lowering the risk of heart disease death. the risk of heart attacks and strokes. the need for certain types of heart and blood vessel procedures to improve blood flow called arterial revascularization in people with known heart, cerebrovascular disease (conditions that affect blood flow and the blood vessels in the brain), peripheral vascular disease (a blood circulation disorder that causes the blood vessels outside of your heart and brain to narrow, block, or spasm), and diabetes, who are at high risk for heart disease problems. The safety and effectiveness of ezetimibe and simvastatin tablets has not been established in children younger than 10 years of age with inherited heterozygous familial hypercholesterolemia (HeFH) or other types of hyperlipidemia. Do not take ezetimibe and simvastatin tablets if you: take certain medicines called CYP3A4 inhibitors such as: certain antifungal medicines (such as itraconazole, ketoconazole, posaconazole, voriconazole). certain antibiotics (including erythromycin, clarithromycin, telithromycin). HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir and cobicistat-containing products such as (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate). certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir). the antidepressant nefazodone. take medicines called cyclosporine, danazol, or gemfibrozil. have liver problems. are allergic to simvastatin, ezetimibe, or any of the ingredients in ezetimibe and simvastatin tablets. See the end of this Patient Information leaflet for a complete list of ingredients in ezetimibe and simvastatin tablets. Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above. Before you take ezetimibe and simvastatin tablets, tell your healthcare provider about all of your medical conditions, including if you: have unexplained muscle aches or weakness. have or have had myasthenia gravis (a disease causing general muscle weakness including in some cases muscles used for breathing), ocular myasthenia (a disease causing eye muscle weakness). have kidney problems. have liver problems or drink more than 2 glasses of alcohol daily. have thyroid problems. are 65 years of age or older. are of Chinese descent. are pregnant or plan to become pregnant. If you become pregnant while taking ezetimibe and simvastatin tablets, call your healthcare provider right away to discuss stopping ezetimibe and simvastatin tablets. are breastfeeding or plan to breastfeed. It is not known if ezetimibe and simvastatin pass into your breast milk. Do not breastfeed while taking ezetimibe and simvastatin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines. Tell your healthcare provider who prescribes ezetimibe and simvastatin tablets if another healthcare provider increases the dose of another medicine you are taking. Ezetimibe and simvastatin tablets may affect the way other medicines work, and other medicines may affect how ezetimibe and simvastatin tablets works. Especially tell your healthcare provider if you take: digoxin (a drug used to treat irregular heartbeat). coumarin anticoagulants (drugs that prevent blood clots, such as warfarin). fibric acid derivatives (such as fenofibrate). Taking ezetimibe and simvastatin tablets with certain substances can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: amiodarone or dronedarone (medicines used to treat an irregular heartbeat). verapamil, diltiazem, amlodipine, or ranolazine (medicines used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions). lomitapide (a medicine used to treat a serious and rare genetic cholesterol condition). daptomycin (a drug used to treat complicated skin and bloodstream infections). large doses of niacin or nicotinic acid, especially if you are of Chinese descent. colchicine (a medicine used to treat gout). grapefruit juice. Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take ezetimibe and simvastatin tablets? Take ezetimibe and simvastatin tablets exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ezetimibe and simvastatin tablets without talking to your healthcare provider. Take ezetimibe and simvastatin tablets 1 time each day in the evening. If you miss a 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 2 doses of ezetimibe and simvastatin tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose. While taking ezetimibe and simvastatin tablets, continue to follow your cholesterol-lowering diet and to exercise as your healthcare provider told you to. Your healthcare provider may do blood tests to check your cholesterol while you take ezetimibe and simvastatin tablets. Your healthcare provider may change your dose of ezetimibe and simvastatin tablets if needed. If you take too much ezetimibe and simvastatin tablets, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of ezetimibe and simvastatin tablets? Ezetimibe and simvastatin tablets may cause serious side effects including: Muscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death. Tell your healthcare provider right away if: you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take ezetimibe and simvastatin tablets. you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking ezetimibe and simvastatin tablets. 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 taking certain other medicines while you take ezetimibe and simvastatin tablets. are 65 years of age or older. are female. have thyroid problems (hypothyroidism) that are not controlled. have kidney problems. are taking higher doses of ezetimibe and simvastatin tablets. are Chinese. Liver problems. Your healthcare provider should do blood tests to check your liver before you start taking ezetimibe and simvastatin tablets and if you have any symptoms of liver problems while you take ezetimibe and simvastatin tablets. Call your healthcare provider right away if you have the following symptoms of liver problems: feeling tired or weak loss of appetite right-sided upper belly pain dark urine yellowing of your skin or the whites of your eyes increase in blood sugar (glucose) levels). Ezetimibe and simvastatin tablets may cause an increase in your blood sugar levels. The most common side effects of ezetimibe and simvastatin tablets include: headache increased liver enzyme levels muscle pain upper respiratory infection diarrhea Tell 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 and simvastatin tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ezetimibe and simvastatin tablets? Store ezetimibe and simvastatin tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep ezetimibe and simvastatin tablets in its original container until you use it. Keep ezetimibe and simvastatin tablets in a tightly closed container. Keep ezetimibe and simvastatin tablets and all medicines out of the reach of children. General information about safe and effective use of ezetimibe and simvastatin tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ezetimibe and simvastatin tablets for a condition for which it was not prescribed. Do not give ezetimibe and simvastatin tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ezetimibe and simvastatin tablets that is written for health professionals. What are the ingredients in ezetimibe and simvastatin tablets? Active Ingredients: ezetimibe and simvastatin Inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric acid anhydrous, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate. Brands listed are the trademarks of their respective owners. Manufactured by: Watson Pharma Private Limited, Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA For more information, call Actavis at 1-888-838-2872. This Patient Information has been approved by the U.S. Food and Drug Administration .                                                                                Rev. D 4/2024

Ezetimibe and simvastatin tablets: • 10 mg/10 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 511 on one side and on opposite side. • 10 mg/20 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 512 on one side and on opposite side. • 10 mg/40 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 513 on one side and on opposite side. • 10 mg/80 mg are light tan, slightly speckled, capsule shaped, unscored, biconvex tablets debossed with 515 on one side and on opposite side.

Ezetimibe and Simvastatin Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe 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 1 (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 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. Simvastatin Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme converts HMG-CoA to mevalonate, a precursor of cholesterol.

Ezetimibe and simvastatin reduces total cholesterol (total-C), LDL-C, apolipoprotein (Apo) B, and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with hyperlipidemia. Ezetimibe In a 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 E and did not impair adrenocortical steroid hormone production. Simvastatin Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low density lipoproteins. The maximum LDL-C reduction of ZOCOR ®  is usually achieved by 4 weeks and is maintained after that.

The results of a bioequivalence trial in healthy subjects demonstrated that the ezetimibe and simvastatin 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe (ZETIA ® ) and simvastatin (ZOCOR ® ) as individual tablets. Absorption Ezetimibe After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (C max ) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. Simvastatin The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction. Effect of Food on Oral Absorption Ezetimibe Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Simvastatin Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. Distribution Ezetimibe Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins. Simvastatin Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier. Elimination Metabolism Ezetimibe Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism 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 a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Simvastatin Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-­hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Excretion Ezetimibe 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 a 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. Simvastatin Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Specific Populations Geriatric Patients Ezetimibe In a 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 (greater than or equal to 65 years) healthy subjects compared to younger subjects. Simvastatin In a trial including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. [See Use in Specific Populations ( 8.5 ).] Gender Ezetimibe In a multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in females than in males. Race Ezetimibe Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black or African American and White subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to those seen in White subjects. Hepatic Impairment Ezetimibe After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh scor e 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose trial (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects. Renal Impairment Ezetimibe After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl less than or equal to 30 mL/min/1.73 m 2 ), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n=9). Simvastatin Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal impairment (as measured by creatinine clearance). Drug Interactions [See also Drug Interactions (7).] No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. No specific pharmacokinetic drug interaction studies with ezetimibe and simvastatin have been conducted other than the following trial with NIASPAN (Niacin extended-release tablets). Niacin: The effect of ezetimibe and simvastatin (10 mg/20 mg daily for 7 days) on the pharmacokinetics of NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast) was studied in healthy subjects. The mean C max and AUC of niacin increased 9% and 22%, respectively. The mean C max and AUC of nicotinuric acid increased 10% and 19%, respectively (N=13). In the same trial, the effect of NIASPAN on the pharmacokinetics of ezetimibe and simvastatin was evaluated (N=15). While concomitant NIASPAN decreased the mean C max of total ezetimibe (1%), and simvastatin (2%), it increased the mean C max of simvastatin acid (18%). In addition, concomitant NIASPAN increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%). Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products. [See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 ).] Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “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. In a trial of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4 and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see Drug Interactions ( 7 )]. Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. Ezetimibe Table 5 displays the effect of coadministered drugs on total ezetimibe. Table 5: Effect of Coadministered Drugs on Total Ezetimibe Coadministered Drug and Dosing Regimen Total Ezetimibe * Change in AUC Change in C max Cyclosporine-stable dose required (75 to 150 mg BID) †, ‡ ↑­240% ↑­290% Fenofibrate, 200 mg QD, 14 days ‡ ↑­48% ↑­64% Gemfibrozil, 600 mg BID, 7 days ‡ ↑­64% ­↑91% Cholestyramine, 4 g BID, 14 days ‡ ↓55% ↓4% Aluminum & magnesium hydroxide combination antacid, single dose § ↓4% ↓30% Cimetidine, 400 mg BID, 7 days ↑­6% ↑­22% Glipizide, 10 mg, single dose ­↑4% ↓8% Statins Lovastatin 20 mg QD, 7 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 a different trial, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m 2 ) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. ‡ See 7. Drug Interactions. § Supralox, 20 mL. Table 6 displays the effects of ezetimibe coadministration on systemic exposure to other drugs. Table 6: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs Coadministered Drug and its Ezetimibe Dosage Change in AUC Change in C max Dosage Regimen Regimen of Coadministered Drug of Coadministered Drug Warfarin, 25 mg single dose on 10 mg QD, 11 days ↓2% (R-warfarin) ↑­3% (R-warfarin) Day 7 ↓4% (S-warfarin) ↑­1% (S-warfarin) Digoxin, 0.5 mg single dose 10 mg QD, 8 days ↑­2% ↓7% Gemfibrozil, 600 mg BID, 10 mg QD, 7 days ↓1% ↓11% 7 days* Ethinyl estradiol & 10 mg QD, Days 8-14 of Ethinyl estradiol Ethinyl estradiol Levonorgestrel, QD, 21 days 21 day oral contraceptive 0% ↓9% cycle Levonorgestrel Levonorgestrel 0% ↓5% Glipizide, 10 mg on Days 1 10 mg QD, Days 2-9 ↓3% ↓5% and 9 Fenofibrate, 200 mg QD, 10 mg QD, 14 days ↑­11% ↑­7% 14 days * Cyclosporine, 100 mg single 20 mg QD, 8 days ↑­15% ↑­10% dose Day 7* Statins Lovastatin 20 mg QD, 10 mg QD, 7 days ↑­19% ↑­3% 7 days Pravastatin 20 mg QD, 10 mg QD, 14 days ↓20% ↓24% 14 days Atorvastatin 10 mg QD, 10 mg QD, 14 days ↓4% ↑­7% 14 days Rosuvastatin 10 mg QD, 10 mg QD, 14 days ↑­19% ↑­17% 14 days Fluvastatin 20 mg QD, 10 mg QD, 14 days ↓39% ↓27% 14 days * See 7. Drug Interactions. Simvastatin Table 7 displays the effects of coadminstration drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions (7)]. Table 7: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect = 1.00 AUC C max Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 12 8.9 15 5.3 Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6 6.2 Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 13.1 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid ‡ simvastatin simvastatin acid ‡ simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid ‡ simvastatin 2.85 1.35 2.18 0.91 Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Verapamil SR 240 mg QD Days 1-7 then 240 mg BID on Days 8-10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Amlodipine 10 mg QD for 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6-9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7 Fenofibrate 160 mg QD for 14 days 80 mg QD on Days 8-14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7.0 to 4.7 ng·eq/mL * Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.

Indications and Usage (1)                                                                                   2/2024 Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5)                                 2/2024 Contraindications, Pregnancy and Lactation (4) Removed                 2/2024 Warnings and Precautions (5.1, 5.2, 5.3)                                                     2/2024

Pregnancy : May cause fetal harm ( 8.1 ) Lactation : Breastfeeding not recommended during treatment with ezetimibe and simvastatin tablets. ( 8.2 )

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ezetimibe and simvastatin tablets dosage. Chinese patients may be at higher risk for myopathy. Discontinue ezetimibe and simvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ezetimibe and simvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing ezetimibe and simvastatin tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue ezetimibe and simvastatin tablets if IMNM is suspected. ( 5.2 ) Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ezetimibe and simvastatin tablets. ( 5.3 )

NDC 45963-565-30 Ezetimibe and Simvastatin Tablets 10 mg/10 mg 30 Tablets Rx Only

Ezetimibe and simvastatin tablets Ezetimibe and simvastatin tablets are a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.

Important Dosage and Administration Information: ( 2.1 ) Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food. Maximum recommended dosage is ezetimibe and simvastatin tablets 10 mg/40 mg once daily. Ezetimibe and simvastatin tablets 10 mg/80 mg daily dosage is restricted to patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 2 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary. Adults : Recommended dosage range of 10 mg/10 mg to 10 mg/40 mg once daily. ( 2.2 ) See full prescribing information for ezetimibe and simvastatin tablets dosage modifications due to drug interactions. ( 2.3 ) Patients with Renal Impairment: Doses exceeding 10 mg/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment. ( 2.4 )

Ezetimibe and simvastatin tablets are supplied as follows: Strength How Supplied NDC Tablet Description 10 mg/10 mg unit of use bottles of 30 45963-565-30 Light tan, slightly speckled, round, unscored, biconvex tablet debossed with 511 on one side and  on opposite side. unit of use bottles of 90 45963-565-08 10 mg/20 mg unit of use bottles of 30 45963-566-30 Light tan, slightly speckled, round, unscored, biconvex tablet debossed with 512 on one side and on opposite side. unit of use bottles of 90 45963-566-08 10 mg/40 mg unit of use bottles of 30 45963-567-30 Light tan, slightly speckled, round, unscored, biconvex tablet debossed with 513 on one side and on opposite side. unit of use bottles of 90 45963-567-08 10 mg/80 mg unit of use bottles of 30 45963-568-30 Light tan, slightly speckled, capsule shaped, unscored, biconvex tablet debossed with 515 on one side and on opposite side. unit of use bottles of 90 45963-568-08 Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed. Dispense in a tight, light-resistant container as defined in the USP.

Ezetimibe and simvastatin tablets are contraindicated in the following conditions: Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see Drug Interactions ( 7.1 )]. Concomitant use of cyclosporine, danazol, or danazol [see Drug Interactions ( 7.1 )]. Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )]. Hypersensitivity to simvastatin, ezetimibe, or any excipients in ezetimibe and simvastatin tablets. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome, have been reported [see Adverse Reactions ( 6.2 )].

Ezetimibe and S imvastatin

Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that ezetimibe and simvastatin tablets may cause myopathy and rhabdomyolysis. Inform patients taking the 80 mg daily dose of simvastatin that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking ezetimibe and simvastatin tablets. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Drug Interactions ( 7.1 )]. Hepatic Dysfunction Inform patients that ezetimibe and simvastatin tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions ( 5.3 )]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with ezetimibe and simvastatin tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions ( 5.4 )]. Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if ezetimibe and simvastatin tablets should be discontinued [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that breastfeeding is not recommended during treatment with ezetimibe and simvastatin tablets [see Use in Specific Populations ( 8.2 )]. Missed Dose Instruct patients to take ezetimibe and simvastatin tablets only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose. Brands listed are the trademarks of their respective owners. Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Rev. E 4/2024

Risk Summary There is no information about the presence of ezetimibe or simvastatin in human breast milk, the effects of the drug on the breastfed infant or the effect of the drug on milk production. However, it has been shown that other statins pass into human milk. Statins, including ezetimibe and simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breast fed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with ezetimibe and simvastatin [see Use in Specific Populations ( 8.2 ) and Clinical Pharmacology ( 12.1 )]. Data Animal 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.

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 and simvastatin 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 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 and simvastatin have not been established in pediatric patients younger than 10 years of age with HeFH, or in pediatric patients with other types of hyperlipidemia.

Advanced age (≥65 years) is a risk factor for ezetimibe and simvastatin-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving ezetimibe and simvastatin for the increased risk of myopathy [see Warnings and Precautions ( 5.1 )]. Of the 10,189 patients who received ezetimibe and simvastatin in clinical studies, 3242 (32%) were 65 and older (this included 844 (8%) who were 75 and older). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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.

Ezetimibe and Simvastatin No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and simvastatin. The combination of ezetimibe with simvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and simvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 600 mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus test. Ezetimibe A 104-week dietary carcinogenicity trial with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). A 104-week dietary carcinogenicity trial with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (greater than 150 times the human exposure at 10 mg daily based on AUC 0-24hr 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 a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a 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 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Simvastatin In a 72-week carcinogenicity trial, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively, (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity trial in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year trial in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity trial with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80-mg daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation trial, an in vitro chromosome aberration trial in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility trial in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either trial. At 180 mg/kg/day (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )]

No specific antidotes for ezetimibe and simvastatin are known. In the event of an overdose with ezetimibe and simvastatin, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdosage management recommendations.

Ezetimibe and simvastatin tablets contain ezetimibe USP, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin USP, an HMG-CoA reductase inhibitor. 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 molecular formula is C 24 H 21 F 2 NO 3 and its molecular weight is 409.4. Ezetimibe, USP is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is: Simvastatin, USP, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin, USP is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7β,8β(2 S *,4 S *),-8aβ]]. The molecular formula of simvastatin, USP is C 25 H 38 O 5 and its molecular weight is 418.57. Simvastatin, USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is: Ezetimibe and simvastatin is available for oral use as tablets containing 10 mg of ezetimibe USP, and 10 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/10 mg), 20 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/20 mg), 40 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/40 mg), or 80 mg of simvastatin, USP (ezetimibe and simvastatin tablets 10 mg/80 mg). Each tablet contains the following inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric acid anhydrous, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Ezetimibe and Simvastatin In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1420 patients (age range 20 to 83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). The most common adverse reactions in the group treated with ezetimibe and simvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). Ezetimibe and simvastatin have been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in greater than or equal to 2% of patients treated with ezetimibe and simvastatin (n=1420) and at an incidence greater than placebo from four placebo-controlled trials. Table 1*: Adverse Reactions Reported greater than or equal to 2% of Patients Treated with Ezetimibe and Simvastatin at an Incidence Greater than Placebo Regardless of Causality % Placebo N=371 % Ezetimibe 10 mg N=302 % Simvastatin † N=1234 % Ezetimibe and Simvastatin † N=1420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin was administered. †All doses. Study of Heart and Renal Protection In SHARP, 9270 patients were allocated to ezetimibe and simvastatin 10 mg/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued trial treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK greater than 10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (greater than 3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin and placebo, respectively. Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue. Simvastatin In a clinical outcome trial in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] greater than 10 times (1200 U/L) upper limit of normal [ULN] ) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%. The incidence of myopathy and rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported with simvastatin in placebo-controlled clinical trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and insomnia. Laboratory Tests Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions ( 5.3 )] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions ( 5.1 )] .

Ezetimibe and Simvastatin Risk Summary Discontinue ezetimibe and simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Ezetimibe and simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ezetimibe and simvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with ezetimibe and simvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m2). 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). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Ezetimibe 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. Simvastatin A Medicaid cohort linkage trial of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Trial limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Ezetimibe 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 embryolethality at any dose tested (250, 500, 1000 mg/kg/day) at exposure equivalent to 10 to 150 times the clinical exposure, based on AUC, in rats and rabbits. 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 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 1000 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 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 1000 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 1000 mg/kg/day (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 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. Simvastatin Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity, or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta.

Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food. The maximum recommended dosage is ezetimibe and simvastatin tablets 10 mg/40 mg once daily. The ezetimibe and simvastatin tablets 10 mg/80 mg daily dosage is restricted to adult patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity  [see Warnings and Precautions ( 5.1 )]. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary.

PATIENT INFORMATION Ezetimibe and Simvastatin ( e zet′  i mibe and sim′′  va stat′  in) Tablets, for oral use Read this Information carefully before you start taking ezetimibe and simvastatin tablets and each time you get ezetimibe and simvastatin tablets. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ezetimibe and simvastatin tablets, ask your healthcare provider. Only your healthcare provider can determine if ezetimibe and simvastatin tablets are right for you. What are ezetimibe and simvastatin tablets? Ezetimibe and simvastatin tablets are a prescription medicine that contains the cholesterol lowering medicines, simvastatin and ezetimibe. Ezetimibe and simvastatin tablets are used along with diet to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in: adults with primary hyperlipidemia (high level of fats in your blood). adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited condition that causes high levels of bad cholesterol. Ezetimibe and simvastatin tablets are also used with other cholesterol lowering treatments to lower elevated LDL-C levels in adults with homozygous familial hypercholesterolemia (HoFH). HoFH is an inherited condition that causes high levels of bad cholesterol. Simvastatin when used as a component of ezetimibe and simvastatin tablets are used to lower: the risk of death by lowering the risk of heart disease death. the risk of heart attacks and strokes. the need for certain types of heart and blood vessel procedures to improve blood flow called arterial revascularization in people with known heart, cerebrovascular disease (conditions that affect blood flow and the blood vessels in the brain), peripheral vascular disease (a blood circulation disorder that causes the blood vessels outside of your heart and brain to narrow, block, or spasm), and diabetes, who are at high risk for heart disease problems. The safety and effectiveness of ezetimibe and simvastatin tablets has not been established in children younger than 10 years of age with inherited heterozygous familial hypercholesterolemia (HeFH) or other types of hyperlipidemia. Do not take ezetimibe and simvastatin tablets if you: take certain medicines called CYP3A4 inhibitors such as: certain antifungal medicines (such as itraconazole, ketoconazole, posaconazole, voriconazole). certain antibiotics (including erythromycin, clarithromycin, telithromycin). HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir and cobicistat-containing products such as (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate). certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir). the antidepressant nefazodone. take medicines called cyclosporine, danazol, or gemfibrozil. have liver problems. are allergic to simvastatin, ezetimibe, or any of the ingredients in ezetimibe and simvastatin tablets. See the end of this Patient Information leaflet for a complete list of ingredients in ezetimibe and simvastatin tablets. Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above. Before you take ezetimibe and simvastatin tablets, tell your healthcare provider about all of your medical conditions, including if you: have unexplained muscle aches or weakness. have or have had myasthenia gravis (a disease causing general muscle weakness including in some cases muscles used for breathing), ocular myasthenia (a disease causing eye muscle weakness). have kidney problems. have liver problems or drink more than 2 glasses of alcohol daily. have thyroid problems. are 65 years of age or older. are of Chinese descent. are pregnant or plan to become pregnant. If you become pregnant while taking ezetimibe and simvastatin tablets, call your healthcare provider right away to discuss stopping ezetimibe and simvastatin tablets. are breastfeeding or plan to breastfeed. It is not known if ezetimibe and simvastatin pass into your breast milk. Do not breastfeed while taking ezetimibe and simvastatin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines. Tell your healthcare provider who prescribes ezetimibe and simvastatin tablets if another healthcare provider increases the dose of another medicine you are taking. Ezetimibe and simvastatin tablets may affect the way other medicines work, and other medicines may affect how ezetimibe and simvastatin tablets works. Especially tell your healthcare provider if you take: digoxin (a drug used to treat irregular heartbeat). coumarin anticoagulants (drugs that prevent blood clots, such as warfarin). fibric acid derivatives (such as fenofibrate). Taking ezetimibe and simvastatin tablets with certain substances can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: amiodarone or dronedarone (medicines used to treat an irregular heartbeat). verapamil, diltiazem, amlodipine, or ranolazine (medicines used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions). lomitapide (a medicine used to treat a serious and rare genetic cholesterol condition). daptomycin (a drug used to treat complicated skin and bloodstream infections). large doses of niacin or nicotinic acid, especially if you are of Chinese descent. colchicine (a medicine used to treat gout). grapefruit juice. Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take ezetimibe and simvastatin tablets? Take ezetimibe and simvastatin tablets exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ezetimibe and simvastatin tablets without talking to your healthcare provider. Take ezetimibe and simvastatin tablets 1 time each day in the evening. If you miss a 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 2 doses of ezetimibe and simvastatin tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose. While taking ezetimibe and simvastatin tablets, continue to follow your cholesterol-lowering diet and to exercise as your healthcare provider told you to. Your healthcare provider may do blood tests to check your cholesterol while you take ezetimibe and simvastatin tablets. Your healthcare provider may change your dose of ezetimibe and simvastatin tablets if needed. If you take too much ezetimibe and simvastatin tablets, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of ezetimibe and simvastatin tablets? Ezetimibe and simvastatin tablets may cause serious side effects including: Muscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death. Tell your healthcare provider right away if: you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take ezetimibe and simvastatin tablets. you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking ezetimibe and simvastatin tablets. 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 taking certain other medicines while you take ezetimibe and simvastatin tablets. are 65 years of age or older. are female. have thyroid problems (hypothyroidism) that are not controlled. have kidney problems. are taking higher doses of ezetimibe and simvastatin tablets. are Chinese. Liver problems. Your healthcare provider should do blood tests to check your liver before you start taking ezetimibe and simvastatin tablets and if you have any symptoms of liver problems while you take ezetimibe and simvastatin tablets. Call your healthcare provider right away if you have the following symptoms of liver problems: feeling tired or weak loss of appetite right-sided upper belly pain dark urine yellowing of your skin or the whites of your eyes increase in blood sugar (glucose) levels). Ezetimibe and simvastatin tablets may cause an increase in your blood sugar levels. The most common side effects of ezetimibe and simvastatin tablets include: headache increased liver enzyme levels muscle pain upper respiratory infection diarrhea Tell 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 and simvastatin tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ezetimibe and simvastatin tablets? Store ezetimibe and simvastatin tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep ezetimibe and simvastatin tablets in its original container until you use it. Keep ezetimibe and simvastatin tablets in a tightly closed container. Keep ezetimibe and simvastatin tablets and all medicines out of the reach of children. General information about safe and effective use of ezetimibe and simvastatin tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ezetimibe and simvastatin tablets for a condition for which it was not prescribed. Do not give ezetimibe and simvastatin tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ezetimibe and simvastatin tablets that is written for health professionals. What are the ingredients in ezetimibe and simvastatin tablets? Active Ingredients: ezetimibe and simvastatin Inactive ingredients: ascorbic acid, butylated hydroxyanisole, citric acid anhydrous, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate. Brands listed are the trademarks of their respective owners. Manufactured by: Watson Pharma Private Limited, Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA For more information, call Actavis at 1-888-838-2872. This Patient Information has been approved by the U.S. Food and Drug Administration .                                                                                Rev. D 4/2024

Ezetimibe and simvastatin tablets: • 10 mg/10 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 511 on one side and on opposite side. • 10 mg/20 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 512 on one side and on opposite side. • 10 mg/40 mg are light tan, slightly speckled, round, unscored, biconvex tablets debossed with 513 on one side and on opposite side. • 10 mg/80 mg are light tan, slightly speckled, capsule shaped, unscored, biconvex tablets debossed with 515 on one side and on opposite side.

Ezetimibe and Simvastatin Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe 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 1 (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 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. Simvastatin Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme converts HMG-CoA to mevalonate, a precursor of cholesterol.

Ezetimibe and simvastatin reduces total cholesterol (total-C), LDL-C, apolipoprotein (Apo) B, and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with hyperlipidemia. Ezetimibe In a 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 E and did not impair adrenocortical steroid hormone production. Simvastatin Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low density lipoproteins. The maximum LDL-C reduction of ZOCOR ®  is usually achieved by 4 weeks and is maintained after that.

The results of a bioequivalence trial in healthy subjects demonstrated that the ezetimibe and simvastatin 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe (ZETIA ® ) and simvastatin (ZOCOR ® ) as individual tablets. Absorption Ezetimibe After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (C max ) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. Simvastatin The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction. Effect of Food on Oral Absorption Ezetimibe Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Simvastatin Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. Distribution Ezetimibe Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins. Simvastatin Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier. Elimination Metabolism Ezetimibe Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism 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 a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Simvastatin Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-­hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Excretion Ezetimibe 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 a 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. Simvastatin Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Specific Populations Geriatric Patients Ezetimibe In a 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 (greater than or equal to 65 years) healthy subjects compared to younger subjects. Simvastatin In a trial including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. [See Use in Specific Populations ( 8.5 ).] Gender Ezetimibe In a multiple-dose trial with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in females than in males. Race Ezetimibe Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black or African American and White subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to those seen in White subjects. Hepatic Impairment Ezetimibe After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve [AUC]) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh scor e 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose trial (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects. Renal Impairment Ezetimibe After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl less than or equal to 30 mL/min/1.73 m 2 ), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n=9). Simvastatin Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal impairment (as measured by creatinine clearance). Drug Interactions [See also Drug Interactions (7).] No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. No specific pharmacokinetic drug interaction studies with ezetimibe and simvastatin have been conducted other than the following trial with NIASPAN (Niacin extended-release tablets). Niacin: The effect of ezetimibe and simvastatin (10 mg/20 mg daily for 7 days) on the pharmacokinetics of NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast) was studied in healthy subjects. The mean C max and AUC of niacin increased 9% and 22%, respectively. The mean C max and AUC of nicotinuric acid increased 10% and 19%, respectively (N=13). In the same trial, the effect of NIASPAN on the pharmacokinetics of ezetimibe and simvastatin was evaluated (N=15). While concomitant NIASPAN decreased the mean C max of total ezetimibe (1%), and simvastatin (2%), it increased the mean C max of simvastatin acid (18%). In addition, concomitant NIASPAN increased the mean AUC of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%). Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products. [See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 ).] Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “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. In a trial of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4 and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see Drug Interactions ( 7 )]. Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. Ezetimibe Table 5 displays the effect of coadministered drugs on total ezetimibe. Table 5: Effect of Coadministered Drugs on Total Ezetimibe Coadministered Drug and Dosing Regimen Total Ezetimibe * Change in AUC Change in C max Cyclosporine-stable dose required (75 to 150 mg BID) †, ‡ ↑­240% ↑­290% Fenofibrate, 200 mg QD, 14 days ‡ ↑­48% ↑­64% Gemfibrozil, 600 mg BID, 7 days ‡ ↑­64% ­↑91% Cholestyramine, 4 g BID, 14 days ‡ ↓55% ↓4% Aluminum & magnesium hydroxide combination antacid, single dose § ↓4% ↓30% Cimetidine, 400 mg BID, 7 days ↑­6% ↑­22% Glipizide, 10 mg, single dose ­↑4% ↓8% Statins Lovastatin 20 mg QD, 7 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 a different trial, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m 2 ) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. ‡ See 7. Drug Interactions. § Supralox, 20 mL. Table 6 displays the effects of ezetimibe coadministration on systemic exposure to other drugs. Table 6: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs Coadministered Drug and its Ezetimibe Dosage Change in AUC Change in C max Dosage Regimen Regimen of Coadministered Drug of Coadministered Drug Warfarin, 25 mg single dose on 10 mg QD, 11 days ↓2% (R-warfarin) ↑­3% (R-warfarin) Day 7 ↓4% (S-warfarin) ↑­1% (S-warfarin) Digoxin, 0.5 mg single dose 10 mg QD, 8 days ↑­2% ↓7% Gemfibrozil, 600 mg BID, 10 mg QD, 7 days ↓1% ↓11% 7 days* Ethinyl estradiol & 10 mg QD, Days 8-14 of Ethinyl estradiol Ethinyl estradiol Levonorgestrel, QD, 21 days 21 day oral contraceptive 0% ↓9% cycle Levonorgestrel Levonorgestrel 0% ↓5% Glipizide, 10 mg on Days 1 10 mg QD, Days 2-9 ↓3% ↓5% and 9 Fenofibrate, 200 mg QD, 10 mg QD, 14 days ↑­11% ↑­7% 14 days * Cyclosporine, 100 mg single 20 mg QD, 8 days ↑­15% ↑­10% dose Day 7* Statins Lovastatin 20 mg QD, 10 mg QD, 7 days ↑­19% ↑­3% 7 days Pravastatin 20 mg QD, 10 mg QD, 14 days ↓20% ↓24% 14 days Atorvastatin 10 mg QD, 10 mg QD, 14 days ↓4% ↑­7% 14 days Rosuvastatin 10 mg QD, 10 mg QD, 14 days ↑­19% ↑­17% 14 days Fluvastatin 20 mg QD, 10 mg QD, 14 days ↓39% ↓27% 14 days * See 7. Drug Interactions. Simvastatin Table 7 displays the effects of coadminstration drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions (7)]. Table 7: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect = 1.00 AUC C max Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 12 8.9 15 5.3 Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6 6.2 Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 13.1 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid ‡ simvastatin simvastatin acid ‡ simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid ‡ simvastatin 2.85 1.35 2.18 0.91 Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Verapamil SR 240 mg QD Days 1-7 then 240 mg BID on Days 8-10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Amlodipine 10 mg QD for 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6-9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7 Fenofibrate 160 mg QD for 14 days 80 mg QD on Days 8-14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7.0 to 4.7 ng·eq/mL * Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.

Indications and Usage (1)                                                                                   2/2024 Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5)                                 2/2024 Contraindications, Pregnancy and Lactation (4) Removed                 2/2024 Warnings and Precautions (5.1, 5.2, 5.3)                                                     2/2024

Pregnancy : May cause fetal harm ( 8.1 ) Lactation : Breastfeeding not recommended during treatment with ezetimibe and simvastatin tablets. ( 8.2 )

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ezetimibe and simvastatin tablets dosage. Chinese patients may be at higher risk for myopathy. Discontinue ezetimibe and simvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ezetimibe and simvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing ezetimibe and simvastatin tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue ezetimibe and simvastatin tablets if IMNM is suspected. ( 5.2 ) Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ezetimibe and simvastatin tablets. ( 5.3 )

NDC 45963-565-30 Ezetimibe and Simvastatin Tablets 10 mg/10 mg 30 Tablets Rx Only