EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin_tablet

Ezetimibe and simvastatin tablets Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin tablets 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 beta-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 tablets 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 tablets (ezetimibe and simvastatin) 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe and simvastatin 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 Simvastatin The availability of the beta-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 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 (>90%) to human plasma proteins. Simvastatin Both simvastatin and its beta-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 Excretion Ezetimibe Following oral administration of 14 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 14 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 (>=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 (<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 score 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 <=30 mL/min/1. 73 m 2 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 tablets have been conducted other than the following trial with NIASPAN (Niacin extended-release tablets). Niacin: max max max max Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (>=1 g/day niacin) of niacin-containing products. [See Warnings and Precautions ( 5. 1 Cytochrome P450: 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. 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) dagger, double dagger up arrow240% up arrow290% Fenofibrate, 200 mg QD, 14 days double dagger up arrow48% up arrow64% Gemfibrozil, 600 mg BID, 7 days double dagger up arrow64% up arrow91% Cholestyramine, 4 g BID, 14 days double dagger down arrow55% down arrow4% Aluminum & magnesium hydroxide combination antacid, single dosesection down arrow4% down arrow30% Cimetidine, 400 mg BID, 7 days up arrow6% up arrow22% Glipizide, 10 mg, single dose up arrow4% down arrow8% Statins Lovastatin 20 mg QD, 7 days up arrow9% up arrow3% Pravastatin 20 mg QD, 14 days up arrow7% up arrow23% Atorvastatin 10 mg QD, 14 days down arrow2% up arrow12% Rosuvastatin 10 mg QD, 14 days up arrow13% up arrow18% Fluvastatin 20 mg QD, 14 days down arrow19% up arrow7% * dagger 2 double dagger section 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 Dosage Regimen Ezetimibe Dosage Regimen Change in AUC of Coadministered Drug Change in C max Warfarin, 25 mg single dose on Day 7 10 mg QD, 11 days down arrow2% (R-warfarin) up arrow3% (R-warfarin) Digoxin, 0. 5 mg single dose 10 mg QD, 8 days up arrow2% down arrow7% Gemfibrozil, 600 mg BID, 7 days * 10 mg QD, 7 days down arrow1% down arrow11% Ethinyl estradiol & 10 mg QD, Days 8 to 14 of 21 day oral contraceptive cycle Ethinyl estradiol 0% Ethinyl estradiol down arrow9% Glipizide, 10 mg on Days 1 and 9 10 mg QD, Days 2 to 9 down arrow3% down arrow5% Fenofibrate, 200 mg QD, 14 days * 10 mg QD, 14 days up arrow11% up arrow7% Cyclosporine, 100 mg single dose Day 7 * 20 mg QD, 8 days up arrow15% up arrow10% Statins Lovastatin 20 mg QD, 7 days 10 mg QD, 7 days up arrow19% up arrow3% Pravastatin 20 mg QD, 14 days 10 mg QD, 14 days down arrow20% down arrow24% Atorvastatin 10 mg QD, 14 days 10 mg QD, 14 days down arrow4% up arrow7% Rosuvastatin 10 mg QD, 14 days 10 mg QD, 14 days up arrow19% up arrow17% Fluvastatin 20 mg QD, 14 days 10 mg QD, 14 days down arrow39% down arrow27% * 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 dagger 200 mg QD for 4 days 80 mg simvastatin acid double dagger 12 15 Nelfinavir dagger 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid double dagger Itraconazole dagger 200 mg QD for 4 days 80 mg simvastatin acid double dagger 13. 1 Posaconazole 100 mg (oral suspension) QD for 13 days 40 mg simvastatin acid double dagger 7. 2 200 mg (oral suspension) QD for 13 days 40 mg simvastatin acid double dagger 8. 5 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin aciddouble dagger 2. 18 Grapefruit Juicesection (high dose) 200 mL of double-strength TID paragraph 60 mg single dose simvastatin acid 7 Grapefruit Juicesection (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid 1. 3 Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid 2. 4 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid 2. 69 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4. 6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid 1. 14 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid 1. 72 Amlodipine 10 mg QD for 10 days 80 mg on Day 10 simvastatin acid 1. 56 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid 2. 28 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid 1. 6 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid 1. 4 Fenofibrate 160 mg QD for 14 days 80 mg QD on Days 8 to 14 simvastatin acid 0. 89 Propranolol 80 mg single dose 80 mg single dose total inhibitor 0. 79 down arrow from 33. 1 ng·eq/mL * dagger double dagger section paragraph #.

Ezetimibe and Simvastatin Ezetimibe and simvastatin is a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): o In adults with primary hyperlipidemia. o 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, 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. Ezetimibe and simvastatin tablets is a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: ( 1.

Important Dosage and Administration Information: (2. 1) Take ezetimibe and simvastatin orally once daily in the evening with or without food. Maximum recommended dosage is ezetimibe and simvastatin 10/40 mg once daily. Ezetimibe and simvastatin 10/80 mg daily dosage is restricted to patients who have been taking ezetimibe and simvastatin 10/80 mg daily chronically (e. , 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 10/40 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, and adjust the dosage if necessary. Adults: See full prescribing information for ezetimibe and simvastatin dosage modifications due to drug interactions. 3) Patients with Renal Impairment: Take ezetimibe and simvastatin orally once daily in the evening with or without food. The maximum recommended dosage is ezetimibe and simvastatin 10/40 mg once daily. The ezetimibe and simvastatin 10/80 mg daily dosage is restricted to adult patients who have been taking ezetimibe and simvastatin 10/80 mg daily chronically (e. , 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 10/40 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe and simvastatin, and adjust the dosage if necessary. The recommended dosage range of ezetimibe and simvastatin 10/10 mg to 10/40 mg once a day. The recommended dosage range of ezetimibe and simvastatin tablets 10/10 mg to 10/40 mg once a day. Renal impairment is a risk factor for statin-associated myopathy. Doses of ezetimibe and simvastatin tablets exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see Warnings and Precautions ( 5. 6 There are no dosage adjustment recommendations for patients with mild renal impairment. Concomitant use of ezetimibe and simvastatin tablets with the following drugs requires dosage modification of ezetimibe and simvastatin tablets [see Warnings and Precautions ( 5. 1 Patients taking Lomitapide Reduce the dosage of ezetimibe and simvastatin tablets by 50%. Do not exceed ezetimibe and simvastatin tablets 10/20 mg once daily (or 10/40 mg once daily for patients who have previously taken ezetimibe and simvastatin tablets 10/80 mg daily chronically while taking lomitapide) [see Dosage and Administration ( 2. 1 Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed ezetimibe and simvastatin tablets 10/10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed ezetimibe and simvastatin tablets 10/20 mg once daily. Patients taking Bile Acid Sequestrants In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or 4 hours after the bile acid sequestrant.

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 Common (incidence >=2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. 1 To report SUSPECTED ADVERSE REACTIONS,contact Ascend Laboratories,LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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 Tablets 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. The most common adverse reactions in the group treated with ezetimibe and simvastatin tablets 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. Ezetimibe and simvastatin tablets has been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in >=2% of patients treated with ezetimibe and simvastatin tablets (n=1420) and at an incidence greater than placebo from four placebo-controlled trials. Table 1*: Adverse Reactions Reported >=2% of Patients Treated with Ezetimibe and Simvastatin Tablets at an Incidence Greater than Placebo Regardless of Causality % Placebo N = 371 % Ezetimibe 10 mg N = 302 % Simvastatindagger N = 1234 % Ezetimibe and Simvastatin Tablets dagger N = 1420 Headache 5. 8 Upper respiratory tract infection 2. 6 Myalgia 2. 6 Diarrhea 2. 8 Pain in extremity 1. 3 Influenza 0. 3 *Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin tablets were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin tablets was administered. dagger Study of Heart and Renal Protection , Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders Infections and infestations: Body as a whole general disorders 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] >10 times (1200 U/L) upper limit of normal [ULN]) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0. 9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0. 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 [see Warnings and Precautions ( 5. 1 The following adverse reactions have been identified during post-approval use of ezetimibe and simvastatin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as Whole: Blood and Lymphatic System Disorders: Gastrointestinal Disorders: Hepatobiliary Disorders: Immune System Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Skin and Subcutaneous Tissue Disorders: Respiratory and Thoracic: Reproductive System Disorders:.

Ezetimibe and simvastatin tablets is contraindicated in the following conditions: Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti­viral 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 Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications and nefazodone). ( 4 Concomitant use of cyclosporine, danazol or gemfibrozil. ( 4 Acute liver failure or decompensated cirrhosis. ( 4 Hypersensitivity to simvastatin, ezetimibe or any excipient of ezetimibe and simvastatin tablets.

Pregnancy: 8. 1 Lactation: 8. 2 Ezetimibe and simvastatin tablets Risk Summary Discontinue ezetimibe and simvastatin tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Ezetimibe and simvastatin tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ezetimibe and simvastatin tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12. 1 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 tablets 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/m 2 (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 1,152 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 en dash including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use en dash 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. 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 to 15) and rabbits (gestation days 7 to 19), there was no evidence of maternal toxicity or embryolethality at any dose tested (250, 500, 1,000 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 1,000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC 0-24hr 0-24hr The animal-to-human exposure multiple for total ezetimibe at the no-observed effect level was 6 times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a maternal dose of 1,000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1. 5 for rats on gestation day 20 and 0. 03 for rabbits on gestation day 22. The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1,000 mg/kg/day (gestation day 6 through lactation day 21). No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC 0-24hr 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. 5 and 25 mg/kg/day (0. 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 to 17 and to pregnant rabbits from gestation days 6 to 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. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6. 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. Risk Summary 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 tablets [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 tablets for this indication is based on a double-blind, placebo-controlled clinical trial in 248 pediatric patients (142 males and 106 postmenarchal females) 10 years of age and older with HeFH [see Clinical Studies (14)] The safety and effectiveness of ezetimibe and simvastatin tablets 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 tablets -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 tablets for the increased risk of myopathy [see Warnings and Precautions ( 5. 1 Of the 10,189 patients who received ezetimibe and simvastatin tablets in clinical studies, 3,242 (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. Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Doses of ezetimibe and simvastatin tablets exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see Dosage and Administration (2. 4) and Warnings and Precautions ( 5. 1 In the SHARP trial of 9,270 patients with moderate to severe renal impairment (6,247 non-dialysis patients with median serum creatinine 2. 5 mg/dL and median estimated glomerular filtration rate 25. 73 m 2 Ezetimibe and simvastatin tablets is contraindicated in patients with acute liver failure or decompensated cirrhosis. [See Contraindications ( 4 5. 3 In a clinical trial in which patients at high risk of CVD were treated with simvastatin 40 mg/day (median follow-up 3. 9 years), the incidence of myopathy was approximately 0. 05% for non-Chinese patients (n=7367) compared with 0. 24% for Chinese patients (n=5468). In this trial the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe and simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1. Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of ezetimibe and simvastatin tablets with lipid-modifying doses of niacin-containing products (>=1 g/day niacin) is not recommended in Chinese patients [see Warnings and Precautions ( 5.

Ezetimibe and Simvastatin Tablets See full prescribing information for details regarding concomitant use of ezetimibe and simvastatin with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. 1 Cholestyramine: 2. 2 Coumarin Anticoagulants: 7. 3 Digoxin: 7. 3 Fenofibrates: 7. 3 Ezetimibe and simvastatin tablets is a substrate of CYP3A4 and of the transport protein OATP1B1. Ezetimibe and simvastatin tablets plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1. Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with ezetimibe and simvastatin tablets and instructions for preventing or managing them [see Warnings and Precautions ( 5. 3 Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Ezetimibe and Simvastatin Tablets Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher ezetimibe and simvastatin tablets dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets is contraindicated [see Contraindications (4)] Examples: Select azole anti-fungals (e. , itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e. , erythromycin and clarithromycin, telithromycin), select HIV protease inhibitors (e. , nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e. , boceprevir and telaprevir), cobicistat-containing products, and nefazodone. Cyclosporine, Danazol, or Gemfibrozil Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with ezetimibe and simvastatin tablets. Gemfibrozil may cause myopathy when given alone. Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with ezetimibe and simvastatin tablets is contraindicated [see Contraindications (4)] Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with ezetimibe and simvastatin tablets. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed ezetimibe and simvastatin tablets 10/10 mg daily. [see Dosage and Administration (2. 3)] Lomitapide Clinical Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased. Intervention: Reduce the dose of ezetimibe and simvastatin tablets by 50% if initiating lomitapide. Do not exceed ezetimibe and simvastatin tablets 10/20 mg daily (or ezetimibe and simvastatin tablets 10/40 mg daily for patients who have previously taken ezetimibe and simvastatin tablets 10/80 mg daily chronically) while taking lomitapide [see Dosage and Administration (2. 3)] Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both ezetimibe and simvastatin tablets and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Intervention: If treatment with daptomycin is required, consider temporarily suspending ezetimibe and simvastatin tablets during the course of daptomycin treatment. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (>=1 gram/day niacin) with ezetimibe and simvastatin tablets. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3. 9 years) of patients at high risk of CVD and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses of niacin Intervention: Concomitant use of ezetimibe and simvastatin tablets with lipid-modifying dosages of niacin is not recommended in Chinese patients [see Use in Specific Populations (8. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with ezetimibe and simvastatin tablets. Intervention: Consider if the benefit of using fibrates concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with ezetimibe and simvastatin tablets. Intervention: Consider if the benefit of using colchicine concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. Grapefruit Juice Clinical Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid grapefruit juice when taking ezetimibe and simvastatin tablets. Table 3 presents drug interactions that may decrease the efficacy of ezetimibe and simvastatin tablets and instructions for preventing or managing them. Table 3: Drug Interactions that Decrease the Efficacy of Ezetimibe and Simvastatin Tablets Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe and simvastatin tablets to cholestyramine may be reduced by this interaction [see Clinical Pharmacology ( 12. 3 Intervention: In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or at least 4 hours after cholestyramine [see Dosage and Administration ( 2. 3 Table 4 presents ezetimibe and simvastatin tablets effect on other drugs and instructions for preventing or managing them. Table 4: Ezetimibe and Simvastatin Tablets Coumarin Anticoagulants Clinical Impact: Ezetimibe and simvastatin tablets may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1. 8 in healthy subjects and from 2. 4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins (with or without ezetimibe) and coumarin anticoagulants. Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting ezetimibe and simvastatin tablets and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. Digoxin Clinical Impact: Concomitant use of digoxin with ezetimibe and simvastatin tablets may result in elevated plasma digoxin concentrations [see Clinical Pharmacology ( 12. 3 Intervention: Monitor digoxin levels in patients taking digoxin when ezetimibe and simvastatin tablets is initiated. Fenofibrates Clinical Impact: Both ezetimibe and fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Intervention: If cholelithiasis is suspected in a patient receiving ezetimibe and simvastatin tablets and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid].

OVERDOSAGE
No specific antidotes for ezetimibe and simvastatin tablets are known. In the event of an overdose with ezetimibe and simvastatin tablets, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for overdosage management recommendations.
NONCLINICAL TOXICOLOGY
Ezetimibe and Simvastatin Tablets 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 Salmonella typhimurium Escherichia coli in vitro in vivo Ezetimibe A 104-week dietary carcinogenicity trial with ezetimibe was conducted in rats at doses up to 1,500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC 0-24hr 0-24hr No evidence of mutagenicity was observed in vitro Salmonella typhimurium Escherichia coli in vitro in vivo In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1,000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC 0-24hr 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 in vitro in vivo 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
CLINICAL STUDIES
Primary Hyperlipidemia in Adults Ezetimibe and simvastatin tablets Ezetimibe and simvastatin tablets reduces LDL-C in adult patients with primary hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy. Ezetimibe and simvastatin tablets is effective in males and females with primary hyperlipidemia. There were insufficient numbers of patients who self-identified as Black or African American, Asian, or other races to determine if these patients responded differently than White patients. Five multicenter, double-blind trials conducted with either ezetimibe and simvastatin tablets or coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets in patients with primary hyperlipidemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin, and one was a comparison with rosuvastatin. In a multicenter, double-blind, placebo-controlled, 12-week trial, 1,528 patients with primary hyperlipidemia were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or ezetimibe and simvastatin tablets (10/10, 10/20, 10/40, or 10/80). When patients receiving ezetimibe and simvastatin tablets were compared to those receiving all doses of simvastatin, ezetimibe and simvastatin tablets significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of ezetimibe and simvastatin tablets on HDL-C were similar to the effects seen with simvastatin. Further analysis showed ezetimibe and simvastatin tablets significantly increased HDL-C compared with placebo. (See Table 8. ) The lipid response to ezetimibe and simvastatin tablets was similar in patients with TG levels greater than or less than 200 mg/dL. Table 8: Response to Ezetimibe and Simvastatin Tablets in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger Treatment (Daily Dose) N Total-C LDL-C Apo B HDL-C TG * Non-HDL-C Pooled data (All Ezetimibe and Simvastatin Tablets doses) double dagger 609 -38 -53 -42 +7 -24 -49 Pooled data (All simvastatin doses) double dagger 622 -28 -39 -32 +7 -21 -36 Ezetimibe 10 mg 149 -13 -19 -15 +5 -11 -18 Placebo 148 -1 -2 0 0 -2 -2 Ezetimibe and Simvastatin Tablets by dose 10/10 152 -31 -45 -35 +8 -23 -41 10/20 156 -36 -52 -41 +10 -24 -47 10/40 147 -39 -55 -44 +6 -23 -51 10/80 154 -43 -60 -49 +6 -31 -56 Simvastatin by dose 10 mg 158 -23 -33 -26 +5 -17 -30 20 mg 150 -24 -34 -28 +7 -18 -32 40 mg 156 -29 -41 -33 +8 -21 -38 80 mg 158 -35 -49 -39 +7 -27 -45 * dagger double dagger In a multicenter, double-blind, controlled, 23-week trial, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C >=130 mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10/10, 10/20, and 10/40) or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg. At Week 5, the LDL-C reductions with ezetimibe and simvastatin tablets 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 9). Table 9: Response to Ezetimibe and Simvastatin Tablets after 5 Weeks in Patients with CHD or CHD Risk Equivalents and an LDL-C 130 mg/dL Simvastatin 20 mg Ezetimibe and Simvastatin Tablets 10/10 Ezetimibe and Simvastatin Tablets 10/20 Ezetimibe and Simvastatin Tablets 10/40 N 253 251 109 97 Mean baseline LDL-C 174 165 167 171 Percent change LDL-C -38 -47 -53 -59 In a multicenter, double-blind, 6-week trial, 1902 patients with primary hyperlipidemia were randomized to one of eight treatment groups: Ezetimibe and simvastatin tablets (10/10, 10/20, 10/40, or 10/80) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg). Across the dosage range, when patients receiving ezetimibe and simvastatin tablets were compared to those receiving milligram-equivalent statin doses of atorvastatin, ezetimibe and simvastatin tablets lowered total-C, LDL-C, Apo B, and non- HDL-C significantly more than atorvastatin. Only the 10/40 mg and 10/80 mg ezetimibe and simvastatin tablets doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of ezetimibe and simvastatin tablets on TG were similar to the effects seen with atorvastatin. (See Table 10. ) Table 10: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger Treatment (Daily Dose) N Total-C double dagger LDL-C double dagger Apo B double dagger HDL-C TG * Non-HDL-C double dagger Ezetimibe and Simvastatin Tablets by dose 10/10 230 -34 section -47 section -37 section +8 -26 -43 section 10/20 233 -37 section -51 section -40 section +7 -25 -46 section 10/40 236 -41 section -57 section -46 section +9 section -27 -52 section 10/80 224 -43 section -59 section -48 section +8 section -31 -54 section Atorvastatin by dose 10 mg 235 -27 -36 -31 +7 -21 -34 20 mg 230 -32 -44 -37 +5 -25 -41 40 mg 232 -36 -48 -40 +4 -24 -45 80 mg 230 -40 -53 -44 +1 -32 -50 * dagger double dagger provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10 to 80). section In a multicenter, double-blind, 24-week, forced-titration trial, 788 patients with primary hyperlipidemia were randomized to receive coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, ezetimibe and simvastatin tablets lowered LDL-C to a greater degree than atorvastatin (see Table 11). Table 11: Response to Ezetimibe and Simvastatin Tablets and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger Treatment N Total-C LDL-C Apo B HDL-C TG * Non-HDL-C Week 6 Atorvastatin 10 mg double dagger 262 -28 -37 -32 +5 -23 -35 Ezetimibe and Simvastatin Tablets 10/10 section 263 -34 paragraph -46 paragraph -38 paragraph +8 paragraph -26 -43 paragraph Ezetimibe and Simvastatin Tablets 10/20 # 263 -36 paragraph -50 paragraph -41 paragraph +10 paragraph -25 -46 paragraph Week 12 Atorvastatin 20 mg 246 -33 -44 -38 +7 -28 -42 Ezetimibe and Simvastatin Tablets 10/20 250 -37 paragraph -50 paragraph -41 paragraph +9 -28 -46 paragraph Ezetimibe and Simvastatin Tablets 10/40 252 -39 paragraph -54 paragraph -45 paragraph +12 paragraph -31 -50 paragraph Week 18 Atorvastatin 40 mg 237 -37 -49 -42 +8 -31 -47 Ezetimibe and Simvastatin Tablets 10/40 Þ 482 -40 paragraph -56 paragraph -45 paragraph +11 paragraph -32 -52 paragraph Week 24 Atorvastatin 80 mg 228 -40 -53 -45 +6 -35 -50 Ezetimibe and Simvastatin Tablets 10/80 Þ 459 -43 paragraph -59 paragraph -49 paragraph +12 paragraph -35 -55 paragraph * dagger double dagger section paragraph # Þ In a multicenter, double-blind, 6-week trial, 2,959 patients with primary hyperlipidemia, were randomized to one of six treatment groups: ezetimibe and simvastatin tablets (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg). The effects of ezetimibe and simvastatin tablets and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 12. Table 12: Response to Ezetimibe and Simvastatin Tablets and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean * dagger Treatment (Daily Dose) N Total-C double dagger LDL-C double dagger Apo B double dagger HDL-C TG * Non-HDL-C double dagger Ezetimibe and Simvastatin Tablets by dose 10/20 476 -37 section -52 section -42 section +7 -23 section -47 section 10/40 477 -39 paragraph -55 paragraph -44 paragraph +8 -27 -50 paragraph 10/80 474 -44 # -61 # -50 # +8 -30 # -56 # Rosuvastatin by dose 10 mg 475 -32 -46 -37 +7 -20 -42 20 mg 478 -37 -52 -43 +8 -26 -48 40 mg 475 -41 -57 -47 +8 -28 -52 * dagger double dagger section paragraph # In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks were randomized to receive either simvastatin 40 mg or the coadministered active ingredients equivalent to ezetimibe and simvastatin tablets 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7. 1%, respectively. Ezetimibe and simvastatin tablets 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for ezetimibe and simvastatin tablets vs. simvastatin were: LDL-C -25% and -5%; total-C-16% and -5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different. Ezetimibe In two multicenter, double-blind, placebo-controlled, 12-week trials in 1719 patients with primary hyperlipidemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), and TG (-8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C. Simvastatin In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Trial (N=4,444 patients) and the Heart Protection Trial (N=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and stroke; and the need for coronary and non-coronary revascularization procedures. No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Heterozygous Familial Hypercholesterolemia (HeFH) in Pediatric Patients The effects of ezetimibe coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in males and females with HeFH. In a multicenter, double-blind, controlled trial followed by an open-label phase, 142 males and 106 postmenarchal females, 10 to 17 years of age (mean age 14. 2 years, 43% females, 82% White, 4% Asian, 2% Black or African American, 13% multi-racial; 14% identified as Hispanic or Latino ethnicity) with HeFH were randomized to receive either ezetimibe coadministered with simvastatin or simvastatin monotherapy. Inclusion in the trial required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered ezetimibe and 40-mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the trial at Week 6 are summarized in Table 13. Results at Week 33 were consistent with those at Week 6. Table 13: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with HeFH Total-C LDL-C Apo B Non-HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% 95% Confidence Interval (-15%,-9%) (-18%,-12%) (-15%,-9%) (-17%,-11%) Homozygous Familial Hypercholesterolemia (HoFH) in Adults A double-blind, randomized, 12-week trial was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced. Chronic Kidney Disease (CKD) in Adults The Trial of Heart and Renal Protection (SHARP) was a multinational, randomized, placebo- controlled, double-blind trial that investigated the effect of ezetimibe and simvastatin tablets on the time to a first major vascular event (MVE) among 9,438 patients with moderate to severe chronic kidney disease (approximately one- third on dialysis at baseline) who did not have a history of myocardial infarction or coronary revascularization. An MVE was defined as nonfatal MI, cardiac death, stroke, or any revascularization procedure. Patients were allocated to treatment using a method that took into account the distribution of 8 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. For the first year, 9,438 patients were allocated 4:4:1, to ezetimibe and simvastatin tablets 10/20, placebo, or simvastatin 20 mg daily, respectively. The 1-year simvastatin arm enabled the comparison of ezetimibe and simvastatin tablets to simvastatin with regard to safety and effect on lipid levels. At 1 year the simvastatin-only arm was re-allocated 1:1 to ezetimibe and simvastatin tablets 10/20 or placebo. A total of 9,270 patients were ever allocated to ezetimibe and simvastatin tablets 10/20 (n=4650) or placebo (n=4620) during the trial. The median follow-up duration was 4. Patients had a mean age of 61 years; 63% were male, 72% were White, and 23% were diabetic; and, for those not on dialysis at baseline, the median serum creatinine was 2. 5 mg/dL and the median estimated glomerular filtration rate (eGFR) was 25. 73 m 2 2 In the primary intent-to-treat analysis, 639 (15. 2%) of 4,193 patients initially allocated to ezetimibe and simvastatin tablets and 749 (17. 9%) of 4,191 patients initially allocated to placebo experienced an MVE. This corresponded to a relative risk reduction of 16% (p=0. 001) (see Figure 1). Similarly, 526 (11. 3%) of 4650 patients ever allocated to ezetimibe and simvastatin tablets and 619 (13. 4%) of 4,620 patients ever allocated to placebo experienced a major atherosclerotic event (MAE; a subset of the MVE composite that excluded non-coronary cardiac deaths and hemorrhagic stroke), corresponding to a relative risk reduction of 17% (p=0. The trial demonstrated that treatment with ezetimibe and simvastatin tablets 10/20 mg versus placebo reduced the risk for MVE and MAE in this CKD population. The trial design precluded drawing conclusions regarding the independent contribution of either ezetimibe or simvastatin to the observed effect. The treatment effect of ezetimibe and simvastatin tablets on MVE was attenuated among patients on dialysis at baseline compared with those not on dialysis at baseline. Among 3023 patients on dialysis at baseline, ezetimibe and simvastatin tablets reduced the risk of MVE by 6% (RR 0. 94: 95% CI 0. 09) compared with 22% (RR 0. 78: 95% CI 0. 89) among 6247 patients not on dialysis at baseline (interaction P=0. Figure 1: Effect of Ezetimibe and Simvastatin Tablets on the Primary Endpoint of Risk of Major Vascular Events The individual components of MVE in all patients ever allocated to ezetimibe and simvastatin tablets or placebo are presented in Table 14. Table 14: Number of First Events for Each Component of the Major Vascular Event Composite Endpoint in SHARP * Outcome Ezetimibe and Simvastatin Tablets 10/20 (N=4650) Placebo (N=4620) Risk Ratio (95% CI) P-value Major Vascular Events 701 (15. 1%) 814 (17. 001 Nonfatal MI 134 (2. 12 Cardiac Death 253 (5. 38 Any Stroke 171 (3. 038 Non-hemorrhagic Stroke 131 (2. 011 Hemorrhagic Stroke 45 (1. 40 Any Revascularization 284 (6. 004 * Among patients not on dialysis at baseline, ezetimibe and simvastatin tablets did not reduce the risk of progressing to end- stage renal disease compared with placebo (RR 0. 97: 95% CI 0. Simvastatin Cardiovascular Outcome Trials in Adults at High Risk of Coronary Heart Disease Events In a randomized, double-blind, placebo-controlled, multi-centered trial [the Scandinavian Simvastatin Survival Trial (Trial 4S)], the effect of therapy with simvastatin on total mortality was assessed in 4,444 adult patients with CHD (history of angina and/or a previous myocardial infarction) and baseline total cholesterol (total-C) between 212 and 309 mg/dL who were on a lipid-lowering diet. In Trial 4S, patients were treated with standard care, including lipid-lowering diet, and randomized to either simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5. Simvastatin significantly reduced the risk of mortality by 30% (p=0. 0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0. 00001, 111 deaths in the simvastatin group vs 189 deaths in the placebo group). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly reduced the risk for the secondary composite endpoint (time to first occurrence of CHD death, definite or probable hospital verified non-fatal MI, silent MI verified by ECG, or resuscitated cardiac arrest) by 34% (p<0. 00001, 431 vs 622 patients with one or more events). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0. 00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0. 033, 75 vs 102 patients). Over the course of the trial, treatment with simvastatin led to mean reductions in total-C, LDL-C and triglycerides (TG) of 25%, 35%, and 10%, respectively, and a mean increase in high-density lipoprotein cholesterol (HDL-C) of 8%. In contrast, treatment with placebo led to increases in total-C, LDL-C and TG of 1%, 1%, and 7%, respectively. Because there were only 53 female deaths (approximately 18% of the trial population was female), the effect of simvastatin on mortality in females could not be adequately assessed. However, simvastatin significantly reduced the risk of having major coronary events in females by 34% (60 vs 91 women with one or more event). Simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in geriatric patients (>=65 years) compared with younger adults. The Heart Protection Trial (Trial HPS) was a randomized, placebo-controlled, double-blind, multi-centered trial with a mean duration of 5 years conducted in 10,269 patients on simvastatin 40 mg and 10,267 on placebo. Patients had a mean age of 64 years (range 40 to 80 years old), 97% were White, and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vascular disease (33%), or they were males >=65 years with hypertension in (6%). At baseline: 3,421 patients (17%) had LDL-C levels below 100 mg/dL, including 953 (5%) below 80 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL. Patients were randomized to simvastatin or placebo using a covariate adaptive method which considered the distribution of 10 important baseline characteristics of patients already enrolled. The Trial HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; and non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 15). Table 15: CHD Mortality and Cardiovascular Events in Adult Patients with High Risk of Developing a Major Coronary Event in Trial HPS Endpoint Simvastatin (N=10,269) n (%)* Placebo (N=10,267) n (%)* Risk Reduction (%) (95% CI) p-Value Primary Secondary Tertiary * n = number of patients with indicated event Two composite endpoints were defined to have enough events to assess relative risk reductions across a range of baseline characteristics: Major coronary events (MCE) was comprised of CHD mortality and non-fatal MI. Analyzed by time-to-first event; 898 patients (8. 7%) treated with simvastatin had events and 1,212 patients (11. 8%) treated with placebo had events. Major vascular events (MVE) was comprised of MCE, stroke, and revascularization procedures including coronary, peripheral and other non-coronary procedures. Analyzed by time-to-first event; 2,033 patients (19. 8%) treated with simvastatin had events and 2,585 patients (25. 2%) on placebo had events. Simvastatin use led to significant relative risk reductions for both composite endpoints (27% for MCE and 24% for MVE, p<0. 0001) and for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at trial entry (i. , CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, baseline levels of LDL-C, baseline concomitant cardiovascular medications (i. , aspirin, beta blockers, or calcium channel blockers), smoking status, or obesity. Patients with diabetes showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity.
Patient Information
Ezetimibe and Simvastatin Tablets (e-ZET-i-mibe / SIM-va-STAT-in) Read this Information carefully before you start taking ezetimibe and simvastatin tablets and each time you get a 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 is right for you. What is ezetimibe and simvastatin tablets? Ezetimibe and simvastatin tablets is a prescription medicine that contains the cholesterol lowering medicines, simvastatin and ezetimibe: Ezetimibe and simvastatin tablets is used along with diet to lower elevated low-density lipoprotein cholesterol (LDL-C) or bad cholesterol in: o adults with primary hyperlipidemia (high level of fats in your blood). o 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 is 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 is used to lower: o the risk of death by lowering the risk of heart disease death. o the risk of heart attacks and strokes. o 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 e if you: take certain medicines called CYP3A4 inhibitors such as: o certain antifungal medicines (such as itraconazole, ketoconazole, posaconazole, voriconazole). o certain antibiotics (including erythromycin, clarithromycin, telithromycin). o HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir and cobicistat-containing products such as (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate). o certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir). o 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 tablets passes into your breast milk. Do not Tell your healthcare provider about all the medicines you take, 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 e ? Take ezetimibe and simvastatin tablets exactly as your healthcare provider tells you to take it. Do not 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 e ? Ezetimibe and simvastatin tablets may cause serious side effects including: Muscle pain, tenderness, and weakness (myopathy). Tell your healthcare provider right away if: o you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take e zetimibe and simvastatin tablets . o 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. Call your healthcare provider right away if you have the following symptoms of liver problems: o feeling tired or weak o loss of appetite o right-sided upper belly pain o dark urine o yellowing of your skin or the whites of your eyes increase in blood sugar (glucose) levels). The most common side effects of e zetimibe 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 e zetimibe and simvastatin tablets ? Store ezetimibe and simvastatin tablets at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Keep ezetimibe and simvastatin tablets in its original container until you use it. Keep ezetimibe and simvastatin tablets in a tightly closed container. Keep e zetimibe and simvastatin tablets and all medicines out of the reach of children. General information about safe and effective use of e zetimibe 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. For more information, call 1-877-272-7901. What are the ingredients in e zetimibe and simvastatin tablets ? Active Ingredients: Inactive Ingredients: Sodium Lauryl Sulfate, Hypromellose, Citric Acid Monohydrate, Propyl Gallate, Butylated Hydroxy Anisole and Magnesium Stearate. This Patient Information has been approved by the U.S. Food and Drug Administration. For Patient Information, please visit: Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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