EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin_tablet

Ezetimibe and simvastatin Ezetimibe 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 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 Simvastatin The results of a bioequivalence trial in healthy subjects demonstrated that the ezetimibe and simvastatin (ezetimibe and simvastatin) 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe (ZETIA registered registered Absorption Ezetimibe Simvastatin Effect of Food on Oral Absorption Ezetimibe Simvastatin Distribution Ezetimibe Simvastatin Elimination Metabolism Ezetimibe 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 Excretion Ezetimibe Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, Simvastatin Specific Populations Geriatric Patients Ezetimibe Simvastatin [See Use in Specific Populations ( 8. 5 Gender Ezetimibe Race Ezetimibe Hepatic Impairment Ezetimibe Renal Impairment Ezetimibe Simvastatin 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: 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 6 displays the effects of ezetimibe coadministration on systemic exposure to other drugs. 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 simvastatin 12 8. 3 Nelfinavir dagger 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid double dagger simvastatin 6 6. 2 Itraconazole dagger 200 mg QD for 4 days 80 mg simvastatin acid double dagger simvastatin 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 double dagger simvastatin simvastatin acid double dagger simvastatin 7. 4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid double dagger simvastatin 2. 91 Grapefruit Juice section (high dose) 200 mL of double-strength TID paragraph 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice section (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1. 9 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 simvastatin 2. 1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2. 88 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 simvastatin 1. 75 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1. 79 Amlodipine 10 mg QD for 10 days 80 mg on Day 10 simvastatin acid simvastatin 1. 47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2. 75 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1. 6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1. 7 Fenofibrate 160 mg QD for 14 days 80 mg QD on Days 8-14 simvastatin acid simvastatin 0. 83 Propranolol 80 mg single dose 80 mg single dose total inhibitor 0. 79 down arrow from 33. 1 ng·eq/mL active inhibitor 0. 79 down arrow from 7. 7 ng·eq/mL * Results based on a chemical assay except results with propranolol as indicated. table-5 table-6.

Ezetimibe and simvastatin tablet is a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: ( 1 Simvastatin Ezetimibe and simvastatin tablets 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 Adults: 2. 3 Patients with Renal Impairment: 2. 4 o Take ezetimibe and simvastatin tablet orally once daily in the evening with or without food. [see Warnings and Precautions (5. 1)] o Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe and simvastatin tablet, and adjust the dosage if necessary. The recommended dosage range of ezetimibe and simvastatin tablet 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. Patients taking Lomitapide [see Dosage and Administration ( 2. Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed ezetimibe and simvastatin tablets 10/10mg 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.

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 Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 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 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 (n=1,420) 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 at an Incidence Greater than Placebo Regardless of Causality * dagger % Placebo % Ezetimibe 10 mg % Simvastatindagger % Ezetimibe and simvastatindagger Headache 5. 8 Upper respiratory tract infection 2. 6 Myalgia 2. 6 Diarrhea 2. 8 Pain in extremity 1. 3 Influenza 0. 3 Study of Heart and Renal Protection Ezetimibe Simvastatin Laboratory Tests [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:.

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 tablet. ( 4 Ezetimibe and simvastatin tablets are contraindicated in the following conditions: [see Drug Interactions ( 7. 1 [see Drug Interactions ( 7. 1 [see Warnings and Precautions ( 5. 3 [see Adverse Reactions ( 6.

Pregnancy: 8. 1 Lactation: 8. 2 Ezetimibe and simvastatin Risk Summary 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/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. 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 Simvastatin Animal Data Ezetimibe 0 to 24hr 0 to 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 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 AUC 0 to 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 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) 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. 1 Data Animal Data 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, 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. 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. 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 m2, and 3,023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of trial treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe and simvastatin tablets 10/20 mg (n=4,650) or placebo (n=4,620) during a median follow-up of 4. Ezetimibe and simvastatin 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=7,367) compared with 0. 24% for Chinese patients (n=5,468). 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-simvastatin with lipid-modifying doses of niacin-containing products (>=1 g/day niacin) is not recommended in Chinese patients [see Warnings and Precautions ( 5.

RECENT MAJOR CHANGES
Indications and Usage ( 1 Dosage and Administration ( 2.1 2.2 2.3 2.4 2.5 Contraindications, Pregnancy and Lactation ( 4 Warnings and Precautions ( 5.1 5.2 5.3
DRUG INTERACTIONS
See full prescribing information for details regarding concomitant use of ezetimibe and simvastatin tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. 1 Cholestyramine: 2. 2 Coumarin Anticoagulants: 7. 3 Fenofibrates: 7. 3 Ezetimibe and simvastatin Ezetimibe and simvastatin are substrate of CYP3A4 and of the transport protein OATP1B1. Ezetimibe and simvastatin 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 are 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 are 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. Intervention : Consider if the benefit of using fibrates concomitantly with ezetimibe and simvastatin 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. Intervention: Consider if the benefit of using colchicine concomitantly with ezetimibe and simvastatin 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. 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 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 Effects on Other Drugs 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 are 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 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.
NONCLINICAL TOXICOLOGY
Ezetimibe and simvastatin Ezetimibe 0 to 24hr No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium Escherichia coli in vitro 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 to 24hr Simvastatin 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 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/m2), 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.
CLINICAL STUDIES
Primary Hyperlipidemia in Adults Ezetimibe and simvastatin Ezetimibe and simvastatin 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 or coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin 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 (10/10, 10/20, 10/40, or 10/80). When patients receiving ezetimibe and simvastatin were compared to those receiving all doses of simvastatin, ezetimibe and simvastatin significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of ezetimibe and simvastatin on HDL-C were similar to the effects seen with simvastatin. Further analysis showed ezetimibe and simvastatin significantly increased HDL-C compared with placebo. (See Table 8. ) The lipid response to ezetimibe and simvastatin was similar in patients with TG levels greater than or less than 200 mg/dL. Table 8: Response to Ezetimibe and Simvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger * dagger double dagger Treatment (Daily Dose) N Total-C LDL-C Apo B HDL-C TG* Non-HDL- Pooled data (All ezetimibe and simvastatin doses) double dagger 609 -38 -53 -42 +7 -24 -49 Pooled data (All simvastatin 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 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 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 (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 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 after 5 Weeks in Patients with CHD or CHD Risk Equivalents and an LDL-C >=130 mg/dL Simvastatin Ezetimibe and simvastatin Ezetimibe and simvastatin Ezetimibe and simvastatin N 253 251 109 97 Mean baseline 174 165 167 171 Percent change -38 -47 -53 -59 In a multicenter, double-blind, 6-week trial, 1,902 patients with primary hyperlipidemia were randomized to one of eight treatment groups: ezetimibe and simvastatin (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 were compared to those receiving milligram-equivalent statin doses of atorvastatin, ezetimibe and simvastatin 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 doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of ezetimibe and simvastatin on TG were similar to the effects seen with atorvastatin. (See Table 10. ) Table 10: Response to Ezetimibe and Simvastatin and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger * dagger double dagger section 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 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 -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 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 (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 lowered LDL-C to a greater degree than atorvastatin (see Table 11). Table 11: Response to Ezetimibe and Simvastatin and Atorvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger * dagger double dagger section paragraph # Þ 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 section 263 -34 paragraph -46 paragraph -38 paragraph +8 paragraph -26 -43 paragraph Ezetimibe and simvastatin # 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 250 -37 paragraph -50 paragraph -41 paragraph +9 -28 -46 paragraph Ezetimibe and simvastatin 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 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 Þ 459 -43 paragraph -59 paragraph -49 paragraph +12 paragraph -35 -55 paragraph 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 (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg). The effects of ezetimibe and simvastatin 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 and Rosuvastatin in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline dagger * dagger double dagger section paragraph # 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 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 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 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7. 1%, respectively. Ezetimibe and simvastatin 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 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 Simvastatin No incremental benefit of ezetimibe and simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Heterozygous Familial Hypercholesterolemia (HeFH) in Pediatric Patients 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 ZETIA 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 Chronic Kidney Disease (CKD) in Adults For the first year, 9,438 patients were allocated 4:4:1, to ezetimibe and simvastatin 10/20, placebo, or simvastatin 20 mg daily, respectively. The 1-year simvastatin arm enabled the comparison of ezetimibe and simvastatin 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 10/20 or placebo. A total of 9,270 patients were ever allocated to ezetimibe and simvastatin 10/20 (n=4,650) or placebo (n=4,620) 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 m2, with 94% of patients having an eGFR < 45 mL/min/1. Eligibility did not depend on lipid levels. Mean LDL-C at baseline was 108 mg/dL. At 1 year, the mean LDL-C was 26% lower in the simvastatin arm and 38% lower in the ezetimibe and simvastatin arm relative to placebo. At the midpoint of the trial (2. 5 years), the mean LDL-C was 32% lower for ezetimibe and simvastatin relative to placebo. Patients no longer taking trial medication were included in all lipid measurements. In the primary intent-to-treat analysis, 639 (15. 2%) of 4,193 patients initially allocated to ezetimibe and simvastatin 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 4,650 patients ever allocated to ezetimibe and simvastatin 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 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 on MVE was attenuated among patients on dialysis at baseline compared with those not on dialysis at baseline. Among 3,023 patients on dialysis at baseline, ezetimibe and simvastatin 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 6,247 patients not on dialysis at baseline (interaction P=0. Figure 1: Effect of Ezetimibe and Simvastatin on the Primary Endpoint of Risk of Major Vascular Events The individual components of MVE in all patients ever allocated to ezetimibe and simvastatin 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 10/20 Placebo Risk Ratio 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 *Intention-to-treat analysis on all SHARP patients ever allocated to ezetimibe and simvastatin or placebo. Among patients not on dialysis at baseline, ezetimibe and simvastatin 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 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. 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 40-80 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: 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 Mortality 1,328 (12. 9%) 1,507 (14. 7%) 13% (6-19%) p=0. 0003 CHD mortality 587 (5. 9%) 18% (8-26%) p=0. 0005 Secondary Non-fatal MI Stroke 357 (3. 7%) 38% (30­46%) 25% (15­34%) p<0. 0001 Tertiary Coronary revascularization Peripheral and other non-coronary revascularization 513 (5%) 450 (4. 2%) 30% (22­38%) 16% (5-26%) p<0. 006 * 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. 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.

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EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin_tablet Product manual source documgent