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💊 EZETIMIBE AND SIMVASTATIN

Generic: EZETIMIBE AND SIMVASTATIN
ORAL FDA Label
Quick reference
RouteORAL
ManufacturerDr.Reddys Laboratories Inc
SourceFDA Label
✅ Indications & Usage ›

1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe and simvastatin tablets, which contain a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), are indicated as adjunctive therapy to diet to: • reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. ( 1.1 ) • reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments. ( 1.2 ) Limitations of Use ( 1.3 ) • No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. • Ezetimibe and simvastatin tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

1.1 Primary Hyperlipidemia Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.

1.2 Homozygous Familial Hypercholesterolemia (HoFH) Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresi... [See full FDA label]

💉 Dosage & Administration ›

2 DOSAGE AND ADMINISTRATION • Dose range is 10 mg/10 mg/day to 10 mg/40 mg/day. ( 2.1 ) • Recommended usual starting dose is 10 mg/10 mg or 10 mg/20 mg/day. ( 2.1 ) • Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10 mg/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. ( 2.2 ) • Patients who are currently tolerating the 10 mg/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. ( 2.2 ) • Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10 mg/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10 mg/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10 mg/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. ( 2.2 ) • Dosing of ezetimibe and simvastatin tablets should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant. ( 2.3 , 7.5 )

2.1 Recommended Dosing The usual dosage range is 10 mg/10 mg/day to 10 mg/40 mg/day. The recommended usual starting dose is 10 mg/10 mg/day or 10 mg/20 mg/day. Ezetimibe and simvastatin tablets should be taken as a single daily dose in the evening, with or without food. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10 mg/40 mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 ). After initiation or titration of ezetimibe and simvastatin tablets, lipid levels may b... [See full FDA label]

🚫 Contraindications ›

4 CONTRAINDICATIONS Ezetimibe and simvastatin tablets are contraindicated in the following conditions: • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [ see Warnings and Precautions ( 5.1 ) ]. • Concomitant administration of gemfibrozil, cyclosporine, or danazol [ see Warnings and Precautions ( 5.1 ) ]. • Hypersensitivity to any component of this medication [ see Adverse Reactions ( 6.2 ) ]. • Active liver disease or unexplained persistent elevations in hepatic transaminase levels [ see Warnings and Precautions ( 5.3 ) ]. • Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin tablets may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and simvastatin tablet use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Ezetimibe and simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin tablets should be discontinue... [See full FDA label]

⚠️ Warnings & Precautions ›

5 WARNINGS AND PRECAUTIONS Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10 mg/80 mg dose. ( 5.1 ) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Ezetimibe and simvastatin tablets should be discontinued immediately if myopathy is diagnosed or suspected. ( 5.1 ). Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 4 , 5.1 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. ( 5.2 ). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3 )

5.1 Myopathy/Rhabdomyolysis Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for myopathy [s... [See full FDA label]

🔴 Adverse Reactions ›

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Rhabdomyolysis and myopathy [ see Warnings and Precautions ( 5.1 ) ] • Liver enzyme abnormalities [ see Warnings and Precautions ( 5.3 ) ] • Common (incidence ≥ 2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Ezetimibe and Simvastatin Tablets 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. In the ezetimibe and simvastatin tablet placebo-controlled clinical trials database of 1,420 patients (age range 20 to 83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin tablets and 2.2% of patients on placebo discontinued due to adverse reactions. 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%) • Back pain (0.4%) The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). Ezetimibe and simvastatin tablets have been evaluated for safety in more than 10,189 patients in clinical trials. Table 2 summarizes the frequency of clinical adverse reactions reported in ≥ ... [See full FDA label]

💊 Drug Interactions ›

7 DRUG INTERACTIONS [ See Clinical Pharmacology ( 12.3 ). ] Ezetimibe and Simvastatin Tablets Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 7.8 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets Niacin (≥1 g/day) For Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil, diltiazem, dronedarone Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Amiodarone, amlodipine, ranolazine Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets 1 Daptomycin Temporally suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1. For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin tablets when taking lomitapide. • Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to starting ezetimibe and simvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of ezetimibe and simvastatin tablet therapy. ( 7.8 ) • Cholestyramine: Combination decreases exposure of ezetimibe. ( 2.3 , 7.5 ) • Other Lipid-lowering Medications: Use with fenofibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with ezetimibe and simvastatin tablets. ( 5.1 , 7.2 , 7.4 ) • Fenofibrates: Combination increases exposure of ezetimibe. If cholelithiasis is suspected... [See full FDA label]

🤰 Pregnancy ›

8.1 Pregnancy Terotogenic Effects Pregnancy Category X. [ See Contraindications ( 4 ). ] Ezetimibe and Simvastatin Tablets Ezetimibe and simvastatin tablets are contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of ezetimibe and simvastatin tablet use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins, such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin tablets may cause fetal harm when administered to a pregnant woman. If ezetimibe and simvastatin tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential, who require ezetimibe and simvastatin tablet treatment for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of ezetimibe and simvastatin tablets should be considered. If pregnancy occurs, ezetimibe and simvastatin tablets should be immediately discontinued. Ezetimibe In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested... [See full FDA label]

🤱 Nursing / Lactation ›

8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [ see Contraindications ( 4 ) ]. In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take ezetimibe and simvastatin tablets [ see Contraindications ( 4 ) ].

👶 Pediatric Use ›

8.4 Pediatric Use The effects of ezetimibe coadministered with simvastatin (n = 126) compared to simvastatin monotherapy (n = 122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multiracial) with HeFH were randomized to receive either ezetimibe coadministered with simvastatin or simvastatin monotherapy. Inclusion in the study 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 study at Week 6 are summarized in Table 3 . Results at Week 33 were consistent with those at Week 6. Table 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia Total-C LDL-C Apo B Non-HDL-C TG

1 HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) (-9, +4) (-3, +3) 1. For triglycerides, median % change from baseline. From the start of the trial to the end of Week 33, discontinuations due to an ... [See full FDA label]

👴 Geriatric Use ›

8.5 Geriatric Use 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. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, ezetimibe and simvastatin tablets should be prescribed with caution in the elderly [ see Clinical Pharmacology ( 12.3 ) ]. Because advanced age (≥ 65 years) is a predisposing factor for myopathy, including rhabdomyolysis, ezetimibe and simvastatin tablets should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥ 65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients < 65 years of age [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ].

🔬 Mechanism of Action ›

12.1 Mechanism of Action Ezetimibe and Simvastatin Tablets Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin tablets contain ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe and simvastatin tablets reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis. 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. In a 2 week clinical study 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. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins [ see Clinical Studies ( 14 ) ]. Simvastatin Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C.

📊 Pharmacokinetics ›

12.3 Pharmacokinetics The results of a bioequivalence study in healthy subjects demonstrated that the ezetimibe and simvastatin 10 mg/10 mg to 10 mg/80 mg combination tablets are bioequivalent to coadministration of corresponding doses of ezetimibe and simvastatin as individual tablets. Absorption Ezetimibe After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Simvastatin The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction. Effect of Food on Oral Absorption Ezetimibe Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10 mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Simvastatin Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. Distribution Ezetimibe Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins. Simvastatin Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier. Metabolism and Excretion 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 approximate... [See full FDA label]

☠️ Overdosage ›

10 OVERDOSAGE Ezetimibe and Simvastatin Tablets No specific treatment of overdosage with ezetimibe and simvastatin tablets can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Ezetimibe In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, was generally well tolerated. A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. Simvastatin Significant lethality was observed in mice after a single oral dose of 9 g/m 2 . No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m 2 , respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools. A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. The dialyzability of simvastatin and its metabolites in man is not known at present.

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