Ezetimibe And Simvastatin
FDA Drug Information • Also known as: Ezetimibe And Simvastatin, Vytorin
- Brand Names
- Ezetimibe And Simvastatin, Vytorin
- Dosage Form
- TABLET
- Product Type
- DRUG FOR FURTHER PROCESSING
Description
11 DESCRIPTION Ezetimibe and simvastatin tablets contain ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, an HMG-CoA reductase inhibitor. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3( R )-[3-(4-fluorophenyl)-3( S )-hydroxypropyl]-4( S )-(4-hydroxyphenyl)-2-azetidinone.The molecular formula is C 24 H 21 F 2 NO 3 and its molecular weight is 409.4. Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is: Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)ethyl]-1-naphthalenyl ester, [1 S -[1α,3 α,7β,8β(2 S *,4 S *),8aβ]].The molecular formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57. Simvastatin is a white to off-white powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is: Ezetimibe and simvastatin tablets are available for oral use containing 10 mg of ezetimibe, and 10 mg of simvastatin (ezetimibe and simvastatin tablets, 10 mg/10 mg), 20 mg of simvastatin (ezetimibe and simvastatin tablets, 10 mg/20 mg), 40 mg of simvastatin (ezetimibe and simvastatin tablets, 10 mg/40 mg), or 80 mg of simvastatin (ezetimibe and simvastatin tablets, 10 mg/80 mg). Each tablet contains the following inactive ingredients: butylated hydroxyanisole, citric acid monohydrate, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate. ezetimibe structural formula simvastatin structural formula
What Is Ezetimibe And Simvastatin Used For?
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 apheresis) or if such treatments are unavailable. 1.3 Limitations of Use 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.Dosage and 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 be analyzed after 2 or more weeks and dosage adjusted, if needed. 2.2 Restricted Dosing for 10 mg/80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, 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 [ see Warnings and Precautions ( 5.1 ) ]. 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. 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...Side Effects (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 ≥ 2% of patients treated with ezetimibe and simvastatin tablets (n = 1,420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials. Table 2 1 Clinical Adverse Reactions Occurring in ≥ 2% of Patients Treated with Ezetimibe and Simvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality Placebo Ezetimibe 10 mg Simvastatin 2 Ezetimibe and Simvastatin 2 Body System/Organ Class (%) (%) (%) (%) Adverse Reaction n = 371 n = 302 n = 1234 n = 1420 Body as a whole – general disorders Headache 5.4 6.0 5.9 5.8 Gastrointestinal system disorders Diarrhea 2.2 5.0 3.7 2.8 Infections and infestations Influenza 0.8 1.0 1.9 2.3 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Musculoskeletal and connective tissue disorders Myalgia 2.4 2.3 2.6 3.6 Pain in extremity 1.3 3.0 2.0 2.3 1. 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 were administered. 2 . All doses. Study of Heart and Renal Protection In SHARP, 9,270 patients were allocated to ezetimibe and simvastatin tablets 10 mg/20 mg daily (n = 4,650) or placebo (n = 4,620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued study treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK > 10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (> 3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence...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 in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. ( 7.2 , 7.7 , 12.3 ) 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol Strong CYP3A4 inhibitors: The risk of myopathy is increased by reducing the elimination of the simvastatin component of ezetimibe and simvastatin tablets. Hence when ezetimibe and simvastatin tablets are used with an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of ezetimibe and simvastatin tablets [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]. Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [ see Contraindications ( 4 ) ]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is...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 discontinued...Pregnancy and Breastfeeding
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...
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 ) ].
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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Ezetimibe and simvastatin tablets are available as follows: 10 mg/10 mg- white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "583" on the other side. They contain 10 mg of ezetimibe and 10 mg of simvastatin. They are available in : Bottles of 30 NDC 43598-742-30 Bottles of 90 NDC 43598-742-90 Bottles of 1000 NDC 43598-742-10 10 mg/20 mg- white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "584" on the other side. They contain 10 mg of ezetimibe and 20 mg of simvastatin. They are available in : Bottles of 30 NDC 43598-744-30 Bottles of 90 NDC 43598-744-90 Bottles of 1000 NDC 43598-744-10 10 mg/40 mg- white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "585" on the other side. They contain 10 mg of ezetimibe and 40 mg of simvastatin. They are available in : Bottles of 30 NDC 43598-743-30 Bottles of 90 NDC 43598-743-90 Bottles of 500 NDC 43598-743-05 10 mg/80 mg- white to off-white, capsule-shaped tablets, debossed with "DRL" on one side of the tablet and with "586" on the other side. They contain 10 mg of ezetimibe and 80 mg of simvastatin. They are available in : Bottles of 30 NDC 43598-745-30 Bottles of 90 NDC 43598-745-90 Bottles of 500 NDC 43598-745-05 Storage Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Keep container tightly closed. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.