Vytorin 10-10 (ezetimibe/simvastatin)

No dosing information is available for this tab.

Ezetimibe is administered orally without regard to meals. Ezetimibe in fixed combination with simvastatin (e.g., Vytorin(R)) is administered orally in the evening without regard to meals. Patients should be placed on a standard cholesterol-lowering diet before initiation of ezetimibe therapy and should remain on this diet during treatment with the drug.

When used in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) or fenofibrate for additive antilipemic effects, ezetimibe may be administered at the same time as the statin or fenofibrate, in accordance with the recommended dosing schedule for these drugs. When used in combination with a bile acid sequestrant, ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant. The manufacturer states that pending further accumulation of data, use of ezetimibe in combination with a fibric acid derivative other than fenofibrate is not recommended. (See Drug Interactions: Antilipemic Agents.)

Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Adherence to lifestyle modifications for ASCVD risk reduction in addition to statin therapy should be reinforced periodically.

Simvastatin is administered orally (as tablets or oral suspension) in the evening. The tablets may be administered without regard to meals. The oral suspension should be administered on an empty stomach. The fixed-combination preparation containing simvastatin and ezetimibe is administered orally as tablets in the evening without regard to meals.

If a dose of simvastatin tablets or the fixed-combination preparation containing simvastatin and ezetimibe is missed, the missed dose may be administered as soon as possible; do not double the next dose.

If the oral suspension is used, shake the bottle well for at least 20 seconds before measuring the dose with an accurate measuring device; do not use a household teaspoon. The 8 mg/mL (40 mg/5 mL) preparation is recommended for doses >= 40 mg.

Store simvastatin tablets at 5-30degreesC.

Store the commercially available oral suspension at 20-25degreesC; do not freeze or refrigerate. The oral suspension should be protected from heat and used within 30 days of opening.

Store the fixed-combination preparation containing simvastatin and ezetimibe in well-closed containers at 20-25degreesC.

No dosing information is available for this tab.

No dosing information is available for this tab.

When using the fixed-combination preparation containing ezetimibe and simvastatin, the drug interactions associated with simvastatin should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation other than that with extended-release niacin. (See Niacin under Drug Interactions: Antilipemic Agents.)

When using the fixed-combination preparation containing ezetimibe and bempedoic acid, the drug interactions associated with bempedoic acid should be considered.

When simvastatin is used in fixed combination with ezetimibe, drug interactions associated with ezetimibe should be considered.

Simvastatin is metabolized by cytochrome P-450 isoenzyme (CYP) 3A4, but has no CYP3A4 inhibitory activity. Simvastatin is a substrate of P-glycoprotein (P-gp) and organic anion transporter protein (OATP) 1B1.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Known hypersensitivity to ezetimibe or any ingredient in the formulation.

Ezetimibe, in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations.

All statins are contraindicated in pregnant or nursing women. If ezetimibe is used in combination with a statin in a woman of childbearing age, the prescribing information for the statin should be consulted for detailed information on contraindications of the drug.

Concomitant use of the fixed combination of ezetimibe and simvastatin with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4, cyclosporine, danazol, or gemfibrozil is contraindicated.

*Concomitant use with strong cytochrome P-450 (CYP) 3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, erythromycin, clarithromycin, nefazodone, and cobicistat-containing products), cyclosporine, danazol, or gemfibrozil.

*Acute liver failure, active liver disease, including unexplained persistent elevations in hepatic transaminase levels, or decompensated cirrhosis.

*Oral suspension: The manufacturer states that this formulation is contraindicated in women who are pregnant or may become pregnant, and in nursing mothers; however, because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.

*Hypersensitivity to simvastatin, ezetimibe, or any component of the formulations.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects occurring in 2% or more of patients receiving ezetimibe and more frequently with the drug than with placebo include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza.

Adverse effects occurring in patients receiving ezetimibe in combination with statins generally were similar to those reported in patients receiving statin therapy alone. However, the incidence of increased transaminase concentrations was higher in patients receiving combination therapy (1.3%) than in those who received statin monotherapy (0.4%). (See Hepatic Effects under Warnings/Precautions: Major Toxicities, in Cautions.) Adverse effects occurring in 2% or more of patients receiving ezetimibe in fixed combination with simvastatin include headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea.

Adverse effects occurring in 2% or more of patients receiving ezetimibe in fixed combination with bempedoic acid include upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, extremity pain, anemia, increased hepatic enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza.

Simvastatin: Adverse effects reported in >=5% of patients include upper respiratory tract infection, headache, abdominal pain, constipation, and nausea.

Simvastatin/ezetimibe: Adverse effects reported in >=2% of patients, and greater than placebo, in clinical trials include headache, increased alanine aminotransferase, myalgia, upper respiratory tract infection, and diarrhea.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

There are no differences in the pharmacokinetics of ezetimibe between adolescents and adults. Pharmacokinetic data are not available for pediatric patients younger than 10 years of age.

Use of ezetimibe in combination with simvastatin has been evaluated in a limited number of adolescent boys and girls with heterozygous familial hypercholesterolemia. In a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia, discontinuance of therapy because of adverse effects occurred in more patients receiving ezetimibe in combination with simvastatin (10-40 mg daily) (6%) than in those receiving simvastatin monotherapy (2%); in addition, increases in aminotransferase or CK concentrations also occurred more frequently in patients receiving combination therapy (3 or 2%, respectively) than in those receiving simvastatin monotherapy (2 or 0%, respectively). There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Use of ezetimibe in combination with simvastatin dosages exceeding 40 mg daily has not been evaluated in adolescents; safety and efficacy of ezetimibe, alone or in fixed combination with simvastatin, have not been evaluated in prepubertal girls or in children younger than 10 years of age.

Safety and efficacy of ezetimibe in fixed combination with bempedoic acid have not been established in pediatric patients.

Safety and effectiveness of simvastatin in pediatric patients with heterozygous familial hypercholesterolemia (HeFH), as an adjunct to diet to reduce LDL-cholesterol, have been established in a randomized, double-blind, placebo-controlled study in boys and postmenarchal girls 10-17 years of age. The adverse effect profile of simvastatin was similar to that of placebo; dosages exceeding 40 mg daily have not been evaluated in this population. There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. If therapy with simvastatin is considered, the manufacturer states that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. Safety and efficacy of simvastatin have not been evaluated in prepubertal girls, or in children younger than 10 years of age or with types of hyperlipidemia other than HeFH.

Safety and effectiveness of simvastatin in combination with ezetimibe in pediatric patients with HeFH have been established in a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age. There was no significant effect on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Safety and efficacy of simvastatin in fixed combination with ezetimibe have not been evaluated in children younger than 10 years of age or in pediatric patients with other types of hyperlipidemia.

Category C. (See Users Guide.)

Category X for fixed combination of ezetimibe and simvastatin (due to simvastatin component). (See Users Guide.)

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. No evidence of maternal toxicity or embryolethality was seen in pregnant rats orally administered simvastatin from gestation days 6 through lactation day 21 at doses that resulted in 0.6-2.5 times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2); slight decreases in maternal and offspring body weight gain were observed. No evidence of maternal toxicity or embryolethality was seen in pregnant rabbits orally administered simvastatin from gestation days 6-18 at doses that resulted in 0.5-2 times the maximum human recommended dosage of 80 mg/day, based on body surface area (mg/m2). In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester. Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use. The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors. The FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects. Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, the FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While the FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with HoFH or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.

Ezetimibe is distributed into milk in rats. It is not known whether ezetimibe is distributed into milk in humans. Because many drugs are distributed into human milk, caution should be used if ezetimibe is used in nursing women; the drug should not be used in nursing women unless the potential benefits justify the possible risks to the infant.

It is not known whether simvastatin is distributed into human milk. However, a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from simvastatin in nursing infants, breastfeeding is not recommended during treatment. Many patients can stop statin therapy temporarily until breastfeeding is complete; patients who require ongoing statin treatment should not breastfeed and should use alternatives such as infant formula.

The manufacturers make no specific simvastatin or simvastatin in fixed combination with ezetimibe dosage recommendations at this time. Dose selection in geriatric patients (>=65 years of age) 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 for the increased risk of myopathy.

In clinical studies in patients receiving ezetimibe, 28% of patients were 65 years of age or older, and 5% of patients were 75 years of age or older. Following administration of ezetimibe (10 mg daily for 10 days), plasma concentrations of the drug were approximately twofold higher in geriatric individuals (65 years of age or older) than in younger adults; however, no overall differences in safety and efficacy of ezetimibe have been observed in geriatric patients relative to younger adults. Nevertheless, the manufacturer states that the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

In clinical studies in patients receiving ezetimibe in fixed combination with simvastatin, 32% of patients were 65 years of age or older, and 8% of patients were 75 years of age or older. No substantial differences in safety or efficacy of the fixed-combination preparation were observed in geriatric patients relative to younger patients; however, greater sensitivity in some older patients cannot be ruled out. Because advanced age (65 years of age or older) is a risk factor for myopathy, including rhabdomyolysis, ezetimibe in fixed combination with simvastatin should be used with caution in geriatric patients.

Of the 2423 patients receiving simvastatin in phase 3 clinical studies and the 10,269 patients receiving the drug in the Heart Protection Study (HPS), 15 and 52%, respectively, were 65 years of age or older; in HPS, 6% of patients were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients receiving simvastatin alone or in combination with ezetimibe, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out. Results of a pharmacokinetic study in a limited number of patients receiving simvastatin (40 mg daily) indicate that mean plasma levels of HMG-CoA reductase inhibitory activity are approximately 45% higher in geriatric patients (70-78 years of age) than in younger adults (18-30 years of age). In the Scandinavian Simvastatin Survival Study (4S) in which 23% of patients were 65 years of age or older, antilipemic effects of simvastatin in these patients were similar to those in younger patients, and simvastatin substantially reduced total mortality and CHD mortality in geriatric patients with a history of CHD; in this study, there were no overall differences in safety between the 2 groups. In HPS in which 52% of patients were 65 years of age or older, reduction in the risk of CHD death, nonfatal MI, stroke, or coronary or noncoronary revascularization procedures was similar in geriatric patients and in younger patients; of the 7 cases of myopathy/rhabdomyolysis reported among over 10,000 patients randomized to receive simvastatin, 4 occurred in patients 65 years of age or older.

In a clinical trial in which patients received higher dosages (i.e., 80 mg daily) of simvastatin, patients 65 years of age and older had an increased risk of myopathy, including rhabdomyolysis, compared with younger patients. Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be used with caution in geriatric patients. Cautious dosage selection of simvastatin is recommended in geriatric patients, whether used alone or in combination with ezetimibe.

Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.