Vytorin

Ezetimibe, simvastatin.

Ezetimibe/Simvastatin (VYTORIN) is available for oral use as tablets containing: 10 mg of ezetimibe and 10 mg of simvastatin; 10 mg of ezetimibe and 20 mg of simvastatin; 10 mg of ezetimibe and 40 mg of simvastatin.

Therapeutic Class: Ezetimibe/Simvastatin (VYTORIN) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.

Prevention of Cardiovascular Disease: Ezetimibe/Simvastatin (VYTORIN) is indicated to reduce the risk of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization), in patients with coronary heart disease (CHD).
Prevention of Major Cardiovascular Events in Chronic Kidney Disease (CKD): Ezetimibe/Simvastatin (VYTORIN) is indicated to reduce the risk of major cardiovascular events (nonfatal myocardial infarction or cardiac death, stroke, or any revascularization procedure) in patients with chronic kidney disease.
Primary Hypercholesterolemia: Ezetimibe/Simvastatin (VYTORIN) is indicated as adjunctive therapy to diet 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 adult and adolescent (10 to 17 years of age) patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
Fenofibrate can be added to Ezetimibe/Simvastatin (VYTORIN) in adult patients with mixed hyperlipidemia who require further reduction in TG and non-HDL-C and increase in HDL-C.
Homozygous Familial Hypercholesterolemia (HoFH): Ezetimibe/Simvastatin (VYTORIN) is indicated for the reduction of elevated total-C and LDL-C levels in adult and adolescent (10 to 17 years of age) patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).

The patient should be placed on a standard cholesterol-lowering diet before receiving Ezetimibe/Simvastatin (VYTORIN) and should continue on this diet during treatment with Ezetimibe/Simvastatin (VYTORIN). The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response. Ezetimibe/Simvastatin (VYTORIN) should be taken as a single daily dose in the evening, with or without food.
In patients with primary hyperlipidemia or mixed hyperlipidemia, the dosage range is 10/10 mg/day through 10/40 mg/day. The recommended usual starting dose is 10/20 mg/day. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. After initiation or titration of Ezetimibe/Simvastatin (VYTORIN), lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.
Patients with Coronary Heart Disease: In the cardiovascular events risk reduction study (IMPROVE-IT), the starting dose was 10/40 mg once a day in the evening. (See PRECAUTIONS.)
Patients with Renal Impairment/Chronic Kidney Disease: In patients with mild renal insufficiency (estimated GFR ≥60 ml/min/1.73 m²) no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate <60 ml/min/1.73 m², the dose of Ezetimibe/Simvastatin (VYTORIN) is 10/20 mg once a day in the evening. In such patients, the use of higher doses should be closely monitored. (See PRECAUTIONS).
Coadministration with Fenofibrate: The dose of Ezetimibe/Simvastatin (VYTORIN) when used concomitantly with fenofibrate is 10/10 mg/day or 10/20 mg/day (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Patients with Homozygous Familial Hypercholesterolemia: The recommended dosage for patients with homozygous familial hypercholesterolemia is Ezetimibe/Simvastatin (VYTORIN) 10/40 mg/day in the evening. Ezetimibe/Simvastatin (VYTORIN) should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
In patients taking lomitapide concomitantly with Ezetimibe/Simvastatin (VYTORIN), the dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/40 mg/day (see Myopathy/Rhabdomyolysis under PRECAUTIONS and INTERACTIONS).
Use in the Elderly: No dosage adjustment is required for elderly patients.
Use in Pediatric (10 to 17 Years of Age) Patients: The recommended usual starting dose is 10/10 mg once a day in the evening. The recommended dosing range is 10/10 to a maximum of 10/40 mg/day. Doses should be individualized according to the recommended goal of therapy.
Children <10 years: Treatment with Ezetimibe/Simvastatin (VYTORIN) is not recommended.
Use in Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6). Treatment with Ezetimibe/Simvastatin (VYTORIN) is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score >9) liver dysfunction. (See PRECAUTIONS.)
Coadministration with other medicines: Dosing of Ezetimibe/Simvastatin (VYTORIN) should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
In patients taking amiodarone, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with Ezetimibe/Simvastatin (VYTORIN), the dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/20 mg/day (see Myopathy/Rhabdomyolysis under PRECAUTIONS and INTERACTIONS).
In patients taking amlodipine concomitantly with Ezetimibe/Simvastatin (VYTORIN), the dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/40 mg/day (see Myopathy/Rhabdomyolysis under PRECAUTIONS and INTERACTIONS).
The safety and effectiveness of Ezetimibe/Simvastatin (VYTORIN) administered with fibrates, except fenofibrate, have not been studied. Therefore, the combination of Ezetimibe/Simvastatin (VYTORIN) and fibrates, except fenofibrate, should be avoided (see CONTRAINDICATIONS, Myopathy/Rhabdomyolysis under PRECAUTIONS and INTERACTIONS).

Ezetimibe/Simvastatin (VYTORIN): No specific treatment of overdosage with Ezetimibe/Simvastatin (VYTORIN) can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Coadministration of ezetimibe (1000 mg/kg) and simvastatin (1000 mg/kg) was well-tolerated in acute, oral toxicity studies in mice and rats. No clinical signs of toxicity were observed in these animals. The estimated oral LD₅₀ for both species was ezetimibe ≥1000 mg/kg/simvastatin ≥1000 mg/kg.
Ezetimibe: In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks, 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: A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

Hypersensitivity to the active substances or to any of the excipients.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and nursing (see USE IN PREGNANCY & LACTATION).
When Ezetimibe/Simvastatin (VYTORIN) is to be administered with fenofibrate, refer to the Package Insert for fenofibrate.
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin nefazodone, and drugs containing cobicistat) (see Myopathy/Rhabdomyolysis under PRECAUTIONS and INTERACTIONS).
Concomitant administration of gemfibrozil, cyclosporine, or danazol (see Myopathy/Rhabdomyolysis under PRECAUTIONS and INTERACTIONS).

When Ezetimibe/Simvastatin (VYTORIN) is to be administered with fenofibrate, refer to the Package Insert for fenofibrate.
Myopathy/Rhabdomyolysis: Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X 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 by high levels of HMG-CoA reductase inhibitory activity in plasma (i.e., elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (see INTERACTIONS). Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.
The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 10/80 mg dose of Ezetimibe/Simvastatin (VYTORIN) should only be used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking Ezetimibe/Simvastatin (VYTORIN) 10/80 mg for whom an interacting agent is needed, a lower dose of Ezetimibe/Simvastatin (VYTORIN) or an alternative statin-ezetimibe regimen with less potential for drug-drug interactions should be used (see as follows, DOSAGE & ADMINISTRATION, and CONTRAINDICATIONS).
All patients starting therapy with Ezetimibe/Simvastatin (VYTORIN), or whose dose of Ezetimibe/Simvastatin (VYTORIN) is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Ezetimibe/Simvastatin (VYTORIN) therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases resolved (see SIDE EFFECTS). Periodic CK determinations may be considered in patients starting therapy with Ezetimibe/Simvastatin (VYTORIN) or whose dose is being increased. Periodic CK determinations are recommended for patients titrating to the 10/80 mg dose. There is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking Ezetimibe/Simvastatin (VYTORIN) merit closer monitoring. Therapy with Ezetimibe/Simvastatin (VYTORIN) should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
In the IMProved Reduction of Outcomes: Ezetimibe/Simvastatin (VYTORIN) Efficacy International Trial (IMPROVE-IT), 18,144 patients with CHD were randomized to receive Ezetimibe/Simvastatin (VYTORIN) 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for Ezetimibe/Simvastatin (VYTORIN) and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for Ezetimibe/Simvastatin (VYTORIN) and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 X ULN and <10 X ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury. (See SIDE EFFECTS.)
In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive Ezetimibe/Simvastatin (VYTORIN) 10/20 mg daily (n=4650) or placebo (n=4620). (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for Ezetimibe/Simvastatin (VYTORIN) and 0.1% for placebo. (See SIDE EFFECTS.)
In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing Ezetimibe/Simvastatin (VYTORIN) to Asian patients and the lowest dose necessary should be employed.
Drug Interactions: Because Ezetimibe/Simvastatin (VYTORIN) contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of Ezetimibe/Simvastatin (VYTORIN) with the following drugs: Contraindicated Drugs: Potent inhibitors of CYP3A4: Concomitant use with medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, or drugs containing cobicistat) is contraindicated. If short-term treatment with potent CYP3A4 inhibitors is unavoidable, therapy with Ezetimibe/Simvastatin (VYTORIN) should be suspended during the course of treatment. (See CONTRAINDICATIONS and INTERACTIONS.)
Gemfibrozil, cyclosporine, or danazol: Concomitant use of these drugs with Ezetimibe/Simvastatin (VYTORIN) is contraindicated (see CONTRAINDICATIONS and INTERACTIONS).
Other Drugs: Fusidic acid: Patients on fusidic acid treated concomitantly with simvastatin may have an increased risk of myopathy/rhabdomyolysis (see Other drug interactions under INTERACTIONS). Co-administration with fusidic acid is not recommended. In patients where the use of systemic fusidic acid is considered essential, Ezetimibe/Simvastatin (VYTORIN) should be discontinued throughout the duration of fusidic acid treatment. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for coadministration of Ezetimibe/Simvastatin (VYTORIN) and fusidic acid should only be considered on a case-by-case basis under close medical supervision.
Amiodarone: In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. The dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone. (See INTERACTIONS.)
Calcium Channel Blockers: Verapamil or diltiazem: Patients on diltiazem treated concomitantly with simvastatin 80 mg had an increased risk of myopathy. The dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/20 mg daily in patients receiving concomitant medication with verapamil or diltiazem. (See Other drug interactions under INTERACTIONS.)
Amlodipine: In a clinical trial, patients on amlodipine treated concomitantly with simvastatin 80 mg had a slightly increased risk of myopathy (see INTERACTIONS). The dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/40 mg daily in patients receiving concomitant medication with amlodipine.
Lomitapide: The dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/40 mg daily in patients with HoFH receiving concomitant medication with lomitapide (see INTERACTIONS.)
Moderate Inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with Ezetimibe/Simvastatin (VYTORIN), particularly higher Ezetimibe/Simvastatin (VYTORIN) doses, may have an increased risk of myopathy. When coadministering Ezetimibe/Simvastatin (VYTORIN) with a moderate inhibitor of CYP3A4, a dose adjustment of Ezetimibe/Simvastatin (VYTORIN) may be necessary.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore, a dose adjustment of Ezetimibe/Simvastatin (VYTORIN) may be necessary. Coadministration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of Ezetimibe/Simvastatin (VYTORIN) should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Other drug interactions under INTERACTIONS).
Fenofibrate: In a study in which Ezetimibe/Simvastatin (VYTORIN) 10/20 mg/day and fenofibrate 160 mg/day were coadministered in 183 patients for up to 12 weeks, there were no reports of myopathy. Doses above Ezetimibe/Simvastatin (VYTORIN) 10/20 mg/day and fenofibrate have not been studied. Caution should be used when prescribing Ezetimibe/Simvastatin (VYTORIN) and fenofibrate, as fenofibrate can cause myopathy when given alone. In another 12-week study, in which 411 patients received simvastatin 20 mg/day and fenofibrate 160 mg/day, coadministration was also well tolerated. If cholelithiasis is suspected in a patient receiving Ezetimibe/Simvastatin (VYTORIN) and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see SIDE EFFECTS and the Package Insert for fenofibrate).
Other Fibrates: The safety and effectiveness of Ezetimibe/Simvastatin (VYTORIN) administered with fibrates, except fenofibrate, have not been studied. Therefore, the concomitant use of Ezetimibe/Simvastatin (VYTORIN) and fibrates, except fenofibrate, should be avoided. Concomitant use of gemfibrozil is contraindicated (see CONTRAINDICATIONS).
Niacin (≥1 g/day): Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day) of niacin. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin. Therefore, the benefit of the combined use of simvastatin with niacin should be carefully weighed against the potential risks of the combination. In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with extended-release niacin/laropiprant 2 g/ 40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in non-Chinese patients, coadministration of Ezetimibe/Simvastatin (VYTORIN) with lipid-modifying doses (≥1 g/day) of niacin is not recommended in Asian patients. (See INTERACTIONS.)
Daptomycin: Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA reductase inhibitors coadministered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to suspending Ezetimibe/Simvastatin (VYTORIN) temporarily in patients taking daptomycin (see INTERACTIONS).
Anticoagulants: If Ezetimibe/Simvastatin (VYTORIN) is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored (see INTERACTIONS).
Liver Enzymes: In controlled coadministration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (≥3 X ULN) have been observed. (See SIDE EFFECTS).
In IMPROVE-IT, 18,144 patients with CHD were randomized to receive Ezetimibe/Simvastatin (VYTORIN) 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for Ezetimibe/Simvastatin (VYTORIN) and 2.3% for simvastatin. (See SIDE EFFECTS).
In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to receive Ezetimibe/Simvastatin (VYTORIN) 10/20 mg daily (n=4650), or placebo (n=4620) (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for Ezetimibe/Simvastatin (VYTORIN) and 0.6% for placebo. (See SIDE EFFECTS.)
It is recommended that LFTs be performed before treatment with Ezetimibe/Simvastatin (VYTORIN) begins and thereafter when clinically indicated. Patients titrated to the 10/80 mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80 mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 X ULN and are persistent, the drug should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see Myopathy/Rhabdomyolysis as previously mentioned).
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Ezetimibe/Simvastatin (VYTORIN), promptly interrupt therapy. If an alternate etiology is not found do not restart Ezetimibe/Simvastatin (VYTORIN).
Ezetimibe/Simvastatin (VYTORIN) should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of Ezetimibe/Simvastatin (VYTORIN).
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Ezetimibe/Simvastatin (VYTORIN) is not recommended in these patients.
Use in Children: Safety and effectiveness of Ezetimibe/Simvastatin (VYTORIN) in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least one year post-menarche. Adolescent patients treated with Ezetimibe/Simvastatin (VYTORIN) had an adverse experience profile similar to that of adult patients treated with Ezetimibe/Simvastatin (VYTORIN). Doses greater than 10/40 mg/day have not been studied in this population. In this controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See DOSAGE & ADMINISTRATION and SIDE EFFECTS) Ezetimibe/Simvastatin (VYTORIN) has not been studied in patients younger than 10 years of age or in pre-menarchal girls.
Use in the Elderly: Because advanced age (≥65 years) is a predisposing factor for myopathy, Ezetimibe/Simvastatin (VYTORIN) 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 compared to patients <65 years of age.

Pregnancy: Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia.
Ezetimibe/Simvastatin (VYTORIN): Ezetimibe/Simvastatin (VYTORIN) is contraindicated during pregnancy.
Simvastatin: The safety of simvastatin in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, Ezetimibe/Simvastatin (VYTORIN) should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Ezetimibe/Simvastatin (VYTORIN) should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see CONTRAINDICATIONS).
Ezetimibe: No clinical data on exposed pregnancies are available for ezetimibe.
When ezetimibe was given with simvastatin, no teratogenic effects were observed in embryo-fetal development studies in pregnant rats. In pregnant rabbits, a low incidence of skeletal malformations was observed.
Nursing Mothers: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active components of Ezetimibe/Simvastatin (VYTORIN) are excreted into human breast milk; therefore, women who are nursing should not take Ezetimibe/Simvastatin (VYTORIN).

Ezetimibe/Simvastatin (VYTORIN) [or coadministration of ezetimibe and simvastatin equivalent to Ezetimibe/Simvastatin (VYTORIN)] has been evaluated for safety in approximately 12,000 patients in clinical trials. Ezetimibe/Simvastatin (VYTORIN) was generally well tolerated.
The following common (≥1/100, <1/10) or uncommon (≥1/1000, <1/100); drug-related adverse experiences were reported in patients taking Ezetimibe/Simvastatin (VYTORIN) (n=2404) and at a greater incidence than placebo (n=1340): Investigations: Common: ALT and/or AST increased; blood CK increased.
Uncommon: blood bilirubin increased; blood uric acid increased; gamma-glutamyltransferase increased; international normalised ratio increased; protein urine present; weight decreased.
Nervous system disorders: Uncommon: dizziness; headache.
Gastrointestinal disorders: Uncommon: abdominal pain; abdominal discomfort; abdominal pain upper; dyspepsia; flatulence; nausea; vomiting.
Skin and subcutaneous tissue disorders: Uncommon: pruritus; rash.
Musculoskeletal and connective tissue disorders: Uncommon: arthralgia; muscle spasms; muscular weakness; musculoskeletal discomfort; neck pain; pain in extremity.
General disorders and administration site conditions: Uncommon: asthenia; fatigue; malaise; edema peripheral.
Psychiatric disorders: Uncommon: sleep disorder.
The following common (≥1/100, <1/10) or uncommon (≥1/1000, <1/100); drug-related adverse experiences were reported in patients taking Ezetimibe/Simvastatin (VYTORIN) (n=9595) and at a greater incidence than statins administered alone (n=8883): Investigations: Common: ALT and/or AST increased. Uncommon: blood bilirubin increased; blood CK increased; gamma-glutamyltransferase increased.
Nervous system disorders: Uncommon: headache; paresthesia.
Gastrointestinal disorders: Uncommon: abdominal distension; diarrhea; dry mouth; dyspepsia; flatulence; gastroesophageal reflux disease; vomiting.
Skin and subcutaneous tissue disorders: Uncommon: pruritus; rash; urticaria.
Musculoskeletal and connective tissue disorders: Common: myalgia.
Uncommon: arthralgia; back pain; muscle spasms; muscular weakness; musculoskeletal pain; pain in extremity.
General disorders and administration site conditions: Uncommon: asthenia; chest pain; fatigue; edema peripheral.
Psychiatric disorders: Uncommon: insomnia.
Ezetimibe/Simvastatin (VYTORIN) Coadministered with Fenofibrate: In a controlled clinical study, the adverse reaction profile reported for coadministered Ezetimibe/Simvastatin (VYTORIN) and fenofibrate was consistent with those reported for Ezetimibe/Simvastatin (VYTORIN) and/or fenofibrate alone.
Pediatric (10 to 17 Years of Age) Patients: In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolemia (n=248), the safety and tolerability profile of the group treated with Ezetimibe/Simvastatin (VYTORIN) was similar to that of adult patients treated with Ezetimibe/Simvastatin (VYTORIN) (see Use in Children under PRECAUTIONS).
Patients with Coronary Heart Disease: In the IMPROVE-IT study, involving 18,144 patients treated with either Ezetimibe/Simvastatin (VYTORIN) 10/40 mg [n=9067; of whom 6% were uptitrated to Ezetimibe/Simvastatin (VYTORIN) 10/80 mg] or simvastatin 40 mg [n=9077; of whom 27% were uptitrated to simvastatin 80 mg], the safety profiles were similar during a median follow-up period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for patients treated with Ezetimibe/Simvastatin (VYTORIN) and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for Ezetimibe/Simvastatin (VYTORIN) and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for Ezetimibe/Simvastatin (VYTORIN) and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 X ULN and <10 X ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury. The incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for Ezetimibe/Simvastatin (VYTORIN) and 2.3% for simvastatin. (See PRECAUTIONS). Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to Ezetimibe/Simvastatin (VYTORIN) and simvastatin, respectively. The incidence of cholecystectomy hospitalizations was 1.5% in both treatment groups. Cancer (defined as any new malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.
Patients with Chronic Kidney Disease: In SHARP, involving over 9000 patients treated with Ezetimibe/Simvastatin (VYTORIN) 10/20 mg daily (n=4650) or placebo (n=4620), the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients treated with Ezetimibe/Simvastatin (VYTORIN), 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Ezetimibe/Simvastatin (VYTORIN) and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (>3X ULN) occurred in 0.7% of patients treated with Ezetimibe/Simvastatin (VYTORIN) compared with 0.6% of patients treated with placebo. (See PRECAUTIONS). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for Ezetimibe/Simvastatin (VYTORIN), 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
Post-marketing Experience: The following additional adverse reactions have been reported in post-marketing use with Ezetimibe/Simvastatin (VYTORIN) or during clinical studies or post-marketing use with one of the individual components. The adverse reactions reported for Ezetimibe/Simvastatin (VYTORIN) are consistent with those previously reported with ezetimibe and/or simvastatin.
Investigations: liver function test abnormal.
Blood and lymphatic system disorders: thrombocytopenia; anemia.
Nervous system disorders: peripheral neuropathy.
Respiratory, thoracic and mediastinal disorders: cough; interstitial lung disease.
Gastrointestinal disorders: constipation; pancreatitis; gastritis.
Skin and subcutaneous tissue disorders: alopecia; hypersensitivity reactions, including rash, lichen planus, urticaria, anaphylaxis, angio-edema; erythema multiforme.
Musculoskeletal and connective tissue disorders: muscle cramps; myopathy/rhabdomyolysis (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
There have been very rare reports of immune-mediated necrotizing myopathy (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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Metabolism and nutrition disorders: decreased appetite.
Vascular disorders: hot flush; hypertension.
General disorders and administration site conditions: pain.
Hepato-biliary disorders: hepatitis/jaundice; fatal and non-fatal hepatic failure; cholelithiasis; cholecystitis.
Reproductive system and breast disorders: erectile dysfunction.
Psychiatric disorders: depression.
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea and malaise.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Ezetimibe Coadministered with Fenofibrate: In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to 1 year. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ezetimibe coadministered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and ezetimibe coadministered with fenofibrate, respectively (see PRECAUTIONS). There were no CPK elevations > 10 X ULN in either treatment group in this study.
Laboratory Values: In controlled clinical coadministration trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 X ULN, consecutive) was 1.7% for patients treated with Ezetimibe/Simvastatin (VYTORIN). These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. (See PRECAUTIONS).
Clinically important elevations of CK (≥10 X ULN) were seen in 0.2% of the patients treated with Ezetimibe/Simvastatin (VYTORIN).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

Ezetimibe/Simvastatin (VYTORIN): No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin.
Ezetimibe/Simvastatin (VYTORIN) is bioequivalent to coadministered ezetimibe and simvastatin.
Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
Contraindicated drugs: Concomitant use of the following drugs is contraindicated: Potent Inhibitors of CYP3A4: In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of the simvastatin component of Ezetimibe/Simvastatin (VYTORIN): Concomitant use of drugs labeled as having a potent inhibitory effect on CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) is contraindicated. (See CONTRAINDICATIONS and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Gemfibrozil, Cyclosporine, or Danazol (see CONTRAINDICATIONS and Myopathy/Rhabdomyolysis under PRECAUTIONS): Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available. (See CONTRAINDICATIONS and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Cyclosporine: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold (range 2.3- to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone. (see CONTRAINDICATIONS and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Other drug interactions: Fenofibrate: In a clinical study, in which Ezetimibe/Simvastatin (VYTORIN) 10/20 mg/day and fenofibrate 160 mg/day were coadministered in 183 patients for up to 12 weeks, there were no reports of myopathy and no patients experienced gallbladder-related events. (See Myopathy/Rhabdomyolysis under PRECAUTIONS).
In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant. The safety and effectiveness of ezetimibe coadministered with fenofibrate have been evaluated in a clinical study (see SIDE EFFECTS).
Other Fibrates: The safety and effectiveness of Ezetimibe/Simvastatin (VYTORIN) administered with fibrates, except fenofibrate, have not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
Coadministration of ezetimibe with other fibrates has not been studied. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, coadministration of Ezetimibe/Simvastatin (VYTORIN) with fibrates, other than fenofibrate, is not recommended until use in patients is studied.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Amiodarone: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone with Ezetimibe/Simvastatin (VYTORIN) (see DOSAGE & ADMINISTRATION and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding Ezetimibe/Simvastatin (VYTORIN) to cholestyramine may be lessened by this interaction.
Calcium Channel Blockers: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine (see DOSAGE & ADMINISTRATION and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Lomitapide: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of lomitapide (see DOSAGE & ADMINISTRATION and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Moderate inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with Ezetimibe/Simvastatin (VYTORIN), particularly higher Ezetimibe/Simvastatin (VYTORIN) doses, may have an increased risk of myopathy (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Inhibitors of the Transport Protein OATP1B1: 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. (see CONTRAINDICATIONS; Myopathy/Rhabdomyolysis under PRECAUTIONS).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Simvastatin is a substrate of the efflux transporter BCRP. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy. When coadministering simvastatin with an inhibitor of BCRP, a dose adjustment of Ezetimibe/Simvastatin (VYTORIN) may be necessary (see DOSAGE & ADMINISTRATION and Myopathy/Rhabdomyolysis under PRECAUTIONS).
Niacin: In a study of 15 healthy adults, concomitant Ezetimibe/Simvastatin (VYTORIN) (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid (19%) administered as NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%).
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day) of niacin (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and Ezetimibe/Simvastatin (VYTORIN) in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin (see PRECAUTIONS, Myopathy/Rhabdomyolysis).
Other Interactions: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250 mL glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, because larger quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity grapefruit juice should be avoided during Ezetimibe/Simvastatin (VYTORIN) therapy (see Myopathy/Rhabdomyolysis under PRECAUTIONS).
Anticoagulants: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting Ezetimibe/Simvastatin (VYTORIN) and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of Ezetimibe/Simvastatin (VYTORIN) is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased International Normalized Ratio in patients who had ezetimibe added to warfarin or fluindione. Most of these patients were also on other medications (see PRECAUTIONS).
The effect of Ezetimibe/Simvastatin (VYTORIN) on the prothrombin time has not been studied.
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.

Store at temperatures not exceeding 30°C, usual climatic temperature excursions permitted. Keep container tightly closed.

Dyslipidaemic Agents

C10BA02 - simvastatin and ezetimibe ; Belongs to the class of HMG CoA reductase inhibitors in combination with other lipid modifying agents. Used in the treatment of hyperlipidemia.

Rx