Vytorin

Vytorin

simvastatin + ezetimibe

Manufacturer:

Merck Sharp & Dohme

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ezetimibe, simvastatin.
Action
Vytorin (ezetimibe/simvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.
Vytorin is available for oral use as tablets containing ezetimibe 10 mg, and simvastatin 10 mg (Vytorin 10/10), simvastatin 20 mg (Vytorin 10/20), or simvastatin 40 mg (Vytorin 10/40).
Pharmacology: Mechanism of Action: Vytorin: Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Vytorin contains ezetimibe and simvastatin, 2 lipid-lowering compounds with complementary mechanisms of action. Vytorin reduces 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 inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (eg, statins, bile acid sequestrants [resins], fibric acid derivatives and plant stanols).
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; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. The molecular mechanism of action is not fully understood.
In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
Simvastatin: After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active β-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy-3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes, the ratios of total- to HDL-C and LDL- to HDL-C are reduced.
Pharmacokinetics: Absorption: Ezetimibe: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1-2 hrs for ezetimibe-glucuronide and 4-2 hrs for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe 10-mg tablets.
Simvastatin: The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be <5% of the dose, consistent with extensive hepatic first-pass extraction. The major metabolites of simvastatin present in human plasma are the β-hydroxyacid and four additional active metabolites.
Relative to the fasting state, the plasma profiles of both active and total inhibitors were not affected when simvastatin was administered immediately before a test meal.
Distribution: Ezetimibe: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88-92% to human plasma proteins, respectively.
Simvastatin: Both simvastatin and the β-hydroxyacid are bound to human plasma proteins (95%).
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the above pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3-2.4 hrs post-dose.
Metabolism: Ezetimibe: Ezetimibe is metabolized primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10-20% and 80-90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hrs.
Simvastatin: Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.
In man, simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is its primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the systemic circulation is low.
Following an IV injection of the β-hydroxyacid metabolite, its half-life averaged 1.9 hrs.
Elimination: Ezetimibe: Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. After 48 hrs, there were no detectable levels of radioactivity in the plasma.
Simvastatin: Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the feces within 96 hrs. The amount recovered in the feces represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Following an IV injection of the β-hydroxyacid metabolite an average of only 0.3% of the IV dose was excreted in urine as inhibitors.
Characteristics in Patients (Special Populations): Pediatric Patients: The absorption and metabolism of ezetimibe are similar between children and adolescents (10-18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available. Clinical experience in pediatric and adolescent patients (ages 9-17) has been limited to patients with HoFH or homozygous sitosterolemia.
Geriatric Patients: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18-45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe.
Hepatic Insufficiency: After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score >9) hepatic insufficiency, ezetimibe is not recommended in these patients (see Precautions).
Renal Insufficiency: Ezetimibe: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9).
An additional patient in this study (post-renal transplant and receiving multiple medications, including cyclosporine) had a 12-fold greater exposure to total ezetimibe.
Simvastatin: In a study of patients with severe renal insufficiency (creatinine clearance <30 mL/min), the plasma concentrations of total inhibitors after a single dose of a related HMG-CoA reductase inhibitor were approximately 2-fold higher than those in healthy volunteers.
Gender: Plasma concentrations for total ezetimibe are slightly higher (<20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe.
Race: Based on a meta-analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between Blacks and Caucasians.
Clinical Studies: In controlled clinical studies, Vytorin significantly reduced 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 increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolemia.
Primary Hypercholesterolemia: Vytorin in a multicenter, double-blind, placebo-controlled, 12-week trial, 887 hypercholesterolemic patients were randomized to 1 of 10 treatment groups: Placebo, ezetimibe (10 mg), simvastatin (10, 20, 40 or 80 mg), or co-administered ezetimibe and simvastatin equivalent to Vytorin (10/10, 10/20, 10/40 and 10/80). When patients receiving Vytorin were compared to those receiving all doses of simvastatin, Vytorin significantly lowered total-C, LDL-C, Apo B, TG, non-HDL-C, and C-reactive protein. The effects of Vytorin on HDL-C were similar to the effects seen with simvastatin. Further analysis showed Vytorin significantly increased HDL-C compared with placebo. (See Table 1).

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In a similarly designed study, results for all lipid parameters were generally consistent. In a pooled analysis of these 2 studies, the lipid response to Vytorin was similar in patients with TG levels > or <200 mg/dL.
In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥130 mg/dL were randomized to 1 of 4 treatment groups: Co-administered ezetimibe and simvastatin equivalent to Vytorin (10/10, 10/20, and 10/40), or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg. At Week 5, the LDL-C reductions with Vytorin 10/10, 10/20 or 10/40 were significantly larger than with simvastatin 20 mg. In addition, at Week 5, significantly more patients receiving Vytorin 10/10, 10/20, or 10/40 attained LDL-C target compared to those receiving simvastatin 20 mg (see Table 2). Week 5 results for LDL-C reduction and percentage attaining LDL-C target were consistent with the end of study results (Week 23).

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In a multicenter, double-blind, 24-week, forced titration study, 788 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive co-administered ezetimibe and simvastatin equivalent to Vytorin (10/10 and 10/20) or atorvastatin 10 mg. For all 3 treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, Vytorin lowered LDL-C to a greater degree than atorvastatin (see Table 3).

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In a double-blind, placebo-controlled, 8-week study, 240 patients with hypercholesterolemia already receiving simvastatin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.6-4.1 mmol/L [100-160 mg/dL], depending on baseline characteristics) were randomized to receive either ezetimibe 10 mg or placebo in addition to their on-going simvastatin therapy. Among simvastatin-treated patients not at LDL-C goal at baseline (~80%), significantly more patients randomized to ezetimibe co-administered with simvastatin achieved their LDL-C goal at study endpoint compared to patients randomized to placebo co-administered with simvastatin, 76% and 21.5%, respectively. The corresponding LDL-C reductions for ezetimibe or placebo co-administered with simvastatin were also significantly different (27% or 3%, respectively). In addition, ezetimibe co-administered with simvastatin significantly decreased total-C, Apo B, and TG compared with placebo co-administered with simvastatin.
In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks with a mean LDL-C of 93 mg/dL, were randomized to receive either simvastatin 40 mg or the co-administered active ingredients equivalent to Vytorin 10/20.
Vytorin 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg in further reducing LDL-C (-21% and 0%, respectively), total-C (-14% and -1%, respectively), Apo B (-14% and -2%, respectively), and non-HDL-C (-20% and -2%, respectively) beyond the reductions observed with simvastatin 20 mg. Results for HDL-C and TG between the 2 treatment groups were not significantly different. Results were not affected by type of thiazolidinedione treatment.
Ezetimibe: In 2, multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered total-C (13%), LDL-C (19%), Apo B (14%), and TG (8%) and increased HDL-C (3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, race, and baseline LDL-C. In addition, ezetimibe had no effect on the plasma concentrations of the fat-soluble vitamins A, D, and E, had no effect on prothrombin time, and did not impair adrenocortical steroid hormone production.
Simvastatin: Vytorin contains simvastatin. In 2 large placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N=4444 patients) and the Heart Protection Study (N=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: The risk of total mortality by reducing CHD deaths, the risk of non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures. The incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has not been established.
Homozygous Familial Hypercholesterolemia (HoFH): A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40-80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Co-administered ezetimibe and simvastatin equivalent to Vytorin (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients co-administered ezetimibe and simvastatin equivalent to Vytorin (10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.
Indications/Uses
Primary Hypercholesterolemia: 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 patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH): Vytorin is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH. Patients may also receive adjunctive treatments (eg, LDL apheresis).
Dosage/Direction for Use
The patient should be placed on a standard cholesterol-lowering diet before receiving Vytorin and should continue on this diet during treatment with Vytorin. The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response. Vytorin should be taken as a single daily dose in the evening, with or without food.
The dosage range is 10/10 mg/day through 10/80 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 (>55%) may be started at 10/40 mg/day. After initiation or titration of Vytorin, lipid levels may be analyzed after ≥2 weeks and dosage adjusted, if needed.
For patients who are currently on both simvastatin and ezetimibe, no dosage adjustment is required when switching to Vytorin.
Patients with Homozygous Familial Hypercholesterolemia: The recommended dosage for patients with homozygous familial hypercholesterolemia is Vytorin 10/40 mg/day or 10/80 mg/day in the evening. Vytorin should be used as an adjunct to other lipid-lowering treatments (eg, LDL pheresis) in these patients or if such treatments are unavailable.
Elderly: No dosage adjustment is required for elderly patients [see Characteristics in Patients (Special Populations) under Actions].
Children: Treatment with Vytorin is not recommended.
Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6). Treatment with Vytorin is not recommended in patients with moderate (Child-Pugh score 7-9) or severe (Child-Pugh score >9) liver dysfunction. [See Precautions and Characteristics in Patients (Special Populations) under Actions].
Use in Renal Impairment: No dosage adjustment is required for patients with moderate renal insufficiency. If treatment in patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) is deemed necessary, dosages >10/10 mg/day should be implemented cautiously. [See Characteristics in Patients (Special Populations) under Actions].
Co-administration with Other Medicines: Dosing of Vytorin should occur either ≥2 hrs before or ≥4 hrs after administration of a bile acid sequestrant.
In patients taking cyclosporine, danazol or ≥1 g/day of niacin concomitantly with Vytorin, the dose of Vytorin should not exceed 10/10 mg/day (see Myopathy/Rhabdomyolysis under Precautions and Interactions).
In patients taking amiodarone or verapamil concomitantly with Vytorin, the dose of Vytorin should not exceed 10/20 mg/day (see Myopathy/Rhabdomyolysis under Precautions and Interactions).
Overdosage
Vytorin: No specific treatment of overdosage with Vytorin can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Co-administration 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 or 40 mg/day to 18 patients with primary hypercholesterolemia 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: A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
Contraindications
Patients with hypersensitivity to ezetimibe and simvastatin or to any of the excipients of Vytorin. Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy and nursing (see Use in pregnancy and Use in lactation under Precautions).
Special Precautions
Myopathy/Rhabdomyolysis: Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) >10 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 by high levels of HMG-CoA reductase inhibitory activity in plasma.
Because Vytorin contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of Vytorin with the following: Potent inhibitors of CYP3A4 eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone, particularly with higher doses of Vytorin (see Interactions).
Other Drugs: Gemfibrozil and other fibrates or ≥1 g/day of niacin, particularly with higher doses of Vytorin (see Interactions).
Cyclosporine or danazol, particularly with higher doses of Vytorin (see Interactions).
Amiodarone or verapamil with higher doses of Vytorin (see Interactions). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.
Diltiazem: Patients on diltiazem treated concomitantly with Vytorin 10/80 have a slightly increased risk of myopathy. In clinical studies, the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltiazem (see Interactions).
The risk of myopathy/rhabdomyolysis is dose related for simvastatin. The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.03% at 20 mg, 0.08% at 40 mg and 0.4% at 80 mg.
Consequently: Use of Vytorin concomitantly with potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors or nefazodone) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Vytorin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
There is an increased risk of myopathy when simvastatin is used concomitantly with gemfibrozil or other fibrates; the safety and effectiveness of ezetimibe administered with fibrates have not been established. Therefore, the concomitant use of Vytorin and fibrates should be avoided (see Interactions).
The dose of Vytorin should not exceed 10/10 mg daily in patients receiving concomitant medication with cyclosporine, danazol or ≥1 g/day of niacin. The benefits of the use of Vytorin in patients receiving cyclosporine, danazol or niacin should be carefully weighed against the risks of these drug combinations, and caution should be exercised when initiating Vytorin in the setting of cyclosporine (see Interactions).
The dose of Vytorin should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of Vytorin at doses >10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
All patients starting therapy with Vytorin or whose dose of Vytorin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Vytorin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or 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. Periodic CK determinations may be considered in patients starting therapy with Vytorin or whose dose is being increased, but 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 Vytorin merit closer monitoring. Therapy with Vytorin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Liver Enzymes: In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (≥3X ULN) have been observed. (See Side Effects.)
It is recommended that LFTs be performed before treatment with 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 (eg, semiannually) for the 1st 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 3X ULN and are persistent, the drug should be discontinued.
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 Vytorin.
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Vytorin is not recommended in these patients [see Characteristics in Patients (Special Populations) under Actions].
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established; therefore, co-administration of Vytorin and fibrates is not recommended (see Interactions).
Cyclosporine: Caution should be exercised when initiating Vytorin in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Vytorin and cyclosporine (see Interactions).
Use in 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.
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 1st 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 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, Vytorin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.
Treatment with 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.
Use in lactation: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active components of Vytorin are excreted into human breast milk; therefore, women who are nursing should not take Vytorin.
Use In Pregnancy & Lactation
Use in 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.
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 1st 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 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, Vytorin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.
Treatment with 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.
Use in lactation: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active components of Vytorin are excreted into human breast milk; therefore, women who are nursing should not take Vytorin.
Side Effects
Vytorin (or co-administration of ezetimibe and simvastatin equivalent to Vytorin) has been evaluated for safety in >3800 patients in clinical trials. Vytorin was generally well tolerated.
The following common (≥1/100, <1/10) drug-related adverse experiences were reported in patients taking Vytorin (n=1236) during 3, similarly designed, placebo-controlled trials: Gastrointestinal Disorders: Flatulence.
Musculoskeletal and Connective Tissue Disorders: Myalgia.
Nervous System Disorders: Headache.
Additional adverse events reported commonly with ezetimibe during clinical trials: Gastrointestinal Disorders: Abdominal pain, diarrhea.
General Disorders and Administration Site Conditions: Fatigue.
During post-marketing use the following adverse events were reported: Blood and Lymphatic System Disorders: Thrombocytopenia.
Hepatobiliary Disorders: Hepatitis.
Musculoskeletal, Connective Tissue and Bone Disorders: Very rarely in patients taking a statin with ezetimibe, rhabdomyolysis (see Precautions).
Laboratory Values: Increased CPK; elevations of liver transaminases.
Skin and Subcutaneous Tissue Disorders: Hypersensitivity reactions, including rash [rare (≥1/10,000, <1/1000)] and angioedema [very rare (<1/10,000)].
Gastrointestinal Disorders: Nausea (rare); pancreatitis (very rare).
Additional adverse events reported rarely with simvastatin during clinical studies and/or post-marketing use: Blood and Lymphatic System Disorders: Anemia.
Gastrointestinal Disorders: Abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, pancreatitis.
General Disorders and Administration Site Conditions: Asthenia.
Hepatic Disorders: Hepatitis/jaundice.
Musculoskeletal, Connective Tissue and Bone Disorders: Muscle cramps, myopathy, rhabdomyolysis (see Precautions).
Nervous System Disorders: Dizziness, paresthesia, peripheral neuropathy.
Skin and Subcutaneous Tissue Disorders: Alopecia, pruritus, rash. 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, increased ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea and malaise.
Laboratory Values: In controlled clinical co-administration 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 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 Vytorin.
Drug Interactions
Vytorin: No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with simvastatin. Vytorin is bioequivalent to co-administered ezetimibe and simvastatin.
CYP3A4 Interactions: In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P-450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by CYP450 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 (listed as follows) increase the risk of myopathy by reducing the elimination of the simvastatin component of Vytorin: (See Precautions: Myopathy/Rhabdomyolysis.) Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone.
Interactions with Lipid-Lowering Drugs that can Cause Myopathy when Given Alone: The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent inhibitors of CYP3A4, but which can cause myopathy when given alone: (See Precautions: Myopathy/Rhabdomyolysis.) Gemfibrozil, other fibrates, niacin (nicotinic acid) (≥1 g/day).
Other Drug Interactions: Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol, particularly with higher doses of Vytorin (see Myopathy/Rhabdomyolysis under Precautions).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of Vytorin (see 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 Vytorin to cholestyramine may be lessened by this interaction.
Diltiazem: Patients on diltiazem treated concomitantly with Vytorin 10/80 have a slightly increased risk of myopathy (see Myopathy/Rhabdomyolysis under Precautions).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5- and 1.7-fold, respectively; however, these increases are not considered clinically significant. The safety and effectiveness of Vytorin administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of Vytorin with fibrates is not recommended until use in patients is studied.
Others: 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, very large quantities (>1 L daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided while taking Vytorin (see Myopathy/Rhabdomyolysis under Precautions).
Coumarin Derivatives: In 2 clinical studies, 1 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 1.7-1.8 and from 2.6-3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting 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 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.
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.
Cyclosporine: In a study of 8 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 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 2-period crossover study in 12 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 Precautions).
Storage
Do not store above 30°C, usual climatic temperature excursions permitted.
ATC Classification
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.
Presentation/Packing
Tab 10/10 mg (white to off-white, capsule shaped, biconvex compressed tablet with marking 311) x 30's. 10/20 mg (white to off-white, capsule shaped, biconvex compressed tablet with marking 312) x 30's. 10/40 mg (white to off-white, capsule shaped, biconvex compressed tablet with marking 313) x 30's.
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