Full Prescribing Info
Contents
Ezetimibe, simvastatin.
Description
Each 10 mg/10 mg-tab contains ezetimibe 10 mg and simvastatin 10 mg. Each 10 mg/20 mg-tab contains ezetimibe 10 mg and simvastatin 20 mg.
Action
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.
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 cholesterol (total-C), low-density lipoprotein-C (LDL-C), apolipoprotein-B (Apo B), triglycerides (TG) and non-high-density lipoprotein-C (non-HDL-C) and increases high-density lipoprotein-C (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 3-hydroxy-3-methylglutaryl CoA (HMG-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 lipoprotein (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.
Animal Pharmacology: Ezetimibe: The hypocholesterolemic effect of ezetimibe was evaluated in Rhesus monkeys, a model for the human metabolism of cholesterol, as well as in dogs. Rhesus monkeys were fed a cholesterol-containing diet that mimics a human Western diet. Ezetimibe was found to have an ED50 of 0.0005 mg/kg/day for inhibiting the rise in plasma cholesterol levels (ED100=0.003 mg/kg/day). The ED50 in dogs was found to be 0.007 mg/kg/day. These results are consistent with ezetimibe being an extremely potent cholesterol absorption inhibitor.
In dogs given ezetimibe (≥0.03 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 3-fold. However, a dose of 300 mg/kg/day administered to dogs for 1 year did not result in gallstone formation or any other adverse hepatobiliary effects. In mice given ezetimibe (0.3-5 mg/kg/day) and fed a normal or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. The relevance of these preclinical findings to humans is unknown.
Simvastatin: Simvastatin is a γ-lactone obtained by chemical modification of lovastatin. Hydrolysis of the lactone by either chemical or enzymatic means results in the dihydroxy open acid designated as β-hydroxyacid. The open acid is the active form of the compound. It is a competitive inhibitor of HMG-CoA reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway. The Ki of inhibition of a solubilized HMG-CoA reductase preparation obtained from rat liver microsomes is approximately 1 x 10-10 M.
Two systems have been utilized to demonstrate that simvastatin is an inhibitor of cholesterol synthesis; mammalian cells grown in culture and in vivo in the rat. The IC50 values for inhibition of sterol synthesis in cultured animal cells by simvastatin, as determined by measuring the incorporation of 14C-acetate into 14C-sterol, are 19.3 nM for mouse L-M cells, 13.3 nM for the rat hepatoma cell line, H4IIE and 15.6 nM for the human hepatoma cell line, Hep-G2. These results demonstrate that simvastatin is active against the human enzyme as well as the rodent 1.
The inhibition of incorporation of 14C-acetate into 14C-cholesterol in rats has been used to assess the in vivo effectiveness of simvastatin. Simvastatin is an orally active inhibitor of cholesterol synthesis with an ID50 value <0.15-0.2 mg/kg and 87% inhibition at 2.4 mg/kg by 1 hr after an oral dose of simvastatin.
Studies have been carried out in the dog in order to assess the effects of simvastatin on serum total lipoprotein cholesterol. This animal model has been shown to respond to HMG-CoA reductase inhibitors with respect to lowering of circulating cholesterol as opposed to rats, which show no sustained effects of these agents on cholesterol levels. In the dog, simvastatin is a potent, orally active agent that lowers circulating cholesterol. This occurs in the presence or absence of the bile acid sequestrant, cholestyramine.
In dogs treated with cholestyramine 12 g/day, cholesterol is decreased by an average of 35%. Treatment of these dogs with simvastatin 1 and 2 mg/kg/day results in an additional 29.1% and 37.6% decrease, respectively, from the baseline established with cholestyramine. Similarly, in chow-fed dogs, cholesterol is decreased 26.2% by treatment with simvastatin 8 mg/kg/day. The effects of simvastatin are primarily on LDL-C in spite of the fact that approximately 70-80% of circulating cholesterol in the dog is in the form of HDL. In the cholestyramine-primed dogs, LDL-C decreased by 57-72% with a 19-38% decrease in HDL.
Similarly, LDL-C decreased by 62% in chow-fed dogs after treatment with simvastatin 8 mg/kg/day with a slight decrease in HDL levels that did not reach significance.
Ancillary pharmacology studies to assess effects on organ systems and biological parameters were conducted with β-hydroxyacid. No major changes were seen. Minor effects were noted on acid secretion and respiratory parameters in dogs.
In conclusion, simvastatin is a competitive inhibitor of the key cholesterol biosynthetic enzyme, HMG-CoA reductase. This inhibition is manifested in cultured animal cells and in vivo in the rat by a block in cholesterol synthesis. In the dog, an animal model that is responsive to HMG-CoA reductase inhibitors, simvastatin is a highly effective agent for lowering circulating total-C and LDL-C. Simvastatin is free of significant effects on ancillary pharmacological parameters.
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 4-12 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 4 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 99.7% and 88-92% bound 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 previously mentioned 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 t½ 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 t½ 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.
Special Populations: Characteristics in Patients: 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 are not available. Clinical experience in pediatric and adolescent patients (ages 9-17) has been limited to patients with homozygous familial hypercholesterolemia (HoFH).
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 scores 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 scores 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 creatinine clearance ≤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 (postrenal 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.
Indications/Uses
Primary Hypercholesterolemia: As adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, TG and non-HDL-C and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH): 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 10/40 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 (>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.
Patients with Homozygous Familial Hypercholesterolemia: Recommended Dose: 10/40 mg/day in the evening. Vytorin should be used as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable.
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 Special Populations in Pharmacology under Actions and Precautions).
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 Special Populations in Pharmacology 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 niacin ≥1 g/day concomitantly with Vytorin, the dose of Vytorin should not exceed 10/10 mg/day (see Precautions and Interactions).
In patients taking amiodarone or verapamil concomitantly with Vytorin, the dose of Vytorin should not exceed 10/20 mg/day (see Precautions and Interactions).
Elderly: No dosage adjustment is required for elderly patients (see Special Populations in Pharmacology under Actions).
Children: Treatment with Vytorin is not recommended.
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.
The dialyzability of simvastatin and its metabolites in man is not known at present.
Contraindications
Hypersensitivity to ezetimibe, simvastatin or to any of the excipients.
Active liver disease or unexplained persistent elevations of serum transaminases.
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.
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.
Special Precautions
Clinical testing has been conducted over the dose range ezetimibe 10 mg/simvastatin 10 mg to ezetimibe 10 mg/simvastatin 80 mg.
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, nefazodone or large quantities of grapefruit juice (>1 L daily), particularly with higher doses of Vytorin (see Interactions); other drugs: Gemfibrozil and other fibrates or niacin ≥1 g/day, 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 on-going clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone; diltiazem: Patients on diltiazem treated concomitantly with ezetemibe 10 mg/simvastatin 80 mg 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).
As with other HMG-CoA reductase inhibitor, the risk of myopathy/rhabdomyolysis is dose-related for simvastatin. In a clinical trial database in which 41,050 patients were treated with simvastatin, with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
Consequently: Use of Vytorin concomitantly with potent CYP3A4 inhibitors [eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors or nefazodone or large quantities of grapefruit juice (>1 L daily)] 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 niacin ≥1 g/day. 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 (≥3 times ULN) have been observed (see Adverse Reactions).
It is recommended that liver function tests (LFTs) be performed before treatment with Vytorin begins and thereafter when clinically indicated. 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 times ULN and are persistent, Vytorin 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.
Information for Patients: Patients should be advised about substances that should not be taken concomitantly with Vytorin and be advised to report promptly unexplained muscle pain, tenderness or weakness.
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 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).
Warfarin: If Vytorin is added to warfarin or another coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored (see Interactions).
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use of machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.
Use in children: There are insufficient data for the safe and effective use of Vytorin in pediatric patients (see Ezetimibe and Simvastatin as follows).
Ezetimibe: The pharmacokinetics of ezetimibe in adolescent (10-18 years) have been shown to be similar to that in adults. Treatment experience with ezetimibe in pediatric population is limited to 4 patients (9-17 years) with homozygous sitosterolemia and 5 patients (11-17 years) with HoFH. Treatment with ezetimibe in children (<10 years) is not recommended.
Simvastatin: Safety and effectiveness of simvastatin in patients 10-17 years with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses >40 mg have not been studied in this population. In this limited 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. Adolescent females should be counseled on appropriate contraceptive methods while on therapy with simvastatin (see Use in pregnancy under Contraindications). Simvastatin has not been studied in patients <10 years, nor in pre-menarchal girls.
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.
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.
Adverse Reactions
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 Disorder: Flatulence.
Musculoskeletal and Connective Tissue Disorder: Myalgia.
Nervous System Disorder: Headache.
Post-Marketing Experience: The adverse reactions reported for Vytorin are consistent with those previously reported with ezetimibe and/or simvastatin.
Additional adverse events reported commonly with ezetimibe during clinical trials:
Gastrointestinal Disorders: Abdominal pain, diarrhea.
General Disorder and Administration Site Condition: Fatigue.
During post-marketing use, the following adverse events were reported, regardless of causality assessment:
Blood and Lymphatic System Disorder: Thrombocytopenia.
Hepatobiliary Disorders: Cholelithiasis, cholecystitis, hepatitis.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia and very rarely, myopathy/rhabdomyolysis (see Precautions).
Laboratory Values: Increased CPK, elevations of liver transaminases.
Skin and Subcutaneous Tissue Disorders: Hypersensitivity reactions, including rash and urticaria [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 Disorder and Administration Site Condition: Asthenia.
Hepatic Disorder: 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 times 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 times ULN) were seen in 0.2% of the patients treated with Vytorin.
Concomitant Lipid-Lowering Therapy: In controlled clinical trial studies in which simvastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with simvastatin or cholestyramine.
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 cytochromes P-450 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 (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, large quantities of grapefruit juice (>1 L daily).
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 Precautions).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of Vytorin (see Precautions).
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe and 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 ezetimibe 10 mg and simvastatin 80 mg have a slightly increased risk of myopathy (see Precautions).
Digoxin: Concomitant administration of simvastatin and digoxin in normal volunteers resulted in a slight elevation (<0.3 ng/mL) in plasma drug concentrations (as measured by digoxin radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when Vytorin is initiated.
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 (see Animal Pharmacology under Actions). 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.
Other Interactions: Grapefruit juice contains ≥1 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 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.
Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of 12 healthy adult males. There have been post-marketing reports of increased International Normalized Ratio in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications (see Precautions).
The effect of 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.
Cyclosporine: In a study of 8 postrenal 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 2-period crossover study in 12 healthy subjects, daily administration of ezetimibe 20 mg 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 single 100-mg dose of cyclosporine alone (see Precautions).
Storage
Store up to 30°C, usual climatic temperature excursions permitted in a tightly-closed container.
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 mg/10 mg x 30's. 10 mg/20 mg x 30's.
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