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VYTORIN (EZETIMIBE / SIMVASTATINA) 10/20 MG 28 TAB

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VYTORIN (EZETIMIBE / SIMVASTATINA) 10/20 MG 28 TAB

SKU: 7501326008402

In stock: 999 units

THERAPEUTIC INDICATIONS:

Primary hypercholesterolaemia: Vytorin ® * is indicated as add-on treatment to diet for reduction of elevated total cholesterol, cholesterol of low density lipoprotein (LDL-C), apolipoprotein B (Apo B), triglycerides and cholesterol from different lipoproteins of high-density (non-HDL-C) and to increase cholesterol high density lipoprotein (HDL-C) in adults and adolescents (10 to 17 years) with primary hypercholesterolemia (heterozygous familial and nonfamilial) or with mixed hyperlipidemia.

Fenofibrate can be added to treatment with VYTORIN ® * in adult patients with mixed hyperlipidemia requiring a greater reduction in triglycerides (TG) and non-HDL-C and an increase in HDL-C.

PRECAUTIONS IN RELATION TO EFFECTS OF CARCINOGENESIS, MUTAGENESIS, Impairment of Fertility:

Carcinogenicity:

Ezetimibe: In the two-year studies in mice and rats, ezetimibe was not carcinogenic.

Simvastatin: In the initial studies conducted with simvastatin carcinogenicity in rats and mice used dosages ranging from 1 to 25 mg / kg / day. In mice not found in any tissue signs of treatment-related tumors. In female rats receiving 25 mg / kg / day of simvastatin (16 times the maximum recommended dose in humans) showed a statistically significant increase (p ≤ 0.05) in the incidence of thyroid follicular adenomas. This benign tumor was limited to female rats, revealed no similar change in the male rats or females who received lower dosages (up to 5 mg / kg / day). These tumors are a secondary effect reflecting an increased clearance of thyroid hormone mediated by simvastatin in the female rat. We did not identify any statistically significant increase in the incidence of tumors in any tissue of rats receiving simvastatin.

Data from these two studies indicated that all dosages occurred hyperplasia of the forestomach squamous epithelium. These gastric changes were limited to an anatomical structure that exists in man. Also, did not affect cells that are identical in other anatomical regions (eg, esophagus and the anorectal junction of the rat, mouse and dog).

The results of a carcinogenicity study of 73 weeks in mice receiving up to 400 mg / kg / day of simvastatin (250 times the maximum recommended dosage for a 50 kg body weight) showed an increased incidence of adenomas and hepatocellular carcinomas, lung adenomas and adenomas of the Harderian glands. Based on this study and the results of the initial 92-week carcinogenicity in mice, we found a free dosage effects of 25 mg / kg / day (16 times the maximum recommended human).

The results of other carcinogenicity study of 106 weeks in rats given doses of simvastatin from 50 to 100 mg / kg / day (31 to 63 times greater than the maximum recommended human) revealed a treatment-related increase in the incidence of hepatocellular neoplasms. The dosage remained void of 25 mg / kg / day (16 times the maximum recommended human) determined in the initial study of carcinogenicity. There was also an increased incidence of thyroid hyperplastic lesions, but this is consistent with previous data that this is a response specific to that species, without any implications for humans.

Mutagenesis: VYTORIN ® *. The combination of ezetimibe and simvastatin was not genotoxic in a series of tests in vitro and in vivo.

Ezetimibe: Ezetimibe was not genotoxic in a series of tests in vitro and in vivo.

Simvastatin: Both simvastatin and open the corresponding ß-hydroxyacid acid have undergone an extensive series of tests for genetic toxicity in vitro and in vivo tests including microbial mutagenesis, mutagenesis in mammalian cells, disruption of DNA single-strand and chromosomal aberrations. These studies revealed no evidence of interaction between simvastatin or beta-hydroxy acid and the genetic material to the highest soluble noncytotoxic concentrations tested in vitro or maximum tolerated doses in vivo.

Reproduction:

Ezetimibe: Ezetimibe had no effect on fertility of male or female rats.

Simvastatin: A maximum tolerated doses in the rat and the rabbit, simvastatin had no effect on fertility or reproductive function.

Fetal development: VYTORIN ® * Coadministration of ezetimibe and simvastatin to pregnant rats was not teratogenic. In pregnant rabbits, there was a low incidence of skeletal malformations in fetuses (fusion and decreased number of caudal vertebrae) when given ezetimibe (1.000 mg / kg, 146 or more times the human exposure at 10 mg daily , based on the AUC 0-24h total ezetimibe) and simvastatin (5 and 10 mg / kg). Exposure to pharmacologically active form of simvastatin was 246 or more times the exposure in humans at 10 mg daily, based on the AUC 0-24h.

Ezetimibe: Ezetimibe was not teratogenic in rats and rabbits, and had no effect on fetal or postnatal development.

Simvastatin: A maximum tolerated doses in the rat and the rabbit, simvastatin produced no fetal malformation and had no effect on neonatal development. However, in rats the administration of 60 mg / kg / day of the hydroxy acid (pharmacologically active metabolite of simvastatin) caused a decrease in body weight of mothers and an increased incidence of resorptions and fetal skeletal malformations compared with witnesses. Further studies with measurements of the metabolite of 60 mg / kg / day showed that these resorptions and skeletal malformations in fetuses were consequences of maternal toxicity (forestomach injuries associated with weight loss) specific in rodents, and it is very unlikely be due to a direct effect on the fetus. Although no studies have been made equal with simvastatin in rats, has shown that treatment of pregnant rats with an inhibitor of HMG-CoA closely associated with it at dosages of 80 and 400 mg / kg / day (10 and 52 times the maximum recommended therapeutic dose based on mg/m2 body surface) decreases plasma concentrations of mevalonate in the fetus.

DOSAGE AND ADMINISTRATION The patient should be on a standard cholesterol-lowering diet before receiving VYTORIN ® *, and must continue on this diet during treatment with VYTORIN ® *. Dosing should be individualized according to the baseline LDL-C, the recommended goal of therapy and patient response. VYTORIN ® * should be taken in one dose a day, at night, with or without food.

The dosage range is from 10/10 mg daily until 10/80 mg daily. The recommended usual starting dose is 10/20 mg daily. You can consider starting treatment with 10/10 mg daily in patients requiring less aggressive LDL-C. Where it is necessary to lower LDL-C more than 55% can start with 10/40 mg daily. After starting the administration or titration of VYTORIN ® * can measure the concentrations of lipids in two or more weeks and dosage adjusted, if necessary. Only those patients who have not reached the target LDL-C recommended using a dose of VYTORIN ® * 10/40 mg, the dose should be adjusted to 10/80 mg (see WARNINGS, Myopathy / Rhabdomyolysis).

Coadministered with fenofibrate: The dose of VYTORIN ® * to be used when co-administered fenofibrate are 10/10 or 10/20 mg / day (see WARNINGS, Myopathy / Rhabdomyolysis).

Dosage in patients with homozygous familial hypercholesterolemia: The dose of VYTORIN ® * recommended in patients with homozygous familial hypercholesterolemia is 10/40 or 10/80 mg once a day, at night. In these patients, VYTORIN ® * is added to other treatments used lipid lowering (eg, LDL apheresis) or if there are no such treatments.

Use in elderly: No need to make any dosage adjustment in elderly patients (see Pharmacokinetics and pharmacodynamics in humans, Characteristics in special patient groups).

Use in pediatric patients (10 to 17): The recommended starting dose is usually 10/10 mg once daily in the afternoon. The recommended dose range is 10/10 up to 10/40 mg / day. The dose should be customized according to the recommended goal of therapy.

Children <10 years: Not recommended for treatment with VYTORIN ® *.

Use in patients with hepatic impairment: No need to make any dosage adjustment in patients with mild hepatic impairment (Child-Pugh score of 5 or 6). We do not recommend treatment with VYTORIN ® * in patients with moderate hepatic impairment (Child-Pugh score 7 to 9) or severe [Child-Pugh score greater than 9]. (See PRECAUTIONS and Pharmacokinetics and pharmacodynamics in humans, Characteristics in special patient groups).

Use in patients with renal impairment: No need to make any dosage adjustment in patients with moderate renal impairment. If deemed necessary to deal with VYTORIN ® * patients with severe renal insufficiency (creatinine clearance 30 mL /

min), dosages above 10/10 mg / day should be used with caution (see Pharmacokinetics and pharmacodynamics in humans, Characteristics in special patient groups).

Coadministration with other drugs: VYTORIN ® * should be administered two or more hours before or four or more hours after administration of a bile acid sequestrant.

In patients taking cyclosporine or danazol, VYTORIN ® dosage * should not be greater than 10/10 mg / day (see WARNINGS, Myopathy / Rhabdomyolysis and Interactions of another kind).

In patients taking amiodarone or verapamil, the dose of VYTORIN ® * should not be greater than 10/20 mg / day (see WARNINGS, Myopathy / Rhabdomyolysis and Interactions of another kind).

In patients taking diltiazem concomitantly with VYTORIN ® *, the dose of VYTORIN ® * should not exceed 10/40 mg / day (see WARNINGS, Myopathy / Rhabdomyolysis and Interactions of another kind).

Regarding fibrates, only The safety and effectiveness of VYTORIN administered with fenofibrate ® *. Because of this the concomitant use of VYTORIN and fibrates ® * except fenofibrate should be avoided (see WARNINGS, Myopathy / Rhabdomyolysis and Interactions of another kind).

There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Therefore, although not recommended, if VYTORIN ® * is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily (see WARNINGS, Myopathy / Rhabdomyolysis and Interactions of another kind).

REPRESENTATIONS AND MANAGEMENT Overdosage: Vytorin ® * Can not recommend any specific treatment of overdosage with VYTORIN ® *. In case of overdose, measures should be symptomatic and supportive. Co-administration of 1.000 mg / kg of ezetimibe and 1.000 mg / kg of simvastatin was well tolerated in acute toxicity studies for VO in mice and rats. There were no clinical signs of toxicity in these animals. The estimated LD50 for both species were 1.000 mg / kg or more of ezetimibe and 1.000 mg / kg or more of simvastatin.

Ezetimibe: In clinical studies, administration of ezetimibe 50 mg daily to 15 healthy subjects for up to 14 days or 40 mg daily to 18 patients with primary hypercholesterolemia for up to 56 days was generally well tolerated. Have reported few cases of overdosage, most of which have not been associated with adverse reactions. Reported adverse reactions were not severe.

Simvastatin, have been reported few cases of overdosage, the maximum dose taken was 3.6 g. All these patients recovered without sequelae.

Homozygous familial hypercholesterolemia: VYTORIN ® * is indicated for the reduction of elevated total cholesterol and LDL-C in adult patients and adolescents (10 to 17 years) with homozygous familial hypercholesterolemia, which may also receive adjunctive treatments (eg LDL apheresis).

Pharmacokinetics in Humans:

Absorption:

Ezetimibe: After oral administration, ezetimibe is absorbed rapidly and extensively transformed by conjugation in a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe glucuronide reached average maximum plasma concentration (Cmax) in one to two hours, and ezetimibe in four to twelve hours. Unable to determine the absolute bioavailability of ezetimibe, as this is practically insoluble in aqueous media suitable for injection.

Concomitant food administration (high fat or fat) had no effect on the bioavailability of ezetimibe administered orally as a tablet with 10 mg.

Simvastatin: It was found that the availability of beta-hydroxy acid in the systemic circulation following an oral dose of simvastatin is less than 5% of the dose, consistent with extensive first-pass hepatic extraction. The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites.

Compared to the fasting state, did not change plasma concentrations of both active and total inhibitors when simvastatin was administered immediately after a test meal.

Distribution:

Ezetimibe: They bind to human plasma proteins 99.7% of ezetimibe and 88 to 92% of ezetimibe glucuronide.

Simvastatin: Both simvastatin and ß-hydroxy acid bind to plasma proteins (95%).

The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all these pharmacokinetic studies, the maximum concentration of inhibitors in plasma reached 1.3 to 2.4 hours after dosing.

Metabolism

Ezetimibe: Ezetimibe is primarily metabolized in the small intestine and liver by conjugation with glucuronic acid (phase II reaction), and is then excreted in the bile. In all species studied was observed Minimal oxidative metabolism (a phase I reaction). Ezetimibe and ezetimibe-glucuronide are the major forms of the drug detected in plasma, constituting 10 to 20% and 80 to 90%, respectively, of total drug in plasma. Both forms are slowly eliminated from plasma with evidence of considerable enterohepatic recycling. The half-life of ezetimibe and its glucuronide is 22 hours.

Simvastatin: Simvastatin is an inactive lactone which rapidly transformed in vivo by hydrolysis into the corresponding beta-hydroxy acid, which is a potent inhibitor of HMG-CoA. The hydrolysis occurs mainly in the liver hydrolysis in human plasma is very slow.

In man simvastatin is well absorbed and undergoes extensive hepatic extraction step. The extraction in the liver is dependent on hepatic blood flow. The liver is the primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, the availability of the active drug in the bloodstream is low.

Following intravenous injection of ß-hydroxy metabolite, its half-life was 1.9 hours on average.

Elimination:

Ezetimibe: Following oral administration of 20 mg of 14C-ezetimibe to people, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. In a ten day period recovered about 78% of the radioactivity in feces and 11% in the urine. At 48 hours, there was no detectable radioactivity in plasma.

Simvastatin: After an oral dose of radioactive simvastatin to people, they excreted 13% of the radioactivity in the urine and 60% in the feces within 96 hours. The amount recovered in the faeces represents absorbed drug equivalents excreted in bile and and unabsorbed. After an intravenous injection of beta-hydroxyacid metabolite are excreted in the urine as inhibitors averaged only 0.3% of the administered dose.

Characteristics in special patient groups:

Children: The absorption and metabolism of ezetimibe are similar in children, adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. No pharmacokinetic data in children under ten years.

Elderly: Plasma concentrations for total ezetimibe are about twice as high in elderly patients (over 65 years) than in younger patients (18 to 45 years). The LDL-C reduction and safety profile are similar in elderly and young people treated with ezetimibe.

Hepatic impairment: Following a single dose of 10 mg of ezetimibe, the mean AUC for total ezetimibe was approximately 1.7 times higher in patients with mild hepatic impairment (Child-Pugh score of 5 or 6) than in healthy subjects. In a multiple dose study (10 mg daily) for 14 days in patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe was approximately four times higher on days 1 and 14 in healthy subjects. No dosage adjustment is necessary in patients with mild hepatic impairment. Because the unknown effects of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment (Child-Pugh score greater than 9) is not recommended with ezetimibe treat these patients (see Precautions).

Renal impairment:

Ezetimibe: In eight patients with severe renal disease (mean creatinine clearance 30 mL /

min/1.73 m2), after a single dose of 10 mg of ezetimibe the mean AUC for total ezetimibe was approximately 1.5 times that in nine healthy subjects.

In another patient in that study (renal transplant and receiving multiple medications, including cyclosporine), exposure to total ezetimibe was 12 times greater.

Simvastatin: In a study in patients with severe renal insufficiency (creatinine clearance <30 ml / min), plasma concentrations of total inhibitors after a single dose of an inhibitor of HMG-CoA associated with simvastatin were approximately twice that in healthy volunteers.

Gender: Plasma concentrations for total ezetimibe are slightly higher (less than 20%) in women than in men. The LDL-C reduction and safety profile are similar in men and in women treated with ezetimibe.

Race: Based on a meta-analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between blacks and whites.

Contraindications

• Hypersensitivity to any component of this product.

• Active liver disease or unexplained persistent elevations of serum transaminases.

• Pregnancy and lactation (see Restrictions on use during pregnancy and lactation).

• When administering fenofibrate with VYTORIN ® *, see prescribing information for fenofibrate.

PRECAUTIONS: When administering fenofibrate with VYTORIN ® *, see prescribing information for fenofibrate.

Myopathy / rhabdomyolysis: Like other reductase inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA), simvastatin occasionally causes myopathy manifested by pain, tenderness or muscle weakness and increased creatine kinase more than ten times the ULN. In Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have patient. A great activity inhibiting HMG-CoA in the plasma increases the risk of myopathy. Among the predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal failure.

Because VYTORIN ® * contains simvastatin, the risk of myopathy / rhabdomyolysis is increased by concomitant use of VYTORIN ® with:

Potent inhibitors of CYP3A4 eg itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, protease inhibitors for HIV or nefazodone, particularly with higher doses of VYTORIN ® * (see Interactions and other genus).

Other drugs: Gemfibrozil and other fibrates, particularly with higher doses of VYTORIN ® *. In one study, which was coadministered with 10/20 mg / day of VYTORIN ® * and 160 mg / day of fenofibrate in 184 patients up to 12 weeks, there were no reports of myopathy. (See Interactions and other genus).

Cyclosporine or danazol particularly with higher doses of VYTORIN ® * (see Interactions and other genus).

Amiodarone with high doses of VYTORIN ® * (see Interactions and other genus): In a clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.

Calcium channel blockers:

Verapamil with higher doses of VYTORIN ® * (see Interactions and other genus).

Diltiazem with high doses of VYTORIN ® *: For patients taking diltiazem and receive simvastatin 80 mg had an increased risk of myopathy. In clinical studies, the risk of myopathy was similar in patients receiving simvastatin 40 mg daily and diltiazem and in those receiving only 40 mg of simvastatin (see Interactions and other genus).

Amlodipine with high doses of VYTORIN ® *: In a clinical study with patients receiving amlodipine 80 mg concomitantly with simvastatin had slightly increased risk of myopathy. The risk of myopathy in patients receiving simvastatin 40 mg was not taking amlodipine increased concomitantly (see Interactions and other genus).

Fusidic acid: Patients treated with fusidic acid being treated concomitantly with VYTORIN ® * may have an increased risk of myopathy (see Interactions and other genus).

Niacin (≥ 1 g / day): Interactions See other gender.

As with other HMG-CoA reductase, the risk of myopathy / rhabdomyolysis is dose related for simvastatin: In a database of several clinical studies in which 41.413 patients were treated with simvastatin and 24.747 of these patients (approximately 60%) who 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 doses of 20, 40 and 80 mg / day respectively. In these trials, patients were carefully monitored and some medicinal products that caused interactions 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 receiving 20 mg / day. Approximately half of these cases with myopathy occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.

Therefore:

1. Avoid concomitant use of VYTORIN ® with potent CYP3A4 inhibitors (eg itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, protease inhibitors for HIV or nefazodone). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, you should stop VYTORIN ® * during therapy with these. Avoid concomitant use of other drugs at therapeutic doses with a potent inhibitor of CYP3A4, unless the benefits of combined therapy outweigh the increased risk.

2. Regarding fibrates, only The safety and effectiveness of VYTORIN administered with fenofibrate ® *. Because of this, concomitant use of VYTORIN and fibrates ® * except fenofibrate should be avoided.

Has not been studied doses greater than 10/20 mg / day and fenofibrate VYTORIN ® *. Caution should be exercised when prescribing VYTORIN ® * and fenofibrate, because fenofibrate monotherapy can cause myopathy. In a 12-week study in which 184 patients received 10/20 mg / day of VYTORIN ® * + 160 mg / day of fenofibrate co-administration was well tolerated. In another study of 12 weeks, in which 411 patients received 20 mg / day of simvastatin and 160 mg / day of fenofibrate co-administration was also well tolerated.

There is an increased risk of myopathy when used concomitantly with fibrates simvatatina (especially gemfibrozil). The combined use of simvastatin with gemfibrozil should be avoided unless the benefits can outweigh the risks of this combination. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant gemfibrozil. Therefore, although not recommended, if VYTORIN ® * is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily.

3. In patients treated concomitantly with VYTORIN ® * and cyclosporine or danazol, VYTORIN ® dosage * should not be greater than 10/10 mg daily. The benefits to the use of VYTORIN ® * in patients receiving cyclosporine or danazol should be carefully evaluated against the risks that may occur with this combination and caution should be used to start managing VYTORIN ® * to a patient already taking cyclosporine (see Interactions and other genus).

4. In patients treated concomitantly with VYTORIN ® * and amiodarone or verapamil, the dose of VYTORIN ® * should not be greater than 10/20 mg daily. Avoid combined use of more than 10/20 mg VYTORIN ® * and amiodarone or verapamil, unless it is very likely that the benefits outweigh the increased risk of myopathy.

5. The dose of VYTORIN ® * should not exceed 10/40 mg daily in patients receiving concomitant medication with diltiazem, unless the potential clinical benefit outweighs the increased risk of myopathy.

6. Caution should be exercised when prescribing amlodipine with VYTORIN ® * 10/80 mg as there is a slight increased risk of myopathy with concomitant use.

7. There have been cases of myopathy / rhabdomyolysis with simvastatin coadministered with niacin (doses ≥ 1 g / day), lipid modifier. In an ongoing study, double-blind, randomized, conducted in China, UK and Scandinavia. An interim analysis of cardiovascular outcomes made by an independent safety monitoring revealed that the incidence of myopathy among patients approximately 4,700 UK / Scandinavian treated with simvastatin 40 mg or ezetimibe / simvastatin 10/40 mg coadministered with niacin / laropiprant 2 g/40 mg extended release (ER) is similar to the overall incidence reported in the database of the clinical trial for simvastatin 40 mg (0.08%). However, about 3,900 Chinese patients in the same treatment arm, the incidence is higher than expected (about 0.9%). Not increase the risk of myopathy among patients 8.600 Chinese, English or Scandinavian in the control arm (placebo plus simvastatin 40 mg or ezetimibe / simvastatin 10/40 mg). There was no apparent contribution of ezetimibe to the increased incidence of myopathy. Because the incidence of myopathy was higher in Chinese patients than in non-Chinese patients, caution should be exercised in treating Chinese patients with VYTORIN ® * (particularly doses of 10/40 mg or more) co-administered with the modifier lipids, niacin dose ≥ 1 g / day or products containing niacin. Because the risk of myopathy is dose related, not recommended the use of VYTORIN ® * 10/80 mg with lipid-modifying niacin (doses ≥ 1 g / day) or niacin-containing products in Chinese patients. It is unknown whether there is an increased risk of myopathy with the coadministration other Asian patients.

8. Patients treated with fusidic acid and VYTORIN ® * must be closely monitored. Should be considered a temporary suspension of treatment with VYTORIN ® *.

9. When starting therapy with VYTORIN ® * or increasing their dosage should be informed all patients about the risk of myopathy and told to report immediately any pain, tenderness or weakness. If diagnosed or suspected myopathy should be discontinued immediately VYTORIN ® *. These symptoms and / or a concentration of creatine kinase more than ten times greater than the upper limit of normal indicates myopathy. In most cases when treatment was stopped immediately simvastatin muscular symptoms and increased creatine kinase. Determinations may be considered regular creatine kinase in patients starting therapy with VYTORIN ® * or the dosage is increased. We recommend periodic determinations of creatine kinase in patients with dose adjustment to 10/80 mg. No assurance that such monitoring will prevent myopathy.

10. Many patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually long-term diabetes mellitus. These patients require closer monitoring. Should be temporarily stopped treatment with VYTORIN ® * a few days before a major surgery and when any major medical or surgical condition.

Liver enzymes: In comparative trials in patients who were coadministered ezetimibe and simvastatin, successive increases in transaminases (three times or more the upper limit of normal values) (see Adverse Effects).

It is recommended that liver function tests before initiating therapy with VYTORIN ® *, and thereafter when clinically indicated. In patients where the dosage is increased to 10/80 mg dose should receive liver function tests before the increase, after three months of this and then periodically (eg every six months) for one year. Pay special attention to patients who develop elevated levels of serum transaminases, in these patients, measurements should be repeated promptly and more frequently. If transaminase levels continue to rise, particularly if they get three times the ULN and are persistent, discontinue the drug.

VYTORIN ® * should be used with caution in patients who consume substantial quantities of alcohol or who have a history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN ® *.

Hepatic impairment: Due to the unknown effects of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment is not recommended to deal with VYTORIN ® * these patients (see Pharmacokinetics and pharmacodynamics in humans, features special groups of patients).

Fibrates: Regarding fibrates, only The safety and effectiveness of VYTORIN administered with fenofibrate ® *. Because of this, concomitant use of VYTORIN and fibrates ® * except fenofibrate should be avoided (see Interactions and other genus).

Fenofibrate: If you suspect the presence of cholelithiasis in a patient taking VYTORIN ® * and fenofibrate is recommended for studies of the gallbladder and should be considered another lipid-lowering therapy (see Adverse Effects and information for prescribing fenofibrate).

Cyclosporine: Caution should be exercised when initiating VYTORIN ® * in patients already taking cyclosporine. Cyclosporine concentrations should vigilararse in patients receiving VYTORIN ® * and cyclosporine (see Interactions and other genus).

Anticoagulants: If VYTORIN ® * is added to another coumarin anticoagulant warfarin or fluindione, international normalized ratio (PNI) should be appropriately monitored (see Interactions and other genus).

Pediatric Use: We evaluated the safety and effectiveness of VYTORIN ® * in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia in a controlled clinical trial in men and women who were at least one year posmenarca. Adolescent patients treated with VYTORIN ® * had an adverse experience profile similar to that of adult patients treated with VYTORIN ® *. Have not been studied doses higher than 10/40 mg / day in this population. In this controlled study, there was no detectable effect on growth or sexual maturation of adolescents, or any effect on menstrual cycle length in girls (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS) VYTORIN ® * has not been studied in patients younger than 10 years or younger premenarcas.

Use in elderly patients: Because the elderly (≥ 65 years) is a predisposing factor for myopathy, VYTORIN ® * should be prescribed with caution in the elderly. In a clinical study of patients treated with simvastatin 80 mg / day, patients ≥ 65 years had an increased risk of myopathy compared with patients? 65 years.

Use in Pregnancy and Lactation

Pregnancy: Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little effect on long-term risk associated with primary hypercholesterolemia. VYTORIN ® * is contraindicated during pregnancy (see PRECAUTIONS effects related to carcinogenesis, mutagenesis, teratogenesis and on fertility, fetal development).

Simvastatin: Not yet determined the safety of simvastatin in pregnant or have comparative trials with simvastatin in them. There have been few reports of congenital anomalies following intrauterine exposure to inhibitors of HMG-CoA, but in a prospective study of 200 pregnancies in which there was exposure of the fetus during the first trimester to simvastatin or another inhibitor of the HMG-CoA closely related to the inhibitor, the incidence of congenital abnormalities was similar to that observed in the general population. This number of pregnancies was statistically sufficient to exclude an increase in congenital anomalies of 2.5 times or more on its incidence in the general population.

Although there is no indication that the incidence of congenital anomalies in offspring of patients taking simvastatin or another inhibitor of HMG-CoA closely related to it differs from that observed in the general population, treatment of pregnant with simvastatin may reduce the fetal levels of mevalonate, a precursor in the synthesis of cholesterol. Therefore, you should not use VYTORIN ® * in pregnant women who are trying to get pregnant or may become pregnant. Therapy with VYTORIN should be discontinued ® * throughout pregnancy or until it has determined that the woman is not pregnant (see Contraindications).

Ezetimibe: No clinical data on administration of ezetimibe in pregnant women.

When ezetimibe with simvastatin was administered to pregnant rats on embryo-fetal development studies, no teratogenic effects were observed. In pregnant rabbits had a low incidence of skeletal malformations (see Precautions effects related to carcinogenesis, mutagenesis, teratogenesis and on fertility, fetal development).

Nursing Mothers Studies in rats have shown that ezetimibe is excreted with the milk. It is not known if the active ingredients of VYTORIN ® * are excreted in human milk, so it should not be given Vytorin ® * women who are breastfeeding.

ADVERSE REACTIONS: We assessed the safety of VYTORIN ® * (or coadministration of ezetimibe and simvastatin equivalent to VYTORIN ® formulations *) in clinical trials on over 3,800 patients. VYTORIN ® * was generally well tolerated.

In patients taking VYTORIN ® * (n = 1.263) in three comparative trials with a placebo of similar design were reported the following common adverse reactions (incidence between 1 and 10%) drug-related:

Gastrointestinal: Flatulence.

Musculoskeletal and connective tissue disorders: myalgia.

Neurological disorders: Headache.

VYTORIN administered with fenofibrate ® *: In a controlled clinical trial, the adverse event profile reported for VYTORIN ® * and fenofibrate was consistent with the profiles reported for VYTORIN ® * and / or fenofibrate alone.

Pediatric patients (10 to 17): In a study of adolescent patients (10 to 17 years of age) with heterozygous familial hypercholesterolemia (n = 248), the safety profile and tolerability of the group treated with VYTORIN ® * were similar to adult patients treated with VYTORIN ® *.

Post-marketing experience: Adverse reactions reported for VYTORIN ® * are consistent with those previously reported with ezetimibe and / or simvastatin.

Other commonly reported adverse reactions to ezetimibe in clinical trials:

Gastrointestinal disorders: abdominal pain, diarrhea.

General disorders and administration site conditions: Fatigue.

After the release was reported the following adverse events regardless of causality assessment:

Blood and lymphatic system disorders: Thrombocytopenia.

Liver and biliary: Cholelithiasis, cholecystitis, hepatitis.

Musculoskeletal, connective tissue and bone disorders: arthralgia, and very rarely, myopathy / rhabdomyolysis (see WARNINGS).

Psychiatric disorders: Depression.

Nervous system disorders: Dizziness, paraesthesia.

Laboratory values: Increases in CPK due to increases in liver transaminases.

Skin and subcutaneous disorders: Hypersensitivity reactions, including rash and urticaria (rare [? 1/10, 000, <1/1, 000]) anaphylaxis and angioedema (very rare [<1/10, 000]), erythema multiforme.

Gastrointestinal disorders: nausea (rare), pancreatitis (very rare).

Ezetimibe coadministered with fenofibrate: In a multicenter, double-blind, placebo-controlled study in patients with mixed hyperlipidemia, treatment was given to 625 patients for up to 12 weeks and 576 for up to 1 year. This study was not designed to compare treatment groups in search of rare events. Incidence rates (95%) for clinically important (> 3 x ULN, consecutive) in serum transaminases was 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ezetimibe coadministered fenofibrate, respectively, adjusted for treatment exposure. The corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and ezetimibe administered with fenofibrate, respectively (see Precautions). No increase in CPK> 10 × ULN in any of the treatment groups in this study.

Other adverse reactions reported rarely with simvastatin in clinical studies and / or after its release:

Blood and lymphatic system disorders: Anemia.

Gastrointestinal disorders: abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, pancreatitis.

General disorders and administration site conditions: Asthenia.

Liver: Hepatitis / jaundice and rarely, liver failure.

Muscle disorders or connective tissue disorders: muscle cramps, myopathy, rhabdomyolysis (see WARNINGS).

Neurological disorders: Dizziness, paresthesia, peripheral neuropathy, memory failure.

Skin and subcutaneous tissue disorders: alopecia, pruritus, rash.

Psychiatric Disorders: Insomnia.

Name of Medicine: Vytorin

Comparable patent medicine: Vytorin

Active ingredient: Ezetimibe / Simvastatin