Composition, form of production and packaging
The tablets covered with a cover of pink color, oval, with engraving "MSD 749" on one side and smooth - on another.
1 tab.
simvastatin 40 mg
Excipients: butyl hydroxy anisole, ascorbic acid, lactose monohydrate (lactose aqueous), citric acid, microcrystalline cellulose, pregelatinized cellulose, magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide, talc, iron oxide red.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
The product description was approved by the manufacturer for the 2009 print edition.
PHARMACHOLOGIC EFFECT
Zocor В® Forte (simvastatin) is a lipid-lowering drug obtained synthetically from the fermentation product of Aspergillus terreus.
After oral administration, simvastatin, which is an inactive lactone, undergoes hydrolysis with the formation of the corresponding beta-hydroxy-acid derivative, which is the main metabolite and has a high inhibitory activity against HMG-CoA- (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme that catalyzes the initial and most significant stage of cholesterol biosynthesis. Clinical studies have shown Zocor's effectiveness in lowering total cholesterol levels in blood plasma, low-density lipoprotein (LDL), triglycerides (TG) and very low density lipoproteins (VLDL), as well as increasing levels of high-density lipoprotein (HDL) in patients with heterozygous family and non-family hypercholesterolemia, as well as mixed hyperlipidemia in those cases where elevated cholesterol is a risk factor and the appointment of one diet is not enough. A noticeable therapeutic effect is observed within 2 weeks of taking the drug, the maximum - 4-6 weeks after the start of treatment. The effect persists with the continuation of therapy. If you stop taking simvastatin, the total cholesterol content returns to the baseline level determined before the start of treatment.
The active metabolite of simvastatin is a specific inhibitor of HMG-CoA reductase, an enzyme that catalyzes the formation of mevalonate from HMG-CoA. Since the conversion of HMG-CoA to mevalonate is an early stage in the biosynthesis of cholesterol, it is believed that the use of Zokor should not cause the accumulation of potentially toxic sterols in the body. In addition, HMG-CoA is readily metabolized to acetyl-CoA, which is involved in many biosynthetic processes in the body.
In the Scandinavian Simvastatin Effects on Survival, the effect of Zocor therapy on overall mortality (median time of participation of patients of 5.4 years) was evaluated in 4444 patients with IHD and baseline total cholesterol of 212-309 mg / dL (5.5-8.0 mmol / L). In this multicenter, randomized, double-blind, placebo-controlled study, Zocor reduced the risk of overall mortality by 30%, mortality from coronary heart disease by 42%, and the incidence of nonfatal, confirmed myocardial infarction by 37%. Zokor also reduced the risk of the need for coronary blood flow restoration (aorto-coronary bypass or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes, the risk of major coronary events decreased by 55%. Moreover, Zokor significantly (by 28%) reduced the risk of fatal and nonfatal cerebrovascular accidents (strokes and transient cerebral circulation disorders).
In a 5-year, multicenter, randomized, double-blind, placebo-controlled HeartProtectionStudy-HPS study, the effectiveness of Zocor therapy was demonstrated in 20536 patients with or without hyperlipidemia who are at high risk of developing coronary artery disease due to diabetes, stroke and other vascular diseases. Before the start of therapy, in 33% of patients, the LDL level was below 116 mg / dl, 25% had an LDL level of 116 mg / dL to 135 mg / dL, and 42% had an LDL level higher than 135 mg / dl. In this study, Zocor at a dose of 40 mg / day compared with placebo reduced total mortality by 13%, the risk of death associated with ischemic heart disease by 18%, the risk of major coronary events (nonfatal myocardial infarction or death associated with coronary artery disease) by 27 %, the risk of the need for surgical interventions to restore coronary blood flow (aorto-coronary bypass and percutaneous transluminal angioplasty) by 30%, the risk of the need for restoring peripheral blood flow and other types of non-coronary red cell the risk of a stroke by 25%. The rate of hospitalization for heart failure decreased by 17%. The risk of developing major coronary and vascular complications decreased by 25% in patients with or without IHD, including patients with diabetes mellitus, peripheral vascular disease and cerebrovascular pathology. In patients with diabetes, Zokor reduced the risk of vascular complications by 21%, including operations to restore peripheral blood flow, amputation of the lower limbs and the occurrence of trophic ulcers.
In another multicenter, placebo-controlled study of 404 patients, Zokor, according to coronary angiography, slowed the progression of coronary atherosclerosis and the emergence of both new areas of atherosclerosis and new total occlusions, whereas patients receiving standard therapy experienced a steady progression of coronary artery atherosclerosis.
The analysis of subgroups of 2 studies in which 147 patients with hypercholesterolemia (Fredrickson type IV hyperlipidemia included) showed that in the Zokor group taken at a dose of 20-80 mg / day, the triglyceride level decreased by 21-39% (in the group placebo - by 11-13%), LDL cholesterol by 23-35% (in the group of spas - by 1-3%), all types of lipoproteins, except for HDL, by 26-43% (in the placebo group - by 1-3% ), and the level of HDL cholesterol increased by 9-14% (in the placebo group - by 3%).
In 7 patients with dysbetalipoproteinemia (type III hyperlipidemia according to Fredrickson classification), Zocor in a dose of 80 mg / day reduced LDL cholesterol including 51% of cholesterol in the placebo group (8% in the placebo group), and the VLDL and cholesterol level by 60 % (in the placebo group - 4%).
PHARMACOKINETICS
The main active metabolites of simvastatin in blood plasma are beta-hydroxyacid and its 6-hydroxy, 6-hydroxymethyl and 6-exomethylene derivatives. C maxmetabolites of simvastatin in blood plasma are achieved through 1.3-2.4 h after a single dose. There are data on the achievement of C max simvastatin and its metabolites in the period up to 4 hours and its slow decrease in 12 hours by approximately 10%. When receiving simvastatin in the recommended therapeutic doses (5-80 mg / day), the linear profile of the AUC profile of active metabolites in the total blood flow is preserved. Linear dependence persists with increasing dose to 120 mg.
Simvastatin is an inactive lactone that is readily hydrolyzed, converting to О±-hydroxy acid, L-654, 969, a potent inhibitor of HMG-CoA reductase. The plasma of the blood contains the metabolite L-654, 969 and 4 more active metabolites. Inhibition of HMG-CoA reductase is the basis of all pharmacokinetic studies of B-hydroxy acid metabolites (active inhibitors). Both those and others are determined in blood plasma when prescribing simvastatin.
Approximately 85% of the dose of simvastatin taken internally is absorbed.
After ingestion, higher concentrations of simvastatin are determined in the liver than in other tissues.
The content of the active form of simvastatin L-654, 969 in the systemic circulation is less than 5% of the inward dose, 95% of this quantity is in the protein-bound state.
The result of active metabolism of simvastatin in the liver (more than 60% in men) is its lower content in the total blood flow.
The possibility of the penetration of simvastatin through the blood-brain barrier and the hematoplacental barrier has not been studied.
At the first passage through the hepatic blood flow, simvastatin is metabolized with subsequent excretion of the drug and its metabolites with bile. In the study, 100 mg of the drug was administered in capsules (5 x 20 mg), labeled simvastatin C14 was accumulated in blood, urine and feces. About 60% of the labeled drug was found in the stool and only about 13% in the urine.
The variation coefficient of AUC in the total blood flow does not depend on the dose of simvastatin. In this study, patients took inward simvastatin tablets at doses of 5, 10, 20, 60, 90 and 120 mg. Eating (within the standard hypocholesterine diet) immediately after taking simvastatin does not interfere with the pharmacokinetic profile of the drug. Pharmacokinetic parameters when taking a single dose and prolonged treatment with simvastatin show that simvastatin does not accumulate in tissues during long-term treatment. C max inhibitors in blood plasma are achieved within 1.3-2.4 hours after taking the drug.
In a study of patients with severe renal failure (crutinin clearance less than 30 ml / min) after taking a single dose of the drug, concentrations of HMG-CoA reductase inhibitors in blood plasma were approximately 2 times higher than in healthy volunteers.
INDICATIONS
Ischemic heart disease (CHD) or high-risk development of coronary heart disease.
In patients with a high risk of developing coronary artery disease (with or without hyperlipidemia), for example, in patients with diabetes mellitus, in patients with a history of stroke or other cerebrovascular disease, in patients with peripheral vascular disease, or in patients with ischemic heart disease or a predisposition to Coronary heart disease is indicated for:
- reducing the risk of overall mortality due to a reduction in mortality due to coronary artery disease;
- reducing the risk of serious vascular and coronary complications;
- non-fatal myocardial infarction;
- coronary death;
- stroke;
- revascularization operations;
- reducing the risk of need for coronary blood flow restoration (such as aorto-coronary bypass and percutaneous transluminal coronary angioplasty);
- reducing the risk of the need for surgical intervention to restore peripheral blood flow and other types of non-coronary revascularization;
- reducing the risk of hospitalization due to attacks of angina pectoris.
Hypercholesterolemia
If the use of diet and other non-medicamentous treatments is not enough, Zocor Forte is prescribed in conjunction with a diet for:
- Decreased elevated levels of total cholesterol, LDL cholesterol, triglycerides, apolipoprotein B (apo-B);
- increase in HDL cholesterol in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson type II hyperlipidemia), or mixed hypercholesterolemia (IIb-type hyperlipidemia according to Fredrickson classification);
- Decreased LDL cholesterol / HDL cholesterol and total cholesterol / HDL cholesterol;
- hypertriglyceridemia (type IV hyperlipidemia according to Fredrickson classification);
- supplement to the diet and other ways of treating patients with homozygous familial hypercholesterolemia to reduce the elevated level of total cholesterol, LDL cholesterol and apolipoprotein B;
- primary dysbetalapoproteinemia (type III hyperlipidemia according to Fredrickson classification);
In patients with diabetes - Zokor Forte reduces the risk of peripheral vascular complications (carrying out revascularization, amputation of the lower extremities, the emergence of trophic ulcers).
In patients with ischemic heart disease and hypercholesterolemia, Zocor Forte slows the development of coronary atherosclerosis, including a reduction in the incidence of new complications.
DOSING MODE
Before the start of treatment with Zocor Fort, the patient should be prescribed a standard hypocholesterol diet, which must be observed throughout the course of treatment.
Recommended doses of Zokora Forte - from 5 to 80 mg, should be taken 1 time / day in the evening. When choosing a dose of Zokora Forte, its change should be made at intervals of not less than 4 weeks, until the maximum daily dose of 80 mg 1 time / day in the evening hours.
Patients with ischemic heart disease (CHD) or a high risk of coronary heart disease
The standard initial dose of Zokor for patients with a high risk of developing coronary artery disease in combination with or without hyperlipidemia (in the presence of diabetes, stroke or other cerebrovascular anemia, peripheral vascular disease, ischemic heart disease) is 40 mg 1 time per day in the evening time. Drug therapy can be prescribed simultaneously with diet and exercise therapy.
Patients with hypercholesterolemia who do not have the above risk factors
The standard initial dose of Zokora Forte is 20 mg 1 time / day in the evening. For patients who need a significant (more than 45%) reduction in LDL cholesterol, the initial dose may be 40 mg 1 time / day in the evening . Patients with mild or moderate hypercholesterolemia Zokor therapy can be prescribed with a dose of 10 mg 1 time / day. If necessary, the choice of doses should be carried out in accordance with the above scheme
Patients with homozygous familial hypercholesterolemia
The recommended dose of Zokora Forte is 40 mg 1 time / day in the evening, or 80 mg / day in 3 divided doses: 20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening. In such patients, Zocor Forte is used in combination with other treatments that lower cholesterol (eg, LDL apheresis) or without them, if they are not available.
Concomitant therapy
Zocor Forte can be administered both in monotherapy and in combination with bile acid sequestrants.
In patients taking cyclosporine, danazol, gemfibrozil or other fibrates (other than fenofibrate), or niacin in lipid lowering doses (> 1 g / day) in combination with simvastatin, the maximum recommended dose of Zokora Forte is 10 mg / day. For patients taking amiodarone or verapamil simultaneously with Zokora Forte, the daily dose of Zokora Forte should not exceed 20 mg
Renal insufficiency
Since Zokora Forte is excreted by the kidneys in small amounts, there is no need to change the doses in patients with moderate renal insufficiency . In patients with severe renal insufficiency (creatinine clearance less than 30 ml / min), the expediency of prescribing the drug at doses exceeding 10 mg / day should be carefully weighed. If such dosages are considered necessary, the drug should be administered with caution.
SIDE EFFECT
Zocor Forte is generally well tolerated, and most side effects are mild and transient. Less than 2% of patients in clinical trials discontinued treatment due to development, the side effects of Zokor Forte.
Prior to the widespread use of the drug, adverse effects occurring at a frequency of 1% or more, which were assessed by researchers as possible, probably or definitely associated with taking the drug, were abdominal pain, constipation and flatulence. Other side effects that occurred in 0.5-0.9% of patients were asthenia and headache.
There are rare reports of the development of myopathy.
In the Heart Protection Study (HPS), the use of Zocor at a dose of 40 mg / s for 5 years confirmed the comparability of the drug safety profile in patients receiving Zocor (n = 10269) compared with placebo (n = 10267). The failure to treat as a result of adverse events was 4.8% in the Zocor group and 5.1% in the placebo group.
In the Scandinavian study, safety and tolerability profiles were comparable in patients taking Zocor (n = 2221) at a dose of 20-40 mg and patients in the placebo group (n = 2223), when they were observed for more than 5.4 years.
There are also reports of the development of the following side effects:
On the part of the digestive system: dyspepsia (nausea, vomiting, diarrhea), pancreatitis; rarely - hepatitis and jaundice.
From the side of the central nervous system and sensory organs: dizziness, peripheral neuropathy, paresthesia.
From the musculoskeletal system: myalgia, muscle cramps; rarely rhabdomyolysis.
Allergic and immunopathological reactions: angioedema, lupus-like syndrome, rheumatic polymyalgia, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis, arthralgia, urticaria, photosensitivity, fever, skin hyperemia, dyspnea, general malaise.
Dermatological reactions: skin rash, itching, alopecia, dermatomyositis.
Other: anemia, general malaise.
Laboratory indicators: there are rare reports of the development of a pronounced and persistent increase in the level of transaminases. An increase in the activity of alkaline phosphatase and gamma-glutamyl transpeptidase was also reported. Deviations of liver function indicators are usually mild and transient. There are cases of increased activity of creatine phosphokinase.
CONTRAINDICATIONS
- liver disease in the active phase or persistent increase in transaminases in the blood plasma of an unknown etiology;
- Pregnancy;
- lactation period;
- Hypersensitivity to any component of the drug.
With caution:
Simvastatin, like other inhibitors of HMG-CoA reductase, can sometimes cause myopathy. Many of the patients who had rhabdomyolysis during therapy with simvastatin have had complicated medical history, including suffered renal insufficiency, usually as a result of diabetes. Such patients require more careful observation. Therapy with simvastatin should be temporarily discontinued in these patients a few days before the big surgical interventions, as well as in the postoperative period.
Patients with sustained elevated levels of serum transaminases greater than 3 times the upper limit of normal, the preparation should be discontinued.
In severe renal failure (creatinine clearance less than 30 mL / min) expediency purpose formulation should carefully weigh at doses exceeding 10 mg / day. If such dosages are deemed necessary, they should be administered with caution.
Alcohol abuse before treatment.
PREGNANCY AND LACTATION
Zocor Forte is contraindicated in pregnancy. Since safety in pregnant women has not been proven, and there is no evidence that treatment with the drug during pregnancy brings obvious benefits, the drug should be discontinued if pregnancy occurs. Simvastatin should be administered to women of childbearing age only when the probability of pregnancy is very small. If during treatment with Zocor arises pregnancy, the drug should be discontinued, and the woman warned of the possible danger to the fetus.
Data on the allocation of simvastatin and its metabolites in breast milk are not available. The appointment Zokora lactating women should be aware that many drugs are excreted in breast milk, and there is a threat of serious adverse reactions; therefore, breast-feeding is not recommended.
APPLICATION FOR FUNCTIONS OF THE LIVER
As Zokora Forte excreted by the kidneys in small amounts, there is no need to change the dose in patients with moderate renal insufficiency . In patients with severe renal failure (creatinine clearance less than 30 mL / min) should carefully weigh the desirability destination of the drug in doses exceeding 10 mg / day. If such dosages are deemed necessary, the drug should be used with caution.
In severe renal failure (creatinine clearance less than 30 mL / min) expediency purpose formulation should carefully weigh at doses exceeding 10 mg / day. If such dosages are deemed necessary, they should be administered with caution.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated:
- liver disease in the active phase or persistent elevation of transaminases in the blood plasma of unknown etiology.
With care:
Patients with sustained elevated levels of serum transaminases exceeding 3 times the upper limit of normal, the drug should be discontinued.
APPLICATION FOR CHILDREN
Data on the efficacy and safety of the children is not enough, therefore the use in children is not recommended.
APPLICATION IN ELDERLY PATIENTS
In patients older than 65 years, the effectiveness of Zocor, which is estimated by the level of reduction of total cholesterol and LDL cholesterol, the same as in the general population, significant increase in the frequency of clinical or laboratory adverse events were observed.
SPECIAL INSTRUCTIONS
Simvastatin, like other inhibitors of HMG-CoA reductase, can cause myopathy, which is manifested in the form of muscle pain, tenderness, or weakness, and general accompanied by an increase of creatine phosphokinase activity more than 10 times the upper limit of normal. Myopathy may be manifested in the form of rhabdomyolysis, sometimes accompanied by acute renal failure due to myoglobinuria. The risk of myopathy is increased by increasing the inhibitory activity of HMG-CoA reductase in blood plasma.
The risk of myopathy / rhabdomyolysis is increased when simvastatin therapy with the concomitant taking the following medications:
- potent inhibitors of CYP3A4: itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone, especially in combination with high doses of simvastatin;
- gemfibrozil and other fibrates (except fenofibrate), and lipid-lowering doses (> 1 g / day), niacin (nicotinic acid), especially in combination with high doses of simvastatin. There is no evidence that the appointment of simvastatin simultaneously with fenofibrate risk of myopathy exceeds the total risks generated by taking each of these drugs;
- cyclosporin or danazol, especially in combination with high doses of simvastatin;
- amiodarone, verapamil, or in combination with high doses of simvastatin. During clinical studies have reported the development of myopathies in 6% of patients treated with simvastatin 80 mg simultaneously with amiodarone;
- patients receiving diltiazem simultaneously with simvastatin 80 mg / day increased risk of myopathy, and is about 1%. The risk of myopathy in patients receiving diltiazem simultaneously with simvastatin 40 mg / d was approximately equal to that when receiving simvastatin 40 mg / day of diltiazem, without a concomitant reception.
The risk of dependence of myopathy / rhabdomyolysis is dose related. In clinical studies in which patients not taking concomitant therapy, the incidence of myopathy / rhabdomyolysis was about 0.03% in patients treated with simvastatin 20 mg / day, 0.08% in patients treated with simvastatin 40 mg / d and 0.4% have patients treated with simvastatin 80 mg / day.
Nosnizheniyu measure of risk of myopathy / rhabdomyolysis
Avoid simultaneous reception of simvastatin with the following preparations: itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone. If therapy following drugs can not be undone, simvastatin therapy should be suspended for the duration of the reception of these drugs. Concomitant any of the CYP3A4 inhibitors should be avoided, if the benefits of the combination therapy do not exceed a possible risk.
Simvastatin dose should not exceed 10 mg / day for patients taking cyclosporin, danazol or gemfibrozil, other fibrates (except fenofibrate) or lipid-lowering doses (> 1 g / day), niacin (nicotinic acid). Avoid concomitant administration of simvastatin with these drugs if the benefits from the effect on lipid levels do not exceed the risk of prescribing combinations. Adding fibrates or niacin therapy simvastatin typically provides little additional reduction in LDL concentration, but can also be achieved by further lowering TG and increasing HDL concentration.
Simvastatin dose for patients receiving amiodarone or verapamil, should not exceed 20 mg / day. Simvastatin in doses not recommended together with amiodarone or verapamil than 20 mg / day, unless the benefits of using such a combination does not exceed the potential risk of myopathy.
All patients who start therapy with simvastatin and patients who need to increase the dose of the drug should be warned about the possibility of myopathy and the need for immediate treatment to the doctor in case of any unexplained pain, pain in the muscles or muscle weakness. Simvastatin therapy should be discontinued immediately if myopathy diagnosed or predpolagaetsya.Nalichie above symptoms and / or more than 10-fold as compared with the upper limit of normal, increased CPK indicate the presence of myopathy. In most cases, immediately after cessation of Myopathy simvastatin symptoms resolved and creatine concentration decreases. At the beginning of therapy with simvastatin or with increasing doses of the drug,it is advisable to carry out periodic determination of creatine phosphokinase levels, but there is no reliable data that such monitoring is able to prevent the development of myopathy.
Many patients who have developed rhabdomyolysis on simvastatin therapy had a complicated medical history, including suffered renal insufficiency, usually as a result of diabetes. Such patients require more careful observation. Therapy with simvastatin should be temporarily discontinued in patients a few days before the big surgical interventions, as well as in the postoperative period.
In patients taking coumarin anticoagulants, prothrombin time should be monitored indicator prior to starting therapy with simvastatin, and in the initial period of treatment in order to avoid significant changes in this index. Once achieved a stable level of prothrombin time, it should be further defined intervals recommended for monitoring patients receiving anticoagulant therapy. The same procedure should be repeated when changing dosage or discontinuation of simvastatin. In patients not taking anticoagulants, Simvastatin therapy has not been associated with the occurrence of bleeding or changes in prothrombin time.
Effect on liver
In clinical studies, some adult patients who received simvastatin, has been a steady increase in liver enzymes (more than 3 times the upper limit of normal). To remove the drug transaminase activity usually returns gradually to the original level. Increase transaminase levels was not associated with jaundice or other clinical symptoms. These reactions are not associated with increased sensitivity. Some of the patients had a rejection of liver function before treatment with simvastatin and / or consume excessive amounts of alcohol.
The study 4S number of patients with more than a single increased levels of serum transaminases (more than 3 times the upper limit of normal) dostaverno did not differ in groups simvastatin and placebo. Raising syvornotochnyh transaminases was the reason for discontinuation of treatment in 8 patients (from 2221) in the simvastatin group and in 5 patients (from 2223) in the placebo group. All patients in this study received an initial dose of simvastatin 20 mg / day, 37% of the dose was increased to 40 mg / day.
In two controlled clinical studies gle participated in 1105 patients, persistent elevation of transaminase levels associated with the use of the drug, was observed in the 0.7% and 1.8% of the cases when taking 40 mg and 80 mg dose, respectively.
The HPS study, which was included 20536 patients when receiving Zocor 40 mg / day increase in serum transaminases (more than 3 times the upper limit of normal) was 0.21% (n = 21) and 0.09% (n = 9 ) Group simvastatin and placebo, respectively.
Before treatment, and then - in accordance with clinical indications, all patients are recommended liver function tests. Patients who plan to increase the dose of simvastatin 80 mg / day, liver function tests should be performed before the start of titration, and then after 3 months after the dose of 80 mg / day, and then be repeated periodically (e.g., 1 time / months) during the first the first year of treatment. Particular attention should be given to patients who have elevated levels of serum transaminases. These patients liver function monitoring should be carried out in a timely manner at the beginning of treatment and more frequently in the future. In those cases where the level of transaminase increases, especially at steady exceeding 3 times the upper limit of normal, the drug should be discontinued.
When treating simvastatin as lipid-lowering drugs and other observed moderate (less than 3 times the upper limit of normal) increase in serum transaminase activity. These changes appeared soon after initiation of treatment, were often transient in nature, were not accompanied by any symptoms and did not require discontinuation of therapy.
Ophthalmologic examination
These long-term clinical studies did not contain information on the adverse effects of simvastatin on the lens of the human eye.
Elderly age
In patients older than 65 years, the effectiveness of Zocor, which is estimated by the level of reduction of total cholesterol and LDL cholesterol, the same as in the general population, significant increase in the frequency of clinical or laboratory adverse events were observed.
OVERDOSE
Several cases of overdose, the maximum dose taken was 3.6 g No patient overdose effects were found.
General measures are used to treat overdoses, including supportive and symptomatic therapy.
DRUG INTERACTION
Simvastatin is metabolized by CYP3A4, however, has no inhibitory activity ratio of the coenzyme. Therefore, the effect of simvastatin on the concentration of drug in the blood plasma is metabolized under the influence of CYP3A4, is not expected.
Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination rate of simvastatin. Such means include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone.
The risk of myopathy / rhabdomyolysis is increased by concomitant use of cyclosporine or danazol with higher doses of simvastatin.
The risk of myopathy is increased by concomitant use of other lipid-lowering drugs that are not potent inhibitors of CYP3A4, but can cause myopathy monotherapy conditions. Such drugs are gemfibrozil and other fibrates (fenofibrate except when combined with admission whom simvastatin, the risk of myopathy is less than that of monotherapy of each drug alone) and niacin (nicotinic acid) in a dose of> 1 g / day.
The risk of myopathy is increased by coadministration of amiodarone or verapamil with higher doses of simvastatin.
The risk of myopathy is increased slightly in patients receiving diltiazem along with simvastatin 80 mg.
Other drug interactions
Simvastatin 20-40 mg / day moderately potentiates the effect of coumarin anticoagulants international normalized ratio (MHO) increases from healthy volunteers from 1.7 to 1.8, and in patients with hypercholesterolemia from 2.6 to 3.4. In patients taking coumarin anticoagulants, prothrombin time or MHOdolzhny determined prior to initiation of therapy with simvastatin and frequently enough during the initial treatment period. Once achieved a stable level indicator prothrombin time or MHO, it further control should be performed at intervals recommended for patients receiving anticoagulant therapy. When changing the dosage or discontinuation of simvastatin should also carry out the control of the prothrombin time or MHOpo foregoing scheme.
Therapy with simvastatin did not cause changes in prothrombin time and bleeding risk in patients not taking anticoagulants.
Other interactions
Grapefruit juice contains one or more components which inhibit CYP3A4 and can increase the plasma concentration of drugs metabolized CYP3A4. Increased activity of HMG-CoA reductase inhibitor after consuming 250 ml juice per day is the maximum is about 13% and has no clinical significance. However, consumption of a large volume of juice (more than 1 L / sous
