medicalmeds.eu Medicines Hypolipidemic means - KOA-reductase GMG inhibitor. Зокор®

Зокор®

Producer: Merck Sharp & Dohme Corp. (Merck Sharp and Doum of the Building) USA

Code of automatic telephone exchange: C10AA01

Release form: Firm dosage forms. Tablets.

Indications to use: Lipidemia. Prevention of a stroke. Prevention of a myocardial infarction. Prevention of sudden coronary death. Gipertriglitseridemiya. Homozygous family hypercholesterolemia. Disbetalipoproteinemiya. Prevention of atherosclerosis.

General characteristics. Structure:

Active ingredient: 10 mg of a simvastatin in 1 tablet.

Excipients: butylhydroxyanisole, ascorbic acid, lactoses monohydrate, citric acid, starch prezhelatinizirovanny, cellulose microcrystallic, magnesium stearate.

Structure of a cover: methylhydroxypropyl cellulose, hydroxypropyl cellulose, titanium dioxide, talc, ferrous oxide red, ferrous oxide yellow.

Pharmacological properties:

Pharmacodynamics. After intake симвастатин, being an inactive lactone, is exposed to hydrolysis in a liver with education active beta and hydroxyacid derivative, being the main metabolite and having the high inhibiting activity concerning GMG-KOA (3-hydroxy-3-metilglyutaril-coenzyme A) of reductase, the enzyme catalyzing an initial and most significant stage of biosynthesis of cholesterol. Clinical trials showed Zokora's efficiency in the relation decrease in the general cholesterol in a blood plasma (X), lipoproteins of the low density (LPNP), triglycerides (TG) and lipoproteins of very low density (LPONP), and also to increase the maintenance of lipoproteins of the high density (LPVP) at patients with heterozygous family and single forms of a hypercholesterolemia, and also the mixed lipidemia when the increased level of cholesterol is risk factor and one dietotherapy it is not enough. The noticeable therapeutic effect was reached within 2 weeks of administration of drug, the maximum therapeutic effect - in 4-6 weeks after an initiation of treatment. The effect remains at treatment continuation. At the therapy termination simvastatiny the general content of cholesterol is returned to the initial level observed prior to treatment.

The active form of a simvastatin is specific inhibitor of GMG-KOA-reduktazy, the enzyme catalyzing reaction of formation of a mevalonat from GMG-KOA. As conversion GMG-KOA in мевалонат represents an early stage of biosynthesis of cholesterol, it is considered that Zokora's use should not cause accumulation in an organism of potentially toxic sterol. Besides, GMG-KOA it is also easily metabolized back to atsetil-KOA which participates in many processes of biosynthesis in an organism.

In the Scandinavian Research of influence of Simvastatin on Survival (4S), influence of therapy by Zokor on the general mortality (a median of time of participation of patients 5.4 years) also 212-309 mg/dl with an initial level of general cholesterol (5.5-8.0 mmol/l) were estimated on 4444 patients with the coronary heart disease (CHD). In this multicenter, randomized, double blind person, placebo - the controlled research Zokor® reduced risk of the general mortality by 30%, mortality from an ischemic heart disease for 42%, the frequency of the not fatal myocardial infarctions confirmed in hospital conditions for 37%. Зокор® also reduced risk to be put at operations on recovery of a blood-groove (aortocoronary shunting or transdermal transluminal coronary angioplasty) for 37%. At patients with a diabetes mellitus the risk of heavy coronary complications was reduced by 55%. Moreover, Zokor® considerably reduced risk of emergence of deadly and not deadly disturbances of cerebral circulation (by 28%) (strokes and passing disturbances of cerebral circulation).

In the 5th summer, multicenter, randomized double blind person, placebo a controlled research on protection of heart (HeartProtectionStudy-HPS) the effektivanost of therapy by Zokor was shown on 20536 patients with or without lipidemia, being in group of high risk in connection with an ischemic heart disease and such associated diseases as a diabetes mellitus, a stroke, other vascular diseases. At 33% of patients the LPNP level below 116 mg/dl, 25% was observed had the LPNP level from 116 mg/dl to 135 mg/dl and 42% the LPNP level had higher than 135 mg/dl.

In this research симвастатин in a dose of 40 mg/days in comparison with placebo reduced risk of the general mortality by 13%, the mortality connected with an ischemic heart disease for 18%, risk of serious coronary complications (including not fatal myocardial infarction or death connected with an ischemic heart disease) for 27%, need of operative measures on recovery of a coronary blood-groove (including aortocoronary shunting and transdermal transluminal angioplasty), and also a peripheral blood-groove and other types of not coronary revascularization for 30% and 16% respectively, for 25% - risk of development of a stroke. Frequency of hospitalization concerning the heart failure (HF) decreased by 17%. The risk of serious coronary and vascular complications decreased by 25% at patients with or without ischemic heart disease, including patients with a diabetes mellitus and patients with cardiovascular diseases, including disturbances of peripheric circulation. At patients with a diabetes mellitus of Zokor® reduced risk of development of serious vascular complications by 21%, including need of carrying out operations on recovery of a peripheral blood-groove (surgical or angioplasty), amputations of the lower extremities and developing of trophic ulcers.

In another multicenter, placebo a controlled research with participation of 404 patients with use of quantitative assessment of a coronary blood-groove at a coronary angiography, Zokor® slowed down progressing of coronary atherosclerosis and development of both new damages, and new total occlusions whereas at the patients receiving standard therapy within 4 years steady progressing of atherosclerotic damages of coronary arteries was observed.

The analysis in subgroups of 2 researches which 147 patients with a hypercholesterolemia entered (a lipidemia of the IV type on Fredrikson's classification) showed that Zokor® in a dose from 20 to 80 mg/days reduces the level of triglycerides to 21-39% (in group of placebo of 11-13%), LPNP to 23-35% (in group of placebo of 1-3%), all lipoproteids, in addition to LPVP, to 26-43% (in group of placebo to 1-3%) and raises LPVP to 9-14% (in group of placebo - to 3%).

At 7 patients with a disbetalipoproteinemiya (a lipidemia of the III type on Fredrikson's classification), Zokor® in a dose of 80 mg/day reduced LPNP, including LPPP to 51% (in group of placebo - to 8%) with LPONP and LPPP to 60% (in group of placebo - to 4%).

Pharmacokinetics. Metabolism. The main active metabolites of a simvastatin in a blood plasma are бетагидроксиацид and its 6 hydroxies, 6 hydroxymethyl, and 6-eksometilen derivatives. Cmax in a blood plasma of metabolites of a simvastatin is reached in 1.3-2.4 h after reception of one dose. There are data on achievement of Cmax of a simvastatin and its metabolites during the period to 4 h and its slow decrease in 12 h approximately for 10%. At reception of a simvastatin in the recommended therapeutic doses (5-80 mg/days) linear character of the AUC profile of active metabolites in the general blood-groove remains. Linear dependence remains at increase in a dose to 120 mg.

Simvastatin is an inactive lactone which is easily hydrolyzed, turning into V-gidroksiaksid, L-654,969, powerful inhibitor of HMG-CoA reductase. In a blood plasma the metabolite of L-654,969 and 4 more active metabolites are presented. The inhibition of HMG-CoA reductase is the cornerstone of all pharmacokinetic researches of metabolites V-gidroksiaksida (active inhibitors) and, following a basis of hydrolysis, active with latent inhibitors (all inhibitors). Both those, and others are defined in a blood plasma at purpose of a simvastatin.

About 85% of the dose of a simvastatin accepted inside are exposed to absorption.

Distribution. After intake in a liver higher concentration of a simvastatin, than in other fabrics are defined.

The maintenance of an active form of a simvastatin of L-654,969 in a system blood-groove makes less than 5% of the dose accepted inside, 95% of this quantity are in the state connected with proteins. In a liver (men have more than 60%) his low contents in the general blood-groove is result of active metabolism of a simvastatin.

The possibility of penetration of a simvastatin through a blood-brain barrier and a gematoplatsentarny barrier is not studied.

Removal. At the first passing through a hepatic blood stream симвастатин it is metabolized with the subsequent removal of drug and its metabolites with bile.

In a research of 100 mg of drug it was appointed in capsules (5 x 20 mg), marked симвастатин C14 collected in blood, urine and excrements. About 60% of marked drug were revealed in fecal masses and only about 13% - in urine.

AUC coefficient of variation in the general blood-groove does not izavisit from a dose of a simvastatin. In this research patients accepted in a tablet of a simvastatin in doses 5, 10, 20, 60, 90 and 120 mg. Meal (within a standard hypocholesteric diet) right after reception of a simvastatin does not break a pharmacokinetic profile of drug. Pharmacokinetic indicators at reception of a single dose and prolonged treatment simvastatiny show what симвастатин does not collect in fabrics at prolonged treatment. Cmax of inhibitors in a blood plasma is reached during 1.3-2.4 h after administration of drug.

In a research at patients with a heavy renal failure (clearance of a kratinin less than 30 ml/min.) after reception of one dose of drug of concentration of total number of inhibitors of HMG-CoA reductase in a blood plasma were approximately twice higher, than at healthy volunteers.

Indications to use:

Patients with high risk have development of an ischemic heart disease (in the presence of a lipidemia or without it), for example, at patients with a diabetes mellitus, at patients with a stroke or other cerebrovascular diseases in the anamnesis, at patients with diseases of peripheral vessels, or at patients with an ischemic heart disease or predisposition to an ischemic heart disease of Zokor® is shown for:

— decrease in risk of the general mortality due to decline in mortality as a result of an ischemic heart disease;

— reduction of risk of serious vascular and coronary complications: not fatal myocardial infarction, coronary death, stroke;

— operations of revascularization;

— reduction of risk of need of carrying out operations on recovery of a coronary blood-groove (such as aortocoronary shunting and transdermal transluminal coronary angioplasty);

— reduction of risk of need of an operative measure on recovery of a peripheral blood-groove and other types not of coronary revascularization;

— decrease in risk of hospitalization in connection with stenocardia attacks.

Hypercholesterolemia - as addition to a diet when use only a diet and other not medicamentous methods of treatment is not enough, for:

— decrease in the increased level of the general cholesterol, LPNP cholesterol, triglycerides. apolipoprotein B (апо In);

— for increase in LPVP cholesterol at patients with primary hypercholesterolemia, including a heterozygous family hypercholesterolemia (a lipidemia of IIA of type on Fredrikson's classification), or the mixed hypercholesterolemia (a lipidemia of IIb of type on Fredrikson's classification);

— decrease in a ratio of LPNP cholesterol to LPVP cholesterol and the general cholesterol to LPVP cholesterol;

— a gipertriglitseridemiya (a lipidemia of the IV type on Fredrikson's classification);

— addition to a diet and other ways of treatment of patients with a homozygous family hypercholesterolemia for decrease in the increased level of the general cholesterol, LPNP of cholesterol and apolipoprotein B;

— primary disbetalipoproteinemiya (a lipidemia of the III type on Fredrikson's classification).

At patients with a diabetes mellitus - Zokor® reduces risk of development of peripheral vascular complications (carrying out operations of revascularization, amputation of the lower extremities, developing of trophic ulcers).

At patients with an ischemic heart disease with the increased content of cholesterol, Zokor® reduces development of coronary atherosclerosis, including development of new damages and complications.

Route of administration and doses:

Prior to treatment by the drug Zokor® the patient should appoint a standard hypocholesteric diet which has to be observed during all course of treatment.

The recommended Zokora's doses - from 5 to 80 mg, it is necessary to accept 1 times/days in the evening. At selection of a dose of Zokora it is necessary to make its change bucketed not less, than in 4 weeks. The maximum daily dose - 80 mg.

Patients with the coronary heart disease (CHD) or high risk of development of coronary heart disease. The standard initial dose of Zokora for patients with high risk of development of an ischemic heart disease (in combination with a lipidemia or without it - patients with a diabetes mellitus, patients with a stroke or other cerebrovascular diseases in the anamnesis, patients with diseases of peripheral vessels), and also for patients with coronary heart disease or risk vozniknoveniyasostavlyat it 40 mg/days of 1 times/days in the evening. Medicamentous therapy has to be begun along with use of a diet and physiotherapy exercises.

Patients with a hypercholesterolemia (the listed above categories of risk which are not entering in). Usually initial dose makes 20 mg/days which is appointed 1 times/days in the evening. For patients who need considerable (more than for 45%) decrease in the LPNP level, an initial dose can make 40 mg of 1 times / сутвечером. Patients with an easy or moderate hypercholesterolemia can appoint Zokor® in an initial dose of 10 mg. Selection of doses, in case of need, has to be carried out by the way stated above.

Patients with a homozygous family hypercholesterolemia. Зокор® it is recommended in the dose of 40 mg/days accepted once in the evening or 80 mg/days in 3 receptions: 20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening. At such patients of Zokor® apply as addition to other treatment reducing cholesterol level (for example, LPNP a plasma exchange) or without other treatment if it is unavailable.

The accompanying therapy. Зокор® it is recommended to use both in the form of monotherapy, and in combination with sekvestrant of bile acids.

At the patients accepting cyclosporine, даназол gemfibrozit or other fibrata (except a fenofibrat), or lipidosnizhayushchy doses (> 1 g/days) Niacinum together with Zokor, the maximum recommended dose of the drug Zokor® makes 10 mg/days. For the patients, along with the drug Zokor® accepting Amiodaronum or verapamil, the daily dose of Zokora should not exceed 20 mg

At a renal failure. As Zokor® is allocated with kidneys in a small amount, the patients having moderately expressed renal failure have no need for change of a dosage. At a heavy renal failure (clearance of creatinine less than 30 ml/min.), it is necessary to weigh carefully expediency of purpose of drug in the doses exceeding 10 mg/days. If such dosages are considered as necessary, it is necessary to appoint them with care.

Features of use:

Use at pregnancy and feeding by a breast. Зокор® it is contraindicated and it should not be appointed pregnant, and also to women at whom pregnancy is supposed or planned.

Since safety for pregnant women is not proved and there are no data that treatment by Zokor at pregnancy brings big benefit, than risk for a fruit, administration of drug it is necessary to stop immediately at pregnancy approach. If in the course of treatment by Zokor there is pregnancy, drug has to be cancelled, and the woman is warned about possible danger to a fruit.

There are no data on allocation of a simvastatin in milk, but as a small amount of other medicines of this class is allocated in women's milk, feeding by a breast in connection with a possibility of development of serious undesirable reactions in children is not recommended to the women accepting Zokor®.

Use at abnormal liver functions. To patients with the steady increased level of serumal transaminases exceeding by 3 times of limit of upper norm, it is necessary to cancel drug.

It is contraindicated:

— a liver disease in an active phase or permanent increase in transaminases in a blood plasma of not clear etiology.

Influence on a liver. In clinical trials at several adult patients receiving симвастатин steady increase in level of liver enzymes was noted (more than by 3 times exceeding an upper limit of norm). At the termination or interruption of purpose of drug activity of transaminases usually gradually are returned to initial level. Increase in level of transaminases is not connected with jaundice or other clinical symptomatology, but can be connected with a deviation in results of functional hepatic trials and/or an alcohol abuse prior to treatment. Hypersensitivity reactions were not revealed.

In a research 4S the number of patients with more than one increase in level of serumal transaminases (more than by 3 times exceeding an upper limit of norm) did not differ authentically in the groups accepting симвастатин and placebo of 0.7% and 0.6%. Increase in level of serumal transaminases became the reason of the termination of treatment at 8 patients (from 2221) in group of a simvastatin and at 5 patients (from 2223) in group of placebo. All patients in this research received an initial dose of 20 mg of a simvastatin, at 37% the dose was increased to 40 mg.

In 2 controlled clinical trials on 1105 patients the permanent increase in level of transaminases connected using drug was observed in 0.7% and 1.8% of cases at reception of 40 mg and 80 mg of drug respectively.

In the research HPS on 20536 patients at Zokora's reception in a dose of 40 mg/days increase in level of serumal transaminases (more than by 3 times exceeding an upper limit of norm) made 0.21% (n=21) and 0.09% (n=9) in the groups accepting симвастатин and placebo respectively.

Before an initiation of treatment, and then - according to clinical indications all patients are recommended to conduct a research of function of a liver. Patients at whom it is planned to raise a dose of a simvastatin to 80 mg/days should conduct additional researches of function of a liver before to pass to the specified dosage, in 3 months later began its uses and further periodically to repeat (for example, 1 time/half a year) for the first year of treatment. Special attention should be paid to patients with the increased level of serumal transaminases. These patients need to repeat a research in the nearest future and in the subsequent to conduct it regularly to normalization of level of serumal transaminases. When the level of transaminases increases, especially at steady exceeding by 3 times of the upper bound of norm, drug it is necessary to cancel.

In the course of treatment simvastatiny, as well as at treatment other hypolipidemic means, observed moderated (less than by 3 times exceeding the upper bound of norm) increase in activity of serumal transaminases. These changes appeared soon after an initiation of treatment, often had passing character, were not followed by any symptoms and did not demand treatment interruption.

Use at renal failures. As Zokor® is allocated with kidneys in a small amount, the patients having moderately expressed renal failure have no need for change of a dosage. At a heavy renal failure (clearance of creatinine less than 30 ml/min.), it is necessary to weigh carefully expediency of purpose of drug in the doses exceeding 10 mg/days. If such dosages are considered as necessary, it is necessary to appoint them with care.

At a heavy renal failure (clearance of creatinine less than 30 ml/min.), it is necessary to weigh carefully expediency of purpose of drug in the doses exceeding 10 mg/days. If such dokhzirovka are considered as necessary, it is necessary to appoint them with care.

Use for elderly patients. At patients 65 years, Zokora's efficiency estimated on the level of decrease in the general cholesterol and LPNP cholesterol same, as well as in population in general are aged more senior, reliable increase in frequency of clinical or laboratory side effects was not observed.

Special instructions. Data on efficiency and safety of use for children are not enough therefore use for children is not recommended.

Myopathy / рабдомиолиз. Зокор®, as well as other inhibitors of GM-KOA-reduktazy, can cause a myopathy which is shown in the form of muscular pain, of morbidity or the general weakness, followed by increase of a kreatinfosfokinaza (is more than 10 times higher than an upper limit of norm). The myopathy can be shown in the form of the rabdomioliz which sometimes is followed by the secondary acute renal failure caused by a myoglobinuria, in rare instances leading to a lethal outcome. The risk of a myopathy increases due to increase in concentration in a blood plasma of the substances possessing an inhibiting effect in the GMG-KOA-reduktazy relation.

The risk of development of a myopathy / рабдомиолиза at therapy simvastatiny increases owing to the accompanying reception of the following medicines:

— active CYP3A4 inhibitors: итраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, inhibitors of HIV protease and нефазодон, especially, in combination with high doses of a simvastatin;

— gemfibrozit also other fibrata (except a fenofibrat), and also lipidosnizhayushchy doses (> 1 g/days) Niacinum (niacin), especially in combination with high doses of a simvastatin. There are no proofs that at purpose of a simvastatin along with fenofibraty, the risk of development of a myopathy exceeds the total risk created by reception of each of these drugs;

— cyclosporine or даназол - risk of development of a myopathy / рабдомиолиза raises especially at purpose of high doses of Zokora;

— Amiodaronum or верапамилв combination to high doses of a simvastatin. During clinical trials it was reported about development of a myopathy in 6% of the patients receiving at the same time симвастатин in a dose of 80 mg and Amiodaronum;

— the risk of development of a myopathy in the patients receiving diltiazem along with simvastatiny in a dose of 80 mg nemnogouvelichivatsya and makes about 1%. The risk of development of a myopathy in the patients receiving diltiazem along with simvastatiny in a dose of 40 mg was approximately identical with risk of development of a myopathy in the patients receiving therapy simvastatiny in a dose of 40 mg without accompanying diltiazem reception.

Dependence of risk of development of a myopathy / рабдомиолиза from a drug dose. In clinical trials with the monitoring controlling lack of any accompanying therapy the frequency of emergence of a myopathy / рабдомиолиза made about 0,03% among the patients receiving симвастатин in a dose of 20 mg/days, 0.08% among the patients receiving симвастатин in a dose of 40 mg/days and 0.4% is at the patients receiving симвастатин in a dose of 80 mg/days.

Measures for decrease in risk of development of a myopathy / рабдомиолиза:

1. It is necessary to avoid a concomitant use of a simvastatin with the following drugs: итраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, inhibitors of HIV protease and нефазодон. If therapy by the listed drugs cannot be cancelled, it is necessary to suspend for the period of a course of treatment these drugs reception of a simvastatin. The accompanying reception of any of the listed CYP3A4 inhibitors in therapeutic doses has to be excluded if advantages from such combination therapy do not exceed possible risk.

2. Simvastatin's dose should not exceed 10 mg/days for patients who accept cyclosporine, даназол or gemfibrozit or other fibrata (except a fenofibrat), or lipidosnizhayushchy doses (> 1 g/days) Niacinum (niacin). It is necessary to avoid co-administration of a simvastatin with these drugs if only advantages of influence on the level of lipids do not exceed risk from use of such medicinal combinations. Therapy addition simvastatiny, as a rule, provides with reception of fibrat or Niacinum small additional decrease in concentration of LPNP, however additional decrease in the TG level and increase in concentration of LPVP can be also reached.

3. Doses of a simvastatin for the patients receiving at the same time Amiodaronum or verapamil should not exceed 20 mg/days. Simultaneous use of a simvastatin in doses over 20 mg of mg/days with Amiodaronum or verapamil has to be excluded if only advantages of use of such combination do not exceed potential risk of development of a myopathy.

4. All patients who begin therapy simvastatiny and also patients who need to increase a dose have to be warned about possibility of a myopathy and are informed on need of the immediate address to the doctor in case of developing of any inexplicable pains or morbidity in muscles or muscular weakness. Therapy simvastatiny has to be immediately stopped if the myopathy is diagnosed or is at least supposed. Existence of above-mentioned symptoms and/or more, than increase in concentration of a kreatinyafosfokinaza, 10-fold in comparison with the upper bound of norm, is pointed to existence of a myopathy. In most cases after the immediate termination of reception of a simvastatin symptoms of a myopathy are resolved, and concentration of a kreatinfosfokinaza decreases. The patients beginning to accept симвастатин or passing to the raised drug doses, reasonablly periodic definition of concentration of a kreatinfosfokinaza however have no guarantees that such monitoring is capable to prevent development of a myopathy.

5. Many of the patients who transferred рабдомиолиз during therapy simvastatiny had the complicated anamnesis, including had a renal failure, as a rule, owing to a diabetes mellitus. Such patients demand more careful observation. Therapy simvastatiny has to be temporarily stopped at patients some days before performance of big operative measures, and also in the postoperative period.

At the patients accepting coumarinic anticoagulants, the indicator of a prothrombin time has to be controlled prior to therapy simvastatiny and during an initial stage of treatment, for an exception of considerable changes of this indicator. As soon as the stable level of a prothrombin time is reached, its further definition should be carried out bucketed, recommended for control of the patients receiving therapy by anticoagulants. The same procedure has to be repeated at change of a dosage or the termination of reception of a simvastatin. At the patients who were not accepting anticoagulants therapy simvastatiny was not connected with developing of bleedings or changes of a prothrombin time.

Influence on an organ of sight. Data of modern long clinical trials do not contain information of rather adverse effect of a simvastatin on lens of the person.

Advanced age. At patients 65 years, Zokora's efficiency estimated on the level of decrease in the general cholesterol and LPNP cholesterol same, as well as in population in general are aged more senior, reliable increase in frequency of clinical or laboratory side effects was not observed.

Side effects:

Зокор® in general it is well transferred, side effects are generally poorly expressed and are passing. Less than 2% of percent of patients were excluded from the clinical trials in connection with the assumption of development connected using Zokora, side effects.

Prior to wide use of drug, the adverse effects arising with a frequency of 1% or more which were estimated by researchers as it is possible, possibly or definitely connected with administration of drug, there were an abdominal pain, a lock and a meteorism. The adynamy and a headache were other side effects arising at 0.5-0.9% of patients. There were rare messages on development of a myopathy.

Broad use of Zokora in a dose of 40 mg/days within 5 years in a research on protection of heart (HPS) confirmed comparability of a profile of safety of Zokora at the patients who are receiving Zokor® (n = 10269) and not receiving drug (n = 10267): the refusal of treatment as a result of the undesirable phenomena made 4.8% in group of the patients receiving Zokor®, and 5.1% in group of the patients receiving placebo. Cases of development of a myopathy in the patients receiving Zokor® made less than 0.1%. Increase in activity of hepatic transaminases (more, than by 3 times exceeding the upper bound of norm and confirmed with a repeated research) – 0.21% of the patients receiving Zokor® and at 0.09% of the patients receiving placebo.

In the Scandinavian research (4S, n=4444), profiles of safety and portability were comparable at the patients accepting Zokor® (n=2221) in a dose of 20-40 mg and patients have groups of placebo (n=2223) at observation of these patients more than 5.4 years.

There are messages on a possibility of development of the following side effects:

From the alimentary system: dyspepsia (nausea, vomiting, diarrhea); seldom - hepatitis and jaundice, pancreatitis

From TsNS: dizziness, peripheral neuropathy,

From a musculoskeletal system: mialgiya; seldom - рабдомиолиз

Allergic and immunopathological reactions: Quincke's disease, volchanochnopodobny syndrome, rheumatic polimialgiya, vasculitis, thrombocytopenia, eosinophilia, increase SOE, arthritis, arthralgia, small tortoiseshell, photosensitization, fever, dermahemia, asthma, febricula.

Dermatological reactions: skin rash, itch, alopecia, dermatomyositis.

Others: anemia, febricula, myotonia, paresthesias.

Laboratory indicators. There are rare messages on development of the expressed and permanent increase in level of transaminases. Also it was reported about increase in activity of an alkaline phosphatase and gamma глютамилтранспептидазы. Deviations in indicators of functional hepatic trials are usually poorly expressed and have passing character. There are data on cases of increase in activity of a kreatinfosfokinaza.

Interaction with other medicines:

Simvastatin is metabolized by CYP3A4, however, has no the inhibiting activity concerning this coenzyme, it assumes that reception of a simvastatin does not exert impact on concentration in a blood plasma of the medicines which are metabolized under the influence of CYP3A4. Powerful CYP3A4 inhibitors (see below) increase risk of a myopathy due to reduction in the rate of removal of a simvastatin. To number of such means относятсяитраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, HIV protease inhibitors, нефазодон.

The risk of development of a myopathy / рабдомиолиза increases at joint purpose of cyclosporine or a danazol with high doses of a simvastatin. Other hypolipidemic means capable to cause development of a myopathy.

The risk of development of a myopathy increases as a result of the accompanying reception of other hypolipidemic means which are not strong CYP3A4 inhibitors, but are capable to cause a myopathy in the conditions of monotherapy. Such drugs are gemfibrozit also other fibrata (except a fenofibrat at whose combined reception with simvastatiny, the risk of emergence of a myopathy does not exceed that at monotherapy by each drug), and also lipidosnizhayushchy doses (> 1 g/days) Niacinum (niacin).

The risk of development of a myopathy increases owing to the accompanying reception of Amiodaronum or verapamil with high doses of a simvastatin.

The risk of development of a myopathy slightly increases at the patients receiving diltiazem along with simvastatiny in a dose of 80 mg.

Simvastatin in a dose of 20-40 mg/days exponentiates effect of coumarinic anticoagulants and increases risk of developing of bleedings: the prothrombin time defined as the International Normal Relation (INR) increases from initial level 1.7 to 1.8 at healthy volunteers, and from 2.6 to 3.4 at the patients suffering from a hypercholesterolemia. At the patients accepting coumarinic anticoagulants, the prothrombin time has to be defined prior to therapy simvastatiny, and also is rather frequent during an initial stage of treatment for an exception of considerable changes of this indicator. As soon as the stable level of an indicator of a prothrombin time is reached, its further definition should be carried out bucketed, recommended for control of the patients receiving therapy by anticoagulants. The same procedure has to be repeated at change of a dosage or the termination of reception of a simvastatin. At the patients who were not accepting anticoagulants therapy simvastatiny was not connected with developing of bleedings or changes of a prothrombin time.

Juice of grapefruit contains one or more components which inhibit CYP3A4 and can increase contents level in a blood plasma of the drugs which are metabolized CYP3A4. The effect of the usual use of juice (one glass of 250 ml/days) is minimum (increase by 13% of activity of inhibitors of GMG-KOA-reduktazy proceeding from measurement of the area under a curve concentration time) and has no clinical value. However very large volumes of consumption of juice (more than 1 l/days) considerably increase the plasma level of activity of inhibitors of GMG-KOA-reduktazy during therapy simvastatiny. In this regard it is necessary to avoid grapefruit juice consumption in large volumes.

Contraindications:

— a liver disease in an active phase or permanent increase in transaminases in a blood plasma of not clear etiology;

— pregnancy;

— lactation period;

— hypersensitivity to any component of drug.

With care:

— many of the patients who transferred рабдомиолиз during therapy simvastatiny had the complicated anamnesis, including had a renal failure, as a rule, owing to a diabetes mellitus. Such patients demand more careful observation. Therapy simvastatiny has to be temporarily stopped at such patients some days before performance of big operative measures, and also in the postoperative period;

— to patients with the steady increased level of serumal transaminases exceeding by 3 times of limit of upper norm, it is necessary to cancel drug;

— at a heavy renal failure (clearance of creatinine less than 30 ml/min.), it is necessary to weigh carefully expediency of purpose of drug in the doses exceeding 10 mg/days. If such dokhzirovka are considered as necessary, it is necessary to appoint them with care;

— an alcohol abuse prior to treatment.