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

Зокор® Forte

Препарат Зокор® Форте. Merck Sharp & Dohme Corp. (Мерк Шарп и Доум Корп.) США

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: Coronary heart disease. Lipidemia. Prevention of a myocardial infarction. Prevention of a stroke. Prevention of sudden coronary death. Stenocardia attack. Hypercholesterolemia. Gipertriglitseridemiya. Homozygous family hypercholesterolemia. Disbetalipoproteinemiya. Prevention of atherosclerosis.

General characteristics. Structure:

Active ingredient: 40 mg of a simvastatin in 1 tablet.

Excipients: butylhydroxyanisole, ascorbic acid, lactoses monohydrate (lactose water), citric acid, cellulose microcrystallic, starch prezhelatinizirovanny, magnesium stearate, gipromelloza, hydroxypropyl cellulose, titanium dioxide, talc, ferrous oxide red.

Pharmacological properties:

Pharmacodynamics. Зокор® Forte (симвастатин) represents the hypolipidemic drug received in the synthetic way from Aspergillus terreus fermentation product.

After intake симватстатин, being an inactive lactone, is exposed to hydrolysis with education corresponding beta and hydroxyacid derivative, being the main metabolite and having the high inhibiting activity concerning ГМГ-КоА-(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 concerning decrease in levels of the general cholesterol in a blood plasma, lipoproteins of the low density (LPNP), triglycerides (TG) and lipoproteins of very low density (LPONP), and also increase in level of lipoproteins of the high density (LPVP) at patients with a heterozygous family and single hypercholesterolemia, and also the mixed lipidemia when the increased level of cholesterol is risk factor and purposes of one diet insufficiently. The noticeable therapeutic effect is noted within 2 weeks of administration of drug, maximum - in 4-6 weeks after an initiation of treatment. The effect remains at therapy continuation. At the termination of reception of a simvastatin the general content of cholesterol is returned to the initial level determined prior to treatment.

The active metabolite 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 easily metabolized to atsetil-KOA which participates in many processes of biosynthesis in an organism.

In the Scandinavian Research of Influence of Simvastatin on Survival, impact of therapy by Zokor on the general mortality (a median of time of participation of patients 5,4 years) it was estimated on 4444 patients from an ischemic heart disease and 212-309 mg/dl with an initial level of general cholesterol (5,5-8,0 mmol/l). In this multicenter, randomized, double blind person, placebo - a controlled research Zokor reduced risk of the general mortality by 30%, mortality from an ischemic heart disease for 42%, the frequency of not fatal confirmed myocardial infarctions for 37%. Zokor also reduced risk of need of carrying out operations on recovery of a coronary blood-groove (aortocoronary shunting or transdermal transluminal coronary angioplasty) by 37%. At patients with a diabetes mellitus the risk of emergence of the main coronary complications decreased by 55%. Moreover, Zokor considerably reduced risk of emergence of deadly and nonlethal disturbances of cerebral circulation (by 28%) (strokes and passing disturbances of cerebral circulation).

In the 5-year-old multicenter, randomized, double blind person, placebo - a controlled Research of Protection of Heart (HeartProtectionStudy-HPS) efficiency of therapy by Zokor was a prodemonstirovana at 20536 patients with a lipidemia or without it, the ischemic heart diseases which are in group of high risk of development in connection with existence of a diabetes mellitus, a stroke and other vascular diseases. Before therapy 33% of patients the LPNP level had lower than 116 mg/dl, 25% 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 Zokor in a dose of 40 mg/days in comparison with placebo reduced the general mortality by 13%, the risk of death connected with an ischemic heart disease for 18%, risk of emergence of the main coronary complications (not fatal myocardial infarction or death connected with an ischemic heart disease) for 27%, risk of emergence of need of operative measures on recovery of a coronary blood-groove (aorto-koronarony shunting and transdermal transluminal angioplasty) for 30%, riskvozniknoveniye of need of recovery of a peripheral blood-groove and other types of not coronary revaslulyarization for 16%, risk of developing of a stroke for 25%. Hospitalization frequency concerning heart failure decreased by 17%. The risk of development of the main coronary and vascular complications decreased by 25% at patients with an ischemic heart disease or without it, including patients with a diabetes mellitus, diseases of peripheral vessels and cerebrovascular pathology. At patients with a diabetes mellitus Zokor reduced risk of development of vascular complications by 21%, including operations on recovery of a peripheral blood-groove, amputation of the lower extremities and developing of trophic ulcers.

In another multicenter, placebo - a controlled research with participation of 404 patients Zokor according to a coronary angiography slowed down progressing of coronary atherosclerosis and emergence of both new sites of atherosclerosis, and new total occlusions whereas at the patients receiving standard therapy steady progressing of atherosclerosis of coronary arteries was observed.

The analysis of subgroups from 2 researches which included 147 patients with a hypercholesterolemia (a lipidemia of the IV type on Fredrikson's classification) showed that in group of Zokora accepted in a dose of 20-80 mg/days, the level of triglycerides decreased by 21-39% (in group of placebo - for 11-13%), LPNP cholesterol for 23-35% (in group плабебо - for 1-3%), all types of lipoproteins, except LPVP, for 26-43% (in group of placebo - for 1-3%), and the level of LPVP cholesterol increased by 9-14% (in group of placebo - for 3%).

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

Pharmacokinetics. The main active metabolites of a simvastatin in a blood plasma are бетагидроксиацид and its 6 hydroxies, 6 hydroxymethyl and 6-eksometilen derivatives. Cmax of metabolites of a simvastatin in a blood plasma is reached in 1,3-2,4 h after a single 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 β-hydroxyacid, 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 of V-hydroxyacid (active 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.

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% from prityaty in a dose, 95% of this quantity are in the state connected with proteins.

Active metabolism of a simvastatin in a liver (men have more than 60%) contents in the general blood-groove is result of it to a nizkra.

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

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 depend on a dose of a simvastatin. In this research patients accepted in a simvastating tablet 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 пациентовс a heavy renal failure (clearance of a kratinin less than 30 ml/min.) after reception of one dose of drug of concentration of inhibitors of HMG-CoA reductase in a blood plasma were approximately twice higher, than at healthy volunteers.

Indications to use:

Coronary Heart Disease (CHD) or high rice of development of coronary heart disease.

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 Zokor Forte 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 of not coronary revascularization;

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

Hypercholesterolemia

If use of a diet and others немедикаментозныз is not enough methods of treatment, Zokor Forte is appointed together with a diet for:

— decrease in the increased level of the general cholesterol, LPNP cholesterol, triglycerides, apolipoprotein B (apo-V);

— increases 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 indicators cholesterol LPVP LPNP/cholesterol and LPVP general cholesterol / 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 cholesterol and apolipoprotein B;

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

At patients with a diabetes mellitus - Zokor Forte 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 and a hypercholesterolemia Zokor Forte slows down development of coronary atherosclerosis, including decrease in frequency of development of new complications.

Route of administration and doses:

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

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

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 (in the presence of a diabetes mellitus, the had stroke or other cerebrovascular diseases in an anemneza, diseases of peripheral vessels, coronary heart disease) makes 40 mg of 1 times/days in the evening. Medicamentous therapy can be appointed along with a diet and physiotherapy exercises.

The patients with a hypercholesterolemia who do not have above-mentioned risk factors. The standard initial dose to Zokora Forta makes 20 mg of 1 times/days in the evening. For patients who need considerable (more than for 45%) decrease in level of LPNP cholesterol, an initial dose can make 40 mg of 1 times/days in the evening. Patients with easy or moderate a giperkholesterinemiyeyterapiya Zokor can appoint 10 mg of 1 times/days from a dose. In case of need selection of doses should be carried out according to the above-mentioned scheme

Patients with a homozygous family hypercholesterolemia. The recommended dose to Zokora Forta makes 40 mg of 1 times/days 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 Zokor Forte apply in a combination with other methods of treatment reducing cholesterol level (for example, LPNP аферез) or without them if they are unavailable.

The accompanying therapy. Zokor Forte can be appointed both in monotherapy, and in combination with sekvestrant of bile acids.

At the patients accepting cyclosporine, даназол gemfibrozit or other fibrata (except a fenofibrat), or Niacinum in lipidosnizhayushchy doses (> 1 g/days) in a combination with simvastatiny, the maximum recommended dose to Zokora Forta makes 10 mg/days. For the patients accepting Amiodaronum or verapamil along with Zokora Fort the daily dose to Zokora Forta should not exceed 20 mg

Renal failure. As to Zokora Forta it is allocated with kidneys in a small amount, patients have no need for change of doses with moderately expressed renal failure. At patients with 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 necessary, it is necessary to appoint drug with care.

Features of use:

Use at pregnancy and feeding by a breast. Zokor Forte is contraindicated to pregnant women. As safety for pregnant women is not proved and there are no data that treatment by drug at pregnancy brings obvious benefit, administration of drug should be stopped immediately at pregnancy approach. Simvastatin women of childbearing age should appoint only when the probability of pregnancy is very small. 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.

Data on allocation of a simvastatin or its metabolites with breast milk are absent. In need of Zokora's appointment the woman in the period of a lactation should consider that many medicines are emitted with breast milk, and there is a threat of development of serious adverse reactions therefore feeding by a breast is not recommended.

Use at abnormal liver functions. It is contraindicated:

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

With care: 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.

Use at renal failures. As to Zokora Forta it is allocated with kidneys in a small amount, patients have no need for change of doses with moderately expressed renal failure. At patients with 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 necessary, it is necessary to appoint drug with care.

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

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

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. Simvastatin, as well as other inhibitors of GMG-KOA-reduktazy, can cause a myopathy which is shown in the form of muscular pain, of morbidity or the general weakness and is followed by increase of activity of a kreatinfosfokinaza of norm more than 10 times higher than the upper bound. The myopathy can be shown in the form of the rabdomioliz which sometimes is followed by the acute renal failure caused by a myoglobinuria. The risk of a myopathy increases due to increase in the inhibiting activity concerning GMG-KOA-reduktazy in a blood plasma.

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

— powerful 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, especially in combination with high doses of a simvastatin;

— Amiodaronum or verapamil in combination with high doses of a simvastatin. During clinical trials it was reported about development of a myopathy in 6% of the patients receiving симвастатин in a dose of 80 mg along with Amiodaronum;

— at the patients receiving diltiazem along with simvastatiny in a dose of 80 mg/days risk of development of a myopathy increases 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/days was approximately equal to that at reception of a simvastatin in a dose of 40 mg/days without accompanying diltiazem reception.

Dependence of risk of development of a myopathy / рабдомиолиза from a drug dose. In clinical trials in which patients did not accept the accompanying therapy the frequency of emergence of a myopathy / рабдомиолиза made about 0.03% at the patients receiving симвастатин in a dose of 20 mg/days, 0.08% at 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 of nosnizheniyu of risk of development of a myopathy / рабдомиолиза. 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 therapy of a simvastatin for the period of reception of these drugs. The accompanying reception of any of the listed CYP3A4 inhibitors has to be excluded if advantages of a combination therapy do not exceed possible risk.

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

Doses of a simvastatin for the patients receiving Amiodaronum or verapamil should not exceed 20 mg/days. Use of a simvastatin in doses over 20 mg/days together with Amiodaronum or verapamil is not recommended if only advantages of use of such combination do not exceed potential risk of development of a myopathy.

All patients beginning therapy simvastatiny, and also patients who need to increase a drug dose have to be warned about possibility of a myopathy and need of the immediate address to the doctor in case of developing of any inexplicable pains, morbidity in muscles or muscular weakness. Therapy simvastatiny has to be immediately stopped if the myopathy is diagnosed or is supposed. Existence of above-mentioned symptoms and/or more, than 10-fold in comparison with the upper bound of norm, increase in level of a kreatinfosfokinaza 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. At the beginning of therapy simvastatiny or at increase in doses of drug, it is reasonable to carry out periodic determination of level of a kreatinfosfokinaza, however there are no reliable data that such monitoring is capable to prevent development of a myopathy.

Many patients at whom developed 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 a liver. In clinical trials at some adult patients receiving симвастатин steady increase in level of liver enzymes was noted (more than by 3 times exceeding the upper bound of norm). At drug withdrawal activity of transaminases usually gradually is returned to initial level. Increase in level of transaminases was not followed by jaundice or other clinical symptomatology. These reactions are not connected with hypersensitivity. Some of patients had a deviation of indicators of function of a liver prior to therapy simvastatiny and/or consumed excess amount of alcohol.

In a research 4S the number of patients with more than single increase in level of serumal transaminases (more than by 3 times exceeding the upper bound of norm) authentically did not differ in groups of a simvastatin and placebo. Increase in level of syvornotochny 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 a simvastatin of 20 mg/days, at 37% the dose was increased to 40 mg/days.

1105 patients took part in two controlled clinical trials, the gl, 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 which included 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 groups of a simvastatin and placebo respectively.

Before an initiation of treatment, and then - according to clinical indications, all patients are recommended to carry out functional hepatic trials. Patients at whom it is planned to raise a dose of a simvastatin to 80 mg/days should carry out functional hepatic trials prior to the beginning of a titration, then in 3 months after achievement of a dose of 80 mg/days then periodically to repeat (for example, 1 time/half a year) for the first 1st year of treatment. Special attention should be paid to patients at whom the level of serumal transaminases is increased. To these patients control of function of a liver has to be carried out timely in an initiation of treatment and is more frequent in the subsequent. 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.

At treatment simvastatiny, as well as 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 therapy cancellation.

Ophthalmologic inspection. Data of 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:

Zokor Forte in general is well had, and the majority of side effects are slight and passing. Less than 2% of patients in clinical trials stopped treatment in connection with development, side effects inherent to Zokor Forte.

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. Other side effects arising at 0.5-0.9% of patients were the adynamy and a headache.

There are rare messages on development of a myopathy.

In the Research of Protection of Heart (HPS) Zokora's use in a dose of 40 mg/sou within 5 years confirmed comparability of a profile of safety of drug at the patients receiving Zokor (n=10269) in comparison with placebo (n=10267). The refusal of treatment as a result of development of the undesirable phenomena made 4.8% in group of the patients receiving Zokor and 5.1% in group of the patients receiving placebo.

In the Scandinavian research profiles of safety and portability were comparable at the patients accepting Zokor (n=2221) in a dose of 20-40 mg and patients in group of placebo (n=2223) at their observation within more than 5.4 years.

Also there are messages on development of the following side effects:

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

From TsNS and sense bodys: dizziness, peripheral neuropathy, paresthesias.

From a musculoskeletal system: mialgiya, myotonia; 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.

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 of indicators of function of a liver 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 in the relation of this coenzyme. Therefore influence of a simvastatin on concentration in a blood plasma of the medicines which are metabolized under the influence of CYP3A4 is not expected.

Powerful CYP3A4 inhibitors increase risk of a myopathy due to reduction in the rate of removal of a simvastatin. Are among such means итраконазол, 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.

The risk of development of a myopathy increases at joint purpose of other hypolipidemic drugs 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 each of drugs separately), and also Niacinum (niacin) in a dose> 1 g/days.

The risk of development of a myopathy increases at joint 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.

Other medicinal interactions. Simvastatin in a dose of 20-40 mg/days moderately exponentiates effect of coumarinic anticoagulants: The international Normalized Relation (MHO) increases at healthy volunteers from 1.7 to 1.8, and at patients with a hypercholesterolemia from 2.6 to 3.4. At the patients accepting coumarinic anticoagulants, a prothrombin time or Mnodolzhny to be defined prior to therapy simvastatiny, and also it is rather frequent during an initial stage of treatment. As soon as the stable level of an indicator of a prothrombin time or MHO is reached, its further control should be carried out bucketed, recommended for the patients receiving therapy by anticoagulants. At change of a dosage or the termination of reception of a simvastatin it is also necessary to carry out control of a prothrombin time or MNOPO to the above scheme.

Therapy simvastatiny does not cause changes of protrombiny time and risk of bleedings in the patients who are not accepting anticoagulants.

Other types of interaction. Juice of grapefruit contains one or more components which inhibit CYP3A4 and can increase concentration in a blood plasma of the drugs which are metabolized CYP3A4. Increase in activity of inhibitors of GMG-KOA-reduktazy after the use of 250 ml of juice a day is maximum, makes about 13% and has no clinical value. However consumption of large volume of juice (more than 1 l/days) at reception of a simvastatin considerably increase the level of the inhibiting activity concerning GMG-KOA-reduktazy in a blood plasma. 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:

Simvastatin, as well as other inhibitors of GMG-KOA-reduktazy, can sometimes cause a myopathy. 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.

Alcohol abuse prior to treatment.