Simvastatin-SZ таб 10/20/40mg No. 30

General characteristics. Structure:

Active agent: simvastatina of 10 mg, 20 mg, 40 mg;
excipients: ascorbic acid – 2,5 mg, 5 mg, 10 mg, potato starch – 20 mg, 40 mg, 80 mg, lactoses monohydrate (sugar milk) – 90 mg, 180 mg, 360 mg, cellulose microcrystallic – 10 mg, 20 mg; 40 mg, butylhydroxyanisole – 0,02 mg, 0,04 mg, 0,08 mg, citric acid – 1,2 mg,
2,4 mg, 4,8 mg, magnesium stearate – 1,28 mg, 2,56 mg, 5,12 mg, silicon dioxide colloid (aerosil) – 2, mg, 4 mg, 8 mg, talc – 1 mg, 2 mg 4 mg;
structure of a cover: Опадрай II: (the polyvinyl alcohol which is partially hydrolyzed – 1,6 mg, 3,2 mg, 6,4 mg, talc – 0,592 mg, 1,184 mg, 2,368 mg, a macrogoal (polyethyleneglycol 3350) – 0,808 mg, 1,616 mg, 3,232 mg, titanium dioxide of E 171 - 0,8748 mg, 1,7496 mg, 3,4992 mg, dye ferrous oxide (II) of yellow E 172 - 0,0012 mg, 0,0024 mg, 0,0048 mg, an aluminum varnish on the basis of dye of quinolinic yellow E 104 - 0,1204 mg, 0,2408 mg, 0,4816 mg, an aluminum varnish on the basis of dye a sunset of yellow E 110 - 0,0028 mg, 0,0056 mg, 0,0112 mg, an aluminum varnish on the basis of indigo carmine of E 132 - 0,0008 mg, 0,0016 mg, 0,0032 mg.

Description: round biconvex tablets, film coated from light yellow till yellow color; on a section of a tablet of white or almost white color.

Pharmacological properties:

Pharmacodynamics. The hypolipidemic means received in the synthetic way from Aspergillus terreus fermentation product is an inactive lactone, in an organism is exposed to hydrolysis with formation of hydroxyacid derivative. The active metabolite inhibits 3-гидрокси-3-метил-глутарил-КоА-редуктазу (GMG KOA-reductase), the enzyme catalyzing initial reaction of formation of a mevalonat from GMG-KOA. As transformation GMG-KOA in мевалонат represents an early stage of synthesis of cholesterol, use of a simvastatin does not cause accumulation in an organism of potentially toxic sterol. GMG-KOA it is easily metabolized to atsetil-KOA which participates in many processes of synthesis in an organism.
Simvastatin causes decrease in contents in a blood plasma of triglycerides (TG), lipoproteids of the low density (LPNP), lipoproteids of very low density (LPONP) and the general cholesterol (in cases of heterozygous family and single forms of a hypercholesterolemia, at the mixed lipidemia when the increased content of cholesterol is risk factor) due to oppression of synthesis of cholesterol in a liver and increases in number of receptors of LPNP at surfaces of cells that leads to strengthening of capture and a catabolism of LPNP.
Increases the maintenance of lipoproteids of the high density (LPVP) and reduces a ratio of LPNP/LPVP and the general cholesterol / LPVP. Has no mutagen effect.
The beginning of manifestation of effect – in 2 weeks from the beginning of reception, the maximum therapeutic effect is reached in 4 - 6 weeks. Action remains at treatment continuation; at the therapy termination the content of cholesterol gradually is returned to initial level.

Pharmacokinetics. Absorption of a simvastatin high, bioavailability – less than 5%. After intake the maximum concentration in a blood plasma is reached approximately in  1,3 2,4 hours and decreases by 90% in 12 hours. Communication with proteins of a blood plasma makes about 95%.
Comes to an organism in an inactive form. It is hydrolyzed in fabrics in the active form – beta hydroxyacid and inactive metabolites. It is metabolized in a liver, has effect of "the first passing" through a liver. Isoenzymes of CYP3A4, CYP3A5 and CYP3A7 participate in metabolism of a simvastatin. The elimination half-life of active metabolites makes 1,9 hours. It is removed preferential through intestines (60%) in the form of metabolites. About 10  15% are removed by kidneys in an inactive form.

Indications to use:

Giperkholesterinemiya:pervichny hypercholesterolemia (heterozygous family and single, the types IIa, IIb and mixed on Fredrikson's classification) – at inefficiency of a dietotherapy with the low content of cholesterol and other non-drug actions (an exercise stress and decrease in body weight) at patients with the increased risk of developing of coronary atherosclerosis,
the combined hypercholesterolemia and gipertriglitseridemiya, the giperlipoproteinemiya which is not giving in to correction by a special diet and an exercise stress;
Coronary heart disease:
secondary prevention for the purpose of decrease in total risk of death, a myocardial infarction (for delay of progressing of coronary atherosclerosis), a stroke and passing disturbances of cerebral circulation, reduction of risk of procedures of revascularization.

Route of administration and doses:

Prior to treatment by drug Simvastatin the patient should appoint a standard hypocholesteric diet which has to be observed during all course of treatment.
Simvastatin it is necessary to accept in 1 times a day in the evening, washing down with enough water.
Time of administration of drug should not be connected with meal.
Duration of use of drug is defined by the attending physician individually.
Hypercholesterolemia
The recommended drug dose Simvastatin for treatment of a hypercholesterolemia varies from 5 to 80 mg of 1 times a day in the evening.
At inefficiency of drug in a dose of 40 mg it is recommended to pass to other type of hypolipidemic therapy. Use of drug in a dose more
40 mg are increased by great risk of a myopathy.
The dose of drug of Simvastatin of 80 mg has to be applied only at those patients who did not reach target concentration of LPNP at use of a dose of 40 mg.
The recommended initial dose of drug for patients with a hypercholesterolemia makes 10 mg. Changes (selection) of a dose should be carried out bucketed in 4 weeks. At most of patients the optimum effect is reached at administration of drug in doses to 20 mg a day.
At patients with a homozygous hereditary hypercholesterolemia the recommended daily dose of drug Simvastatin makes 40 mg
(2 tablets on 20 mg) 1 time a day in the evening or 80 mg in three steps
(20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening). To such patients Simvastatin in combination with other hypolipidemic therapy is recommended to apply (for example, aferezy LPNP).
Coronary heart disease
At treatment of patients with the coronary heart disease (CHD) or high risk of development of an ischemic heart disease, with a lipidemia or without it, effective doses of drug Simvastatin make 20 - 40 mg a day. Therefore the recommended initial dose at such patients – 20 mg a day. Changes (selection) of a dose should be carried out bucketed in 4 weeks, if necessary it is possible to increase a dose to 40 mg a day (2 tablets on 20 mg of drug симвастатин). If the maintenance of LPNP less than 75 mg/dl (1,94 mmol/l), content of the general cholesterol – less than 140 mg/dl (3,6 mmol/l), a dose of drug it is necessary to reduce.
The accompanying therapy
At the patients receiving treatment by cyclosporine, danazoly, gemfibrozily, other fibrata (except a fenofibrat) or niacin in lipidsnizhayushchy doses (more than 1 g/days), the recommended maximum daily dose of drug of Simvastatin should not exceed 10 mg. Further increase in a dose in such situations is not recommended.
For the patients who are at the same time accepting Amiodaronum or verapamil, the daily dose of drug of Simvastatin should not exceed 20 mg.
For the patients who are at the same time accepting diltiazem, the daily dose of drug of Simvastatin should not exceed 40 mg.
And at patients with the slight or moderately expressed renal failure of dose adjustment of drug it is not required from patients of advanced age.
At patients with the expressed renal failure (clearance of creatinine less than 30 ml/min.) the recommended dose of drug of Simvastatin should not exceed 10 mg a day. In need of increase in a dose careful observation of such patients is made.

Features of use:

At the beginning of therapy by Simvastatin perhaps passing increase in activity of "hepatic" enzymes.
Before therapy and further regularly to conduct a research of function of a liver (to control activity of "hepatic" enzymes each 6 weeks within the first 3 months, further each 8 weeks within the remained first year and then 1 time in half a year), and also at increase in doses it is necessary to carry out the test for definition of function of a liver. At increase in a dose to
80 mg it is necessary to carry out the test each 3 months. At permanent increase in activity of transaminases (by 3 times in comparison with initial level) Simvastatin's reception should be stopped.
Simvastatin, as well as other inhibitors of GMG-KOA-reduktazy, it is not necessary to apply at the increased risk of development of a rabdomioliz and a renal failure (against the background of a heavy acute infection, arterial hypotension, the planned big surgery, injuries, heavy metabolic disturbances).
Cancellation of hypolipidemic means during pregnancy has no significant effect on results of prolonged treatment of primary hypercholesterolemia.
At patients with the lowered function of a thyroid gland is (hypothyroidism) or in the presence of some diseases of kidneys (a nephrotic syndrome) at increase in level of cholesterol it is necessary to carry out therapy of the cornerstone disease at first.
Simvastatin about care appoint to persons who abuse alcohol and/or have in the anamnesis of a disease of a liver.
Prior to the beginning of and during treatment the patient has to be on a hypocholesteric diet.
The concomitant use of grapefruit juice can strengthen degree of manifestation of the by-effects connected with Simvastatin's reception therefore it is necessary to avoid their concomitant use.
Simvastatin is not shown when there is a gipertriglitseridemiya I, IV and V types.
Treatment by Simvastatin can cause the myopathy leading to a rabdomioliz and a renal failure. The risk of developing of this pathology increases at the patients receiving one or several of the following medicines along with Simvastatin: fibrata (gemfibrozit, фенофибрат), cyclosporine, нефазадон, macroleads (erythromycin, кларитромицин), antifungal means from group of "azoles" (кетокеназолинтраконазол) and inhibitors of HIV proteases (ритонавир). The risk of development of a myopathy increases also at patients with a heavy renal failure.
For development of a myopathy distinguish advanced age (65 years are more senior), belonging to a female, an uncontrollable hypothyroidism and a renal failure from the contributing factors.
All patients beginning therapy by Simvastatin and also patients who need to increase a drug dose have to be warned about possibility of a myopathy of need of the immediate address to the doctor in case of emergence inexplicable pains, morbidity in muscles, slackness or muscular weakness, especially if it is followed by an indisposition or fever. Therapy by drug has to be immediately stopped if the myopathy is diagnosed or is supposed.
For diagnosing of development of a myopathy it is recommended to take measurements of concentration of a kreatinfosfokinaza (KFK) regularly.
At treatment by Simvastatin increase of concentration of serumal KFK is possible that should be considered at differential diagnosis of pains behind a breast. As criterion of drug withdrawal serves increase in concentration of KFK in blood serum more than by 10 times of rather upper bounds of norm. At patients with a mialgiya, an iila myasthenia with the expressed increase in concentration of KFK treatment with drug is stopped.
Drug is effective both in the form of monotherapy, and in combination with sekvestrant of bile acids
In case of the admission of the current dose drug needs to be accepted as soon as possible. If came time of the following dose, a dose not to double.
To patients with a heavy renal failure treatment is carried out under control of function of kidneys.
Duration of use of drug is defined by the attending physician individually.
Use of drug is not recommended at the women of childbearing age who are not using reliable methods of contraception.
Influence on ability to driving of motor transport and to control of mechanisms
It is necessary to be careful at control of vehicles and various mechanisms (risk of development of dizziness).

Side effects:

From the alimentary system
Lock, abdominal pain, meteorism, dyspepsia, nausea, vomiting, diarrhea, pancreatitis, hepatitis, cholestatic jaundice, abnormal liver function, increase in activity of "hepatic" transaminases, alkaline phosphatase and kreatinfosfokinaza (KFK).
From the central nervous system and sense bodys
Adynamy, headache, paresthesias, dizziness, peripheral neuropathy, sleeplessness, memory disturbance, muscular spasms, illegibility of visual perception, disturbance of flavoring feelings, myasthenia, weakness.
From a musculoskeletal system
Myopathy, рабдомиолиз, mialgiya, muscular spasms.
Allergic and immunopathological reactions
The developed hypersensitivity syndrome (a Quincke's disease, a volchanopodobny syndrome, a rheumatic polimialgiya, a dermatomyositis, a vasculitis, thrombocytopenia, an eosinophilia, increase in the blood sedimentation rate (BSR), arthritis, an arthralgia, a small tortoiseshell, a photosensitization, fever, "inflows" of blood to face skin, an asthma).
Dermatological reactions
Skin rash, itch, alopecia.
Others
Anemia, heart consciousness, acute renal failure (owing to a rabdomioliz), decrease in a potentiality.

Interaction with other medicines:

Simultaneous use of a simvastatin with fibrata, niacin in lipidsnizhayushchy doses (more than 1 g/days) increases risk of development of a myopathy, including рабдомиолиз (at simultaneous use with fenofibraty increase in risk of development of a myopathy in comparison with monotherapy by each drug separately is not proved).
At simultaneous use of medicine Amlodipin with drug Simvastatin in a dose of 80 mg is available slightly increased risk of development of a myopathy.
Pharmacokinetic types of interaction
The CYP3A4 cytochrome isoenzyme inhibitors (итраконазол, кетоконазол, erythromycin, кларитромицин, телитромицин, inhibitors of HIV protease and нефазодон) participating in metabolic transformation of a simvastatin in a liver increase risk of development of a myopathy and rabdomioliz against the background of therapy simvastatiny. Simultaneous use with these drugs is contraindicated. Carefully it is necessary to appoint along with less powerful inhibitors of an isoenzyme CYP3A4: cyclosporine, verapamil and diltiazem.
The daily dose of drug симвастатин at simultaneous use with cyclosporine should not exceed 10 mg.
The daily dose of drug симвастатин against the background of simultaneous use of Amiodaronum or verapamil should not exceed 20 mg, and 40 mg – against the background of simultaneous use of diltiazem if only the expected advantage obviously does not surpass potential risk of development of a myopathy and rabdomioliz.
Simvastatin in a dose of 20 - 40 mg/days at healthy volunteers and patients with a hypercholesterolemia exponentiates effects of nepryaty anticoagulants – coumarin derivatives (for example, warfarin), in particular increase in a prothrombin time and the international normalized relation (INR). Therefore at the patients accepting coumarinic anticoagulants, the prothrombin time and MNO needs to be defined before therapy simvastatiny, in an initial stage of treatment, at change of a dose of a simvastatin or drug withdrawal. At achievement of a stable indicator of a prothrombin time and MNO, further control needs to be carried out bucketed, recommended for the patients receiving therapy by anticoagulants. Therapy simvastatiny does not cause changes of a prothrombin time and risk of development of bleedings in the patients who are not accepting anticoagulants.
Colestyraminum and колестипол reduce bioavailability (drug use симвастатин perhaps in 4 hours after use of the specified medicines, at the same time is noted the additive effect).
Simvastatin increases concentration of digoxin in a blood plasma.
Juice of grapefruit contains one or more components which inhibit an isoenzyme of CYP3A4 and can increase concentration in a blood plasma of the means which are metabolized by means of CYP3A4 isoenzyme. Increase in activity of inhibitors of GMG-KOA-reduktazy after the use of 250 ml of juice a day is minimum and has no clinical value. However consumption of large volume of juice (more than 1 l a day) at drug use симвастатин considerably increases the inhibiting activity concerning GMG-KOA-reduktazy in a blood plasma. In this regard it is necessary to avoid grapefruit juice consumption in large numbers.

Contraindications:

Hypersensitivity to a simvastatin or to other components of drug, and also to other drugs of a statinovy row (GMK-KOA-reduktazy inhibitors) in the anamnesis,
liver diseases in an active phase or permanent increase in activity of "hepatic" transaminases of not clear etiology,
concomitant use of inhibitors of P450 3A4 cytochrome (CYP3A4 isoenzyme) (for example, итраконазол, кетоконазол, HIV protease inhibitors, erythromycin, кларитромицин, телитромицин and нефазодон),
diseases of skeletal muscles (myopathy),
pregnancy and period of a lactation,
age up to 18 years (efficiency and safety of use are not studied),
deficit of lactase, lactose intolerance, syndrome of glyukozo-galaktozny malabsorption.
With care
alcoholism, liver diseases in the anamnesis, heavy disturbances of water and electrolytic balance, the expressed endocrine and metabolic disturbances, arterial hypotension, heavy acute infections (sepsis), a myopathy / an acute necrosis of skeletal muscles, uncontrollable epilepsy, extensive surgical interventions, an injury; a concomitant use with gemfibrozily and other fibrata (except a fenofibrat), cyclosporine, niacin in lipidsnizhayushchy doses (more than 1 g/days), Amiodaronum, verapamil, diltiazem, grapefruit juice; the expressed renal failure (clearance of creatinine less than 30 ml/min.), advanced age (65 years, especially are more senior than the woman), a renal failure.
Pregnancy and period of a lactation
Simvastatin can make an adverse effect on a fruit and is contraindicated to use for pregnant women. There are several messages on development of anomalies in newborns which mothers accepted симвастатин.
The women of reproductive age accepting симвастатин have to avoid conception. Drug use симвастатин is not recommended at the women of childbearing age who are not using reliable methods of contraception. If in the course of treatment pregnancy nevertheless occurred, симвастатин has to be cancelled, and the woman has to be warned about possible danger to a fruit.
Data on allocation of a simvastatin with breast milk are absent. In need of drug use симвастатин during feeding by a breast it is necessary to consider that many medicines are allocated with breast milk and there is a threat of development of heavy reactions therefore feeding by a breast during administration of drug needs to be stopped.

Overdose:

In one of the known several cases of overdose (most accepted dose – 450 mg) specific symptoms were not revealed.
Treatment: symptomatic, it is necessary to hold the general events: monitoring and maintenance of the vital functions, prevention of further absorption of medicine (gastric lavage, reception of absorbent carbon or purgatives). It is necessary to control functions of a liver and kidneys, concentration of KFK in blood serum. The specific antidote does not exist.
At development of a myopathy with rabdomiolizy and an acute renal failure (rare, but heavy side effect) it is necessary to stop immediately administration of drug and to enter to the patient diuretic and sodium hydrobicarbonate (intravenous infusion).
Rabdomioliz can cause a hyperpotassemia which can be eliminated with intravenous administration of Calcii chloridum or calcium of a gluconate, infusion of a dextrose (glucose) with insulin of short action, use of potassium ion-exchange resins or, in hard cases, by means of a hemodialysis.

Storage conditions:

In the dry, protected from light place, at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity: 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 10 mg, 20 mg and 40 mg.
On 10 tablets in a blister strip packaging.
On 20 or 30 tablets in bank of light-protective glass either in bank polymeric or in a bottle polymeric.
Each can or bottle or 2 or 3 blister strip packagings together with the application instruction are placed in a pack from a cardboard.