Atorvastatin

General characteristics. Structure:

Active ingredient: 10 mg, 20 mg, 40 mg or 80 mg of an atorvastatin of calcium of trihydrate (in terms of аторвастатин).

Excipients: cellulose microcrystallic – 103,72 mg, lactoses monohydrate – 100,00 mg, calcium a carbonate – 20,00 mg, кросповидон – 15,00 mg, sodium carboxymethylstarch (sodium of starch glikolit) – 9,00 mg, a hypro rod (hydroxypropyl cellulose) – 6,00 mg, magnesium stearate – 3,00 mg.

Film cover: [a gipromelloza – 4,500 mg, talc – 1,764 mg, a hypro rod (hydroxypropyl cellulose) – 1,746 mg, titanium dioxide – 0,990 mg] or [the dry mix for a film covering containing a gipromelloza (50,0%), talc (19,6%), a hypro rod (hydroxypropyl cellulose) (19,4%), titanium dioxide (11,0%)] – 9,000 mg.

Synthetic hypolipidemic means.

Pharmacological properties:

Pharmacodynamics. Atorvastatin – the selection competitive inhibitor of GMG-KOA-reduktazy, the key enzyme turning 3-gidroksi-3-metilglyutaril-KOA in мевалонат – the predecessor of steroids, including cholesterol; synthetic hypolipidemic means.

At patients with a homozygous and heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed dislipidemiya аторвастатин reduces concentration in a blood plasma of the general  cholesterol  (Хс), cholesterol of lipoproteids of the low density (Hs-LPNP) and apolipoprotein B (apo-V), and also concentration of lipoproteids of very low density (Hs-LPONP) and triglycerides (TG), is caused by unstable increase in concentration of cholesterol of lipoproteids of the high density (Hs-LPVP).

Atorvastatin reduces concentration of cholesterol and lipoproteids in a blood plasma, inhibiting GMG-KOA-reduktazu and synthesis of cholesterol in a liver and, increasing number of "hepatic" receptors of LPNP by surfaces of cells, leads to strengthening of capture and a catabolism of Hs-LPNP.

Atorvastatin reduces education Hs-LPNP and number of particles of LPNP, causes the expressed and permanent increase in activity of LPNP-receptors in combination with favorable qualitative changes of LPNP-particles, and also reduces concentration of Hs-LPNP at patients with the homozygous hereditary family hypercholesterolemia steady against therapy by other hypolipidemic means.

Atorvastatin in doses from 10 to 80 mg reduces concentration of the general cholesterol by 30-46%, Hs-LPNP - for 41-61%, apo-V - for 34-50% and TG - for 14-33%. Results of therapy are similar at patients to a heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed lipidemia, including patients with a diabetes mellitus have 2 types.

At patients with the isolated gipertriglitseridemiya аторвастатин reduces concentration of the general cholesterol, Hs-LPNP, Hs-LPONP, apo-V and TG also increases concentration of Hs-LPVP. At patients with a disbetalipoproteinemiya reduces concentration of cholesterol of lipoproteids of the intermediate density (Hs-LPPP).

Patients with a giperlipoproteinemiya have IIA and IIb of type on Fredrikson's classification average value of increase in concentration Hs-LPVP at treatment atorvastatiny (10-80 mg) in comparison with an initial indicator makes 5,1-8,7% and does not depend on a dose. There is a considerable dozozavisimy decrease in size of ratios: the general cholesterol / Hs-LPVP and Hs-LPNP/Hs-LPVP for 29-44% and 37-55% respectively.

Atorvastatin in a dose of 80 mg authentically reduces risk of ischemic complications and mortality by 16% after a 16 weeks course, and risk of repeated hospitalization concerning the stenocardia which is followed by symptoms of ischemia of a myocardium – for 26%. With various initial concentration of Hs-LPNP (with a myocardial infarction without tooth Q and unstable stenocardia, men and women, at patients younger and 65 years are more senior) аторвастатин causes decrease in risk of ischemic complications and mortality in patients.

Decrease in concentration in a blood plasma of Hs-LPNP correlates with a dose of an atorvastatin better, than with its concentration in a blood plasma. The dose is selected taking into account therapeutic effect (see the section "Route of Administration and Doses").

The therapeutic effect is reached in 2 weeks after the beginning of therapy, reaches a maximum in 4 weeks and remains during the entire period of therapy.

Pharmacokinetics. Absorption. Atorvastatin is quickly soaked up after intake: time of achievement of its maximum concentration (TCmax) in a blood plasma reaches a maximum in 1-2 hours. At women the maximum concentration of an atorvastatin (Cmax) is 20% higher, and the area under a curve "concentration time" (AUC) – is 10% lower, than at men. Extent of absorption and concentration in a blood plasma raise in proportion to a dose. Absolute bioavailability – about 14%, and system  bioavailability   of the inhibiting  activity    concerning GMG-KOA-reduktazy – about 30%. Low system bioavailability is caused by presistemny metabolism in a mucous membrane of digestive tract and/or at "primary passing" through a liver. Meal reduces the speed and extent of absorption of drug a little (by 25% and 9% respectively what  results of definition of Cmax and AUC testify to), however decrease in Hs-LPNP is similar to that at reception of an atorvastatin on an empty stomach. In spite of the fact that after reception of an atorvastatin in the evening its concentration in a blood plasma is lower (Cmax and AUC approximately for 30%), than after reception in the morning, decrease in concentration of Hs-LPNP does not depend on time of day in which accept drug.

Distribution. The average volume of distribution of an atorvastatin makes about 381 l. Communication of an atorvastatin with proteins of a blood plasma not less than 98%. The relation of concentration of an atorvastatin in erythrocytes/blood plasma makes about 0,25, i.e. аторвастатин badly gets into erythrocytes.

Metabolism. Atorvastatin is substantially metabolized with education orto-and parahydroxylated derivatives and various products of beta oxidation. In vitro orto-and parahydroxylated metabolites have an inhibiting effect on GMG-KOA-reduktazu, comparable to that at an atorvastatin. The inhibiting activity concerning GMG-KOA-reduktazy approximately for 70% is caused by activity of the circulating metabolites. Results of the researches in vitro give the grounds to assume that the isoenzyme of CYP3A4 of a liver plays an important role in metabolism of an atorvastatin. It is confirmed by increase in concentration of an atorvastatin in a blood plasma of the person at a concomitant use of erythromycin which is inhibitor of this isoenzyme.

The researches in vitro also showed what аторвастатин is weak inhibitor of an isoenzyme CYP3A4. Atorvastatin did not exert clinically significant impact on concentration in a blood plasma of a terfenadin who is metabolized, mainly, by CYP3A4 isoenzyme therefore its significant effect on pharmacokinetics of other substrates of an isoenzyme of CYP3A4 is improbable.

Removal. Atorvastatin and his metabolites are removed mainly with bile after hepatic and/or extrahepatic metabolism (аторвастатин is not exposed to the expressed enterohepatic recirculation). The elimination half-life (T1/2) makes about 14 hours, at the same time the inhibiting effect of drug concerning GMG-KOA-reduktazy approximately is defined on 70% by activity of the circulating metabolites and about 20-30 hours thanks to their existence remain. After administration of drug inside in urine find less than 2% of a dose of an atorvastatin.

Pharmacokinetics at special groups of patients. Elderly patients. Concentration of an atorvastatin in a blood plasma at elderly patients (at the age of ≥65 years) is higher (Cmax approximately for 40%, AUC approximately for 30%), than at adult patients of young age. Distinctions in safety, efficiency or achievement of goals of hypolipidemic therapy at elderly patients in comparison with the general population are not revealed.

Children. Drug pharmacokinetics researches at children were not conducted.

The renal failure does not influence concentration of an atorvastatin in a blood plasma or its impact on indicators of lipidic exchange, in this regard change of a dose with a renal failure is not required from patients. Atorvastatin is not brought during a hemodialysis owing to intensive linkng with proteins of plasma. 

Concentration of an atorvastatin considerably increase (Cmax approximately by 16 times, AUC approximately by 11 times) at patients with alcoholic cirrhosis (a class B on a scale of Chayld-Pyyu).

Indications to use:

• primary hypercholesterolemia (a heterozygous family and single hypercholesterolemia (IIA type across Fredrikson); 
• the combined (mixed) lipidemia (IIA and IIb types across Fredrikson); 
• disbetalipoproteinemiya (the III type across Fredrikson) (as addition to a diet); 
• family endogenous gipertriglitseridemiya (the IV type across Fredrikson), resistant to a diet; 
• homozygous family hypercholesterolemia at insufficient efficiency of a dietotherapy and other not pharmacological methods of treatment; 
• primary prevention of cardiovascular complications at the patients without clinical signs of an ischemic heart disease (coronary heart disease) but having several risk factors of its development (the age is more senior than 55 years, nicotine addiction, arterial hypertension, a diabetes mellitus, genetic predisposition, including against the background of a dislipidemiya); 
• secondary prevention of cardiovascular complications at patients with an ischemic heart disease for the purpose of decrease in total rate of mortality, a myocardial infarction, a stroke, repeated hospitalization concerning stenocardia and need for revascularization.

Route of administration and doses:

Inside. To accept at any time irrespective of meal. Before an initiation of treatment drug Atorvastatin it is necessary to try to achieve control of a hypercholesterolemia by means of a diet, physical exercises and decrease in body weight from patients with obesity, and also treatment of a basic disease.

At purpose of drug the patient needs to recommend a standard gipokholesterinemichesky diet to which he has to adhere during the entire period of treatment.

The dose of drug varies from 10 mg to 80 mg of 1 times a day and is titrated taking into account initial concentration of Hs-LPNP, the purpose of therapy and individual effect on the carried-out therapy.

The maximum daily dose makes 80 mg. In an initiation of treatment and/or during increase in a dose of drug Atorvastatin it is necessary to control each 2-4 weeks concentration of lipids in a blood plasma and as appropriate to adjust a dose.

Primary hypercholesterolemia and the combined (mixed) lipidemia. Treatment begin with the recommended initial dose 10 mg of 1 times a day which is increased after four weeks depending on reaction of the patient. The maximum daily dose makes 80 mg.

Homozygous family hypercholesterolemia. Range of doses same, as well as at other types of a lipidemia. The initial dose is selected individually depending on expressiveness of a disease. At most of patients with a homozygous hereditary hypercholesterolemia the optimum effect is observed at use of drug in a daily dose of 80 mg (once). Atorvastatin is applied as additional therapy to other methods of treatment (plasma exchange) or as the main treatment if therapy by means of other methods is impossible.

At patients with abnormal liver functions care is necessary (in connection with delay of removal of an atorvastatin from an organism). In a similar situation it is necessary to control carefully clinical and laboratory indicators (regular control of activity of aspartate aminotransferase (ACT) and alaninaminotranspherase (ALT)). At substantial increase of activity of "hepatic" transaminases the dose of drug has to be reduced or treatment has to be stopped.

At patients of advanced age and at patients with diseases of kidneys the dose of drug should not be changed. The renal failure does not exert impact on concentration of an atorvastatin in a blood plasma or extent of decrease in concentration of Hs-LPNP at therapy atorvastatiny therefore dose adjustment of drug is not required.

Use in a combination with other medicines. In need of simultaneous use with cyclosporine, telapreviry or a combination tiprapavir/ritonavir the dose of drug should not exceed 10 mg a day.

It is necessary to be careful and apply the lowest effective dose of an atorvastatin at simultaneous use with HIV protease inhibitors, hepatitis C inhibitors, klaritromitsiny and itrakonazoly.

Recommendations for definition of the purpose of treatment. Recommendations of the European society of atherosclerosis. At patients with the confirmed diagnosis of an ischemic heart disease and other patients with high risk of ischemic complications the purpose of treatment is decrease in concentration of Hs-LPNP to concentration lower than 2,5 mmol/l (or less than 100 mg/dl) and the general cholesterol to concentration lower than 4,5 mmol/l (or less than 175 mg/dl).

Features of use:

Use at pregnancy and during breastfeeding. Drug use Atorvastatin is contraindicated at pregnancy and during breastfeeding. Women of reproductive age during treatment have to use adequate methods of contraception. Atorvastatin women of reproductive age can appoint only if probability of pregnancy at them very low, and the patient is informed on possible risk for a fruit during treatment.

It is unknown whether it is removed аторвастатин with breast milk. Considering a possibility of development of the undesirable phenomena in babies, in need of drug use breastfeeding should be stopped.

Before therapy by drug Atorvastatin the patient needs to appoint a standard gipokholesterinemichesky diet which he has to observe during the entire period of treatment.

At emergence of heavy undesirable effects drug use Atorvastatin should be stopped.

Action on a liver. As well as at use of other hypolipidemic means of this class, after treatment atorvastatiny noted moderated (more than by 3 times in comparison with the upper bound of norm) increase in serumal activity of "hepatic" transaminases of nuclear heating plant and ALT. Increase in activity of "hepatic" transaminases usually was not followed by jaundice or other clinical manifestations. At a dose decline of an atorvastatin, temporary or full drug withdrawal activity of "hepatic" transaminases was returned to initial level. Most of patients continued reception of an atorvastatin in a reduced dose without any clinical effects.

Prior to therapy, in 6 weeks and 12 weeks later there began drug uses Atorvastatin or after increase in its dose, and also during all course of treatment it is necessary to control indicators of function of a liver. Function of a liver should be investigated also at emergence of clinical signs of damage of a liver. In case of increase in activity of "hepatic" transaminases their activity should be controlled until it is not normalized. If increase in activity of nuclear heating plant or ALT more than by 3 times in comparison with the upper bound of norm remains, the dose decline or drug withdrawal is recommended.

Atorvastatin it is necessary to apply with care at patients who consume significant amounts of alcohol and/or have a liver disease in the anamnesis. The active disease of a liver or constantly a superactivity of "hepatic" transaminases in a blood plasma of not clear genesis are a contraindication to drug use Atorvastatin.

Action on skeletal muscles. At the patients receiving аторвастатин the mialgiya was noted. The diagnosis of a myopathy (muscle pains and weakness in combination with increase in activity of a kreatinfosfokinaza more than by 10 times in comparison with the upper bound of norm) should be assumed at patients with a diffusion mialgiya, morbidity or weakness of muscles and/or the expressed increase in activity of KFK. Therapy by drug Atorvastatin should be stopped in case of the expressed increase in activity of KFK or in the presence of the confirmed or estimated myopathy. The risk of a myopathy at treatment by other drugs of this class increased at simultaneous use of cyclosporine, fibrat, erythromycin, niacin in lipidsnizhayushchy doses (more than 1 g/days), a nefazodona, some antibiotics, azolny antifungal drugs, HIV protease inhibitors. Many of these drugs inhibit the metabolism mediated by CYP3A4 isoenzyme and/or transport of medicines.

It is known that CYP3A4 isoenzyme – the main isoenzyme of a liver participating in biotransformation of an atorvastatin. Appointing drug Atorvastatin in a combination with fibrata, erythromycin, immunodepressants, azolny antifungal drugs or niacin in lipidsnizhayushchy doses, it is necessary to weigh carefully expected advantage and possible risk. It is regularly necessary to observe patients for the purpose of detection of pains or weakness in muscles, especially within the first months of treatment and during the periods of increase in a dose of any of the specified means. In case of need the combination therapy should consider the possibility of use of the specified drugs in lower initial and maintenance doses. In similar situations it is possible to recommend periodic definition of activity of KFK though such monitoring does not allow to prevent development of a heavy myopathy.

At use of an atorvastatin, as well as other statines, exceptional cases of a rabdomioliz with the acute renal failure caused by a myoglobinuria are described. At emergence of symptoms of a possible myopathy or existence of risk factor of a renal failure against the background of a rabdomioliz (for example, a heavy acute infection, arterial hypotension, extensive surgical intervention, injuries, metabolic, endocrine and water and electrolytic disturbances and uncontrollable spasms) therapy by drug Atorvastatin should be stopped temporarily or to cancel completely.

At the differential diagnosis of pains behind a breast it is necessary to consider a possibility of increase in serumal activity of KFK at drug use Atorvastatin.

Attention! Patients need to be warned that they should see immediately a doctor at emergence of inexplicable pains or muscular weakness, especially if they are followed by an indisposition or fever.

Drug Atorvastatin contains lactose in this connection its use by patients with deficit of lactase, a lactose intolerance and a syndrome of glyukozo-galaktozny malabsorption is contraindicated.

Influence on ability to control of vehicles and mechanisms. It is necessary to be careful at control of the vehicles and other technical devices demanding the increased concentration of attention and speed of psychomotor reactions (risk of development of dizziness).

Side effects:

Classification of frequency of development of side effects of the World Health Organization (WHO):  ≥1/10 is very frequent,  from ≥1/100 to <1/10, infrequently  from ≥1/1000 to is frequent <1/100,  from ≥1/10000 to is rare <1/1000,  <1/10000, including separate messages is very rare, frequency is unknown to  according to the available data to establish the frequency of emergence it was not represented possible.
From a nervous system: often - sleeplessness, a headache, dizziness, paresthesia, an asthenic syndrome; infrequently - peripheral neuropathy, amnesia, a hypesthesia.

From sense bodys: infrequently - a sonitus; seldom - a nasopharyngitis, nasal bleeding.

From cardiovascular system: heart consciousness, vazodilatation symptoms, migraine, postural hypotension, increase in arterial pressure, phlebitis, arrhythmia.

From system of a hemopoiesis: infrequently - thrombocytopenia.

From respiratory system: often - a stethalgia.

From the alimentary system: often - nausea, diarrhea, an abdominal pain, dyspepsia, a lock, a meteorism (abdominal distention); infrequently - disturbance of flavoring perception, vomiting, pancreatitis; seldom - hepatitis, cholestatic jaundice.

From a musculoskeletal system and connecting fabric: often - a mialgiya, arthralgias, a dorsodynia, a swelling of joints; infrequently - a myopathy, myotonia; seldom - a miositis, рабдомиолиз, a tendopatiya (in certain cases with a rupture of sinews).

From urinogenital system: infrequently - sexual dysfunction, a secondary renal failure.

From integuments: often - skin rash, a skin itch; infrequently - a small tortoiseshell; very seldom - a Quincke's disease, an alopecia, violent rash, a multiformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis.

Allergic reactions: often - allergic reactions; very seldom - an anaphylaxis.

Laboratory indicators: infrequently - increase in activity of aminotransferases (nuclear heating plant, ALT), increase in activity of a serumal kreatinfosfokinaza (KFK); very seldom - a hypoglycemia, a hyperglycemia.

Others: often - peripheral hypostases; infrequently  - weakness, increased fatigue, fever, anorexia, increase in body weight.

During post-marketing use of statines, including an atorvastatin, it was reported about the following side effects: loss or decrease in memory, a depression, a sleep disorder, including sleeplessness and "dreadful" dreams, sexual dysfunction, a gynecomastia, a hyperglycemia, increase in concentration of glikozilirovanny hemoglobin, isolated cases of an intersticial disease of lungs (especially at prolonged use), cases of the immunomediated nekrotizirushchy myopathy, thrombocytopenia.

Interaction with other medicines:

The risk of development of a myopathy with rabdomiolizy and a renal failure during treatment by inhibitors of GMG-KOA-reduktazy increases at simultaneous use with cyclosporine, antibiotics (erythromycin, кларитромицин, hinupristin/dalfopristin), HIV protease inhibitors (индинавир, ритонавир), antifungal drugs (флуконазол, итраконазол, кетоконазол), nefazodony. All these drugs inhibit an isoenzyme of CYP3A4 which takes part in metabolism of an atorvastatin in a liver.

Similar interaction is possible at simultaneous use of an atorvastatin with fibrata and niacin in lipidsnizhayushchy doses (more than 1 g a day).

At simultaneous use with HIV protease inhibitors, hepatitis C inhibitors, klaritromitsiny and itrakonazoly it is necessary to be careful and apply the lowest effective dose of an atorvastatin.

CYP3A4 isoenzyme inhibitors. As аторвастатин it is metabolized by CYP3A4 isoenzyme, combined use of an atorvastatin with inhibitors of an isoenzyme CYP3A4 can lead to increase in concentration of an atorvastatin in a blood plasma. Extent of interaction and effect of potentiation are defined by variability of impact on CYP3A4 isoenzyme.

Inhibitors of transport protein OATP1B1. Atorvastatin and his metabolites are substrates of transport protein OATP1B1. OATP1B1 inhibitors (for example, cyclosporine) can increase bioavailability of an atorvastatin.

Erythromycin / кларитромицин. At simultaneous use of an atorvastatin and erythromycin or a klaritromitsin which inhibit CYP3A4 isoenzyme increase in concentration of an atorvastatin in a blood plasma was observed.

Inhibitors of proteases. Simultaneous use of an atorvastatin with the inhibitors of proteases known as CYP3A4 isoenzyme inhibitors, is followed by increase in concentration of an atorvastatin in a blood plasma.

Diltiazem. Combined use of an atorvastatin in a dose of 40 mg with diltiazem in a dose of 240 mg leads to increase in concentration of an atorvastatin in a blood plasma.

Itrakonazol. Simultaneous use of an atorvastatin and itrakonazol led to increase in concentration of an atorvastatin in a blood plasma.

Grapefruit juice. As grapefruit juice contains one or more components which inhibit CYP3A4 isoenzyme, its overconsumption (more than 1,2 l a day) can cause increase in concentration of an atorvastatin in a blood plasma.

CYP3A4 isoenzyme inductors. Combined use of an atorvastatin with CYP3A4 isoenzyme inductors (for example, efavirenzy, Phenytoinum or rifampicin) can lead to decrease in concentration of an atorvastatin in a blood plasma. Owing to the dual mechanism of interaction with rifampicin (the inductor of an isoenzyme CYP3A4 and inhibitor of transport protein of hepatocytes OATP1B1) simultaneous use of an atorvastatin and rifampicin as the delayed reception of an atorvastatin after reception of rifampicin leads to essential decrease in concentration of an atorvastatin in a blood plasma is recommended.

Antacids. At a concomitant use in an atorvastatin and the suspension containing magnesium and aluminum hydroxides concentration of an atorvastatin in a blood plasma decreases.

Phenazone. Atorvastatin does not influence phenazone pharmacokinetics therefore interaction with other drugs, the metabolized same enzymes of cytochrome, is not expected.

Kolestipol. At simultaneous use of a kolestipol concentration of an atorvastatin in a blood plasma decreased approximately by 25%, however the hypolipidemic effect of a combination of an atorvastatin and kolestipol surpassed that of each drug separately.

Digoxin. At use of digoxin in a combination with atorvastatiny in a dose of 80 mg/days concentration of digoxin increased approximately by 20% therefore such patients have to be under observation.

Oral contraceptives. At simultaneous use of the atorvastatin and oral contraceptive containing Norethisteronum and ethinylestradiol increase in absorption of contraceptives and increase in their concentration in a blood plasma is possible. This effect should be considered at the choice of an oral contraceptive for the woman accepting аторвастатин.

Terfenadin. Atorvastatin at simultaneous use did not exert clinically significant impact on pharmacokinetics of a terfenadin.

Warfarin. Simultaneous use of an atorvastatin with warfarin can increase impact of warfarin on blood coagulation indicators (reduction of a prothrombin time) in the first days. This effect disappears after 15 days of simultaneous use of the specified drugs.

Amlodipin. At simultaneous use of an atorvastatin in a dose of 80 mg and an amlodipina in a dose of 10 mg the pharmacokinetics of an atorvastatin in an equilibrium state did not change.

Fuzidovy acid. Cases of development of a rabdomioliz in the patients applying аторвастатин and fuzidovy acid are noted.

Colchicine. Myopathy cases at simultaneous use of an atorvastatin and colchicine were registered. At a combination therapy these drugs it is necessary to be careful.

Cimetidinum. When studying interaction of an atorvastatin with Cimetidinum of signs of clinically significant interaction it is not revealed.

Other accompanying therapy. Simultaneous use of an atorvastatin with the medicines reducing concentration of endogenous steroid hormones (including Cimetidinum, кетоконазол, Spironolactonum), increases risk of decrease in endogenous steroid hormones (it is necessary to be careful).

In clinical trials аторвастатин applied in combination with antihypertensives and estrogen which appointed as replacement therapy; symptoms of clinically significant undesirable interaction are noted. Interaction researches with specific drugs were not conducted.

Contraindications:

- hypersensitivity to any of drug components; 
- a liver disease in an active stage; 
- increase in activity of "hepatic" transaminases in a blood plasma of not clear genesis more than by 3 times in comparison with the upper bound of norm; 
- diseases of skeletal muscles; 
- deficit of lactase, lactose intolerance, syndrome of glyukozo-galaktozny malabsorption; 
- pregnancy and period of breastfeeding; 
- age up to 18 years (not enough clinical data on efficiency and safety for this age group).

With care. Use for the patients abusing alcohol or at the patients having in the anamnesis of a disease of a liver.

Overdose:

Cases of overdose are not described. In case of overdose the following general events are necessary: monitoring and maintenance of vital signs of an organism, and also prevention of further absorption of drug (gastric lavage, reception of absorbent carbon or purgatives).

At development of a myopathy with the subsequent rabdomioliz and an acute renal failure drug it is necessary to cancel and begin infusion of diuretic and sodium bicarbonate immediately.

Rabdomioliz can lead to a hyperpotassemia which elimination requires intravenous administration of solution of Calcii chloridum or solution of calcium of a gluconate, infusion  of 5% of solution of a dextrose (glucose) with insulin, use of kaliyobmenny pitches.

As drug actively contacts proteins of a blood plasma, the hemodialysis is not effective.

Storage conditions:

To store in the place protected from light at a temperature not over 25 ºС. To store in the place, unavailable to children. Period of validity 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 10 mg, 20 mg, 40 mg and 80 mg. 10, 15 or 30 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. 30, 60 or 90 tablets in bank from polyethylene of high density. 1, 2 or 3 blister strip packagings on 10 tablets, 1, 2 or 4 blister strip packagings on 15 tablets, 1, 2 or 3 blister strip packagings on 30 tablets or one bank together with the instruction on a medical use in a pack from a cardboard.