Atorvastatin OBL

General characteristics. Structure:

Active ingredient: 10 mg, 20 mg, 40 mg or 80 mg of an atorvastatin (in the form of calcic salt) in 1 tablet.

Excipients: Mannitolum, macrogoal 6000 (polyethyleneglycol 6000), кросповидон, sodium of a kroskarmelloz, magnesium stearate.

Excipients for a cover: Опадрай II (series 85), polyvinyl alcohol; a macrogoal, talc, titanium dioxide, an aluminum varnish on the basis of indigo carmine dye, dye ferrous oxide a yellow, aluminum varnish on the basis of dye quinolinic yellow, an aluminum varnish on the basis of dye charming red, an aluminum varnish on the basis of azoruby dye, an aluminum varnish on the basis of dye a sunset yellow.

Pharmacological properties:

Pharmacodynamics. Atorvastatin is the selection competitive inhibitor of GMG-KOA-reduktazy - the enzyme turning 3-hydroxy-3-methylglutaryl-coenzyme A into mevalonovy acid, being the predecessor of sterol including cholesterol.

Triglycerides (TG) and cholesterol are included lipoproteins of very low density (LPONP) at synthesis in a liver, come to a blood plasma and are transported in peripheral fabrics. Lipoproteins of the low density (LPNP) are formed of LPONP during interaction with LPNP receptors. Researches showed that increase in concentration of the general cholesterol in a blood plasma, LPNP and apolipoprotein B (apo-V) promotes development of atherosclerosis and enter into group of risk factors of developing of cardiovascular diseases while increase in concentration of lipoproteins of the high density (LPVP) reduces risk of development of cardiovascular diseases.

Atorvastatin reduces concentration of cholesterol and lipoproteins in a blood plasma due to oppression of GMG-KOA-reduktazy of inhibitor, synthesis of cholesterol in a liver and increases in number of "hepatic" receptors of LPNP at surfaces of cells that leads to strengthening of capture and a catabolism of LPNP.

Atorvastatin reduces synthesis and concentration holesterina-LPNP, the general cholesterol, apo-V at patients with a homozygous and heterozygous family hypercholesterolemia, primary hypercholesterolemia and the mixed lipidemia.

Causes also decrease in concentration holesterina-LPONP both TG and increase in concentration holesterina-LPVP and apolipoprotein A (apo-A).

At patients with a disbetalipoproteinemiya reduces concentration of lipoproteins of intermediate density holesterina-LPPP.

Atorvastatin in doses of 40 mg reduces concentration of the general cholesterol by 37%, LPNP - for 50%, apo-V - for 42% and TG - for 29%; causes increase in concentration holesterina-LPVP and apo-A.

Dozozavisimo reduces concentration of LPNP at patients with a homozygous family hypercholesterolemia, resistant to therapy by other hypolipidemic means.

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

Pharmacokinetics. Absorption and distribution. Absorption – high. The maximum concentration (Cmax) in a blood plasma after intake is reached in 1-2 h Cmax at women 20% higher, the area under a curve "concentration time" (AUC) – is 10% lower, than at men that has no clinical value. Cmax at patients with alcoholic cirrhosis (a class B on a scale of Chayld-Pyyu) by 16 times, and AUC – is 11 times higher than norm.

Meal reduces the speed and extent of absorption of drug a little (approximately by 25% and 9% respectively), however decrease holesterina-LPNP is similar to that at use of an atorvastatin without concomitant use of food.

After intake of an atorvastatin in the evening concentration in a blood plasma is lower (Cmax and AUC approximately for 30%), than after reception in the morning, however, decrease in concentration holesterina-LPNP does not depend on time of day in which accept drug. Linear dependence between extent of absorption and a dose of drug is revealed.

Bioavailability – 12%, system bioavailability of the inhibiting activity concerning GMG-KOA-reduktazy – about 30%. Low system bioavailability is caused by presistemny metabolism in digestive tract and at "primary passing" through a liver.

The average volume of distribution – 381 l, communication with proteins of a blood plasma – 98%.

The relation of concentration of an atorvastatin in erythrocytes/blood plasma makes about 0,25, that is аторвастатин badly gets into erythrocytes.

Metabolism and removal. Atorvastatin is metabolized preferential in a liver under the influence of isoenzymes of CYP3A4, CYP3A5 and CYP3A7 with formation pharmacological of active metabolites (orto-and para-hydroxylated derivatives, beta oxidation products). In vitro orto-and para-hydroxylated metabolites have an inhibiting effect on GMG-KOA-reduktazu, comparable to that of an atorvastatin. The inhibiting effect of drug concerning GMG-KOA-reduktazy approximately is defined on 70% by activity of the circulating metabolites which remains approximately during 20-30 h, thanks to their existence.

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 at a concomitant use of erythromycin which is also inhibitor of this isoenzyme.

Atorvastatin is weak inhibitor of an isoenzyme CYP3A4.

It is removed generally through intestines after hepatic and/or extrahepatic metabolism (drug is not exposed to the expressed enterohepatic recirculation). An elimination half-life (T1/2) – about 14 h. Less than 2% of the dose accepted inside are defined in urine.

It is not removed during a hemodialysis owing to intensive linkng with proteins of a blood plasma.

Cmax and AUC drug at elderly patients (65 years are also more senior) for 40 and 30% respectively, above, than at patients of young age, however it has no clinical value.

The renal failure does not influence concentration of drug in a blood plasma.

Indications to use:

In combination with a diet for decrease in the increased concentration of the general cholesterol, cholesterol/LPNP, apolipoprotein B and triglycerides and increase concentration of LPVP cholesterol at patients with primary hypercholesterolemia, a heterozygous family and single hypercholesterolemia and the combined (mixed) lipidemia (the IIa and IIb types across Fredrikson).

In combination with a diet for treatment of patients with the increased serumal concentration of triglycerides (type IV across Fredrikson) and patients with a disbetalipoproteinemiya (type III across Fredrikson) at whom the dietotherapy does not give adequate effect.

For decrease in concentration of the general cholesterol and cholesterol/LPNP at patients with a homozygous family hypercholesterolemia when the dietotherapy and other not pharmacological methods of treatment are insufficiently effective.

Route of administration and doses:

Inside at any time, irrespective of meal time. The dose of drug fluctuates ranging from 10 mg to 80 mg a day, and is selected taking into account initial concentration holesterina-LPNP, the purposes of therapy and the individual therapeutic response to the carried-out therapy. For most of patients the initial dose makes 10 mg of 1 times a day.

In an initiation of treatment and/or during increase in a dose of the drug Atorvastatin-OBL, it is necessary to control each 2-4 weeks concentration of lipids in a blood plasma and as appropriate to korrigirovat a drug dose.

Primary hypercholesterolemia and the mixed lipidemia, and also type III and IV across Fredrikson. In the majority cases there is enough use of a dose of 10 mg of 1 times a day. The essential therapeutic effect is observed in 2 weeks, as a rule, and the maximum therapeutic effect is usually observed in 4 weeks. At prolonged treatment this effect remains. The maximum daily dose – 80 mg/days.

Homozygous family hypercholesterolemia. The drug Atorvastatin-OBL is used in a dose 80 mg of 1 times a day.

Dose adjustments of the drug Atorvastatin-OBL at patients with a renal failure and at patients are more senior than 65 years it is not required.

The drug Atorvastatin-OBL dose at patients with insufficiency of function of a liver needs to be reduced at constant control of activity of "hepatic" transaminases: aspartate aminotransferases (nuclear heating plant) and alaninaminotranspherase (ALT).

Features of use:

Use at pregnancy during breastfeeding. The drug Atorvastatin-OBL is contraindicated during pregnancy.

In case of diagnosing of pregnancy in the course of therapy atorvastatiny, administration of drug has to be stopped as soon as possible, and the patient is warned about potential risk for a fruit. The drug Atorvastatin-OBL is contraindicated during breastfeeding.

Atorvastatin is allocated in breast milk therefore in need of use of drug in the period of a lactation, breastfeeding should be stopped.

Before drug Atorvastatin-OBL use the patient needs to recommend a standard gipokholesterinemichesky diet which he has to continue to observe during the entire period of therapy.

Drug can be used at women of reproductive age only if probability of pregnancy at them very low, and the patient is informed on possible risk for a fruit during treatment. Women of reproductive age during treatment by drug have to apply reliable methods of contraception.

Influence 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 activity of "hepatic" ACT and ALT transaminases which usually was not followed by jaundice or other clinical manifestations.

At a dose decline, temporary or full drug withdrawal activity of "hepatic" transaminases is returned to initial level.

Prior to therapy, in 6 weeks and 12 weeks later began uses of drug or after increase in a dose, and also at emergence of clinical signs of damage of a liver it is necessary to control indicators of function of a liver. In case of increase in activity of "hepatic" transaminases control is exercised until activity is not normalized. If increase in activity of ACT or ALT more than by 3 times in comparison with the upper bound of norm remains, the dose decline or drug withdrawal is recommended. Drug should be used with care at the patients abusing alcohol and/or with liver diseases in the anamnesis.

Action on skeletal muscles. At the patients receiving аторвастатин mialgiya cases were noted. It is necessary to assume the diagnosis of a myopathy at patients with a diffusion mialgiya, morbidity or weakness of muscles and/or the expressed increase in activity of KFK (more than by 10 times in comparison with the upper bound of norm). Therapy by drug should be stopped in case of the expressed increase in activity of KFK, in the presence of the confirmed myopathy or suspicion on its development. The risk of a myopathy at treatment by other drugs of this class increases at simultaneous use of cyclosporine, fibrat, erythromycin, niacin in lipidsnizhayushchy doses (more than 1 g/days) or azolny antifungal means. Many of these drugs inhibit the metabolism mediated by CYP3A4 isoenzyme and/or transport of medicinal substances. CYP3A4 isoenzyme - the main isoenzyme of a liver participating in biotransformation of an atorvastatin.

In need of a concomitant use with fibrata, erythromycin, immunodepressants, azolny antifungal means or niacin in lipidsnizhayushchy doses (more than 1 g/days), the doctor has to correlate carefully expected advantage of treatment and possible risk of development of a myopathy. It is regularly necessary to observe patients for the purpose of detection of pains or weakness in muscles, especially within the first months of therapy and during increase in a dose of any of the specified means. In case of need the combination therapy should consider the possibility of use of lower initial and maintenance doses of above-mentioned means. Temporary cancellation of an atorvastatin can be fuzidovy acid, reasonable during treatment. In similar situations it is possible to recommend periodic control of activity of KFK though such monitoring does not allow to prevent development of a heavy myopathy.

At use of drug exceptional cases of a rabdomioliz with the acute renal failure caused by a myoglobinuria are described. The previous renal failure can be risk factor of development of a rabdomioliz. Such patients should provide more careful control of a condition of skeletal muscles. At emergence of symptoms of a possible myopathy or existence of risk factors of development 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 electrolytic disturbances, uncontrollable spasms) therapy by drug should be stopped temporarily or to cancel completely.

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

Influence on ability to control of vehicles and to service of moving mechanisms.  Data on influence of an atorvastatin on ability to control of vehicles, to service of moving mechanisms and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions no. However, considering a possibility of development of dizziness, it is necessary to be careful when performing of the listed types of activity.

Side effects:

Undesirable reactions are listed according to the following gradation: often (≥1%, <10%); infrequently (> 0,1%, <1%); seldom (> 0,01%, <0,1%); very seldom (<0,01%), including separate messages.

Allergic reactions: often – a skin itch, skin rash; infrequently – a small tortoiseshell; very seldom – a Quincke's disease, violent rash, a polymorphic exudative erythema (including Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease).

From a nervous system: often – a headache, dizziness, sleeplessness, an asthenic syndrome, an indisposition, weakness, paresthesias, hypesthesias; infrequently – peripheral neuropathy, amnesia.

From digestive tract: often – a lock, a meteorism, dyspepsia, nausea, diarrhea, an abdominal pain; infrequently – anorexia, vomiting, pancreatitis; seldom – hepatitis, cholestatic jaundice (including obstructive).

From skeletal and muscular and connecting fabric: often – a mialgiya, a joint pain, a dorsodynia; infrequently – a myopathy, myotonia, an arthralgia; seldom – a miositis, рабдомиолиз.

From an acoustic organ and labyrinth disturbances: infrequently – a sonitus.

From endocrine system: infrequently – an alopecia, a hyperglycemia, a hypoglycemia, increase in activity of a serumal kreatininfosfokinaza (KFK).

From blood and lymphatic system: infrequently – thrombocytopenia.

Others: often – a stethalgia, peripheral hypostases; infrequently – increased fatigue, increase in body weight, disturbance of a potentiality, a secondary renal failure; there are separate messages on development of an atonic fasciitis (connection using an atorvastatin is definitely not established).

If any of the side effects specified in the instruction are aggravated, or you noticed any other side effects which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

During treatment by GMG-KOA-reduktazy inhibitors at simultaneous use of cyclosporine, fibrat, erythromycin, a klaritromitsin, antifungal means, derivatives of an azol, and niacin in lipidsnizhayushchy doses (more than 1 g/days) the risk of development of a myopathy increases.

Inhibitors of an isoenzyme of CYP 3 A 4. As аторвастатин it is metabolized by means of 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 of OATP 1 B 1. Atorvastatin and his metabolites are substrates of transport protein OATP1B1. OATP1B1 inhibitors (for example, cyclosporine) can increase bioavailability of an atorvastatin. Combined use of an atorvastatin in a dose of 10 mg and cyclosporine in a dose of 5,2 mg/kg/days led to increase in concentration of an atorvastatin in a blood plasma by 7,7 times.

Erythromycin / кларитромицин. At simultaneous use of an atorvastatin and erythromycin (on 500 mg 4 times a day) or a klaritromitsina (on 500 mg 2 times a day), CYP3A4 isoenzyme inhibitors, increase in concentration of an atorvastatin in a blood plasma was observed.

Inhibitors of proteases. Simultaneous use of an atorvastatin with inhibitors of proteases, the known inhibitors of an isoenzyme CYP3A4, is followed by increase in concentration of an atorvastatin in a blood plasma (at simultaneous use with Cmax erythromycin of an atorvastatin increases by 40%).

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.

Cimetidinum. Clinically significant interaction of an atorvastatin with Cimetidinum is not revealed.

Itrakonazol. Simultaneous use of an atorvastatin in doses from 20 mg to 40 mg and an itrakonazol in a dose of 200 mg carried out to increase in AUC value of an atorvastatin.

Grapefruit juice. As grapefruit juice contains one or more components which inhibit CYP3A4 isoenzyme, its overconsumption (more than 1,2 l during

5 days) can raise AUC of an atorvastatin by 2,5 times and concentration of an atorvastatin and its active metabolites in a blood plasma by 1,3 times.

Inductors of an isoenzyme of CYP 3 A 4. Combined use of an atorvastatin with CYP3A4 isoenzyme inductors (for example, efavirenzy 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 a rnfampitsin leads to essential decrease in concentration of an atorvastatin in a blood plasma is recommended.

Antacids. The concomitant use in the suspension containing magnesium hydroxide and aluminum hydroxide reduced concentration of an atorvastatin in a blood plasma approximately by 35%, however extent of decrease in maintenance of LPNP at the same time did not change.

Phenazone. Atorvastatin does not influence phenazone pharmacokinetics therefore interactions with other drugs, the metabolized same isoenzymes of cytochrome, it 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.

Гемфиброзил / derivatives of fibroyevy acid. The risk of the atorvastatin-induced myopathy can increase at simultaneous use of an atorvastatin and derivatives of fibroyevy acid (fibrata), owing to inhibition gemfibrozily (according to in vitro) a glyukuronidny way of metabolism of an atorvastatin.

Digoxin. At repeated reception of digoxin and an atorvastatin in a dose of 10 mg equilibrium concentration of digoxin in a blood plasma did not change. However at use of digoxin in a combination with atorvastatnny in a dose of 80 mg/days concentration of digoxin increased approximately by 20%. The patients receiving digoxin in combination with atorvastatiny demand the corresponding observation.

Azithromycin. At simultaneous use of an atorvastatin in a dose of 10 mg of 1 times a day and azithromycin in a dose of 500 mg of 1 times a day concentration of an atorvastatin in a blood plasma did not change.

Oral contraceptives. At the simultaneous use of an atorvastatin and oral contraceptives containing Norethisteronum and ethinylestradiol substantial increase of AUC of Norethisteronum and ethinylestradiol approximately for 30% and 20% respectively was observed. This effect should be considered at the choice of an oral contraceptive for the woman accepting аторвастатин.

Terfenadin. At simultaneous use of an atorvastatin and terfenadin of clinically significant changes of pharmacokinetics of a terfenadin it is not revealed.

Warfarin. Signs of clinically significant interaction of an atorvastatin with warfarin are not revealed.

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. During the post-market researches noted cases of development of a rabdomioliz in the patients accepting at the same time fuzidovy acid and аторвастатин. For patients it is necessary to observe and consider carefully that temporary cancellation of an atorvastatin can be reasonable.

Other interactions. In clinical trials use of an atorvastatin along with hypotensive and hypoglycemic drugs did not reveal clinically significant interaction.

Contraindications:

Hypersensitivity to any of drug components; active diseases of a liver or increase in activity of "hepatic" enzymes of not clear genesis (more than by 3 times in comparison with the upper bound of norm); myopathy; pregnancy and the period of breastfeeding, and also use for the women of reproductive age who are not using adequate methods of contraception; age up to 18 years (efficiency and safety of use are not established).

With care. Alcoholism, liver diseases in the anamnesis, diseases of muscular system (in the anamnesis from use of other representatives of group of inhibitors of GMG-KOA-reduktazy), heavy disturbances of electrolytic balance, endocrine (hyperthyroidism) and metabolic disturbances, arterial hypotension, heavy acute infections (sepsis), uncontrollable epilepsy, extensive surgical interventions, injuries.

Overdose:

Treatment: The specific antidote is absent. In case of overdose it is necessary to carry out a symptomatic treatment. The hemodialysis is inefficient (as аторвастатин contacts proteins of a blood plasma).

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 10 mg, 20 mg, 40 mg, 80 mg. On 10, 14, 15, 20 or 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2, 3, 4, 5 or 6 blister strip packagings together with the application instruction place in a pack from a cardboard.