Атомакс®

General characteristics. Structure:

Active agent: Atorvastatin of 10 mg and 20 mg in the form of an atorvastatin of calcium of trihydrate.
Excipients: Calcium a carbonate easy, lactose, starch, croscarmellose sodium, povidone (k-30), magnesium stearate, silicon dioxide colloid anhydrous, кросповидон, a primelloza 15 CPS, the talc purified titanium dioxide, triacetin.
Description: Round biconvex tablets, coated almost white color, with risky on one party. The easy roughness is allowed.

Pharmacological properties:

Pharmacodynamics. Hypolipidemic drug. Atorvastatin — the selection competitive inhibitor of HMG-CoA reductase — the key enzyme turning 3-hydroxy-3-metilglyutarilkoenzim, And in mevalonovy acid — the predecessor of steroids, including cholesterol. In a liver triglycerides and cholesterol are included lipoproteins of very low density (LPONP), come to a blood plasma and are transported in peripheral fabrics. Lipoproteins of the low density (LPNP) which catabolize at interaction with highly - affine receptors of LPNP are formed of LPONP.

Atorvastatin reduces levels of cholesterol and lipoproteins in a blood plasma, inhibiting HMG-CoA reductase in a liver and, increasing number of "hepatic" LPNP of receptors by surfaces of cells that leads to strengthening of capture and a catabolism of cholesterol/LPNP.

Atorvastatin reduces education cholesterol/LPNP and number of particles of LPNP. It causes the expressed and permanent increase in activity of LPNP of receptors, and also has favorable effect on quality of the circulating LPNP. Atorvastatin effectively reduces the cholesterol/LPNP level at patients with a homozygous hypercholesterolemia which usually does not give in to therapy by other hypolipidemic means.

When studying a dozozavisimost of effect of an atorvastatin it was shown that drug (in a dose of 10-80 mg) reduced levels of the general cholesterol (by 30–46%), cholesterol/LPNP (for 41–61%), apolipoprotein B (for 34–50%) and triglycerides (for 14–33%).

Patients had similar results of treatment with a heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed lipidemia, including at patients with a non-insulin-dependent diabetes mellitus.

Atorvastatin reduces levels of the general cholesterol, cholesterol/LPNP, cholesterol / ЛПОНП, apolipoprotein B, triglycerides and the cholesterol which is not a part of LPVP and increases the cholesterol/LPVP level at patients with the isolated gipertriglitseridemiya. Atorvastatin reduces the level of cholesterol of lipoproteins of intermediate density at patients with a disbetalipoproteinemiya.

As well as LPNP, lipoproteins containing triglycerides, including LPONP, lipoproteins of intermediate density and the remains also accelerate development of atherosclerosis.

Increase in level of triglycerides in a blood plasma is often found in a combination to decrease in the cholesterol/LPVP level and existence of particles of LPNP of the small size, and also in combination with nonlipid metabolic risk factors of the coronary heart disease (CHD). It is not proved yet that increase in the general level of triglycerides in a blood plasma is independent risk factor of an ischemic heart disease. Also it is not proved that increase in the cholesterol/LPVP level or decrease in level of triglycerides in itself influences risk of coronary and other cardiovascular complications and mortality of patients.

Atorvastatin and some of his metabolites pharmacological are active.

Primary target organ of action of an atorvastatin is the liver where synthesis of cholesterol and clearance of LPNP is carried out.

Dynamics of the cholesterol/LPNP level correlates with a drug dose better, than with its concentration in a blood plasma.
The dose of an atorvastatin should be selected taking into account therapeutic effect.

Pharmacokinetics. Absorption
Atorvastatin is quickly absorbed after intake; The Maximum concentration in a blood plasma (Cmax) is reached in 1–2 h. Extent of absorption and concentration of an atorvastatin in a blood plasma raise in proportion to a dose.

Bioavailability of tablets of an atorvastatin in comparison with solution makes 95–99%. Absolute bioavailability is equal about 14%, and system bioavailability of the inhibiting activity concerning HMG-CoA reductase — about 30%.

Low system bioavailability is explained with presistemny clearance in a mucous membrane of digestive tract and/or metabolism at "the first passing" through a liver.

Though food reduces the speed and extent of absorption approximately by 25% and 9% respectively (what results of definition of Cmax and the relation of the area under curve/concentration — time (AUC), however the cholesterol/LPNP level testify at reception of an atorvastatin on an empty stomach to and during food decreases to the same extent. After reception of an atorvastatin in the evening levels in a blood plasma are lower than it (Cmax and AUC approximately for 30%), than after reception in the morning. However extent of decrease in the cholesterol/LPNP level does not depend on time of administration of drug during the day.

Distribution
The average volume of distribution makes about 381 l. Extent of linkng with proteins of a blood plasma — 98%. The relation of levels of an atorvastatin in erythrocytes/plasma makes about 0,25 that indicates low penetration of an atorvastatin into erythrocytes.

Metabolism
Atorvastatin is actively metabolized with education орто — and parahydroxylated derivatives and various products of beta oxidation. In vitro the inhibiting effect орто — and parahydroxylated metabolites concerning HMG-CoA reductase is comparable to that of an atorvastatin. The inhibiting activity concerning HMG-CoA reductase in a blood plasma approximately for 70% is caused by active metabolites. The researches in vitro testify to importance of metabolism of an atorvastatin under the influence of hepatic P450 3A4 cytochrome; 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 P450 3A4 cytochrome.

At animals the ortho-hydroxymetabolite is exposed to a further glyukuronirovaniye.

Removal
Atorvastatin and his metabolites are removed mainly with bile after hepatic and/or extrahepatic metabolism; however аторвастатин, apparently, is not exposed to enterohepatic recirculation. The elimination half-life (T1/2) makes about 14 h, however the elimination half-life of the inhibiting activity concerning HMG-CoA reductase is equal to 20-30 h that is explained by existence of active metabolites. After intake in urine find less than 2% of a dose of drug.
Pharmacokinetics in special clinical cases

Concentration of an atorvastatin in a blood plasma at elderly people (at the age of more than 65 years) is higher (Cmax approximately for 40%, AUC approximately for 30%), than at adult patients of young age. However, distinctions in safety, efficiency or achievement of goals of hypolipidemic therapy at elderly people in comparison with the general population it was revealed not.

Drug pharmacokinetics researches at children were not conducted.

Concentration of an atorvastatin in a blood plasma at women differ (Cmax about 20% higher, and AUC 10% lower) from those at men. However, clinically significant distinctions of influence of drug on lipidic exchange at men and women it is not revealed.

Diseases of kidneys do not exert impact on concentration of an atorvastatin in a blood plasma or its effect on indicators of lipidic exchange. In this regard change of a dose with a renal failure is not required from patients.

Though researches at patients with end-stages of diseases of kidneys were not conducted, however the hemodialysis is hardly capable to strengthen considerably clearance of an atorvastatin as it actively contacts proteins of plasma.

Concentration of an atorvastatin considerably increase (Cmax and AUC approximately in 16 and 11 times respectively) at patients with alcoholic cirrhosis (on Chayld-Pyyu In).

Indications to use:

In combination with a diet for decrease in the increased levels of the general cholesterol, cholesterol/LPNP, apolipoprotein B and triglycerides and increase in level 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 levels 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 levels 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:

Before purpose of ATOMAKCA sick it is necessary to recommend a standard hypolipidemic diet which it has to continue to observe during the entire period of therapy.

The initial dose averages 10 mg of 1 times/days. The dose varies from 10 to 80 mg of 1 times/days. Drug can be accepted with food or irrespective of meal time at any time. The dose is selected taking into account the cholesterol/LPNP initial levels, by the purposes of therapy and individual effect. In an initiation of treatment and/or during increase in a dose of Atomaks it is necessary to control each 2–4 weeks levels of lipids in a blood plasma and as appropriate to korrigirovat a dose.

Primary hypercholesterolemia and the mixed lipidemia
In the majority cases there is enough purpose of a dose of 10 mg of drug of Atomaks 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.

Use of drug for patients with a renal failure and diseases of kidneys does not exert impact on the level of an atorvastatin in a blood plasma or extent of decrease in maintenance of cholesterol/LPNP at its use therefore change of a dose of drug is not required.

At use of drug for elderly patients of distinctions in safety, efficiency or achievement of goals of hypolipidemic therapy in comparison with the general population it was not noted.

Features of use:

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

Use of inhibitors of GMG-KOA-reduktazy for decrease in level of lipids in blood can lead to change of the biochemical indicators reflecting function of a liver. Function of a liver should be controlled before therapy, in 6 weeks, 12 weeks after the beginning of reception of Atomaks and after each increase in a dose, and also periodically, for example, each 6 months. Increase in activity of "hepatic" enzymes in blood serum can be observed during therapy by Atomaks. Patients at whom increase in level of transaminases is noted have to be under control before return of level of enzymes to norm. If values of alaninaminotranspherase (ALT or asparaginaminotransferaz (nuclear heating plant) more than by 3 times exceed the level of an upper admissible limit, it is recommended to lower Atomaks's dose or to stop treatment.

Атомакс it is necessary to apply with care at the patients who are abusing alcohol and/or having a liver disease. The active disease of a liver or permanent increase in activity of aminotransferases of not clear genesis serve contraindications to purpose of Atomaks.

Treatment atorvastatiny can cause a myopathy. The diagnosis of a myopathy (pains and weakness in muscles in combination with increase in activity of a kreatinfosfokinaza (KFK) more than by 10 times in comparison with the upper bound of norm) should be discussed at patients with widespread mialgiya, morbidity or weakness of muscles and/or the expressed increase in activity of KFK. Patients need to be warned that they should report immediately to the doctor about emergence of inexplicable pains or weakness in muscles if they are followed by an indisposition or fever. Therapy by Atomaks 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, Niacinum or azolny antifungal means. Many of these drugs inhibit the metabolism mediated by P450 3A4 cytochrome and/or transport of medicines. Atorvastatin biotransformirutsya under the influence of CYP 3A4. Appointing аторвастатин in a combination with fibrata, erythromycin, immunosuppressive means, azolny antifungal drugs or Niacinum in hypolipidemic doses, it is necessary to weigh carefully expected advantage and risk of treatment and to regularly 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 drug. In similar situations it is possible to recommend periodic definition of activity of KFK though such control does not allow to prevent development of a heavy myopathy.

At use of an atorvastatin, as well as other means of this class, cases of a rabdomioliz with the acute renal failure caused by a myoglobinuria are described. Therapy by Atomaks should be stopped temporarily or to cancel completely at emergence of signs of a possible myopathy or existence of risk factor of development of a renal failure against the background of a rabdomioliz (for example, a heavy acute infection, arterial hypotension, serious operation, an injury, heavy exchange, endocrine and electrolytic disturbances and uncontrollable spasms).

Before therapy by Atomaks it is necessary to try to achieve control of a hypercholesterolemia by an adequate dietotherapy, increase in physical activity, decrease in body weight from patients with obesity and treatments of other states.

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

Influence on ability of driving and work with mechanisms: about adverse influence of Atomaks on ability to drive the car and work with mechanisms it was not reported.

Side effects:

From the central nervous system: headache, dizziness, asthenic syndrome, sleeplessness or drowsiness, dreadful dreams, amnesia, paresthesias, peripheral neuropathy, emotional lability, ataxy, hyperkinesias, depression, hypesthesia.
From sense bodys: an amblyopia, a ring in ears, dryness of a conjunctiva, accommodation disturbance, a hematopsia, deafness, increase in intraocular pressure, a parosmiya, a food faddism, loss of flavoring feelings.
From cardiovascular system: stethalgia, heartbeat, vazodilatation, orthostatic hypotension, phlebitis, arrhythmia.
From system of a hemopoiesis: anemia, lymphadenopathy, thrombocytopenia.
From respiratory system: bronchitis, rhinitis, диспноэ, bronchial asthma, nasal bleeding.
From the alimentary system: nausea, heartburn, a lock or diarrhea, a meteorism, a gastralgia, an abdominal pain, anorexia or increase in appetite, dryness in a mouth, an eructation, a dysphagy, vomiting, stomatitis, an esophagitis, a glossitis, a gastroenteritis, hepatitis, hepatic colic, a cheilitis, a duodenum ulcer, pancreatitis, cholestatic jaundice, increase in activity of "hepatic" enzymes, rectal bleeding, a melena, bleeding of gums, tenesmus.
From a musculoskeletal system: arthritis, myotonia of legs, bursitis, miositis, myopathy, arthralgia, mialgiya, рабдомиолиз, contractures of joints, dorsodynia.
From urinogenital system: urogenital infections, peripheral hypostases, a dysuria (including a pollakiuria, a nocturia, an incontience of urine or a delay of an urination, imperative desires on urinations), nephrite, cystitis, a hamaturia, vaginal bleedings, uterine bleeding, an urolithiasis, a metrorrhagia, an epididymite, decrease in a libido, impotence, disturbance of an ejaculation.
From integuments: alopecia, perspiration, eczema, seborrhea, ecchymoma.

Allergic reactions: a skin itch, skin rash, contact dermatitis, it is rare — a small tortoiseshell, a Quincke's disease, a face edema, a photosensitization, an anaphylaxis, a multiformny exudative erythema (including Stephens-Johnson's syndrome), a toxic epidermal necrolysis (Lyell's disease).

Laboratory indicators: hyperglycemia, hypoglycemia, increase in a serumal kreatinfosfokinaza (KFK), albuminuria, increase in activity of nuclear heating plant, ALT.

Others: increase in body weight, gynecomastia, aggravation of a course of gout, fervescence.

Interaction with other medicines:

The risk of a myopathy during treatment by other medicines of this class increases at simultaneous use of cyclosporine, fibrat, erythromycin, the antifungal drugs relating to azoles and Niacinum.

At a concomitant use in an atorvastatin and suspension, containing magnesium and Aluminium hydroxydatum, concentration of an atorvastatin in plasma approximately decreased by 35%, however extent of reduction of the cholesterol/LPNP level at the same time did not change.

At simultaneous use аторвастатин does not influence antipyrine pharmacokinetics therefore interaction with other drugs, the metabolized same isoenzymes of cytochrome is not expected.

At simultaneous use of a kolestipol of 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.

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 atorvastatiny in a dose of 80 mg/days concentration of digoxin increased approximately by 20%. The patients receiving digoxin in combination with atorvastatiny should be observed.

At simultaneous use of an atorvastatin and erythromycin (500 mg of 4 times/days) or a klaritromitsina (500 mg of 2 times/days) which inhibit P450 3A4 cytochrome increase in concentration of an atorvastatin in a blood plasma was observed.

At simultaneous use of an atorvastatin (10 mg of 1 times/days) and azithromycin (500 mg of 1 times/days) concentration of an atorvastatin in a blood plasma did not change.

Atorvastatin did not exert clinically significant impact on concentration of a terfenadin in a blood plasma which is metabolized mainly by P450 3A4 cytochrome; in this regard it is represented a little probable that аторвастатин it is capable to influence pharmacokinetic parameters of other substrates of P450 3A4 cytochrome significantly.

At simultaneous use of the atorvastatin and oral contraceptive containing norethindrone and ethinylestradiol substantial increase of AUC norethindrone 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 receiving аторвастатин.

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

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

Simultaneous use of an atorvastatin with the inhibitors of proteases known as inhibitors of P450 3A4 cytochrome, was followed by increase in concentration of an atorvastatin in a blood plasma.

Clinically significant undesirable interaction of an atorvastatin and anti-hypertensive means, and also with estrogen is noted. Interaction researches with all specific drugs were not conducted.

Pharmaceutical incompatibility is not known.

Contraindications:

Hypersensitivity to drug components;
Active diseases of a liver or increase in serumal activity of transaminases (more than by 3 times in comparison with the upper bound of norm) not clear genesis;
Pregnancy;
Lactation period;
Age up to 18 years (efficiency and safety are not established).
With care: an alcohol abuse, liver diseases in the anamnesis, heavy disturbances of electrolytic balance, endocrine and metabolic disturbances, arterial hypotension, heavy acute infections (sepsis), uncontrollable epilepsy, extensive surgical interventions, injuries, diseases of skeletal muscles.

Overdose:

Treatment: there is no specific antidote, symptomatic therapy is carried out. The hemodialysis is inefficient.

Storage conditions:

List B. In dry, protected from light and the place, unavailable to children, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated, 10 mg and 20 mg.

On 10 tablets in a blister strip packaging (blister) from a film of PVC and aluminum foil or in a blister strip packaging (blister) from aluminum foil. 3, 4 or 5 blister strip packagings together with the application instruction place in a pack from a cardboard.