Atorvastatin

General characteristics. Structure:

Active agent: аторвастатин calcium of 10,85 mg, 21,70 mg, 43,40 mg, in terms of аторвастатин 10 mg, 20 mg and 40 mg;
excipients: cellulose microcrystallic, phosphate calcium dihydrate, potato starch, magnesium stearate, sodium carboxymethylstarch (sodium starch glycollate, примогель); structure of a film cover: gipromelloz (gidroksipropilmetiltsellyuloz), macrogoal (polyethyleneglycol 6000), коповидон (пласдон S–630), titanium dioxide, talc.

Opisaniye:tabletki, film coated white or almost white color, round, biconvex form.

Pharmacological properties:

Pharmacodynamics. Hypolipidemic means from group of statines. The selection competitive inhibitor of GMG-KOA-reduktazy — the enzyme turning Z-gidroksi-3-metilglutaril coenzyme A into mevalonovy acid, being the predecessor of sterol including cholesterol. Triglycerides (TG) and cholesterol in a liver 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) are formed of LPONP during interaction with LPNP receptors. Atorvastatin reduces levels of cholesterol and lipoproteins in a blood plasma inhibiting GMG-KOA-reduktazu, 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. Reduces formation of LPNP, causes the expressed and permanent increase in activity of LPNP-receptors. Reduces the LPNP level at patients with a homozygous family hypercholesterolemia which usually does not give in to therapy by hypolipidemic means. Reduces the level of the general cholesterol by 30–46%, LPNP - for 41–61%, apolipoprotein B — for 34–50% and TG — for 14–33%; causes increase in level holesterina-LPVP (lipoproteins of high density) and A. Dozozavisimo's apolipoprotein reduces the LPNP level at patients with a homozygous hereditary hypercholesterolemia, resistant to therapy by other hypolipidemic means.

Pharmacokinetics. Absorption — high. The maximum concentration (Stakh) in a blood plasma is reached in 1–2 h, Stakh at women is 20% higher, the area under curve/concentration, time (AUC) — is 10% lower; Stakh at patients with alcoholic cirrhosis by 16 times, AUC — is 11 times higher than norm.

Food reduces the speed and duration of absorption of drug a little (by 25% and 9% respectively), however decrease in LPNP cholesterol is similar to that at Atorvastatin's use without food. Atorvastatin's concentration at use is lower in the evening, than in morning (approximately for 30%). 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 — 30%. Low system bioavailability is caused by presistemny metabolism in a mucous membrane of digestive tract and at "the first passing" through a liver. The average volume of distribution — 381 l, communication with proteins of a blood plasma — 98%. It is metabolized preferential in a liver under the influence of CYP3A4, CYP3A5 and CYP3A7 cytochrome with formation pharmacological of active metabolites (orto-and parahydroxylated derivatives, beta oxidation products). In vitro orto-and parahydroxylated metabolites have an inhibiting effect on GMG-KOA-reduktazu, comparable to that of Atorvastatin. The inhibiting effect of drug concerning GMG-KOA-reduktazy approximately is defined on 70% by activity of the circulating metabolites.

It is removed with bile after hepatic and/or extrahepatic metabolism (is not exposed to the expressed enterohepatic recirculation).

Elimination half-life — the 14th hour. The inhibiting activity concerning GMG-KOA-reduktazy remains about 20-30 h thanks to existence of active metabolites. Less than 2% of the dose of drug accepted inside are defined in urine. It is not removed during a hemodialysis.

Indications to use:

Atorvastatin is applied:
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 (types of Pa and lib 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 Atorvastatin's appointment the patient needs to recommend a standard hypolipidemic diet which he 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 Atorvastatin 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. and also type 111 iivpofredriksonu.

In the majority cases there is enough purpose of a dose of 10 mg of drug Atorvastatin of 1 time 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.

Homozygous family hypercholesterolemia.

Appoint in a dose 80 mg (4 tablets on 20 mg) 1 time a day.

Use of drug for patients with a renal failure and diseases of kidneys does not exert impact on Atorvastatin's level 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 a liver failure of a dose it is necessary to reduce (see the section "With Care" and "Special Instructions").

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 Atorvastatin the patient needs to appoint a standard gipokholestesterinovy 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 Atorvastatin 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 Atorvastatin. Patients at whom increase in level of enzymes is noted have to be under control before return of level of enzymes to norm. If values of alaninaminotranspherase (ALT) or an asparaginaminotransferaza (ACT) more than by 3 times exceed the level of an upper admissible limit, it is recommended to lower Atorvastatin's dose or to stop treatment. Atorvastatin 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 Atorvastatin's appointment.

Treatment by Atorvastatin can cause a myopathy. The diagnosis of a myopathy (pain 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 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 or azolny antifungal means. Many of these drugs inhibit the metabolism mediated by P450 ZA4 cytochrome and/or transport of medicines. Atorvastatin biotransformirutsya under the influence of CYP 3A4. Appointing Atorvastatin in a combination with fibrata, erythromycin, immunosuppressive means, azolny antifungal means or niacin in hypolipidemic doses, it is necessary to weigh carefully expected iolza 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 Atorvastatin's use, 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 Atorvastatin 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 Atorvastatin 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 of a pas ability of driving and work with mechanisms: About adverse influence of Atorvastatin on ability to drive the car and work with mechanisms it was not reported.

Side effects:

From a nervous system - 2% — sleeplessness, dizziness are more often; more rare than 2% — a headache, an adynamy, an indisposition, drowsiness, dreadful dreams, paresthesias, a peripheral neuropathy, amnesia, emotional lability, an ataxy, paralysis of a facial nerve, hyperkinesias. migraine, depression, hypesthesia, loss of consciousness.

From sense bodys: more rare than 2% — an amblyopia, a ring in ears, dryness of a conjunctiva, accommodation disturbance, hemorrhage in a mesh cover of an eye, deafness, glaucoma, a parosmiya, loss of flavoring feelings, a food faddism.

From cardiovascular system: more often than 2% - a stethalgia; more rare than 2% — heartbeat, vazodilatation symptoms. orthostatic hypotension, increase in arterial pressure, phlebitis, arrhythmia, stenocardia.

From system of a hemopoiesis: more rare than 2% — anemia, a limfoadenopatiya, thrombocytopenia.

From respiratory system: more often than 2% — bronchitis, rhinitis; more rare than 2% — pneumonia, диспноэ, an exacerbation of bronchial asthma, nasal bleeding.

From the alimentary system: more often than 2%,-nausea; more rare than 2% — heartburn, a lock or diarrhea, a meteorism, a gastralgia, an abdominal pain, decrease or increase in appetite, dryness in a mouth, an eructation, a dysphagy. vomiting, stomatitis, esophagitis, glossitis, erosive cankers of a mucous membrane of an oral cavity, gastroenteritis, hepatitis, bilious colic, cheilitis, ulcer of a 12-perstny gut, pancreatitis, cholestatic jaundice, abnormal liver function, rectal bleeding, melena, bleeding of gums, tenesmus.

From a musculoskeletal system: more often than 2% — arthritis; more rare 2% — myotonia of legs, a bursitis, tendosinovit. miositis, myopathy, arthralgias, mialgiya, рабдомиолиз, wryneck, muscle hyper tone, contractures of joints.

From urinogenital system: more often than 2% — urogenital infections, peripheral hypostases; more rare than 2% — a dysuria (including a pollakiuria. nocturia. an incontience of urine or a delay of an urination, imperative desires on an urination), nephrite, a hamaturia, vaginal bleeding, нефроуролитиаз, a metrorrhagia, an epididymite. decrease in a libido, impotence. disturbance of an ejaculation.

From integuments: more often than 2% — an alopecia, a xerodermia, the increased sweating, eczema, seborrhea, ecchymomas, petechias.

Allergic reactions: more rare 2% — a skin itch, skin rash, contact dermatitis, are 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: more rare than 2% — a hyperglycemia, a hypoglycemia, increase in serumal KFK, an albuminuria.

Others: more rare than 2% — increase in body weight, a gynecomastia, a mastodynia, an exacerbation of gout.

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 means relating to azoles and niacin.

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

At simultaneous use Atorvastatin does not influence pharmacokinetics of antipyrine (phenazone) therefore interaction with other means, the metabolized same isoenzymes of cytochrome is not expected.

At simultaneous use of a kolestipol of concentration of Atorvastatin in a blood plasma decreased approximately by 25%. However the hypolipidemic effect of a combination of Atorvastatin and a kolestipol surpassed that of each drug separately.

At repeated reception of digoxin and 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 Atorvastatin in a dose of 80 mg/days concentration of digoxin increased approximately by 20%.

The patients receiving digoxin in combination with Atorvastatin should be observed.

At simultaneous use of Atorvastatin and erythromycin (500 mg of 4 times/days) or a klaritromitsina (500 mg of 2 times/days) which inhibit P450 ZA4 cytochrome increase in concentration of Atorvastatin in a blood plasma was observed.

At simultaneous use of Atorvastatin (10 mg of 1 times/days) and azithromycin (500 mg of 1 times/days) Atorvastatin's concentration 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 ZA4 cytochrome; in this regard it is represented a little probable that Atorvastatin is capable to influence pharmacokinetic parameters of other substrates of P450 ZA4 cytochrome significantly

At simultaneous use of Atorvastatin and a contraceptive for the intake 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 Atorvastatin.

Simultaneous use with the medicines reducing concentration of endogenous steroid hormones (including Cimetidinum, ketokonazoly, Spironolactonum), increases risk of decrease in endogenous steroid goromon (it is necessary to be careful).

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

At simultaneous use of Atorvastatin of 80 mg and an amlodipina of 10 mg Atorvastatin's pharmacokinetics in an equilibrium state did not change.

Clinically significant undesirable interaction of Atorvastatin and anti-hypertensive means is noted.

Simultaneous use of Atorvastatin with the inhibitors of proteases known as inhibitors of P450 ZA4 cytochrome, was followed by increase in concentration of Atorvastatin in a blood plasma.

Pharmaceutical incompatibility is not known.

Contraindications:

• hypersensitivity to 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);
• a liver failure (severity on classification of Chayld-Pyyuga And yes In)
• 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.

Use at pregnancy and in the period of a lactation: Atorvastatin is contraindicated to use during pregnancy and in the period of a lactation (breastfeeding). It is unknown whether Atorvastatin with breast milk is brought. Considering a possibility of the undesirable phenomena at babies, in need of use of drug in the period of a lactation it is necessary to resolve an issue of the breastfeeding termination. 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 of treatment for a fruit.

Overdose:

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

Storage conditions:

List B. 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 apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

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