Vazoklin

General characteristics. Structure:

Active ingredient: atorvastatin;

1 tablet contains an atorvastatin of calcium in terms of аторвастатин 10 mg or 20 mg;

excipients: the carbonate, the hydroxypropyl cellulose low-replaced of calcium attracts (Е 421), calcium stearate, talc; опадрай white (gipromeloza, titanium dioxide       (Е 171), macrogoal 6000).

Pharmacological properties:

Pharmacodynamics. Vazoklin – synthetic hypolipidemic drug. 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.

At patients with a homozygous and heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed dislipidemiya аторвастатин reduces the content in plasma in blood of the general cholesterol (Хс), Hs-LPNP and apolipoprotein B (apo-V), and also the maintenance of Hs-LPONP and triglycerides (TG), causes unstable increase in the Hs-LPVP level.

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 that 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. Reduces the Hs-LPNP level at patients with a homozygous hereditary hypercholesterolemia steady against therapy with other hypolipidemic means.

Atorvastatin in doses of 10-80 mg reduces the level of the general cholesterol by 30-46%, Hs-LPNP – for 41-61%, apo-V – for 34-50% and TG – for 14-33%. Results of treatment are similar at patients to a heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed lipidemia, including at patients to a non-insulin-dependent diabetes mellitus.

At patients with the isolated gipertriglitseridemiya аторвастатин reduces the level of the general cholesterol, Hs-LPNP, Hs-LPONP, apo-V, TG and Hs-LPNEVP and increases the Hs-LPVP level. At patients with a disbetalipoproteinemiya reduces LPPP cholesterol level.

At patients with a giperlipoproteinemiya of the IIA and IIb type on Fredrikson's classification average value of increase in the Hs-LPVP level 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 fatal cases 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%. At patients with various initial Hs-LPNP levels аторвастатин causes decrease in risk of ischemic complications and fatal cases in patients with a myocardial infarction without tooth with Q and unstable stenocardia equally at men and women and at patients as to 65, and 65 years are more senior.

Decrease in contents in a blood plasma of Hs-LPNP correlates with a drug dose better, than with its concentration in a blood plasma.

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 absorbed after intake; Cmax is reached in 1-2 h. Extent of absorption and concentration of an atorvastatin in a blood plasma raises in proportion to a dose. Absolute bioavailability of an atorvastatin makes 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 "the first passing" through a liver. Food reduces the speed and extent of absorption approximately by 25% and 9% respectively (what results of definition of Cmax and AUC testify to), however the Hs-LPNP level at reception of an atorvastatin on an empty stomach and during food decreases almost to the same extent. In spite of the fact that after reception of an atorvastatin in the evening levels in plasma are lower than it (Cmax and AUC approximately for 30%), than after reception in the morning, decrease in Hs-LPNP does not depend on time of day in which accept drug.

Distribution. Average Vd of an atorvastatin makes about 381 l. Linkng of an atorvastatin with proteins of plasma – not less than 98%. The relation of levels 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 concerning GMG-KOA-reduktazy, comparable to action of 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 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 of a terfenadin in a blood plasma which is metabolized, mainly, by CYP3A4 isoenzyme; in this regard the significant influence of an atorvastatin 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). T1/2 makes about 14 h, at the same time the inhibiting effect of drug concerning ГМГ-КоА-reductases approximately is defined on 70% by activity of the circulating metabolites and about 20-30 h thanks to their existence remain. After intake in urine find less than 2% of a dose of an atorvastatin.

Pharmacokinetics in special clinical cases.

Age. Concentration of an atorvastatin in a blood plasma at elderly people (aged ≥ 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 people, in comparison with the general group of patients it was revealed not.

Drug pharmacokinetics researches at children were not conducted.

Floor. Concentration of an atorvastatin in 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 are not revealed.

Renal failure. The renal failure does not influence concentration of an atorvastatin in a blood plasma or its action 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.

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

Pharmaceutical characteristics.

Main physical and chemical properties: tablets of white color, oval form, biconvex, coated.

Indications to use:

– Primary hypercholesterolemia (a heterozygous family and single hypercholesterolemia (the IIA type on Fredrikson's classification);

– the combined (mixed) lipidemia (the IIA and IIb types on Fredrikson's classification);

– a disbetalipoproteinemiya (type III on Fredrikson's classification) (as addition to a diet);

– a family endogenous gipertriglitseridemiya (type IV on Fredrikson's classification), resistant to a diet;

– a 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 but having several risk factors of its development – age is more senior than 55 years, nicotine addiction, arterial hypertension, a diabetes mellitus, low concentration of Hs-LPVP in a blood plasma, 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:

Before therapy by Vazoklin it is necessary to determine hypercholesterolemia level against the background of the corresponding diet, to appoint the physical exercises and actions directed to a body degrowth at patients with obesity and to carry out treatment of other diseases. During treatment by Vazoklin patients should keep to a standard anti-cholesteric diet. Drug appoint in a dose 10-80 mg of 1 times a day daily, during any period of day, irrespective of meal. An initial and maintenance dose can be individualized according to the H-LPNP initial level, problems of therapy and its efficiency. In 2-4 weeks from an initiation of treatment and/or the lipidogramm should define dose adjustments of Vazoklin and according to it to correct a dose.
Primary hypercholesterolemia and the combined (mixed) lipidemia.

In most cases it is enough to appoint 10 mg of 1 times a day. The result of treatment becomes noticeable in 2 weeks, the maximum effect is observed in 4 weeks. Positive changes are supported by prolonged use of drug. Homozygous family hypercholesterolemia. At most of patients with a homozygous family hypercholesterolemia the result is achieved as a result of use of 80 mg of Vazoklin of 1 times a day that provides decrease in the H-LPNP level more than for 15% (18 - 45%).

The renal failure does not influence concentration of an atorvastatin in a blood plasma or extent of decrease in maintenance of Hs-LPNP at use Vazoklin therefore dose adjustment of drug is not required.

At use of drug for patients of advanced age of distinctions in safety, efficiency in comparison with the general group of patients, it is not revealed, and dose adjustment is not required.

Use in a combination with other medical supplies.

In need of combined use with cyclosporine Vazoklin's dose should not exceed 10 mg.

Features of use:

Influence on a liver. As well as at use of other gipolipoproteinemichesky means of the same class, at treatment by Vazoklin there can be a moderate increase in activity of transaminases of blood serum (three times more, than the top level of norm – VUN). Increase in activity of transaminases is not followed by jaundice or other clinical manifestations. If the dose of an atorvastatin decreases, the break becomes or treatment stops, the level of transaminases is normalized. Treatment continuation by smaller doses of an atorvastatin does not lead to negative effects.
Function of a liver has to be defined before an initiation of treatment and be controlled periodically during a course of treatment. Patients who have manifestations of an abnormal liver function should define indicators of its function. Patients at whom increase in activity of transaminases is observed have to be under observation before normalization of indicators. In case of more than triple growth of activity of ALAT or ASAT many dose of Vazoklin it is necessary to reduce or stop treatment. Vazoklin can cause increase in activity of transaminases.
Vazoklin the patients taking alcohol and/or with liver diseases in the anamnesis should appoint with care. Liver diseases in an active phase or increase in activity of transaminases for the unclear reasons is a contraindication for Vazoklin's appointment.

Action on skeletal muscles. During treatment by Vazoklin at patients the myopathy can be observed. It is necessary to understand muscle pain or weakness of muscles in combination with growth of the KFK level by 10 times of more VUN as a myopathy. The probability of emergence of this state should be assumed at patients with a diffusion mialgiya, morbidity or weakness of muscles and/or essential increase in the KFK level. Patients should be warned about possible developing of pain in muscles and weakness of muscles, sometimes with an indisposition or temperature increase. In cases of increase in the KFK level specified or the possible diagnosis of a myopathy, treatment by Vazoklin should be stopped. The risk of emergence of a myopathy at treatment by drugs of this group increases at simultaneous use of cyclosporine, derivative fibrinous acids, erythromycin, Niacinum or azolovy antifungal means. The majority of these means oppress metabolism of P450 3A4 cytochrome and/or distribution of drug in an organism. Vazoklin biotransformirutsya, first of all, by means of CYP 3A4 liver enzyme. Doctors who appoint Vazoklin in a combination with derivatives of fibrinous acids, erythromycin, immunosuppressors or azolovy antifungal means or Niacinum doses modifying lipoproteins have to weigh possible positive takes and harmful effects and observe patients for the purpose of identification of such manifestations as muscle pain and weakness of muscles, especially in the first months of treatment and after increase in a dose of one of these drugs. Thereof it is necessary to consider need of decrease in an initial and maintenance dose of Vazoklin at simultaneous use with above-mentioned drugs. Periodic definition of KFK is for this purpose recommended, but it is necessary to remember that this test happens insufficiently for timely diagnosing of a heavy myopathy. Vazoklin can cause growth of the KFK level.

At treatment by Vazoklin, as well as at use of similar drugs of this group, cases of a rabdomioliz in a combination to the secondary renal failure caused by a myoglobinuria were occasionally observed. Therapy by Vazoklin should be interrupted or stopped in case of serious condition of the patient at suspicion that these changes are caused by a myopathy, or with risk factors of development of a secondary renal failure at a rabdomioliza (for example, a heavy acute infection, arterial hypotension, serious surgical interventions, an injury, heavy endocrine, metabolic or electrolytic disturbances and uncontrollable spasms).

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

Therapy atorvastatiny in a dose of 80 mg at patients without cardiovascular diseases which in 6 and less months prior to treatment had a stroke or the tranzitorny ischemic attack increases the frequency of developing of hemorrhagic strokes. At patients at whom the hemorrhagic stroke arose at the beginning of therapy atorvastatiny the risk of a repeated hemorrhagic stroke increased. Atorvastatin in a dose of 80 mg reduces total quantity of strokes and reduces quantity of cases of cardiovascular diseases.

Ability to influence speed of response at control of motor transport or work with other mechanisms.

Data on influence of an atorvastatin on ability to manage motor transport and on occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions are not available.

Side effects:

Atorvastatin is usually well had. Side effects, as a rule, easy and passing.

Organism in general: thorax pains, face edema, fever, rigidity of a neck, indisposition, photosensitization, generalized hypostasis, adynamy.

From a digestive tract: nausea, a gastroenteritis, an abnormal liver function, colitis, vomiting, gastritis, dryness in a mouth, rectal bleeding, an esophagitis, an eructation, a language inflammation, anorexia, increase in appetite, stomatitis, liver pain, a cheilitis, a duodenal ulcer, a dysphagy, enteritis, a melena, bleeding of gums, development of an ulcer in a gullet, tenesmus, a stomacace, hepatitis, pancreatitis, cholestatic jaundice, diarrhea, an abdominal pain, dyspepsia, a lock, a meteorism.

From respiratory system: bronchitis, rhinitis, pneumonia, short wind, asthma, nasal bleeding.
From a nervous system: sleeplessness, dizziness, paresthesia, drowsiness, sleep disorder, decrease libido, emotional lability, lack of coordination, peripheral neuropathy, wryneck, front paralysis, hyperkinesias, depression, hypesthesia, headache.

From a musculoskeletal system: arthritis, arthralgia, dorsodynia, spasms of legs, bursitis, tendovaginitis, myasthenia, contracture of sinews, miositis, mialgiya, myopathy, myotonia, ruptures of sinews.

From skin: an itch, contact dermatitis, an alopecia, rash, a xeroderma, the increased perspiration, an acne, eczema, seborrhea, a skin ulceration.

From urinogenital system: an infection of an urinary system, a hamaturia, an albuminuria, a frequent urination, cystitis, impotence, a dysuria, stones in kidneys, a nocturia, an epididymite, a fibrosing adenosis of a mammary gland, bleeding from a vagina, increase in a mammary gland, a metrorrhagia, nephrite, an urine incontience, disturbance of an ejaculation, a secondary renal failure.

From sense bodys: an amblyopia, a ring in ears, a xerophthalmus, disturbances of a refraction, a hematopsia, deafness, glaucoma, a parosmiya, taste loss, taste change.
From cardiovascular system: heart consciousness, vazodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, stenocardia, arterial hypertension.
From metabolism: peripheral hypostases, hyperglycemia, increase in a kreatininfosfokinaza (KFK), gout, increase in body weight, hypoglycemia, anorexia.
From system of blood: ecchymoma, anemia, lymphadenopathy, thrombocytopenia, petechia.
Allergic reactions: urticaria, an itch, rash on skin, anaphylactic reactions, violent rash, a multiformny erythema, a toxic epidermal necrolysis (Lyell's disease), a malignant erythema (Stephens-Johnson's syndrome).

Interaction with other medicines:

The risk of a myopathy during treatment by other drugs of this class increases at simultaneous use of cyclosporine, fibrat, erythromycin, antifungal drugs of derivatives of an azol and niacin in hypolipidemic doses.

CYP3A4 cytochrome inhibitors. As аторвастатин it is metabolized by CYP3A4 isoenzyme, combined use of an atorvastatin with inhibitors of this isoenzyme 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. So, combined use of an atorvastatin in a dose of 10 mg and cyclosporine in a dose of 5,2 mg/kg/days leads 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/days) or a klaritromitsina (on 500 mg 2 times/days) which inhibit CYP3A4, 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 inhibitors, was 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.

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 a day) can cause increase in concentration of an atorvastatin in a blood plasma.

CYP3A4 cytochrome inductors. Combined use of an atorvastatin with CYP3A4 cytochrome isoenzyme inductors (for example, эфавиренз, the rifampicin, a St. John's Wort which is made a hole) can lead to decrease in concentration of an atorvastatin in a blood plasma. Owing to the double mechanism of interaction with rifampicin (the inductor of an isoenzyme of CYP3A4 cytochrome 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 plasma decreased approximately by 35%, however extent of reduction of the Hs-LPNP level at the same time did not change.

Antipyrine. As Vazoklin does not change antipyrine pharmacokinetics, interaction between other drugs which are metabolized by means of the same cytochrome (for example, терфенадин, Tolbutamidum, to triazoles, oral contraceptives), is improbable.

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

Holestipol. At simultaneous use of a holestipol concentration of an atorvastatin in plasma decreased approximately by 25%. However the hypolipidemic effect of a combination of an atorvastatin and holestipol surpassed that of each drug separately.

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 atorvastatiny in a dose of 80 mg/days concentration of digoxin increased approximately by 20%. The patients receiving digoxin in combination with atorvastatiny need clinical control.

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 plasma did not change.

Oral contraceptives. At simultaneous use of the atorvastatin and oral contraceptive 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 receiving аторвастатин.

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

Warfarin. Symptoms 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.

Other accompanying therapy. At use of an atorvastatin in combination with anti-hypertensive means and estrogen which appointed as replacement therapy symptoms of clinically significant undesirable interaction are noted. The interaction research with specific drugs was not conducted.

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 (UBN) of not clear genesis;

– children's age (not enough clinical data on efficiency and safety for this age group);

– pregnancy, the feeding period a breast, reproductive age at women (for the period of treatment reliable contraception is necessary).

Use during pregnancy or feeding by a breast.

Vazoklin is contraindicated to use at pregnancy and in the period of a lactation (breastfeeding).

Women of reproductive age during treatment have to use adequate contraceptives. Vazoklin 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 in breast milk. Considering possibility of the undesirable phenomena at babies, in need of use of drug in the period of a lactation breastfeeding should be stopped.

Children. Drug is not used in pediatric practice.

Overdose:

Symptoms: myopathy (рабдомиолиз), abnormal liver functions, nausea, vomiting, diarrhea.

Treatment: if necessary carry out symptomatic therapy. Atorvastatin highly contacts proteins of a blood plasma therefore the hemodialysis is inefficient. There is no specific antidote.

Storage conditions:

Period of validity 2 years from the date of production of "in bulk". To store in the place, unavailable to children, in original packaging at a temperature not over 25 ºС.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in a blister strip packaging. On 3 planimetric cell packagings in a pack.