Atorvastatin

General characteristics. Structure:

Active ingredient: 10 mg or 20 mg of an atorvastatin in 1 tablet.

Excipients: povidone, sodium lauryl sulfate, calcium a carbonate, cellulose microcrystallic, lactose monohydrate, croscarmellose sodium, magnesium stearate, talc, titanium dioxide (E171), a macrogoal 3000, the polyvinyl alcohol which is partially hydrolyzed.

Pharmacological properties:

Pharmacodynamics. Atorvastatin belongs to group of medicines which main effect is decrease in level of content in blood of the general cholesterol and cholesterol LLD (lipoproteins of low density). Drug also reduces the level of triglycerides and increases cholesterol levels LHD (lipoproteins of high density) in blood.

The mechanism of action of an atorvastatin generally consists in inhibition of activity of enzyme of 3-hydroxy-3-methylglutaryl-coenzyme A - (ГМГ-КоА-) reductase which catalyzes transformation GMG-KOA into mevalonovy acid. This transformation is one of early stages in a chain of synthesis of cholesterol in an organism. Suppression atorvastatiny synthesis of cholesterol leads to a hyperreactivity of receptors of LNP in a liver, and also in extrahepatic fabrics. These receptors connect particles of LNP and delete them from a blood plasma that leads to decrease in level of cholesterol in blood.

As аторвастатин also inhibits secretion of cholesterol of lipoproteins of very low density in a liver, it, most likely, and is the mechanism of decrease in level of content of triglycerides as their linkng with ApoB carrier protein is weakened and, thereby, their plasma clearance increases. The increase mechanism atorvastatiny the level of LVP cholesterol remains obscure. Except impact on the level of maintenance of lipids in plasma, аторвастатин renders also some other effects which are a part of its anti-atherogenous potential. Among other things, аторвастатин suppresses synthesis of the isoprenoids which are growth factors of cells of smooth muscles of an internal cover of vessels. Atorvastatin reduces viscosity of plasma and activity of some factors of coagulation and aggregation. Thereby it improves a hemodynamics and makes a contribution to creation of favorable balance of blood coagulation. GMG-KOA-reduktazy inhibitors also influence metabolism of macrophages and, thereby, inhibit activation of macrophages and a rupture of atherosclerotic plaques.

Pharmacokinetics. In structure аторвастатин is present at the active form – in the form of calcic salt.

Atorvastatin approximately for 80% is soaked up from digestive tract. Absorption happens quickly (tmax = 1 – 4 hour). Though meal reduces absorption level, it does not influence efficiency of an atorvastatin. Owing to intensive metabolism at "the first passing" through a liver bioavailability of an atorvastatin makes only 12%. The average volume of distribution (Vd) of an atorvastatin makes 381 l. More than 98% of an atorvastatin contact proteins of plasma. Atorvastatin does not get through a blood-brain barrier. In a liver it is metabolized to orto-and parahydroxylated derivatives, and also various metabolites of beta oxidation. About 70% of the inhibiting activity concerning GMG-KOA-reduktazy charge to these active metabolites of an atorvastatin. The elimination half-life (t1/2) on average equals to 14 hours; the elimination half-life of the inhibiting activity for enzyme target makes 20 – 30 hours. About 46% of an atorvastatin are removed with excrements and less than 2% are allocated with urine. Distinctions of pharmacokinetics depending on age or a sex of the patient are not too considerable to demand correction of a dose.

As a rule, Atorvastatin's action is shown in 2 weeks after the beginning of use, and maximum efficiency is reached in 4 weeks after an initiation of treatment.

Indications to use:

Hypercholesterolemia. Atorvastatin is appointed as addition to a diet for treatment of patients with the increased level of the general cholesterol, cholesterol LLD (lipoproteins of low density), an apoliproteina of B and triglycerides, and also for increase in level of cholesterol LHD (lipoprotein of high density) at patients with primary hypercholesterolemia (a hereditary heterozygous and not hereditary hypercholesterolemia) combined (mixed) lipidemia (the Fredriksonovsky IIa and IIb type), the increased triglyceride level in plasma (Fredriksonovsky type III) when the diet does not render sufficient effect.

Atorvastatin is also shown for lowering of the level of the general cholesterol and LNP cholesterol at patients with a homozygous hereditary hypercholesterolemia when there is no sufficient reaction to a diet or other not medicinal actions.

Prevention of cardiovascular complications. With a dislipidemiya or without it, but with multiple factors of risk of coronary heart disease, such as smoking, arterial hypertension, a diabetes mellitus, the LVP (H-LVP) low cholesterol or with early coronary heart disease in the family anamnesis, Atorvastatin's use is shown to patients without clinical signs of a cardiovascular disease for:

· reduction of risk of a lethality at coronary heart disease and not fatal myocardial infarction;

· reduction of risk of development of a stroke;

· reduction of risk to undergo operations of revascularization and risk of development of stenocardia;

· reduction of risk of hospitalization concerning XCH;

· reduction of risk of development of stenocardia.

Use for children (patients at the age of 10 – 17 years). Atorvastatin is shown as addition to a diet for decrease in level of the general cholesterol, cholesterol LLD (lipoproteins of low density), apolipoprotein B at girls after menarche and at boys at the age of 10 – 17 years with a heterozygous hereditary hypercholesterolemia in the anamnesis if after the corresponding trial medical diet there are following indicators:

and. cholesterol level – LNP remains> 190 mg/dl or

. cholesterol level – LNP remains> 160 mg/dl and at the same time:

* there is genetic predisposition to a prematurity of cardiovascular diseases or

* at the moment children have 2 or more other risk factors of development of cardiovascular diseases.

Route of administration and doses:

Prior to treatment by Atorvastatin the patient has to be transferred to the diet providing decrease in maintenance of lipids in blood which needs to be observed during therapy by drug.

The recommended initial dose makes 10 mg daily. Depending on required effect the daily dose can be increased no more, than to 80 mg. The patient has to accept Atorvastatin once at any time, but at the same time every day. Drug is accepted irrespective of meal. The essential therapeutic effect is noted after two weeks of treatment, and the maximum effect develops in four weeks. Therefore the dosage should not be changed earlier, than in four weeks after the beginning of administration of drug in the previous dose.

Primary (heterozygous family and polygenic) a hypercholesterolemia (IIA type) and the mixed lipidemia (IIb type). Treatment begins with the recommended initial dose which depending on effect is increased after four weeks of treatment by originally chosen dose. The maximum daily dose makes 80 mg.

Homozygous family hypercholesterolemia. Adult patients. 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 was observed when using drug in a daily dose of 80 mg. Atorvastatin is used 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 elderly people and at patients with a renal failure it is not necessary to change the recommended Atorvastatin's doses.

At patients with abnormal liver functions care in connection with delay of removal of drug from an organism is necessary. In a similar situation it is necessary to control carefully clinical and laboratory indicators, and at identification of considerable pathological changes the dose has to be reduced, or treatment has to be stopped.

Use in pediatrics. Clinical data on efficiency and safety of use of drug for children are absent. Atorvastatin can be appointed to children only the specialist doctor. Experience of use of an atorvastatin for treatment of children is limited only to small population of patients (age of 10 - 17 years) suffering from some forms of a heavy dislipidemiya (as, for example, a homozygous family hypercholesterolemia). The recommended initial daily dose of Atorvastatin for this group of patients makes 10 mg; depending on efficiency and portability of drug it can be increased to 80 mg a day. The subsequent observation of development of these children was not carried out.

Heterozygous hereditary hypercholesterolemia at children (at the age of 10 – 17 years). The recommended starting dose of an atorvastatin makes 10 mg/day, the maximum recommended dose – 20 mg/day (doses of 20 mg are not given in researches at this population of patients above). The dose should be selected individually depending on the recommended treatment purpose. Change of a dose it is necessary to spend bucketed 4 weeks or more.

Features of use:

Atorvastatin it is necessary to apply with care at the patients abusing alcohol and also with liver diseases in the anamnesis.

Treatment by Atorvastatin can lead to increase in activity of "hepatic" enzymes in serum. This increase, as a rule, small has also no clinical value; however it is recommended to define activity of "hepatic" enzymes in blood serum prior to treatment, and then to regularly control their activity during treatment. If more than triple increase in activity of nuclear heating plant and/or ALT in comparison with the upper bound of normal range is noted, then treatment by Atorvastatin should be stopped.

At the women of childbearing age who are not applying well-tried remedies of contraception, Atorvastatin's use is not recommended. If pregnancy is planned, then the patient has to stop Atorvastatin's reception at least a month before approach of the planned pregnancy.

Treatment by Atorvastatin can cause a myopathy which can lead to a rabdomioliz and a renal failure At emergence of symptoms of a myopathy it is recommended to define activity of a creatine kinase in serum. At essential increase in activity of this enzyme (more than by 10 times of rather upper bound of norm) it is necessary to cancel treatment. Increase in activity of a creatine kinase at treatment by Atorvastatin should be taken into account at differential diagnosis of retrosternal pains.

Medicine contains lactose. This drug does not suit patients with rare hereditary intolerance of a galactose, deficit of enzyme of lactase or a sprue of glucose and a galactose.

Pregnancy and lactation. Atorvastatin is contraindicated to pregnant women and nursing mothers. During the researches on animals it was shown that the risk for pre-natal fetation exceeds favorable impact on mother. It is unknown whether Atorvastatin with breast milk is excreted. Some animal species in blood had same Atorvastatin's concentration, as well as in maternal milk.

Influence on ability to drive the car and work with potentially dangerous mechanisms. Atorvastatin does not exert impact on ability to drive the car and to work with mechanisms.

Side effects:

Side effects which can arise in the course of treatment atorvastatiny are subdivided into the following groups on emergence frequency: very frequent (≥1/10), frequent (≥1/100 to <1/10), infrequent (≥1/1000 to <1/100), rare (≥1/10.000 to <1/1000), very rare (<1/10.000), unknown (cannot be estimated on the basis of the available data).

Disturbances from system of a hemopoiesis: infrequent: thrombocytopenia.

Disturbances from immune system: frequent: allergic reactions, very rare: anaphylaxis.

Disturbances of metabolism and food: infrequent: anorexia.

Psychiatric frustration: infrequent: impotence, amnesia.

Disturbances from a nervous system: frequent: headache, sleeplessness, dizziness, paresthesias, infrequent: peripheral neuropathy.

Disturbances from respiratory system, a thorax and a mediasteniye: frequent: stethalgia.

Gepatobiliarny disturbances: rare: hepatitis, cholestatic jaundice.

Disturbances from a GIT: frequent: nausea, meteorism, dyspepsia, lock, diarrhea, infrequent: vomiting, pancreatitis.

Disturbances from skin and hypodermic fabrics: frequent: skin rash, itch, infrequent: small tortoiseshell, very rare: Quincke's disease, alopecia, violent rash (multiformny erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis).

Disturbances from skeletal and muscular system: frequent: mialgiya, arthralgia, dorsodynia, infrequent: myopathy, rare: miositis, рабдомиолиз.

General disturbances: frequent: adynamy, peripheral hypostases, infrequent: indisposition, increase in body weight.

Laboratory indicators: frequent: the increased levels of a kreatininkinaza (KK) in blood, infrequent: the increased levels of serumal transaminases (ALT, nuclear heating plant), very rare: hyperglycemia, hypoglycemia.

For some side reactions which are classified as "very rare" relationship of cause and effect is not established with drug.

Indicators of levels of serumal transaminases depend on the size of a dose and are reversible for all patients. KK the levels exceeding a normal upper limit by 10 times are revealed for 0,4% of patients; 0,1% from which felt muscular pains or weakness. In case of serious side reactions treatment has to be stopped.

Interaction with other medicines:

Simultaneous use of Atorvastatin with cyclosporine, antibiotics (erythromycin, кларитромицин, kvinupristin/dalfopristin), inhibitors of proteases (ампренавир, индинавир, ритонавир), antifungal means (флуконазол, итраконазол, кетоконазол) or with nefazodony can lead to increase in maintenance of an atorvastatin in serum that increases risk of emergence of a myopathy with rabdomiolizy and a renal failure. All these drugs are inhibitors of CYP450 3A4 enzyme which participates in Atorvastatin's metabolism in a liver. Similar interaction is possible at the combined reception of Atorvastatin with derivatives of fibroyevy acid and Niacinum; the mechanism of such interaction remains to unknown.

Simultaneous use of Atorvastatin and some drugs can reduce Atorvastatin's efficiency. Such effect can be shown at a concomitant use of medicine with Phenytoinum which is the inductor of CYP450 3A4 enzyme. The concomitant use of Atorvastatin and antiacid drugs (suspension of magnesium hydroxides and aluminum) leads to decrease in maintenance of an atorvastatin in plasma for 35%. It, however, does not make essential impact on efficiency of drug. At a concomitant use of an atorvastatin with kolestipoly Atorvastatin's concentration in plasma goes down for 25%, but the therapeutic effect of a combination is higher, than one Atorvastatin's action.

At the patients who are at the same time receiving 80 mg of an atorvastatin and digoxin, the content of digoxin increases in plasma approximately for 20%. Therefore it is necessary to watch such patients.

At joint reception of Atorvastatin with oral contraceptives (a combination of norethindrone and ethinylestradiol) strengthening of absorption of contraceptives and increase in their concentration in a blood plasma is possible.

The concomitant use of Atorvastatin with Warfarin can strengthen impact of Warfarin on blood coagulation indicators. Researches showed that simultaneous use of these drugs leads to reduction of a prothrombin time in the first few days treatments. After 15 days of joint reception of the specified drugs indicators are returned to norm. Monitoring of a prothrombin time at the initial stage of joint treatment by Atorvastatin and Warfarin is recommended.

The use of grapefruit juice during treatment by Atorvastatin can lead to increase in concentration of drug in a blood plasma.

Contraindications:

- hypersensitivity to active agent or to any of drug components;

- liver diseases in an active stage;

- the persistent increased content of serumal transaminases of not clear genesis;

- diseases of skeletal muscles;

- pregnancy and period of a lactation;

- the women of reproductive age who are not using appropriate measures of contraception.

Overdose:

It was not reported about cases of overdose of Atorvastin. In case of overdose the following general events are necessary: monitoring and maintenance of vital signs, and also prevention of further absorption of drug (gastric lavage, reception of absorbent carbon or purgatives).

At development of a myopathy with the subsequent rabdomiolizy and an acute renal failure (rare, but heavy side effect) drug has to be immediately cancelled, and the patient needs to enter diuretic and solution of Natrii hydrocarbonas. If necessary it is necessary to carry out a hemodialysis. Also the hyperpotassemia which elimination requires intravenous administration of chloride or a gluconate of calcium, infusion of glucose with insulin, use of potassium ion exchangers, and in hard cases – carrying out a hemodialysis can be a consequence of a rabdomioliz. As Atorvastatin is substantially connected with proteins of a blood plasma, the hemodialysis is rather ineffective way of removal of this substance from an organism.

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use medicine after the termination of a period of validity.

Issue conditions:

According to the recipe

Packaging:

In a blister strip packaging No. 10, in packaging No. 10×3, No. 10×6.