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Atorvasterol

Препарат Аторвастерол. Polpharma/Medana Pharma S. A. («Польфарма»/ Медана Фарма С. А.) Польша

Producer: Polpharma/Medana Pharma S. A. (Polfarm / Medan of Pharm S.A.) Poland

Code of automatic telephone exchange: C10AA05

Release form: Firm dosage forms. Tablets.

Indications to use: Chronic heart failure. Prevention of attacks of stenocardia. Prevention of a stroke. Prevention of a myocardial infarction. Coronary heart disease. Diabetes mellitus. Dislipidemiya. Homozygous family hypercholesterolemia. Disbetalipoproteinemiya. Lipidemia. Heterozygous family hypercholesterolemia. Primary hypercholesterolemia.

General characteristics. Structure:

Active agent: аторвастатин 10 mg

Other ingredients: mannitol (E421), cellulose microcrystallic, calcium carbonate, povidone, sodium of a kroskarmelloz, sodium lauryl sulfate, silicon dioxide colloid anhydrous, magnesium stearate, gipromelloz, titanium dioxide (E171), macrogoal 6000, talc.

Active agent: аторвастатин 20 mg

Active agent: аторвастатин 40 mg

Pharmacological properties:

Pharmacodynamics. Atorvasterol is the selection competitive inhibitor of GMG-KOA-reduktazy, the enzyme reducing speed and 3-hydroxy-3-metilglyutarilkoenzima A, responsible for transformation, in мевалонат (a precursor of sterol, including XC). In a liver of TG and XC are built in structure of LPONP and come to a blood plasma for transportation in peripheral fabrics. LPNP which are formed of LPONP catabolize generally at interaction with high-affine receptors of LPNP. Atorvasterol reduces level XC and lipoproteins in a blood plasma, inhibiting activity of GMG-KOA-reduktazy and synthesis of XC in a liver. Atorvasterol also increases the number of hepatic receptors of LPNP by surfaces of a cellular membrane of hepatocytes that leads to strengthening of capture and a catabolism of LPNP.
Atorvasterol reduces formation of LPNP and quantity of particles of LPNP, causes the expressed and long increase in activity of LPNP-receptors that has favorable effect on quality of the circulating LPNP fractions. Atorvastatin considerably reduces the LPNP level XC at patients with a homozygous family hypercholesterolemia which usually does not give in to therapy by other hypolipidemic medicines.
In dozozavisimost researches аторвастатин reduced the level of the general XC (by 30–46%), the XC LPNP (for 41–61%), apolipoprotein B (for 34–50%) and TG (for 14–33%), but caused non-constant increase in the LPVP level XC and A1 apolipoprotein. Such results are received at patients with a heterozygous family hypercholesterolemia, a single hypercholesterolemia and the mixed lipidemia, including patients with a non-insulin-dependent diabetes mellitus.
It is confirmed that decrease in level of the general XC, XC LPNP and a lipoprotein In reduces risk of development of a myocardial infarction and quantity of lethal outcomes at such state. Now researches of influence of an atorvastatin on the course of diseases and rate of mortality are conducted.
In the research MIRACL concerning prevention of an early recurrence of ischemic states use of an atorvastatin in a dose of 80 mg by 3086 patients is analyzed (аторвастатин n=1538; placebo =1548) with acute diseases of coronary vessels, including stenocardia. Treatment was begun in 24–96 h after hospitalization of the patient. The risk of repeated hospitalization because of stenocardia with accurate symptoms of an ischemic heart disease was reduced by 26% (p=0,018).

Frmakokinetika. Absorption. Atorvastatin is quickly absorbed after oral administration and reaches Cmax in a blood plasma in 1–2 h. The volume of absorption increases in proportion to a dose of an atorvastatin. Bioavailability of an atorvastatin after reception in the form of tablets, coated, makes 95–99% in comparison with bioavailability of an atorvastatin in the form of solution. Absolute bioavailability makes about 12%, and system availability of active inhibitor of GMG-KOA-reduktazy makes about 30%. Low system availability is explained by presistemny clearance in a mucous membrane of a GIT and/or metabolism at the first passing through a liver.
In spite of the fact that the quantity and extent of absorption of drug decrease at reception along with food approximately by 25 and 9% respectively, estimating on Cmax and AUC, reduction of the LPNP level XC did not depend on that, accepted аторвастатин along with food or not. At reception of an atorvastatin in the evening its concentration in a blood plasma was lower (about 30% for Cmax and AUC), than at reception in the morning. However decrease in the LPNP level XC does not depend on time of administration of drug.
Distribution. The average volume of distribution of an atorvastatin makes about 381 l. Atorvastatin on> 98% contacts proteins of a blood plasma.
Metabolism. Atorvastatin is metabolized with the participation of P450 ZA4 cytochrome to orto-and parahydroxylated derivatives and different products of beta oxidation. Such substances are metabolized by a glyukuronization further. In vitro GMG-KOA-reduktazy inhibition owing to action orto-and parahydroxylated metabolites is equivalent to inhibition atorvastatiny. About 70% of the inhibiting impact on GMG-KOA-reduktazu exert active metabolites.
Removal. Atorvastatin is brought mainly with bile after hepatic and/or ekstrapechenochny metabolism. However drug is not exposed to the expressed ekstrapechenochny recirculation. Average Т½ the atorvastatina at people makes about 14 h of a blood plasma. Thanks to active metabolites the half-cycle of the inhibiting activity concerning GMG-KOA-reduktazy makes about 20-30 h.
Separate groups of patients
Patients of advanced age. Concentration of an atorvastatin and its active metabolites in a blood plasma at healthy volunteers of advanced age are higher, than those at young patients, but influence on levels of lipids in blood are similar in both age groups.
Children. Children have no data on pharmacokinetics.
Floor. Concentration of an atorvastatin and its active metabolites at women (Cmax in a blood plasma is about 20% higher, and AUC value about 10% lower) differ from indicators at men. Such differences have no clinical value, and distinction of influence on the level of lipids in blood at men and women is not significant.
Renal failure. At diseases of kidneys influence on concentration of an atorvastatin and its metabolites in a blood plasma, and also on efficiency of their influence on levels of lipids in blood is noted.
Abnormal liver function. Concentration of an atorvastatin and its metabolites in a blood plasma considerably increase (Cmax — approximately by 16 times, AUC — by 11 times) at patients with a chronic alcoholic disease of a liver (a class B on Chayld-Pyyu).
Data of preclinical trials
Atorvastatin not cancerogenic at animals. The maximum doses which were applied were 63 times higher than the maximum dose for the person (80 mg/days) at recalculation on body weight mg/kg 8-16 times above on the AUC0-24 values established on the general inhibiting activity. In a 2-year research on animals the frequency of development of hepatocellular adenoma in males and a hepatocellular carcinoma at females was increased at introduction by an animal of the maximum doses which exceeded by 250 times the maximum dose for the person in terms of body weight mg/kg. At animals influence was 6-11 times higher that is established on AUC0-24 indicator. Atorvastatin had no mutagen effect, did not lead to malformation of reproductive organs in 4 researches in vitro and in one in vivo test. In researches on animals аторвастатин did not influence fertility of males at introduction in doses to 175 mg/kg of body weight a day and females at introduction in doses to 225 mg/kg/days, and also did not lead to malformation.

Indications to use:

As addition to a diet for treatment of patients with the increased level of the general XC, XC LPNP, apolipoprotein V, TG, for the purpose of increase in the XC LPNP at patients with primary hypercholesterolemia (a heterozygous hereditary and not hereditary hypercholesterolemia) combined (mixed) lipidemia (the IIa and IIb type across Fredrikson), the increased TG level in a blood plasma (type IV across Fredrikson) and at patients with a disbetalipoproteinemiya (type ІІІ across Fredrikson) in cases when the diet does not provide appropriate effect.
For decrease in level of the general XC and XC LPNP at patients with a homozygous hereditary hypercholesterolemia when the diet and other non-drug means do not provide appropriate effect.
To patients without clinical displays of cardiovascular diseases, with existence or lack of a dislipidemiya which have several risk factors of development of cardiovascular diseases for example smoking, AG, a diabetes mellitus, low level is XC LPVP or existence in the family anamnesis of cardiovascular diseases in young age on purpose:

• decrease in risk of fatal manifestations of an ischemic heart disease and not fatal myocardial infarction;
• decrease in risk of developing of a stroke;
• decrease in risk of developing of stenocardia and need of performing procedures of revascularization of a myocardium.
At patients with clinical symptoms of coronary diseases аторвастатин it is shown for:

• decrease in risk of development of not fatal myocardial infarction;
• decrease in risk of development of a fatal and not fatal stroke;
• decrease in risk when holding procedures of revascularization;
• decrease in risk of hospitalization concerning congestive heart failure;
• decrease in risk of developing of stenocardia.
Children at the age of 10–17 years
Atorvasterol is appointed in addition to a diet for decrease in level of the general XC, XC LPNP and an apoliprotein In at boys and girls during the postmenarkhialny period, at the age of 10–17 years with a heterozygous hereditary hypercholesterolemia, even on condition of observance of an adequate diet if:
a) the LPNP level XC remains to ≥190 mg/dl;
b) the LNNP level XC remains to ≥160 mg/dl and:
c) in the family anamnesis there are cardiovascular diseases at young age;
d) at sick children 2 and more risk factors of developing of cardiovascular diseases are defined.

Route of administration and doses:

Before therapy by Atorvasterol it is necessary to try to control hypercholesterolemia level by means of the corresponding diet, to appoint the physical exercises and measures directed to a body degrowth at patients with obesity and to carry out treatment of other associated diseases. During treatment by Atorvasterol patients should keep to a standard gipokholesterinemichesky diet. Drug appoint in a dose 10–80 mg of 1 times a day daily, at any time, irrespective of meal. The initial and supporting doses have to approach individually, according to a reference value of the LPNP level XC, the purpose of treatment and sensitivity of the patient drug. In 2–4 weeks after an initiation of treatment and/or after titration of a dose of Atorvasterol it is necessary to carry out control of level of lipoproteins and depending on results of the analysis respectively to otkorrigirovat a drug dose.
Primary hypercholesterolemia and the combined (mixed) lipidemia. For most of patients the dose of 10 mg/days is effective. The therapeutic effect is reached for 2 weeks, the maximum therapeutic effect — for 4 weeks. The effect is supported throughout long treatment.
Homozygous family hypercholesterolemia. For most of patients with a homozygous family hypercholesterolemia the result is achieved at use of 80 mg of Atorvasterol of 1 times a day that provides decrease in the LPNP level XC more than for 15% (18–45%).
Heterozygous family hypercholesterolemia in pediatric practice (patients at the age of 10–17 years). Atorvasterol in an initial dose on 10 mg of 1 times a day is recommended to appoint. The maximum recommended dose makes 20 mg of 1 times a day (the doses exceeding 20 mg were not studied at patients of this age group). The dose is defined individually, depending on the treatment purpose. In each 4 weeks or it is necessary to korrigirovat a drug dose more.
Use for treatment of patients with a liver failure. See CONTRAINDICATIONS and SPECIAL INSTRUCTIONS.
Use for treatment of patients with a renal failure. Diseases of kidneys do not influence concentration of an atorvastatin or decrease in the LPNP level XC in a blood plasma. Therefore there is no need for dose adjustment.
Use for treatment of patients of advanced age. In safety, efficiency or achievement of the goal in treatment of a hypercholesterolemia patients of advanced age and patients of other age groups have no distinction.
Use in a combination with other medicines. In need of simultaneous use of an atorvastatin and cyclosporine the dose of an atorvastatin should not exceed 10 mg (see. Special INSTRUCTIONS and INTERACTIONS).

Features of use:

Influence on a liver
As well as at use of other gipolipoproteinemichesky medicines of this group, at treatment by Atorvasterol activity of transaminases of a blood plasma can moderately increase (3 times higher, than the top level of norm).
Before an initiation of treatment and periodically during treatment it is necessary to define indicators of function of a liver. Monitoring of function of a liver should be carried out at emergence of signs or symptoms of its possible defeat. Atorvasterol is capable to cause increase in activity of transaminases. The condition of patients at whom the level of transaminases increased should be controlled before disappearance of pathological changes. In case the level of transaminases increases by 3 times in comparison with average value of the upper bound of norm, it is recommended to lower Atorvasterol's dose or to cancel drug. Increase in activity of transaminases was not followed by jaundice or other clinical manifestations. If the dose of drug was reduced, did a break or stopped treatment, the level of transaminases was normalized. Most of patients continued treatment by the lowest doses of Atorvasterol without negative effects.
Atorvasterol it is necessary to apply with care at patients who abuse alcohol and/or have a liver disease in the anamnesis. Liver diseases in an active phase or increase in activity of transaminases for the unclear reason are a contraindication for drug use.
Influence on skeletal muscles
As well as other inhibitors of GMG-KOA-reduktazy, аторвастатин it is very seldom capable to exert impact on skeletal muscles and to cause a mialgiya, a miositis and a myopathy which can progress before emergence of a rabdomioliz — a state which potentially threatens life of the patient and is characterized by substantial increase of the KFK level (more than 10 times in comparison with the upper bound of norm), a myoglobinemia and a myoglobinuria which lead to a renal failure.
The probability of emergence of this state needs to be considered 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 fervescence. In cases of increase in the KFK level or the specified or probable diagnosis of a myopathy treatment by Atorvasterol should be stopped. The risk of emergence of a myopathy during treatment by drugs of this group increases at simultaneous use of cyclosporine, derivatives of fibrinous acid, erythromycin, Niacinum or azolovy antifungal means. The majority of these means suppress metabolism of P450 ZA4 cytochrome and/or distribution of drug in an organism. Atorvasterol biotransformirutsya first of all by means of ZA4 RMS liver enzyme. At Atorvasterol's appointment in a combination with derivatives of fibrinous acid, erythromycin, immunosuppressors or azolovy antifungal means, or gipolipoproteinemichesky doses of Niacinum it is necessary to weigh possible positive takes and negative effects and to observe patients for the purpose of definition 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. Periodic definition of KFK is for this purpose recommended, but it is necessary to remember that this test is not enough for timely diagnosing of a heavy myopathy. Atorvasterol can cause increase in the KFK level.
At treatment by Atorvasterol, as well as at use of similar drugs of this group, sometimes noted cases of a rabdomioliz in a combination to a secondary renal failure which is shown by a myoglobinuria. Therapy by drug 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).
Before an initiation of treatment
Atorvastatin it is necessary to apply with care at the patients inclined to development of a rabdomioliz. It is necessary to determine the KFK level before an initiation of treatment statines in such cases:

• renal failure;
• hypothyroidism;
• a genetic myopathy in the anamnesis;
• the myopathy (in the anamnesis) connected with the previous use of statines or fibrat;
• abnormal liver functions and/or alcohol abuse;
• at patients of advanced age (70 years are also more senior).
Need of definition of indicators should be estimated taking into account above-mentioned.
In such cases it is necessary to analyze carefully the risk connected with treatment and possible advantages. It is recommended to carry out full clinical monitoring. If the KFK level very high (is 5 times higher than the upper bound of norm), it is not necessary to begin treatment.
Determination of the KFK level
It is not necessary to determine the KFK levels after an exercise stress or in the presence of any obvious reasons for increase in KFK as it influences interpretation of results of analyses. If the KFK level is much higher (5 times higher than the upper bound of norm), the analysis should be repeated in 5–7 days for confirmation of result.
During treatment:

• it is necessary to explain to patients importance of the immediate message to the doctor about emergence of a mialgiya, spasms or weakness, especially after an indisposition and fever;
• if symptoms arise during treatment atorvastatiny, it is necessary to determine the KFK level, and in case of the expressed increase in level (is 5 times higher than the upper bound of norm) to stop treatment;
• if symptoms from muscular system heavy or are the reason of daily discomfort, it is necessary to consider a question of drug withdrawal even if the KFK levels do not exceed the upper bound of norm by 5 times;
• if symptoms disappear, and value of the KFK levels is normalized, it is possible to consider a question of treatment atorvastatiny or other statines in the minimum dose and under careful monitoring;
• in case of the expressed increase in the KFK levels (is 10 times higher than the upper bound of norm) or at manifestations of a rabdomioliz, or at suspicion of such state treatment atorvastatiny should be stopped.
Use during pregnancy and feeding by a breast. Atorvasterol is contraindicated during pregnancy and feeding by a breast. Women of reproductive age have to apply effective remedies of contraception throughout treatment. Safety of use of an atorvastatin during pregnancy and feeding by a breast is not established.
In researches on animals it is established that inhibitors of GMG-KOA-reduktazy can exert impact on development of an embryo and a fruit. After introduction of an atorvastatin to females of animals in doses higher than 20 mg/kg/days development of posterity was slowed down, and the indicator of post-natal survival — is lowered. At animals concentration of an atorvastatin and its metabolites in plasma and milk is similar. It is unknown whether it is excreted аторвастатин in breast milk of the person.
Children. At children drug should be used under observation of the specialist.
Controlled clinical trials of use of an atorvastatin for patients with a heterozygous family hypercholesterolemia are aged younger than 10 years were not carried out.
Ability to influence speed of response at control of vehicles and work with other mechanisms. There are no data on any influence of an atorvastatin on ability to manage vehicles and to work with mechanisms.

Side effects:

It is expected that by-effects which note most often are symptoms from a GIT, including a lock, a meteorism, dyspepsia, an abdominal pain. They, as a rule, disappear at treatment continuation. Because of emergence of the by-effects caused atorvastatiny participation in clinical tests was stopped by less than 2% of patients.
The following list of side reactions is made on the basis of the data obtained in clinical trials and throughout the post-marketing period.
Classification of frequency of emergence of side reactions: often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10 000, <1/1000); very seldom (<1/10 000).
From a GIT: often: lock, meteorism, dyspepsia, nausea, diarrhea; infrequently: anorexia, vomiting.
From system of blood and lymphatic system: infrequently: thrombocytopenia.
From immune system: often: hypersensitivity; very seldom: anaphylaxis.
From endocrine system: infrequently: alopecia, hyperglycemia or hypoglycemia, pancreatitis.
From mentality: often: sleeplessness; infrequently: amnesia.
From a nervous system: often: headache, dizziness, paresthesias, hypesthesia; infrequently: peripheral neuropathy.
From gepatobiliarny system: seldom: hepatitis, cholestatic jaundice.
From an acoustic organ and balance: infrequently: a ring in ears.
From skin and hypodermic cellulose: often: rashes, itch; infrequently: small tortoiseshell; very seldom: a Quincke's disease, violent rashes (including a multiformny erythema, Stephens's syndrome — Johnson and a toxic epidermal necrolysis).
From a musculoskeletal system: often: mialgiya, arthralgia; infrequently: myopathy; seldom: miositis, рабдомиолиз, spasms.
From reproductive system: infrequently: impotence.
General disturbances: often: weakness, thorax pain, dorsodynia, peripheral hypostases; infrequently: indisposition, disturbance of metabolism and food, adynamy.
Children at the age of 10–17 years
At patients noted side reactions, similar to that at the persons receiving placebo. Infections were the most cumulative side effects which noted in both groups not in view of a causal relationship.

In post-market researches it was reported about such side reactions:
• from system of blood and lymphatic system: thrombocytopenia;
• from immune system: allergic reactions (including anaphylaxis);
• from metabolism: increase in body weight;
• from a nervous system: hypesthesia, amnesia, dizziness;
• from an acoustic organ: a ring in ears;
• from skin and hypodermic cellulose: Stephens's syndrome — Johnson, a toxic epidermal necrolysis, a multiformny erythema, violent rashes, a small tortoiseshell;
• from a musculoskeletal system and connecting fabric: рабдомиолиз, arthralgia, dorsodynia;
• general disturbances: thorax pain, peripheral hypostases, indisposition, fatigue.
Researches
As well as at use of other inhibitors of GMG-KOA-reduktazy, it was reported about increase in levels of transaminases in a blood plasma at the patients applying аторвастатин. Such changes were more often easy and temporary; there was no need for drug phase-out. Clinically significant increase in levels of transaminases in a blood plasma (levels are 3 times higher than average values of the upper bound of norm) was noted in 0,8% of patients who received аторвастатин. All patients had dozozavisimy such increases and reversible. During clinical trials increase in levels of a kreatinfosfokinaza in a blood plasma (levels are 3 times higher than average values of the upper bound of norm) at 2,5% of patients which applied аторвастатин that is characteristic also at use of other inhibitors of GMG-KOA-reduktazy was observed. Levels which were 10 times higher than average values of the upper bound of norm revealed at 0,4% of patients who applied аторвастатин.

Interaction with other medicines:

The risk of emergence of a myopathy during treatment by inhibitors of GMG-KOA-reduktazy increases at simultaneous use of cyclosporine, fibrat, makrolidny antibiotics, including erythromycin, antifungal drugs of group of azoles, or Niacinum and very seldom leads to development of a rabdomioliz and a renal failure owing to a myoglobinuria. It is necessary to consider carefully a ratio of possible advantages and risk which is noted at the accompanying treatment.
Inhibitors of P450 3A4 cytochrome. Atorvastatin is metabolized by means of P450 3A4 cytochrome. Interactions can reveal at simultaneous use of an atorvastatin and inhibitors of P450 ZA4 cytochrome (for example cyclosporine, makrolidny antibiotics, including erythromycin and a klaritromitsin, a nefazodon, azolny antifungal means, including итраконазол, HIV protease inhibitors). With extra care at the same time apply аторвастатин and the specified drugs as it can lead to increase in concentration of an atorvastatin in a blood plasma.
Erythromycin / кларитромицин. Simultaneous use of an atorvastatin in a dose of 10 mg/days and such inhibitors of P450 3A4 cytochrome as erythromycin (500 mg 4 times a day) or кларитромицин (500 mg 2 times a day), leads to increase in concentration of an atorvastatin in a blood plasma. Klaritromitsin raises Cmax of an atorvastatin for 56%, and AUC indicator — for 80%.
R-glycoprotein inhibitors. Atorvastatin and his metabolites are substrates for the R-glycoprotein. R-glycoprotein inhibitors (for example cyclosporine) can increase bioavailability of an atorvastatin.
Itrakonazol. At simultaneous use of an atorvastatin of 40 mg and an itrakonazola of 200 mg/days the indicator of AUC of an atorvastatin raised by 3 times.
Inhibitors of proteases. Simultaneous use of an atorvastatin with the inhibitors of proteases oppressing effect of P450 3A4 cytochrome is followed by increase in concentration of an atorvastatin in a blood plasma.
Grapefruit juice. Contains one or more CYP 3A4 inhibitors and can cause increase in concentration in a blood plasma of those drugs which are metabolized by CYP 3A4. AUC value of an atorvastatin increases by 37%, an AUC of an active orthohydroxymetabolite decreases by 20,4% after reception of 240 ml of grapefruit juice. The use of grapefruit juice in large volumes (it is more than 1,2 l/days for 5 days), leads to increase in AUC of an atorvastatin by 2,5 times and increases by 1,3 times of an indicator of AUC of the GMG-active inhibitors of KOA-reductase (an atorvastatin and active metabolites). Therefore the use of a large number of grapefruit juice during treatment atorvastatiny is not recommended.
Inductors of P450 3A4 cytochrome. Influence of inductors of P450 ZA4 cytochrome (for example rifampicin or Phenytoinum) on аторвастатин is unknown. Possible interactions with other substrates of this isoenzyme are unknown, but they should be considered in case of use of drugs with a narrow therapeutic window, for example, of antiarrhytmic means ІІІ a class, including Amiodaronum.
Antipyrine. As Atorvasterol does not change antipyrine pharmacokinetics, interaction between other drugs which are metabolized by means of the same cytochrome (such as терфенадин, Tolbutamidum, to triazoles, oral contraceptives), it is improbable.
Simultaneous use of other drugs
Azithromycin. Simultaneous use of an atorvastatin (10 mg/days) and azithromycin (500 mg/days) did not change concentration of an atorvastatin in a blood plasma.
Gemfibrozil/fibrata. The risk of emergence of the myopathy caused by use of an atorvastatin can increase at simultaneous use of fibrat. According to results of the researches in vitro gemfibrozit suppresses a glyukuronization of an atorvastatin. It can cause increase in concentration of an atorvastatin in a blood plasma.
Digoxin. At prolonged use of digoxin and simultaneous use of 10 mg of an atorvastatin digoxin level in a blood plasma did not change. Nevertheless concentration of digoxin increased approximately by 20% at simultaneous use of 80 mg of an atorvastatin a day. Such interaction arises owing to inhibition of membrane protein which transports the R-glycoprotein. The condition of patients who apply digoxin should be controlled carefully.
Oral contraceptives. At simultaneous use with oral contraceptives concentration of Norethisteronum and ethinylestradiol increase. This effect should be considered at selection of doses of oral contraceptives.
Kolestipol. Concentration of an atorvastatin and its active metabolites in a blood plasma decreases (approximately by 25%) at simultaneous use of an atorvastatin and kolestipol. At the same time hypolipidemic action of a combination of an atorvastatin and kolestipol exceeded the efficiency noted at use of each of these drugs separately.
Antacids. At simultaneous use of an atorvastatin and antacids in the form of liquid forms for oral administration which contain sodium hydroxide and aluminum hydroxide concentration of an atorvastatin in a blood plasma decrease approximately by 35%, however there is no influence on decrease in the LPNP level XC.
Warfarin. Simultaneous use of an atorvastatin and warfarin leads to insignificant decrease in a prothrombin time in the first days of such treatment, however in 15 days of use of an atorvastatin this indicator is normalized. Nevertheless constant control behind a condition of the patients accepting warfarin is necessary if add to the scheme of treatment аторвастатин.
Phenazone. Simultaneous use of an atorvastatin and phenazone throughout certain time leads to insignificant influence on clearance of phenazone or such influence does not reveal.
Amlodipin. At simultaneous use of 80 mg of an atorvastatin and 10 mg of an amlodipin pharmacokinetic indicators of an atorvastatin in an equilibrium state did not change.
Terfenadin. Simultaneous use of an atorvastatin and terfenadin did not cause essential changes of pharmacokinetics of a terfenadin.
Other drugs. In clinical trials clinically significant interactions at co-administration of an atorvastatin and anti-hypertensive or estrogenzameshchayushchy means are noted.

Contraindications:

• hypersensitivity to active ingredient or any other component of drug in the anamnesis;
• liver diseases in an active phase or long increase in level of transaminases (is 3 times higher than the average upper bound of norm) in a blood plasma of an unknown etiology;
• myopathy;
• period of pregnancy and feeding by a breast;
• to women of reproductive age who do not apply effective methods of contraception;
• children aged up to 10 years.

Overdose:

There is no specific treatment at overdose of an atorvastatin. In overdose cases treatment of the patient has to be symptomatic and supporting (if necessary). It is necessary to control indicators of function of a liver and the KFK level. As аторвастатин contacts proteins of a blood plasma, it is not expected that carrying out a hemodialysis considerably will increase clearance of an atorvastatin.