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medicalmeds.eu Medicines Hypolipidemic means - KOA-reductase GMG inhibitor. Atorvakor

Atorvakor

Препарат Аторвакор. ОАО "Фармак" Украина


Producer: JSC Pharmak Ukraine

Code of automatic telephone exchange: C10AA05

Release form: Firm dosage forms. Tablets.

Indications to use: Hypercholesterolemia. Dislipidemiya. Arterial hypertension. Diabetes mellitus. Stenocardia. Stroke. Coronary heart disease.


General characteristics. Structure:

Active ingredient: atorvastatin;

1 tablet contains an atorvastatin of calcium of trihydrate of 10,34 mg or 20,68 mg in terms of 100% anhydrous substance аторвастатин 10 mg or 20 mg;

 excipients: calcium carbonate sorbite (calcium carbonate (Е 170), sorbite (E 420)), cellulose microcrystallic, sodium lauryl sulfate, polyethyleneglycol (macrogoal) 6000, коповидон, sodium of a kroskarmeloz, talc, magnesium stearate, Opadry II 85F18422 white (polyvinyl alcohol, polyethyleneglycol, talc, titanium dioxide (Е 171)).




Pharmacological properties:

Pharmacodynamics. Atorvastatin – the selection competitive inhibitor 3-hydroxy-3-metilglyutaril-coenzyme A (GMG-KOA) of reductase – the key enzyme turning GMG-KOA into mevalonovy acid – the predecessor of sterol, including cholesterol. Triglycerides and cholesterol in a liver are included lipoproteins of very low density (LPONP), come to plasma and are transported in peripheral fabrics. Lipoproteins of the low density (LPNP) which catabolize by interaction with vysokoafinny receptors of LPNP are formed of LPONP. Atorvastatin reduces levels of cholesterol and lipoproteins in plasma, oppressing HMG-CoA reductase in a liver and increasing number of hepatic LPNP-receptors by surfaces of cells that leads to strengthening of capture and a catabolism of LPNP cholesterol.

Atorvastatin reduces formation of LPNP cholesterol and quantity of particles of LPNP. It causes substantial and permanent increase of activity of LPNP-receptors, and also causes favorable changes of quality of the circulating LPNP. Atorvastatin effectively reduces LPNP cholesterol level at patients with a homozygous family hypercholesterolemia which usually does not give in to therapy by other hypolipidemic means.

Primary scene of action of an atorvastatin is the liver playing the leading role in synthesis of cholesterol and clearance of LPNP. Decrease in level of LPNP cholesterol correlates with a dose of drug and its concentration in an organism. Atorvastatin reduces the level of the general cholesterol, LPNP cholesterol, apolipoprotein B and triglycerides and, somewhat, increases LPVP cholesterol level. At patients with a disbetalipoproteinemiya аторвастатин reduces the level of cholesterol of lipoproteins of the average density (LPSP).

Pharmacokinetics. Atorvastatin is quickly absorbed after intake. The maximum concentration is reached in 1-2 hours. Extent of absorption and concentration in plasma raise in proportion to a dose. Absolute bioavailability low (     about 12%) that is connected with presistemny clearance in a mucous membrane of a digestive tract and/or biotransformation at the first passing through a liver. About 98% of drug contact proteins of plasma. Atorvastatin biotransformirutsya with the participation of P450 3A4 cytochrome with formation of active metabolites (orto-and parahydroxylated derivatives and products of beta oxidation). Also its metabolites with bile Eliminirutsya аторвастатин, are not exposed to enterohepatic recirculation. The elimination half-life of an atorvastatin makes about 14 hours, but the inhibiting activity on key enzyme remains till 30 o'clock. With urine less than 2% of the dose of an atorvastatin accepted inside are removed.
Pharmaceutical characteristics

Main physical and chemical properties: tablets of a round form, biconvex, white color, film coated.


Indications to use:

As addition to a diet for treatment of patients with the increased level of the general cholesterol, cholesterol lipoproteins of low density, apolipoprotein B, triglycerides, for the purpose of increase cholesterol lipoproteins of high density at patients with primary hypercholesterolemia (a heterozygous family and not hereditary hypercholesterolemia) combined (mixed) lipidemia (Fredriksonovsky type ІІ and and ІІ b), the increased level of triglycerides in blood serum (Fredriksonovsky type IV) and patients with a disbetalipoproteinemiya (Fredriksonovsky type III) in cases when the diet does not provide due effect.

For decrease in level of the general cholesterol and H-LNP at patients with a homozygous family hypercholesterolemia at inefficiency of a diet and other non-drug means.

To patients without clinical displays of cardiovascular diseases, with existence or lack of a dislipidemiya, but having several risk factors of cardiovascular diseases, such as smoking, arterial hypertension, a diabetes mellitus, the H-LVP low level or existence in the family anamnesis of information on cardiovascular diseases in young age on purpose:
decrease in risk of fatal displays of coronary 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 holding 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 (10-17 years)

Atorvakor is appointed as addition to a diet for decrease in level of the general cholesterol, cholesterol lipoproteins of low density and apolipoprotein B at boys and girls during the postmenarkhialny period, aged from 10 up to 17 years with a heterozygous family hypercholesterolemia, even on condition of observance of an adequate diet if:

a) the H-LNP level remains to ≥1,9 g/l or

b) the H-LNP level remains to ≥1,6 g/l and:
in the family anamnesis developing of cardiovascular diseases at young age takes place;
at sick children two or more other risk factors of developing of cardiovascular diseases take place.


Route of administration and doses:

Before therapy by Atorvakor it is necessary to try to achieve control of a hypercholesterolemia by means of an adequate dietotherapy, the increased physical activity, decrease in body weight from patients with obesity and to carry out treatment of other associated diseases.

Treatment is carried out against the background of cholesterol - the reducing diet. To appoint drug in a dose 10-80 mg of 1 times a day daily, during any period of day in one and too time, irrespective of meal. To select an initial and maintenance dose individually taking into account initial levels of LPNP cholesterol, the purpose of therapy and efficiency. The recommended initial dose makes 10 mg. If necessary the dose is raised gradually with an interval of 2-4 weeks and more, controlling the level of lipids of a blood plasma. The maximum daily dose – 80 mg.

Primary hypercholesterolemia and the combined (mixed) lipidemia. It is enough to accept 10 mg once daily. Efficiency of treatment becomes noticeable in    2 weeks, reaching a maximum on the 4th week. The effect remains at long treatment.

Homozygous family hypercholesterolemia. In most cases the result is achieved by use of 80 mg of Atorvakor of 1 times a day, at the same time LPNP cholesterol can decrease from 18% to 45%.

Heterozygous family hypercholesterolemia at detey10-17 years. Atorvakor to appoint in a dose 10 mg once a day daily. The maximum dose makes 20 mg once a day daily. The dose can be picked individually up according to problems of therapy; dose adjustment is possible with an interval of 4 weeks and more.

Use for treatment of patients with a liver failure. See the section "Contraindications" and "Features of Use".

Use for treatment of patients with a renal failure. Diseases of kidneys do not influence concentration of an atorvastatin or decrease in the H-LNP level in a blood plasma. Thus, there is no need for dose adjustment.

Use for treatment of elderly patients. In safety, efficiency or achievement of the goal in treatment of a hypercholesterolemia elderly patients and patients of other age groups have no difference.

Use in a combination with other medicines. If there is a need of simultaneous use of an atorvastatin and cyclosporine, the dose of an atorvastatin should not exceed 10 mg (see the section "Features of Use" – influence on skeletal muscles and the section "Interaction with Other Medicines" – transfer inhibitors).


Features of use:

Use during pregnancy or feeding by a breast.

Drug is contraindicated to women during pregnancy or feeding by a breast. Women of reproductive age have to use effective methods of contraception. Atorvakor appoint to women of reproductive age only in that case when the probability to become pregnant very low and the patient is informed on potential risk for a fruit.

Atorvakor is contraindicated during feeding by a breast. It is unknown whether this drug in breast milk is excreted. As there is a potential risk of development of side effects in children on breastfeeding, the women accepting drug have to stop feeding by a breast.
Children

The controlled clinical trials of an atorvastatin at patients with a heterozygous family hypercholesterolemia are younger than 10 years were not carried out.

Influence on a liver. As well as at use of other gipolipoproteinemichesky means of this class, at treatment by Atorvakor there can be a moderate increase in activity   of transaminases of blood serum (three times more upper bound of norm – VGN). Function of a liver should be checked prior to treatment and to control periodically throughout a therapy course. Patients who have manifestations of abnormal liver functions should define indicators of its function. Patients at whom increase in activity of transaminases is noted have to be under observation before normalization of indicators. In case of growth of activity of ALAT or ASAT more than by 3 times in comparison with norm treatment by drug should be stopped.

The patients who are taking alcohol and/or having liver diseases in the anamnesis should appoint drug with care. Liver diseases in an active phase or increase in activity of transaminases for the unclear reasons is a contraindication for purpose of an atorvastatin.

Influence on skeletal muscles. In cases of inexplicable pain or muscular weakness, especially if it is followed by an indisposition and fever, patients are recommended to see a doctor immediately. Treatment atorvastatiny needs to be stopped in cases of substantial increase of activity of KFK, and also at the diagnosed or suspected myopathy. The risk of emergence of a myopathy during treatment by drugs of this group increases at a concomitant use of cyclosporine, fibrat, erythromycin, niacin or azolny antifungal drugs. Some of these drugs are inhibitors of metabolism P450 3A4 and/or transportation of drug. CYP 3A4 is the primary gepatoizoferment promoting biotransformation of an atorvastatin. Doctors have to weigh carefully potential advantage and risk of simultaneous use of an atorvastatin and fibrat, erythromycin, immunosuppressive drugs, antifungal drugs and niacin in hypolipidemic doses. Within the first months of treatment and during increase in a dose of drugs it is necessary to watch closely a condition of patients. Thus, it is necessary to appoint the initial and supporting doses of an atorvastatin it is less at its simultaneous use with the stated above medicines. In such cases it is recommended to check periodically the KFK level, but it does not exclude possibility of a heavy myopathy. Atorvastatin can cause increase in activity of KFK.

As well as at use of other drugs of this class, during use of an atorvastatin it was reported about isolated cases of development of a rabdomioliz and the secondary renal failure caused by a myoglobulinuria. Treatment atorvastatiny needs to be stopped temporarily at all patients with the sudden serious condition reminding a myopathy or in the presence of factors of tendency to developing of the secondary renal failure caused rabdomiolizy (for example heavy acute infectious diseases, hypotonia, an extensive operative measure, an injury, serious violations of a metabolism, endocrine disturbances, an imbalance of electrolytes, uncontrollable spasms).

Influence on endocrine system. Statines interfere with synthesis of cholesterol and theoretically can negatively influence products adrenal glands of sex steroid hormones. Atorvastatin does not reduce basal concentration of cortisol in plasma or negatively influences reserves of adrenal glands. Influence of statines on male fertility was not studied at enough patients. Effects if those are available, namely pituitary and gonadal in a premenopause of women, are unknown. It is necessary to adhere to care if statines are appointed along with drugs which can reduce the level or activity of endogenous steroid hormones, such as кетоконазол, Spironolactonum and Cimetidinum.

Hemorrhagic stroke. At the patients without the coronary heart disease (CHD) who recently transferred the tranzitorny ischemic attack (TIA) which it was appointed аторвастатин in a dose of 80 mg the frequency of a hemorrhagic stroke is higher, than at patients to whom this drug was not appointed. Especially expressed growth of risks is characteristic of the patients who earlier already had a hemorrhagic stroke or a lacunary heart attack. For the patients who earlier had a hemorrhagic stroke or a lacunary heart attack, the ratio of risks and advantage of an atorvastatin of 80 mg is not finalized. At patients with a hemorrhagic stroke or a lacunary heart attack in the anamnesis prior to treatment it is necessary to weigh carefully potential advantage of treatment and risk of development of a hemorrhagic stroke.

Prior to treatment

Atorvastatin the patients having factors of tendency to development of a rabdomioliz should appoint with care. Prior to treatment by statines at the patients inclined to development of a rabdomioliz, it is necessary to determine the KFK level in such situations:
renal failure;
hypofunction of a thyroid gland;
hereditary frustration of muscular system in the family or personal anamnesis;
the cases of toxic influence of statines or fibrat postponed in the past on muscles;
the diseases of a liver postponed in the past and/or the use of large amounts of alcohol;
at patients of advanced age (70 years are more senior) need of holding the specified actions should be estimated taking into account existence of other factors of tendency to development of a rabdomioliz;
situations in which increase in levels of drugs in a blood plasma, in a detail of interactions and use to special populations of patients, including patients with hereditary diseases is possible.

In similar cases it is recommended to estimate a ratio of risks and possible advantage of treatment and to carry out clinical monitoring of a condition of patients. If prior to treatment the KFK level is considerably increased (exceeds the upper bound of norm (UBN) more than by 5 times), treatment should not be begun.

Measurement of level of a kreatinfosfokinaza

The KFK level should not be determined after intensive exercise stresses or in the presence of any possible alternative reasons of increase in the KFK level as it can complicate interpretation of results. If at the initial level substantial increase of KFK is observed (exceeding of VGR more than by 5 times), then in 5-7 days it is necessary to carry out repeated definition for confirmation of result.

During treatment

Patients have to know about need to report immediately about development of pain in muscles, spasms or weakness, especially when they are followed by an indisposition or fever. In case of these symptoms during treatment atorvastatiny it is necessary to determine the KFK level at this patient. If it is found out that the KFK level is considerably increased (exceeds VGN more than by 5 times), treatment should be stopped.

The possibility of the termination of treatment should be considered also if increase in the KFK level does not reach fivefold exceeding of VGN, but symptoms from muscles have difficult character and daily become the reason of unpleasant feelings.

After disappearance of symptoms and normalization of the KFK level it is possible to consider the possibility of resuming of treatment atorvastatiny or an initiation of treatment alternative statine on condition of use of minimum possible dose of drug and careful observation of a condition of the patient.

Treatment atorvastatiny needs to be stopped if clinically significant increase in the KFK level (increase in VGN more than by 10 times) or in case of diagnosing of a rabdomioliz is observed (or suspicions on development of a rabdomioliz).

Simultaneous use with other medicines

The risk of development of a rabdomioliz increases at simultaneous use of an atorvastatin with certain medicines which can increase concentration of an atorvastatin in a blood plasma. As examples of such drugs powerful CYP 3A4 inhibitors or transport proteins can act: cyclosporine, телитромицин, кларитромицин, делавирдин, стирипентол, кетоконазол, вориконазол, итраконазол, посаконазол and inhibitors of HIV proteases, including ритонавир, лопинавир, атазанавир, индинавир, дарунавир, etc. At simultaneous use with gemfibrozily and other derivatives of fibroyevy acid, erythromycin, Niacinum and ezetimiby the risk of emergence of myopathies can also grow. If it is possible, it is necessary to consider the possibility of use of other medicines (which do not interact with atorvastatiny) instead of above-stated.

In cases when it is necessary to carry out simultaneous treatment atorvastatiny and the specified drugs, it is necessary to weigh carefully advantage and risks of simultaneous treatment. If patients accept the medicines increasing concentration of an atorvastatin in a blood plasma it is recommended to reduce a dose of an atorvastatin to minimum. Besides, in case of use of powerful CYP 3A4 inhibitors it is necessary to consider the possibility of use of a smaller initial dose of an atorvastatin. Also it is recommended to carry out appropriate clinical monitoring of a condition of these patients.

It is not recommended to appoint at the same time аторвастатин and fuzidovy acid therefore it should be taken into account the possibility of temporary cancellation of an atorvastatin for treatment by fuzidovy acid.

Intersticial pulmonary disease. During treatment some statines (especially during prolonged treatment) described exceptional cases of development of an intersticial pulmonary disease. It is possible to carry an otdyshka, unproductive cough and the general deterioration in health (fatigue, weight reduction and fever) to displays of this disease. In case of suspicion emergence that at the patient the intersticial pulmonary disease developed, it is necessary to stop treatment by statines.

Fillers. Sorbitol therefore drug should not be accepted to patients with the rare hereditary diseases connected with intolerance of fructose is Atorvakor's part.
Ability to influence speed of response at control of motor transport or work with other mechanisms

Has insignificant influence on speed of response during control of motor transport or works with other mechanisms.


Side effects:

Atorvakor is usually well had. Side effects in most cases easy severity and temporary.

Disturbances from a metabolism: hypoglycemia, hyperglycemia, anorexia, increase in body weight, diabetes mellitus.

Mental disorders: sleeplessness, nightmares, depression.

Disturbances from the central nervous system: headache, peripheral neuropathy, paresthesia, hypesthesia, amnesia, dizziness, dysgeusia, stroke.

Disturbances from respiratory system, thoracic and mediastinal disturbances: a pharyngalgia and in throats, nasal bleeding.

Disturbances from a digestive tract: nausea, diarrhea, abdominal pain, dyspepsiaeructation, lock, meteorism, pancreatitis, vomiting.

Disturbances from gepatobiliarny system: hepatitis, cholestatic jaundice, cholestasia, liver failure.

Disturbances from a musculoskeletal system and connecting fabric: a mialgiya, a myopathy, a miositis, myotonia, muscular spasms, weakness of muscles, a tendinopatiya (sometimes complicated by a rupture of a sinew), рабдомиолиз, an arthralgiahypostases in joints, neck pain, a dorsodynia, extremity pain.

Disturbances from skin and a hypodermic fatty tissue: alopecia, itch, rash, Stephens-Johnson's syndrome, toxic epidermal necrolysis, multiformny erythema, violent rashes, small tortoiseshell.

Disturbances from reproductive system: disorders of sexual function, impotence.

Frustration of reproductive system and mammary glands: gynecomastia.

Disturbances from an urinary path: infection of an urinary path.

From blood and lymphatic system: thrombocytopenia.

Disturbances from immune system: allergic reactions (including an anaphylaxis), a Quincke's disease, an acute anaphylaxis.

Disturbances from acoustic organs: sonitus, hearing loss.

Disturbances from organs of sight: illegibility of sight, vision disorder.

Infections and invasions: nasopharyngitis.

Damages, poisonings and complications of procedures: rupture of a sinew.

General manifestations: adynamy, thorax pain, peripheral hypostases, indisposition, fatigue, fever.

Disturbances from laboratory indicators: a deviation of results of functional trials of a liver, increase in activity of a kreatinfosfokinaza (KFK), increase in activity of alaninaminotranspherase, positive result of the analysis on the maintenance of leukocytes in urine.

As well as in a case with other inhibitors of GMG-KOA-reduktazy, at the patients accepting аторвастатин observed increase in activity of transaminases of blood serum. These changes usually were poorly expressed, temporary and did not demand intervention or treatment. Clinically significant increase in activity of transaminases of serum (exceeding of the upper bound of norm more than by 3 times) was observed at 0,8% of the patients accepting аторвастатин. This increase has dozozavisimy character and is reversible at all patients. At 2,5% of the patients accepting аторвастатин increase in activity of a kreatinfosfokinaza of serum which more than by 3 times exceeds the upper bound of norm is observed. It matches observations concerning other inhibitors of HMG-CoA reductase in clinical trials. At 0,4% of the patients receiving аторвастатин the levels exceeding the upper bound of norm (UBN) more than by 10 times were observed.

Developing of an intersticial pulmonary disease is in exceptional cases possible, especially during prolonged treatment.

Children of 10-17 years.

At the patients receiving аторвастатин side reactions, similar were observed by that which was observed at the patients receiving placebo. Infections were the most widespread collateral manifestations if not to take relationship of cause and effect into account. Proceeding from available data, consider that frequency, children will have the same type and severity of undesirable reactions, as at adults. Experiment on safety of drug at its long use at children is limited today.


Interaction with other medicines:

The risk of emergence of a myopathy during treatment by inhibitors of HMG-CoA reductase increases at simultaneous use of cyclosporine, fibrat, niacin or inhibitors of P450 3A4 cytochrome (for example erythromycin, antifungal drugs of a class of azoles and Niacinum).

Inhibitors of P450 3A4 cytochrome. Atorvastatin is metabolized by means of P450 3A4 cytochrome. Simultaneous use of an atorvastatin with inhibitors of P450 3A4 cytochrome can provoke increase in concentration of an atorvastatin in a blood plasma. Force of interaction and potentiation of effect depends on variability of action on P450 3A4 cytochrome.

Transfer inhibitors. Atorvastatin and his metabolites are conveyor OATP1B1 substrates. OATP1B1 inhibitors (for example cyclosporine) can increase bioavailability of an atorvastatin. Simultaneous use of 10 mg of an atorvastatin and cyclosporine (5,2 mg/kg a day) causes increase in exposure of an atorvastatin by 7,7 times.

Erythromycin / кларитромицин. Simultaneous use of an atorvastatin and erythromycin  (500 mg 4 times a day) or a klaritromitsina (500 mg twice a day) which are inhibitors of P450 3A4 cytochrome, was followed by increase in concentration of an atorvastatin in a blood plasma.

Protease inhibitors. Simultaneous use of an atorvastatin and inhibitors of protease, well-known inhibitors of P450 3A4 cytochrome is followed by increase in concentration of an atorvastatin in a blood plasma.

Diltiazem hydrochloride. Simultaneous use of an atorvastatin (40 mg) and diltiazem  (240 mg) causes increase in concentration of an atorvastatin in a blood plasma.

Cimetidinum. Essential effects of interaction between this drug and atorvastatiny are not revealed.

Itrakonazol. Simultaneous use of an atorvastatin (20-40 mg) and an itrakonazola (200 mg) is followed by increase in AUC of an atorvastatin.

Grapefruit juice. Contains the substances inhibiting CYP 3A4 therefore can increase concentration of an atorvastatin in a blood plasma, especially at the use of grapefruit juice more than 1,2 l a day.

CYP3A4 inhibitors

It is known that powerful CYP3A4 inhibitors  lead to substantial increase of concentration of an atorvastatin (see Table 1 and detailed information given below). It is necessary to avoid, whenever possible, simultaneous use with powerful CYP3A4 inhibitors (for example cyclosporine, телитромицин, кларитромицин, делавирдин, стирипентол, кетоконазол, вориконазол, итраконазол, посаконазол) and inhibitors of HIV proteases, including ритонавир, лопинавир, атазанавир, индинавир, дарунавир. In cases when it is impossible to avoid simultaneous use of these drugs with atorvastatiny, it is necessary to consider the possibility of use of smaller initial and maximum doses of an atorvastatin. Also it is recommended to carry out appropriate clinical monitoring of a condition of the patient (see Table 1).

Moderate CYP3A4 inhibitors (for example erythromycin, diltiazem, verapamil and fluconazole) can increase concentration of an atorvastatin in a blood plasma (see Table 1). Simultaneous use of erythromycin and statines is followed by increase in risk of development of a myopathy. Researches of interaction of medicines for impact assessment of Amiodaronum or verapamil on аторвастатин were not conducted. It is known that Amiodaronum and verapamil oppress activity of CYP3A4, so, co-administration of these drugs with atorvastatiny can lead to increase in exposure of an atorvastatin. Thus, at simultaneous use of an atorvastatin and these moderate CYP3A4 inhibitors it is necessary to consider the possibility of use of smaller maximum doses of an atorvastatin. It is also recommended to carry out clinical monitoring of a condition of the patient. After an initiation of treatment or after correction of its dose it is recommended to carry out by inhibitor clinical monitoring of a condition of the patient.

Inductors of P450 3A4 cytochrome. Simultaneous use of an atorvastatin and inductors of P450 3A4 cytochrome (for example rifampicin, эфавиренз) can be followed by decrease in different level of concentration of an atorvastatin in a blood plasma. In view of the double mechanism of effect of rifampicin (induction of P450 3A4 cytochrome and an ingibition of OATP1B1 enzyme carrier in a liver), simultaneous use with atorvastatiny because the delayed use of an atorvastatin after therapy by rifampicin was followed by considerable decrease in concentration of an atorvastatin in a blood plasma is recommended.

Antacids. Simultaneous use of an atorvastatin and suspension of the peroral antacids containing aluminum hydroxides and magnesium reduces concentration of an atorvastatin in a blood plasma approximately by 35%. At the same time hypolipidemic action of an atorvastatin did not change.

Antipyrine. As аторвастатин 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.

Kolestipol. Concentration of an atorvastatin in a blood plasma decreases by 25% at simultaneous use with kolestipoly. However the hypolipoprotein effect was more expressed at simultaneous use of an atorvastatin and kolestipol, than at use of one of these drugs.

Digoxin. At prolonged simultaneous use of digoxin and 10 mg of an atorvastatin digoxin level in plasma did not change. However concentration of digoxin increased approximately by 20% at simultaneous use from 80 mg of an atorvastatin a day. It is necessary to control carefully a condition of the patients accepting digoxin.

Azithromycin. Simultaneous use of an atorvastatin (10 mg a day) and azithromycin     (500 mg a day) did not change concentration of an atorvastatin in a blood plasma.

Inhibitors of transport proteins. Inhibitors of transport proteins (for example cyclosporine) are capable to increase the level of system exposure of an atorvastatin (see Table 1). Influence of oppression of accumulative transport proteins on concentration of an atorvastatin in cells of a liver is unknown. If it is impossible to avoid co-administration of these drugs, the dose decline and carrying out clinical monitoring of efficiency of an atorvastatin is recommended (see Table 1).

Гемфиброзил / derivatives of fibroyevy acid. In some cases use of fibrat in monotherapy was followed by development of the phenomena from muscular system, including a rabdomioliz. At simultaneous use with derivatives of fibroyevy acid and atorvastatiny the risk of development of these phenomena can increase. If it is impossible to avoid simultaneous use, it is necessary to appoint the minimum possible dose of an atorvastatin which allows to achieve the therapeutic goal and to properly control a condition of patients.

Эзетимиб. Use of an ezetimib in monotherapy is connected with development of the phenomena from muscular system, including a rabdomioliz. Thus, at simultaneous use of an ezetimib and atorvastatin the risk of development of these phenomena can increase. It is recommended to carry out appropriate clinical monitoring of a condition of such patients.

Oral contraceptives. Simultaneous use with the oral contraceptives containing norethindrone and ethinylestradiol is increased by AUC of these two drugs approximately by 30% and 20%. This effect should be considered at the choice of a contraceptive for the women accepting аторвастатин.

Fuzidovy acid. Researches of interaction of an atorvastatin and fuzidovy acid were not conducted. As well as in a case with other statines, at a concomitant use of an atorvastatin and fuzidovy acid the phenomena from muscular system were described (including рабдомиолиз). The mechanism of this interaction remains to unknown. Patients demand careful observation, perhaps, it is required to suspend temporarily treatment atorvastatiny.

Warfarin. At a concomitant use of warfarin at prolonged treatment and the atorvastatina in a dose of 80 mg daily slightly decreases a prothrombin time (approximately for  1,7 seconds) during the first 4 days of administration of drugs. This indicator further (within 15 days of treatment atorvastatiny) is returned to norm. Clinically significant interactions with anticoagulants were described only in exceptional cases. However, to guarantee lack of considerable deviations of a prothrombin time at the patients accepting coumarinic anticoagulants it is necessary to define at them a prothrombin time prior to treatment atorvastatiny and to often control this indicator in an initiation of treatment. After registration of a stable prothrombin time control of this indicator can be carried out through the usual intervals recommended for the patients accepting coumarinic anticoagulants. In case of cancellation of an atorvastatin or change of a dose of drug it is necessary to repeat the procedure described above. At the patients who were not accepting anticoagulants, treatment atorvastatiny was not followed by bleedings or changes of a prothrombin time.

Amlodipin. At simultaneous use of 80 mg of an atorvastatin and 10 mg of an amlodipin concentration of an atorvastatin in a blood plasma approximately increases by 18% that has no clinical value.

Other medicines. Atorvastatin at simultaneous use with anti-hypertensive means does not show essential interaction and its use in the course estrogen replacement therapy was not followed by clinically significant side effects. Interaction researches with other drugs were not conducted.

The accompanying medicine and the mode of dosing
 
Atorvastatin

          Dose (mg)                                   of Change AUC&                                Clinical recommendations

Tipranavir of 500 mg 2 times a day         ↑ by 9,4 times                     In cases when it is necessary to carry out
40 mg in day 1,                                                                           treatment along with reception
Ritonavir of 200 mg 2 times a day,                                                 an atorvastatina, a daily dose
10 mg a day 20                                                                           atorvastatin has to be no more than 10
8 days (days with 14 on 21)                                                                mg. It is recommended to carry out  
                                                                                                    clinical monitoring of a condition        of such patients.

Cyclosporine of 10 mg once a day          ↑ by 8,7 times
within 28 days
5,2 mg/kg/day, stable dose

Lopinavir of 400 mg 2 times a day          ↑ by 5,9 times                In cases when it is necessary to carry out
20 mg once a day within 4 days                                          treatment along with reception
Ritonavir 100 mg 2 times in day                                                of an atorvastatin, it is recommended to reduce
                                                                                               maintenance doses of an atorvastatin. 
                                                                                                 In cases when doses of an atorvastatin exceed      
                                                                                                 20 mg, are recommended to carry out clinical 
                                                                                                  monitoring of a condition of such patients.

Klaritromitsin of 500 mg                           ↑ by 4,4 times
80 mg once a day within 8 days
2 times a day, 9 days

Sakvinavir of 400 mg 2 times a day           ↑ by 3,9 times               In cases when it is necessary to carry out
40 mg once a day within 4 days                                          treatment along with reception
Ritonavir 300 mg 2 times in day                                                of an atorvastatin, it is recommended to reduce
since days 5-7 with increase                                           maintenance doses of an atorvastatin. In
to 400 mg 2 times a day per day 8,                                             cases, when doses of an atorvastatin
days 5-18 in 30 minutes later                                                 exceed 40 mg, it is recommended
reception of an atorvastatin                                                               to carry out clinical monitoring
                                                                                                     conditions of such patients.

Darunavir of 300 mg 2 times a day               ↑ by 3,3 times
10 mg once a day within 4 days
Ritonavir of 100 mg 2 times a day, 9 days

Itrakonazol of 200 mg once a day,                
40 mg of RD 4 days                                              ↑ by 3,3 times


Forsamprenavir of 700 mg 2 times a day      ↑ by 2,5 times
10 mg once a day within 4 days
Ritonavir of 100 mg 2 times a day, 14 days
 
Forsamprenavir of 10 mg once a day in       ↑ by 2,3 times
current of 4 days
1400 mg 2 times a day, 14 days

Nelfinavir of 1250 mg 10 mg once a day in  ↑ by 1,7 times ˆ        Is not present special recommendations
current of 28 days
2 times a day, 14 days
 
                      ↑ 37%              it is not recommended to use grapefruit juice, 40 mg of RD
240 ml once a day *                                                            аторвастатин along with big 
                                                                                           amounts of grapefruit juice
Diltiazem of 240 mg once a day, 28 days      ↑ 51%              After an initiation of treatment or later
                                                                               It is recommended to carry out 40 mg of RD of change of a dose 
                                                                                           appropriate clinical monitoring 
                                                                                           conditions of such patients

Erythromycin of 500 mg 4 times a day,             ↑ 33% ˆ            Are recommended to use smaller
7 days, 10 mg of RD                                                                  the maximum dose and to carry out appropriate 
                                                                                            clinical monitoring of a state 
                                                                                            such patients
Amlodipin of 10 mg, a single dose                    ↑ 18%             Is not present special recommendations
80 mg of RD

Cimetidinum of 300 mg 4 times a day,             ↓ less than 1%   there are no special recommendations
10 mg once a day within 4 weeks
2 weeks

Antiacid suspension of hydroxides         ↓ 35% ˆ                Is not present special recommendations
magnesium and aluminum, on 30 ml 4 times in
day, within 2 weeks
10 mg once a day within 4 weeks

Efavirents of 600 mg once a day, 14 days   ↓ 41%               Is not present special recommendations
On 10 mg within 3 days

Rifampicin of 600 mg once a day,              ↑ 30%              If to avoid a concomitant use
7 days (concomitant use)                                          are impossible, it is recommended to accept
40 mg of RD                                                                             аторвастатин and rifampicin at the same time and 
                                                                                           to carry out clinical monitoring 
                                                                                           conditions of patients
Rifampicin of 600 mg once a day               ↓ 80%            
5 days (reception at different times)
40 mg of RD

Gemfibrozil 600 mg 2 times a day,            ↑ 35%              It is recommended to appoint reduced
7 dney40                                                                    an initial dose and to carry out by RD mg clinical 
                                                                                          monitoring of a condition of such patients

Fenofibrat 160 mg once a day, 7 days   ↑ 3%               It is recommended to appoint reduced
40 mg of RD                                                                           an initial dose and to carry out clinical 
                                                                                        monitoring of a condition of such patients
The data provided in a type of x-fold change display a simple ratio between a concomitant use and reception of an atorvastatin in monotherapy (i.e. 1-fold change = is not present changes). The data provided in a type of % of changes display a difference as a percentage in comparison with reception of an atorvastatin in monotherapy (i.e. there are no 0% = changes).

* Is a part one or more components oppressing activity of CYP3A which can lead to increase in concentration in plasma of the medicines which are exposed to metabolic transformations under the influence of this enzyme. The use of one glass of grapefruit juice (240 ml) also led to decrease by 20,4% of AUC of an orthohydroxylic metabolite. The use of a significant amount of grapefruit juice (more than 1,2 liters within 5 days) raises AUC of an atorvastatin by 2,5 times and AUC of active connections (an atorvastatin and metabolites).

 ˆ General equivalent activity of an atorvastatin.

Increase is displayed by a  symbol, decrease – a  symbol.

RD = single dose.

Table 2. Influence of an atorvastatin on pharmacokinetics of the accompanying medicines
Atorvastatin and           Accompanying Medicine mode
dosing                          Medicinal                  Changes         Clinical recommendations       
                                             drug/dose (mg)             AUC&
80 mg during   Digoxin of 0,25 mg             ↑ 15%                Follow once a day properly
10 days                                                                                    to watch patients once a day, 
                                                                                                                  accepting digoxin
                                       There are no 40 mg during Peroral ↑ 28% special recommendations once a day
22 days                                  contraceptives
                                             within 2 months          ↑ 19%
                                              - mg norethindrone 1
                                              - ethinylestradiol of 35 mkg
                            There are no 80 mg during * Phenazone of 600 mg of RD ↑ 3% special recommendations once a day
15 days


& the Data provided in a type of % of change display a difference as a percentage in comparison with reception of an atorvastatin in monotherapy (i.e. there are no 0% = izmeniye).

* The concomitant use of repeated doses of an atorvastatin and phenazone did not exert noticeable impact on clearance of phenazone.


Contraindications:

Atorvakor is contraindicated to patients at hypersensitivity to any component of drug, at liver diseases in an acute phase or at permanent increase (unknown genesis) in levels of transaminases in blood serum in three or more times, to the women of reproductive age who are not using effective methods of contraception.


Overdose:

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

Treatment: when developing nausea, vomiting, diarrhea wash out a stomach, appoint a symptomatic treatment. The specific antidote is absent. Considering essential linkng with proteins of plasma the hemodialysis is not effective.


Storage conditions:

Period of validity. 2 years. Not to use drug after the termination of the period of validity specified on packaging. To store in the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children.


Issue conditions:

According to the recipe


Packaging:

On 10 tablets in the blister.

Tablets on 10 mg: on 3 or 6 blisters in a pack.

Tablets on 20 mg: on 3 or 4 blisters in a pack.



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