Atorvastatin - TEVA

General characteristics. Structure:

Active agent: аторвастатин calcium (in terms of аторвастатин) 10,36 mg (10 mg), 20,72 mg (20 mg), 41,44 mg (40 mg) and 82,88 mg (80) mg.
Excipients: lactoses monohydrate, povidone, are eudragit E 100 (бутилметакрилата,диметиламиноэтилметакрилата and methylmethacrylate copolymer 1:2:1), macrogoal alpha tocopherol by succinate, croscarmellose sodium, the sodium stearylfumarating; OPADRAY YS-1R-7003: (titanium dioxide, gipromeloza of 2910 ZSR (E464), gipromeloz of 2910 5 Wednesday (E464), macrogoal 400, polysorbate 80).

DESCRIPTION:
Tablets of 10 mg white or almost white kapsuloobrazny tablets, film coated, with an engraving "93" on the one hand and "7310" with another.
Tablets of 20 mg white or almost white kapsuloobrazny tablets, film coated, with an engraving "93" on the one hand and "7311" with another.
Tablets of 40 mg white or almost white kapsuloobrazny tablets, film coated, with an engraving "93" on the one hand and "7312" with another.
Tablets of 80 mg white or almost white kapsuloobrazny tablets, film coated, with an engraving "93" on the one hand and "7313" with another.

Pharmacological properties:

Pharmacodynamics. Atorvastatin is the selection competitive inhibitor of HMG-CoA reductase - the enzyme determining the speed limit of biosynthesis of the cholesterol responsible for transformation of Z-gidroksi-Z-metil-glyutaril-koenzima A in мевалонат, the predecessor of sterol including cholesterol. In a liver triglycerides and cholesterol are included lipoproteins of very low density (LPONP), come to a blood plasma and are transported to peripheral fabrics. Lipoproteins of the low density (LPNP) which catabolize preferential by means of • interactions with high-affine receptors of LPNP are formed of LPONP.
Atorvastatin reduces levels of cholesterol and lipoproteins in a blood plasma at the expense of inhibition of GMG-KOA-reduktazy and synthesis of cholesterol in a liver, and also due to increase in number of "hepatic" receptors of LPNP at surfaces of cells increasing capture and a catabolism of LPNP.
Atorvastatin reduces products of LPNP and quantity of particles of LPNP. Atorvastatin causes the expressed and permanent increase in activity of receptors of LPNP in combination with favorable changes of quality of the circulating LPNP particles.
Dozozavisimo reduces the LPNP level at patients with a homozygous hereditary hypercholesterolemia, resistant to therapy by other hypolipidemic means.
Ratio researches dose/effect showed that аторвастатин reduces the level of the general cholesterol (by 30-46%), LPNP cholesterol (for 41-61%), apolipoprotein B (for 34-50%) and triglycerides (for 14-33%), at the same time causing, in a varying degree, increase of levels of LPVP cholesterol and apolipoprotein A. These results were similar at patients with a heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed lipidemia, including patients with a non-insulin-dependent diabetes mellitus.
In connection with decrease in level of the general cholesterol, LPNP cholesterol and apolipoprotein B the risk of cardiovascular diseases decreases and, respectively, the risk of death decreases. Researches of influence of an atorvastatin on cardiovascular incidence and mortality are still not complete.
When using drug at elderly patients of distinctions in safety, efficiency or achievement of goals of hypolipidemic therapy in comparison with the general population it was not noted.

Pharmacokinetics.
Absorption
After intake аторвастатин it is quickly soaked up in blood. The maximum concentration (Stakh) in a blood plasma is reached within 1-2 hours, Sshakh at women is 20% higher, the area on a curve "concentration time" (AUC) - is 10% lower; Stakh at patients with alcoholic cirrhosis raises by 16 times, AUC - by 11 times. Meal reduces the speed and duration of absorption of drug a little (by 25% and 9% respectively), however decrease in cholesterol is similar to that at reception of an atorvastatin without food. Absolute bioavailability of an atorvastatin makes about 12%, the system bioavailability defining the inhibiting activity concerning GMG-KOA-reduktazy - 30%. Low system bioavailability is caused by presistemny metabolism in mucous digestive tract and at "the first passing" through a liver.
Distribution
The average volume of distribution of an atorvastatin makes about 381 l. Communication with proteins of a blood plasma - 98%.

Metabolism
Atorvastatin is metabolized preferential in a liver with participation of isoenzymes of CYP3A4, CYP3A5 and CYP3A7 of P450 cytochrome with formation pharmacological of active metabolites (orto-and parahydroxylated derivatives, beta oxidation products). In vitro orto-and parahydroxylated metabolites have an inhibiting effect on GMG-KOA-reduktazu, comparable to that at an atorvastatin. The inhibiting effect of drug concerning GMG-KOA-reduktazy about 70% is defined by activity of the circulating metabolites.
Removal
Atorvastatin is brought preferential with bile after hepatic and/or extrahepatic metabolism (is not exposed to the expressed enterohepatic recirculation).

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

Indications to use:

- at patients with primary hypercholesterolemia, a heterozygous family and single hypercholesterolemia and the combined (mixed) lipidemia (types On and P across Fredrikson) in combination with a diet for decrease in the increased levels of the general cholesterol, LPNP cholesterol * apolipoprotein B and triglycerides and increase in level of LPVP cholesterol
- for treatment of patients with the increased serumal levels of triglycerides (type IV across Fredrikson) and patients with a disbetalipoproteinemiya (type III across Fredrikson) at whom the dietotherapy does not give adequate effect
- at patients with a homozygous family hypercholesterolemia for decrease in levels of the general cholesterol and LPNP cholesterol when the dietotherapy and other not pharmacological methods of treatment are insufficiently effective;

Route of administration and doses:

Usually initial dose is equal to 10 mg of 1 times a day. The dose varies from 10 to 80 mg/days. Drug can be accepted at any time once a day irrespective of meal. Doses should be selected individually taking into account the initial level of LPNP cholesterol, the purpose of therapy and reaction of the patient to treatment. At the beginning and/or during increase in a dose of Atorvatatin-Tev it is necessary to control each 2-4 weeks levels of lipids in a blood plasma and as appropriate to korrigirovat a dose.
It is necessary to carry out dose adjustment bucketed not less than 4 weeks. Maximum
the daily dose makes 80 mg. /1

 
For patients with the established coronary heart disease (CHD) and other patients having high risk of cardiovascular complications statement of the following purposes of correction of levels of lipids is recommended: LPNP cholesterol less than 3,0 mmol/l (or less than 115 mg/dl) and general cholesterol less than 5,0 mmol/l (or less than 190 mg/dl).

Primary hypercholesterolemia and combined (the mixed 1 lipidemia
At most of patients necessary control of levels of lipids is provided with reception of 10 mg of Atorvastatin-Tev once a day. The essential therapeutic effect is observed usually in 4 weeks. At prolonged treatment this effect remains.

Heterozygous family hypercholesterolemia
Treatment of patients it is necessary to begin with appointment 10 mg of Atorvastatin-Tev a day. Carrying out individual dose adjustment each 4 weeks, it is necessary to bring it to 40 mg/day. After that it is possible to increase a dose to the maximum level equal to 80 mg/day, or to apply the combined purpose of 40 mg of Atorvastatin-Tev and a sekvestrant of bile acids.

Homozygous family hypercholesterolemia
Appoint in a dose 80 mg of 1 times a day.
At patients with a renal failure
Diseases of kidneys do not influence concentration of an atorvastatin in a blood plasma or extent of decrease in lipids at its use; in this regard, any dose adjustment with a disease of kidneys is not required from patients.
At patients with a liver failure
At a liver failure the dose decline or drug withdrawal can be required (see the section "Special Instructions").

Features of use:

Before Atorvastatinom-Tev's therapy the patient needs to appoint a standard gipokholestesterinovy diet which he has to observe during the entire period of treatment.
Use of inhibitors of GMG-KOA-reduktazy for decrease in level of lipids in blood - can lead to change of the biochemical indicators reflecting function of a liver. Function of a liver should be controlled before therapy, in 6 weeks, 12 weeks after the beginning of reception of an atorvastatin and after each increase in a dose, and also periodically, for example, each 6 months. Increase in activity of "hepatic" enzymes in blood serum can be observed during therapy atorvastatiny. Patients at whom increase in level of enzymes is noted have to be under control before return of level of enzymes to norm. In case of permanent increase in values of alaninaminotranspherase (ALT) or aspartate aminotransferase (ACT) to the level exceeding more than by 3 times an upper admissible limit it is recommended to lower Atorvastatin-Tev's dose or to stop treatment.
Atorvastatin-Tev it is necessary to apply with care at the patients who are abusing alcohol and/or having a liver disease. The active disease of a liver or permanent increase in activity of aminotransferases of not clear genesis serve contraindications to Atorvastatin-Tev's appointment.
Treatment atorvastatiny, as well as other inhibitors of GMG-KOA-reduktazy, can cause a myopathy. The diagnosis of a myopathy (pain and weakness in muscles in combination with increase in activity of a kreatinfosfokinaza (KFK) more than by 10 times in comparison with the upper bound of norm) should be discussed at patients with widespread mialgiya or weakness of muscles and/or the expressed increase in activity of KFK. Patients need to be warned that they should report immediately to the doctor about emergence of inexplicable pains or weakness in muscles if they are followed by an indisposition or fever. Therapy atorvastatiny should be stopped in case of the expressed increase in activity of KFK or in the presence of the confirmed or estimated myopathy. The risk of a myopathy at treatment by other drugs of this class increased at simultaneous use of cyclosporine, fibrat, erythromycin, niacin or azolny antifungal means. Many of these drugs inhibit the metabolism mediated by P450 ZA4 cytochrome, ■ and/or transport of medicines. Atorvastatin biotransformirutsya under the influence of CYP ZA4.
Appointing аторвастатин in a combination with fibrata, erythromycin, immunosuppressive means, azolny antifungal means or niacin in hypolipidemic doses, it is necessary to estimate carefully risk and the expected advantage of treatment and to regularly observe patients for the purpose of detection of pains or weakness in muscles, especially within the first months of treatment and during the periods of increase in a dose of any drug. In similar situations it is possible to recommend periodic definition of activity of KFK though such control does not allow to prevent development of a heavy myopathy.
At use of an atorvastatin, as well as other means of this class, cases of a rabdomioliz with the acute renal failure caused by a myoglobinuria are described.
 
Therapy atorvastatiny should be stopped temporarily or to cancel completely at emergence of signs of a possible myopathy or existence of risk factor of development of a renal failure against the background of a rabdomioliz (for example, a heavy acute infection, arterial hypotension, serious operation, an injury, heavy exchange, endocrine and electrolytic disturbances and uncontrollable spasms).
Before therapy of an atorvastatinom-Tev it is necessary to try to achieve control of a hypercholesterolemia by an adequate dietotherapy, increase in physical activity, decrease in body weight from patients with obesity and treatments of other states.
Influence on ability of driving and work with mechanisms About adverse influence of an atorvastatin on ability to drive the car and work with mechanisms it was not reported.

Side effects:

Most often (1% and more): sleeplessness, headache, asthenic syndrome; nausea, diarrhea, abdominal pain, dyspepsia, meteorism, lock; mialgiya. Less often (less than 1%):
From a nervous system: indisposition, dizziness, amnesia, paresthesia, peripheral neuropathy, hypesthesia.
From the alimentary system: vomiting, anorexia, hepatitis, pancreatitis, holestatitchesky jaundice.
From a musculoskeletal system: dorsodynia, myotonia, miositis, myopathy, mialgiya, arthralgia, рабдомиолиз.
Allergic reactions: urticaria, skin itch, rash, anaphylaxis, violent rash, polymorphic exudative erythema (including Stephens-Johnson's syndrome), Lyell's disease, Quincke's disease.
From bodies of a hemopoiesis: thrombocytopenia.
From a metabolism: hypo - or a hyperglycemia, increase in activity of a serumal kreatinfosfokinaza (KFK).
Others: impotence, peripheral hypostases, increase in body weight, stethalgia, secondary renal failure, alopecia, sonitus, exhaustion.
Most often undesirable effects from digestive tract develop: lock, meteorism, dyspepsia, abdominal pains; usually these phenomena weaken in process of treatment continuation. During clinical trials drug withdrawal owing to side effects was required less than from 2% of patients.

Interaction with other medicines:

The risk of a myopathy at treatment by inhibitors of GMG-KOA-reduktazy increases at their use in combination with cyclosporine, fibrata, makrolidny antibiotics (including erythromycin), azolny antifungal means or niacin.
In some exceptional cases these combinations cause рабдомиолиз, followed by a renal failure in connection with a myoglobinuria. In this regard, careful assessment of a ratio of risks and advantage of the combined treatment is necessary (see the section "Special Instructions").

Inhibitors of an isoenzyme of P450 CYP cytochrome 3A4
Metabolism of an atorvastatin is carried out with the participation of an isoenzyme of ZA4 P450 CYP cytochrome. When using an atorvastatin in combination with inhibitors of an isoenzyme of ZA4 P450 CYP cytochrome (for example, medicinal interactions can arise cyclosporine, makrolidny antibiotics, for example, erythromycin and klaritromitsiny, nefazodony, azolny antifungal drugs, for example, itrakonazoly, and HIV protease inhibitors). At the combined use of drugs the increased concentration of an atorvastatin in plasma can be noted. In this regard, it is necessary to show extra care when using an atorvastatin in combination with above-mentioned drugs (see the section "Special Instructions").
Simultaneous use with the medicines reducing concentration of endogenous steroid hormones (including Cimetidinum, ketokonazoly, Spironolactonum), increases risk of decrease in endogenous steroid goromon (it is necessary to be careful).

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. Erythromycin, кларитромицин
At simultaneous use of an atorvastatin and erythromycin (500 mg of 4 times/days) or a klaritromitsina (500 mg of 2 times/days) which inhibit P450 ZA4 cytochrome increase in concentration of an atorvastatin in a blood plasma was observed.
At simultaneous use of an atorvastatin (10 mg of 1 time/days) and azithromycin (500 mg of 1 time/days) concentration of an atorvastatin in a blood plasma did not change.

Itrakonazol
At the combined use of an atorvastatin in a dose of 40 mg and an itrakonazola in a dose of 200 mg increase in AUC up to the level which exceeded norm three times was revealed once a day.

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

Grapefruit juice
Grapefruit juice contains not less than one ingredient, being CYP3A4 inhibitor, and can cause increase in concentration in plasma of those drugs which are metabolized by CYP3A4. Daily consumption of 240 ml of grapefruit juice increased AUC of an atorvastatin by 37% and reduced AUC of active orthohydroxy metabolite by 20,4%. Consumption of a large number of grapefruit juice (more than 1,2 l a day within 5 days) increased AUC of an atorvastatin by 2,5 times, an AUC of active inhibitors of GMG-KOA-reduktazy (an atorvastatin + its metabolites) - by 1,3 times. In this regard consumption of large numbers of grapefruit juice during treatment atorvastatiny is not recommended.

P450 cytochrome inductors.
Influence of the medicines inducing an isoenzyme of ZA4 P450 CYP cytochrome. (for example, rifampicin and phenazone), on аторвастатин it is unknown. Interactions with atorvastatiny and other substrates of this isoenzyme are unknown; however, the possibility of these interactions should be considered when using drugs with a low therapeutic index - in particular, antiarrhytmic means of the III class, for example, of Amiodaronum.

L Gemfibroz / фибраты
The risk of the myopathy caused atorvastatiny can increase at the accompanying use of fibrat. The researches in vitro demonstrate to what gemfibrozit can also interact with atorvastatiny by means of inhibition of its glyukuronirovaniye that can cause increase in concentration of an atorvastatin in plasma (see the section "Special Instructions").

Digoxin
At repeated reception of digoxin and an atorvastatin in a dose of 10 mg equilibrium concentration of digoxin in a blood plasma did not change. However, at use of digoxin in a combination with atorvastatiny in a dose of 80 mg/days concentration of digoxin increased approximately by 20%. The patients receiving digoxin in combination with atorvastatiny should be observed.

Oral contraceptives
Reception of an atorvastatin in combination with the oral contraceptive containing Norethisteronum and ethinylestradiol was caused by increase in concentration of Norethisteronum and ethinylestradiol in plasma. These increases in concentration should be considered at the choice of doses of oral contraceptives. At simultaneous use of an atorvastatin and contraceptive for the intake containing Norethisteronum and ethinylestradiol substantial increase of AUC of Norethisteronum and ethinylestradiol approximately for 30% and 20% respectively was observed. This effect should be considered at the choice of an oral contraceptive for the woman receiving аторвастатин.

Kolestipol
At introduction of a kolestipol in combination with atorvastatiny decrease in concentration of an atorvastatin in a blood plasma approximately for 25% was noted. However, at the combined use of an atorvastatin and kolestipol impact on lipids was more expressed, than when using each of these drugs separately.

Antacids
At a concomitant use in an atorvastatin and the suspension containing magnesium and aluminum гидрокисид concentration of an atorvastatin in plasma decreased approximately by 35%; however, extent of decrease in the LPNP level at the same time did not change.

Warfarin
At reception of an atorvastatin in combination with warfarin small reduction of a prothrombin time in the first days of reception of an atorvastatin was noted; however, in the next 15 days the indicator of a prothrombin time was returned to norm. Nevertheless, in case of combined use of an atorvastatin and warfarin, patients it is necessary to observe carefully.

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

Cimetidinum
The research of the combined introduction of Cimetidinum and an atorvastatin did not reveal significant interaction between these drugs. Amlodipin
At the combined introduction of 80 mg of an atorvastatin and 10 mg of an amlodipin of changes of pharmacokinetic parameters of an atorvastatin in an equilibrium state were not revealed.
 
Others
Clinically significant undesirable interaction of an atorvastatin and anti-hypertensive means is noted. Interaction researches with all specific drugs were not conducted.
Atorvastatin did not exert clinically significant impact on concentration of a terfenadin in a blood plasma which is metabolized mainly by P450 ZA4 cytochrome; in this regard it is represented a little probable that аторвастатин it is capable to influence pharmacokinetic parameters of other substrates of P450 ZA4 cytochrome significantly.

Contraindications:

- hypersensitivity to drug components;
- active diseases of a liver or increase in activity of "hepatic" enzymes of not clear genesis (more than by 3 times in comparison with the upper bound of norm);
- a liver failure (severity on classification of Chayld-Pyyu And yes In);
- pregnancy;
- lactation period;
- age up to 18 years (efficiency and safety are not established)

With care: an alcohol abuse, liver diseases in the anamnesis, heavy disturbances of electrolytic balance, endocrine and metabolic disturbances, arterial hypotension, heavy acute infections (sepsis), uncontrollable epilepsy, extensive surgical interventions, injuries, diseases of skeletal muscles.

Pregnancy and period of a lactation.
Atorvastatin is contraindicated to use at pregnancy and during breastfeeding.
It is unknown whether it is removed аторвастатин with breast milk. Considering a possibility of the undesirable phenomena at babies, in need of use of drug in the period of a lactation it is necessary to resolve an issue of the breastfeeding termination.
Women of reproductive age during treatment have to use adequate contraceptives. Atorvastatin women of reproductive age can appoint only if probability of pregnancy at them very low, and the patient is informed on possible risk of treatment for a fruit.

Overdose:

There is no specific antidote. In case of overdose the necessary symptomatic and maintenance therapy has to be carried out. Control of function of a liver and уровсня is necessary for KFK in blood serum. The hemodialysis is inefficient.

Storage conditions:

At a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to apply after the date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, on 10, 20, 40 and 80 mg. On 10 tablets in the blister from kimbinirovanny material PVC / aluminum foil. On 3 blisters together with the application instruction in a cardboard pack.