Atoris 30 mg tablets №90

Author Ольга Кияница

2017-05-11

Amount in a package 90
Product form Pills
Manufacturer KRKA (Slovenia)
Registration certificate UA/8671/01/02
The main medicament Atoris
morion code 285409

Atoris (Instructions for use)

Composition

active ingredient : atorvastatin;

1 film coated tablet contains 30 mg, 60 mg or 80 mg of atorvastatin in the form of calcium atorvastatin

auxiliary substances: lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, crospovidone, polysorbate 80, sodium hydroxide, magnesium stearate

Sheath: polyvinyl alcohol, talc, macrogol 3000, titanium dioxide (E171).

Dosage form

Tablets coated with a film coat.

Basic physical and chemical properties:

  • 30 mg: white or almost white, round, slightly biconvex, coated with a film sheath, with a bevelled edge;
  • 60 mg: white or almost white, oval, biconvex, film coated
  • 80 mg: white or almost white, in the form of capsules, biconvex, film coated.

Pharmacological group

Hypilipidemic means. HMG-CoA reductase inhibitors. Atorvastatin Code АТХ С10А А05.

Pharmacological properties.

Pharmacodynamics.

Atrix contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of MMC-CoA-reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A into mevalonate, a precursor of sterols, in particular cholesterol. Triglycerides and cholesterol in the liver are embedded in very low density lipoprotein molecules (LPONP), enter the blood plasma and are transported to the peripheral tissues. Low density lipoprotein (LDL) is formed from LPONP and is catabolized, mainly by interaction with high-affinity LDL receptors (LDL receptors).

Atorvastatin reduces cholesterol concentrations in blood plasma and lipoprotein in the serum by inhibiting GMC-CoA reductase, and subsequently biosynthesis of cholesterol in the liver, as well as increasing the number of hepatic LDL receptors on the cell surface, which leads to increased LDL capture and catabolism.

Atorvastatin reduces the formation of LDL and the number of LDL particles. Atorvastatin causes a pronounced and persistent increase in the activity of LDL receptors in combination with favorable changes in the quality of LDL particles circulating. Atorvastatin effectively lowers cholesterol (CHO) levels of LDL in patients with homozygous familial hypercholesterolemia, and this is a group that has not always responded to hypolipidemic therapy.

Apart from the effect on plasma lipids, atorvastatin has other effects that enhance its anti-atherosclerotic effect. It suppresses the synthesis of isoprenoids - substances that act as growth factors on the proliferation of smooth muscle cells, decreases plasma viscosity and activates certain factors of coagulation and aggregation. Thanks to this action, it improves hemodynamics and helps to normalize blood clotting processes. In addition, HMG-CoA reductase inhibitors have an effect on the metabolism of macrophages and thus inhibit activation, reducing the risk of rupture of atherosclerotic plaques.

It has been shown that atorvastatin reduces the concentrations of total cholesterol (30-46%), LDL cholesterol (41-61%), apolipoprotein B (34-50%) and triglycerides (14-33%), causing a variable increase in the level of HDL-C and apolipoprotein And in the course of the study, which studied the dose dependence of its effect. These results are consistent with those in patients with heterozygous familial hypercholesterolemia, unrelated hypercholesterolemia and mixed hyperlipidemia, including patients with non-insulin dependent diabetes mellitus.

It has been shown that lowering the level of total cholesterol, LDL cholesterol and Apolipoprotein B reduces the risk of cardiovascular complications and mortality from cardiovascular disease.

Pharmacokinetics.

absorption

Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentrations in 1-2 hours. The absorption rate and the concentration of atorvastatin in the plasma are dependent on the dose of atorvastatin. The bioavailability of atorvastatin in tablet form is 95% and 99%, respectively. The bioavailability of atorvastatin is approximately 14%, and the system availability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic clearance in the mucous membrane of the gastrointestinal tract and biotransformation during the primary passage through the liver. Food intake reduces the rate and extent of absorption of the drug by about 25% and 9%, respectively, which is confirmed by the level of maximum concentration and AUC, a decrease in the level of LDL cholesterol does not depend on the time of application. The concentration of atorvastatin in the blood plasma after taking the drug in the evening is lower than that after taking in the morning (exceeding the maximum concentration and AUC level by about 30%). Despite this, the decrease in the level of LDL cholesterol does not depend on the timing of the drug.

Distribution

The average volume of distribution of atorvastatin is about 381 liters. Binding to plasma proteins is> 98%. If the erythrocyte / plasma ratio is approximately 0.25, this indicates a low level of penetration of the drug into erythrocytes.Based on observations from rats, it is considered that atorvastatin is able to penetrate female breast milk (see sections "Contraindications", "Use during pregnancy or breastfeeding" and "Application features").

Metabolism

Atorvastatin is largely metabolized to form ortho and parahydroxylated derivatives and various b-oxidation products. In vitro, ortho- and parahydroxylated metabolites exhibit inhibitory activity against HMG-CoA reductase, equivalent to the effect of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites. In vitro studies confirm the importance of atorvastatin biotransformation under the influence of cytochrome P450 Za4. Simultaneous administration of atorvastatin and erythromycin, a cytochrome P450AP4 inhibitor, results in an increase in the concentration of atorvastatin in the blood plasma. In vitro studies also confirm the fact that atorvastatin is a weak inhibitor of cytochrome P450 ZA4. At the same time, the use of atorvastatin and terfenadine, which is mainly metabolized by the cytochrome P450ZA4 system, does not change the concentration of the latter in plasma. Thus, it is unlikely that the use of cytochrome can significantly alter the pharmacokinetics of other substrates of cytochrome P450. In animals, the ortho-hydroxylated metabolite undergoes further glucuronidation.

Isolation

Atorvastatin and its metabolites are mainly excreted with bile after hepatic and / or extrahepatic biotransformation, but do not experience gastrointestinal recirculation. The half-life of atorvastatin in humans is approximately 14 hours. The inhibitory activity against HMG-CoA reductase is maintained for 20-30 hours due to the presence of active metabolites.After taking less than 2%, atorvastatin is determined in urine.

Population of patients

Older people

The concentration of atorvastatin in the plasma of the healthy elderly (> 65 years) is higher than that of the younger (approximately 40% of the maximum concentration and 30% of the AUC). During the ACCESS study, the effectiveness of the drug in elderly people was studied to achieve the NCEP goal of treatment. The study involved 1087 patients under 65 years of age, 815 patients over 65 and 185 patients over 75 years of age. Efficacy and safety in elderly people did not differ from those in the general population.

Where are you

No information is available on the pharmacokinetics of atorvastatin in children.

Paul

The concentration of atorvastatin in the blood plasma in women is different from that in men (maximum concentration is higher by about 20% and the AUC is lower by 10%). However, these differences do not have clinical significance, and the hypolipidemic effect of the drug in men and women is almost the same.

kidney failure

The method of administration and dose do not affect the concentration of atorvastatin in the plasma and its hypolipidemic effect. Therefore, there is no need to adjust the dose of the drug.

hemodialysis

The study of the effect of atorvastatin in patients with kidney disease in the terminal stage was not conducted. Despite the fact that the drug is actively bind to plasma protein proteins, hemodialysis can not significantly increase the clearance of atorvastatin.

hepatic failure

In patients with alcoholic cirrhosis of the liver, the concentration of atorvastatin in the plasma is significantly increased (maximum concentration - approximately 16 times, AUC - 11 times).

Indications

Prevention of cardiovascular disease

Adult patients without clinically significant coronary heart disease (CHD) but with several risk factors for CHD, such as elderly, smoking, arterial hypertension, low levels of HDL or a history of early CHD, is indicated for:

  • reducing the risk of myocardial infarction
  • reducing the risk of stroke;
  • reduction of the risk of angina and the need for procedures for the revascularization of the myocardium.

Patients with type 2 diabetes and without clinically significant coronary heart disease, but with several risk factors for CHD, such as retinopathy, albuminuria, smoking or arterial hypertension, the drug is indicated for:

  • reducing the risk of myocardial infarction
  • reducing the risk of stroke.

For patients with clinically pronounced ischemic heart disease, the drug is indicated for:

  • reduction of the risk of non-lethal myocardial infarction
  • reduction of the risk of lethal and non-lethal stroke;
  • reducing the risk of having to perform procedures for myocardial revascularization
  • reducing the risk of hospitalization due to congestive heart failure,
  • reducing the risk of angina pectoris.
  • hyperlipidemia
  • Primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (type IIA and IIb by Fredrickson classification). In addition to the diet, to reduce elevated levels of total cholesterol (OSH), low density lipoprotein cholesterol (LDL cholesterol), apolipoprotein B and triglycerides, and to increase high cholesterol lipoprotein (HDL HDL).
  • Hypertriglyceridemia (type IV according to Fredrickson classification). In addition to the diet for the treatment of patients with elevated serum triglycerides.
  • Primary dysbetainipoproteinemia (type III according to Fredrickson classification). For the treatment of patients in cases where compliance with the diet is not effective.
  • Homozygous familial hypercholesterolemia. To reduce total cholesterol and LDL cholesterol as an add-on to other hypolipidemic treatments (such as apheresis LDL) or if such treatments are unavailable.
  • Heterozygotic familial hypercholesterolemia in children of childhood (aged 10-17 years) . As an adjunct to a diet to reduce the levels of OCs, LDL cholesterol, and apolipoprotein B in adolescent boys and girls after the onset of menstruation at the age of 10 to 17 years, if, after adequate diet therapy, the results of the tests are as follows:

a) LDL cholesterol remains ≥ 5.0 mmol / l (≥ 190 mg / dl) or

b) cholesterol LDL ≥ 4.2 mmol / l (³ 160 mg / dl) and:

  • in a family history there are early cardiovascular diseases or
  • two or more other risk factors for developing cardiovascular disease are present in a child of the child.

Contraindications

  • Hypersensitivity to any ingredient of the drug.
  • Liver dysfunctions in the acute phase or persistent elevation (unknown genesis) of serum transaminases levels three or more times.
  • The drug is contraindicated in pregnancy, breastfeeding and women of reproductive age, who do not use appropriate contraceptive methods. Athisios are intended for women of reproductive age only when the pregnancy is unlikely and the patient is informed of the potential undesirable consequences for the fetus.

Interaction with other drugs and other types of interactions

The effect on atorvastatin drugs that are taken at the same time

Atorvastatin is metabolised with cytochrome P450 3A4 (CYP3A4) and is a substrate for transport proteins, for example, the hepatic carrier OATP1B1. Concomitant use of drugs that are CYP3A4 inhibitors or transport proteins may increase the concentration of atorvastatin in the bloodstream and increase the risk of myopathy. This risk may also increase with concomitant administration of atorvastatin with other drugs that may lead to myopathy, such as cyclosporine , fibrates, nicotinic acid, or cytochrome P450ZA4 inhibitors (eg erythromycin, azole antifungal agents).

CYP3A4 inhibitors

It is known that potent CYP3A4 inhibitors result in a significant increase in the concentration of atorvastatin (see Table 1 and the detailed information below). Following the possibility of co-administration with potent inhibitors of CYP3A4 (eg, cyclosporine, telithromycin, clarithromycin, delivirin, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, daranavir and t .d) If it is not possible to avoid the simultaneous use of these drugs with atorvastatin, the use of lower initial and maximum doses of atorvastatin should be considered. It is also advisable to conduct proper clinical monitoring of the patient's condition (see Table 1).

Moderate CYP3A4 inhibitors (eg erythromycin, diltiazem, verapamil, and fluconazole) may increase the concentration of atorvastatin in the blood plasma (see Table 1). The simultaneous use of erythromycin and statins is accompanied by an increased risk of developing myopathy. Drug interaction studies to evaluate the effect of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to suppress CYP3A4 activity, and therefore the simultaneous administration of these drugs with atorvastatin may increase the exposure to atorvastatin.Thus, when co-administration of atorvastatin with these moderate CYP3A4 inhibitors should be considered, the feasibility of administering lower maximal doses of atorvastatin should be considered. It is also recommended to conduct clinical monitoring of a patient's condition after initiation of treatment with an inhibitor or after dose correction.

Stimulants CYP3A4

Concomitant administration of atorvastatin with cytochrome P450 3A stimulants (e.g., efavirenz, rifampin, and St. John's wort) may result in an unstable decrease in atorvastatin concentrations in plasma. Due to the mechanism of double interaction of rifampin (stimulation of cytochrome P450 3A and inhibition of hepatic transducer OATP1B1), simultaneous administration of atorvastatin and rifampin is recommended, since taking atorvastatin over a long period of time after rifampin is associated with a significant decrease in atorvastatin plasma concentrations. However, the effect of rifampin on the concentrations of atorvastatin in cells liver is unknown, and if it is impossible to avoid simultaneous administration, one should carefully monitor the effectiveness patsyenta of treatment.

Transfer inhibitors

Transport protein inhibitors (eg cyclosporine) may increase the systemic effect of atorvastatin (see Table 1). The effect of inhibition of hepatic carriers on the concentration of atorvastatin in liver cells is unknown. If it is not possible to avoid simultaneous administration, it is recommended to reduce the dose and conduct clinical monitoring of the effectiveness of the treatment (see Table 1).

Gemfibrozil / derivatives of fibrous acid

The use of fibrates only sometimes binds to complications from the muscles, including rhabdomyolysis. The risk of these phenomena increases with the simultaneous use of derivatives of fibrous acid and atorvastatin. If it is not possible to avoid simultaneous administration, low doses of atorvastatin should be used which allow the therapeutic goals to be achieved, and the patient should be carefully observed.

Ezetimib

Only ezetimibe is associated with complications from the muscles, including rhabdomyolysis. Therefore, the risk of these events may increase with the simultaneous use of ezetimibe and atorvastatin. Proper clinical observation of such patients is recommended.

Kolespolopol

Concentrations in atorvastatin plasma and its active metabolites were less (about 25%) when colestipol was taken concomitantly with atorvastatin. However, lipid эffektы Big bыly, when atorvastatin and colestipol prynymaly simultaneously, than togda, when one IZ lekarstvennыh prynymaly assets separately.

fusidic acid

Study interaction with atorvastatin and fuzydovoyu kyslotoy not conducted. As in cases with a second statin poslerehystratsyonnoho simultaneously with atorvastatin and Application fuzydovoy acid nablyudalys about complications storony co muscles, vkljuchaja rabdomyolyz.Mehanyzm эtoho interaction Unknown. It should Patsyentы vnymatelno nablyudat, and Can okazatsya tselesoobraznыm temporarily prekraschenyy pryema atorvastatin.

Erythromycin / clarithromycin

When simultaneously Application atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), which will javljajutsja inhibitor of cytochrome P450 ZA4, povыshaetsya Concentration of atorvastatin in plasma.

Ynhybytorы proteazy

Value atorvastatin AUC Significantly povыshalos while simultaneously Application with Several kombynatsyyamy ynhybytorov proteazy HIV, as well as with an inhibitor of hepatitis C virus proteazy telaprevyr compared to primeneniem Only drugs (see. Section "Farmakolohycheskye properties"). Therefore patients, prynymayuschym proteazy inhibitor of HIV + typranavyr rytonavyr inhibitor proteazy virus or hepatitis C telaprevyr, sleduet yzbehat simultaneously Application atorvastatin. It should be drug with caution assign patients, kotoryya prynymayut inhibitor proteazy lopynavyr HIV + and rytonavyr Apply Samoa neobhodymoy dose. In patsyentov, prynymayuschyh ynhybytorы proteazy sakvynavyr HIV + rytonavyr, darunavyr + rytonavyr, fosamprenavyr or fosamprenavyr + rytonavyr dose Atorys not dolzhna prevыshat 20 mg and prymenyatsya with caution (see.Sections "Application Features" and "Method and Application dozы"). When Application in patsyentov, prynymayuschyh proteazy inhibitor or HIV nelfynavyr proteazy inhibitor boceprevir hepatitis C virus, not dolzhna prevыshat dose of 40 mg, and also recommended tschatelnoho Conducting Clinical Monitoring STATUS patients.

diltiazema hydrochloride

Odnovremennыy pryem atorvastatin (40 mg) and diltiazema (240 mg) Increase accompanied concentrations of atorvastatin in plasma.

Cimetidine

Vaud TIME pryznakov interaction of research and atorvastatin cimetidine have been detected.

Itraconazole

Application simultaneous atorvastatin (20 and 40 mg) and itraconazole (200 mg) Increase soprovozhdalos indicators atorvastatin AUC.

Hreypfrutovыy juice

Hreypfruktovыy juice Containing one or more than components, kotoryya ynhybyruyut CYP 3A4 and mogut povыshat concentrations of atorvastatin in plasma, especially when juice consumption more than 1.2 liters / day.

antacids

Inside the simultaneous appointment of atorvastatin and oral suspensions antacids, soderzhascheho magnesium and aluminum hydroxide, accompanied Reduction concentrations of atorvastatin in plasma by 35%. With this action hypolypydemycheskoe atorvastatin unchanged.

antipyrine

So something is not atorvastatin vlyyaet on antipyrine pharmacokinetics, interaction with Ability second lekarstvennыmy funds, kotoryya usvayvayutsya same theme tsytohromnыmy isoenzyme, is believed maloveroyatnoy.

Azithromycin

Simultaneous appointment of atorvastatin (10 mg 1 per day) and azithromycin (500 mg once a day) were soprovozhdalos Changes concentrations of atorvastatin in plasma.

amlodipine

In simultaneous zdorovыh persons Application of atorvastatin 80 mg and 10 mg amlodipine soprovozhdalos Increase concentrations of atorvastatin in plasma by 18% and not ymelo Clinical value.

Other Pharmaceuticals sredstva

Clinical research showed that simultaneous Application of atorvastatin and antihypertensive drugs and s Application in the course of estrogen-therapy zamestytelnoy no blog znachymыh Clinical pobochnыh effects. Studies interaction with the second drug is not carried out.

Effect of atorvastatin on sredstva Pharmaceuticals, kotoryya simultaneously prynymayut

Niacin. Risk occurrence pobochnыh phenomena co storony skeletnыh muscles at uvelychyvaetsya Application drug in kombynatsyy with niacin, and under such terms mean sleduet rassmotret Reduction Ability dozы drugs (see. Section "Features Application").

Digoxin

When simultaneously prynymayut mnohokratnыe dozы digoxin and 10 mg atorvastatin nemnoho rastut importance plateau concentrations of digoxin. Patsyentы, prynymayuschye digoxin, dolzhnы nahodytsya pod sootvetstvuyuschym observation.

oral contraceptives

Odnovremennыy pryem atorvastatin and led peroralnыh contraceptives for Increase in plasma concentrations of ethinyl estradiol and norэtyndrona. This sleduet uchytыvat with oral contraceptives Choice for Women, kotoraja prynymaet Atorys.

Warfarin is not okazыval Clinical meaningful action on prothrombin Time in patsyentov, prohodyvshyh dlytelnoe Treatment with warfarin.

Colchicine. With Application atorvastatin simultaneously with colchicine was reported cases of myopathy, including a volume rabdomyolyza, Therefore It should be with caution assign atorvastatin with colchicine.

Table 1.

Effect lekarstvennыh funds, kotoryya prynymayut simultaneously on the pharmacokinetics of atorvastatin

Lekarstvennoe funds, prynymayut simultaneously,

and mode dozyrovanyya

atorvastatin
Dose (mg) Changing AUC * Clinical recommendations

Typranavyr

500 mg 2 times a day /

rytonavyr 200 mg 2 times a day,

8 days (from 14 to 21 days)

40 mg Day 1,

10 mg after 20 days

↑ 9.4 times In cases, when odnovremennыy pryem with atorvastatin neobhodimo, prevыshat dozы 10 mg atorvastatin ezhednevno.Rekomenduetsya klynycheskoe observation эtyh patients.
Cyclosporin 5.2 mg / kg per day dose stabylnaya 10 mg 1 time per day in 28 days techenye ↑ 8.7 times

Lopynavyr 400 mg 2 times a day /

rytonavyr 100 mg 2 times a day, 14 days

20 mg 1 time per day in 4 days techenye ↑ 5,9 times В случаях, когда одновременный прием с аторвастатином необходимо, рекомендованные ниже поддерживающие дозы аторвастатина. При дозах аторвастатина, превышающих 20 мг, рекомендуется клиническое наблюдение пациентов

Кларитромицин 500 мг 2 раза в день,

9 дней

80 мг 1 раз в день в течение 8 дней ↑ 4,4 раза

саквинавир

400 мг 2 раза в день /

ритонавир 300 мг 2 раза в день, от 5 до 7 дней, на 8 день увеличить до 400 мг 2 раза в день, от 5 до 18 дней, принимать через 30 мин после приема аторвастатина

40 мг 1 раз в день в течение 4 дней ↑ 3,9 раза В случаях, когда одновременный прием с аторвастатином необходимо, рекомендованные ниже поддерживающие дозы аторвастатина. При дозах аторвастатина, превышающих 40 мг, рекомендуется клиническое наблюдение пациентов

Дарунавир 300 мг 2 раза в день /

ритонавир 100 мг 2 раза в день, 9 дней

10 мг 1 раз в день в течение 4 дней ↑ 3,3 раза
Итраконазол 200 мг 1 раз в день, 4 дня 40 мг, однократно ↑ 3,3 раза

Фосампренавир 700 мг 2 раза в день /

ритонавир 100 мг 2 раза в день, 14 дней

10 мг 1 раз в день в течение 4 дней ↑ 2,5 раза
Фосампренавир 1400 мг 2 раза в день, 14 дней 10 мг 1 раз в день в течение 4 дней ↑ 2,3 раза

Нелфинавир 1250 мг

2 раза в день, 14 дней

10 мг 1 раз в день в течение 28 дней ↑ 1,7 раза ^ Специфических рекомендаций нет.

Грейпфрутовый сок,

240 мл 1 раз в день **

40 мг, однократно ↑ 37% Одновременное употребление большого количества грейпфрутового сока и аторвастатина не рекомендуется.
Дилтиазем 240 мг 1 раз в день, 28 дней 40 мг, однократно ↑ 51% После начала приема или коррекции дозы дилтиазема рекомендуется соответствующее клиническое наблюдение пациентов.

Эритромицин 500 мг

4 раза в день,

7 дней

10 мг, однократно ↑ 33% ^ Рекомендуемая ниже максимальная доза и клиническое наблюдение пациентов.
Amlodipine 10 mg once 80 mg once ↑ 18% Spetsyfycheskyh recommendations no.

Cimetidine 300 mg

4 times a day

2 Nedeli

10 mg 1 per day techenye

4 weeks

↓ less than 1% ^ Spetsyfycheskyh recommendations no.
Antatsydnoe suspensions magnesium hydroxides and aluminum 30 ml 4 times a day, 2 Nedeli

10 mg 1 per day techenye

4 weeks

↓ 35% ^ Spetsyfycheskyh recommendations no.

Эfavyrents 600 mg

1 per day, 14 days

10 mg techenye

3 days

↓ 41% Spetsyfycheskyh recommendations no.
Rifampicin 600 mg 1 time a day, 7 days (odnovremennыy pryem) 40 mg once ↑ 30% If pryema impossible simultaneously avoided, recommended odnovremennыy pryem atorvastatin and ryfampyna at Clinical observation.
Rifampicin 600 mg 1 time per day, 5 days (razdelnыy pryem) 40 mg once ↓ 80%

hemfybrozyl

600 mg 2 times a day,

7 days

40 mg once ↑ 35% Rekomenduemaya below nachalnaya klynycheskoe dose and observation patients.

fenofybratы

160 mg 1 time a day,

7 days

40 mg once ↑ 3% Rekomenduemaya below nachalnaya klynycheskoe dose and observation patients.

* AUC - площадь под фармакокинетической кривой. Данные, представленные как кратная смена, представляют собой простое отношение показателей для одновременного приема и приема только аторвастатина (т.е. 1-кратный = без изменений). Данные, представленные как изменение в%, представляют собой процентную разницу относительно приема только аторвастатина (то есть 0% = без изменений).
** Содержит один или более компонентов, которые ингибируют CYP3A4 и могут повысить концентрации в плазме лекарственных средств, которые метаболизируются с помощью CYP3A4. Потребление 240 мл грейпфрутового сока также приводит к уменьшению AUC активного ортогидроксиметаболиту на 20,4%.Большое количество грейпфрутового сока (более 1,2 л ежедневно в течение 5 дней) увеличивала AUC аторвастатина в 2,5 раза, а также AUC активных веществ (аторвастатин и метаболиты).
^ Общая эквивалентная активность аторвастатина.
Повышение обозначено как "↑", снижение - как "↓"

Таблица 2.

Влияние аторвастатина на фармакокинетику лекарственных средств, которые принимают одновременно

Аторвастатин и режим дозирования Лекарственное средство, принимают одновременно
Лекарственное средство / доза (мг) Изменение AUC * Клинические рекомендации

80 мг 1 раз в день в течение

10 days

Дигоксин 0,25 мг 1 раз в день, 20 дней ↑ 15% Пациенты, принимающие дигоксин, должны находиться под соответствующим наблюдением.

40 мг 1 раз в день в течение

22 дней

Пероральный контрацептив 1 раз в день, 2 месяца:

    • норэтиндрон 1 мг
    • этинилэстрадиол 35 мкг

↑ 28%

↑ 19%

Специфических рекомендаций нет.

80 мг 1 раз в день в течение

15 дней

Феназон 600 мг, однократно ** ↑ 3% Специфических рекомендаций нет.

* AUC - площадь под фармакокинетической кривой. Данные, представленные как изменение в%, представляют собой процентную разницу относительно приема только аторвастатина (то есть 0% = без изменений).
** Одновременный прием многократных доз аторвастатина и феназона дал небольшой или такой, который не определяется, влияние на клиренс феназона.

Повышение обозначено как "↑", снижение - как "↓".

Application features

Влияние на печень

Аторис следует осторожно назначать пациентам, которые злоупотребляют алкоголем или с заболеваниями печени в анамнезе.

Во время лечения Аторисом может наблюдаться повышение активности ферментов печени. Такое повышение бывает в большинстве случаев незначительным и не имеет клинического значения, однако рекомендуется контролировать активность ферментов печени перед началом лечения и регулярно во время лечения. Если наблюдается превышение нормальных уровней АСТ и / или АЛТ более чем в 3 раза, лечение аторвастатином следует прекратить.

Влияние на эндокринную систему

Статины вмешиваются в синтез холестерина и теоретически могут замедлить выработку надпочечниками полового стероидного гормона. Следует соблюдать осторожность, если статины назначают одновременно с препаратами, которые могут уменьшать уровень или активность эндогенных стероидных гормонов, таких как кетоконазол, спиронолактон и циметидин.

Геморрагический инсульт

В ходе ретроспективного анализа подтипов инсульта среди пациентов, которые не страдали ишемической болезнью сердца (ИБС) и пережили недавно инсульт или транзиторное нарушение мозгового кровообращения (ТПМК), было больше случаев геморрагического инсульта у пациентов, которые начали принимать аторвастатин в дозе 80 мг, по сравнению с теми, кто получал плацебо.Повышенный риск имели пациенты, у которых уже был геморрагический инсульт или лакунарной инфаркт в начале участия в исследовании. Для пациентов с геморрагическим инсультом или лакунарным инфарктом в анамнезе соотношение рисков и пользы от приема аторвастатина в дозе 80 мг не определено, поэтому, прежде чем начать лечение, следует внимательно рассмотреть потенциальный риск геморрагического инсульта.

Влияние на скелетные мышцы

Поступали редкие сообщения о случаях рабдомиолиза с острой почечной недостаточностью вследствие миоглобинурии при применении препарата и других лекарственных препаратов этого класса. Наличие в анамнезе нарушения функции почек может быть фактором риска для развития рабдомиолиза. Такие пациенты нуждаются в более тщательном мониторинга для выявления нарушений со стороны скелетных мышц.

Atorvastatin, How and others Preparations groups statins, myopathy vыzыvaet Sometimes, kotoraja How is determined to muscle pain or weakness in muscles The combination with indicators Increase CPK (CPK) something more than 10 times the upper boundaries Above rules. Simultaneous Application High-dose atorvastatin with opredelennыmy lekarstvennыmy drugs such cyclosporin As a moschnыe ynhybytorы CYP3A4 (for example, clarithromycin, itraconazole and HIV protease ynhybytorы) povыshaet risk of myopathy / rabdomyolyza.

Redkye messages acted on cases mediated immunological nekrotycheskoy myopathy (YONM) - autoimmune myopathy, svyazannoy primeneniem with statins. YONM signs harakteryzuetsya follows: proximal muscle weakness and povыshennыy Level CPK in whey, kotoryya sohranyayutsya, Despite prekraschenye of treatment with statins; mыshechnaya biopsy vыyavlyaet necrotic myopathy without inflammation Significantly; Application with immunosuppressive funds polozhytelnaya observed dynamics.

Ability development myopathy sleduet rassmatryvat a dear patsyenta with diffuse myalgia, muscle slabostyu or boleznennostyu and / or znachytelnыm Increase CPK. It should Patsyentam porekomendovat nemedlenno Report cases of pain in the muscles, muscle weakness or boleznennosty neyzvestnoy aetiology, especially accompanied oschuschenyem If This nedomohanyya Increase or temperature, or muscle disease symptoms If sohranyayutsya after prekraschenyya pryema drug. Treatment sleduet prekratyt sluchae Increase in CPK urovnja , dyahnostyrovanyya or podozrenyya for myopathy.

The risk of myopathy during treatment with this class of medicines is increased with concomitant use of cyclosporine, fibroic acid derivatives, erythromycin, clarithromycin, hepatitis C virus telaprevir inhibitor, combination of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, daranavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or antimycotics of the azole group. Doctors who are considering the possibility of combination therapy of the drug and the derivative of fibroic acid, erythromycin, clarithromycin, combination of saquinavir + ritonavir, lopinavir + ritonavir, daranavir + ritonavir, fosamprenavir, combinations of fosamprenavir + ritonavir, antimycotics of the group of azoles, or lipid-modifying doses of niacin should carefully weigh the potential benefits. and risks, as well as carefully monitor the patient's state of any symptoms of pain, soreness or weakness in the muscles, especially in the initial x months of therapy and during titration periods of any of the drugs in the direction of increase. The use of low initial and maintenance doses of atorvastatin should be considered when co-administered with the above drugs (see Section "Interaction with other drugs"). In such situations, it may be expedient to periodically determine the CPR, but there is no guarantee that such monitoring will help prevent the occurrence of severe myopathy.

Cases of myopathy, including rhabdomyolysis, have been reported when atorvastatin is co-administered with colchicine, therefore, atorvastatin with colchicine should be prescribed to patients with caution (see Section "Interaction with other medicinal products").

The therapy should be temporarily stopped or completely stopped in any patient with an acute, severe condition, indicating the development of myopathy, or in the presence of a risk factor for developing renal failure due to rhabdomyolysis (eg, severe acute infection, arterial hypotension, surgery, trauma, severe metabolic, endocrine and electrolytic disorders, as well as uncontrolled convulsions).

Before you start treatment

Atorvastatin should be prescribed with caution to patients who have an increased risk of developing rhabdomyolysis.The level of QC before treatment should be determined in the following situations:

  • kidney failure
  • hypothyroidism
  • hereditary muscle disorders in a personal or family history
  • cases of toxic effects of statins or fibrates on muscles in the past;
  • liver disease in the history and / or when consuming significant amounts of alcohol.

For elderly patients (> 70 years), the need for such an analysis should be considered depending on the presence of factors that increase the risk of developing rhabdomyolysis.

Determining the level of QC before treatment is also required in cases where plasma concentrations may be increased, for example when interacting (see Section "Interaction with other drugs and other types of interactions") and in patients of special populations, including genetic subpopulations (see " Pharmacological properties. Pharmacokinetics. ").

In such situations, the risk of treatment should be weighed against the potential benefits. Clinical observation is also recommended.

If the KFK level is significantly elevated (> 5 times the BMI), no treatment should be initiated before starting treatment.

Definition of the level of KFK

The level of CKC (CK) should not be measured after intense physical activity, or if there is another possible reason for an increase in CK level, since this makes it difficult to interpret the result. If the KFK level is significantly elevated before treatment (> 5 times the BMI), the analysis should be repeated within 5-7 days to confirm the results.

During the treatment

  • Patients should immediately report muscle aches, convulsions or weakness, especially if they are simultaneously experiencing malaise or an increase in body temperature.
  • If these symptoms occur during treatment with atorvastatin, the patient should be assessed at the level of the CK. If it turns out that these levels are significantly elevated (> 5 times the BMI), treatment should be discontinued.
  • If symptoms of muscle disorders are severe and cause daily discomfort, even if the level of KFK is elevated to ≤ 5 times the BMD, consideration should be given to stopping treatment.
  • If the symptoms disappear and the KFK level returns to normal, consideration may be given to resuming atorvastatin or alternate low-dose statin and under close observation.
  • Atorvastatin should be discontinued if there is a clinically significant increase in CK levels (> 10 times the BMI) or if rhabdomyolysis is diagnosed or suspected.

Simultaneous use with other medications

The risk of developing rhabdomyolysis is increased when atorvastatin is co-administered with some drugs that can increase the concentration of atorvastatin in the blood plasma. Examples of such drugs include potent inhibitors of CYP3A4 or transport proteins cyclosporine, telithromycin, clarithromycin, delivirin, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, daranavir, and the like. At simultaneous application with gemfibrozil and other derivatives of fibrous acid, erythromycin, niacin and ezetimiba, there is also a risk of myopathy. If possible, other medications (not interacting with atorvastatin) should be used instead of the above.

If atorvastatin and these drugs are to be treated concurrently, the benefits and risks of simultaneous treatment should be weighed carefully. If patients take medications that increase the concentration of atorvastatin in plasma, it is recommended that the dose of atorvastatin be reduced to a minimum. In addition, in the case of the use of potent CYP3A4 inhibitors, consideration should be given to the use of a lower initial dose of atorvastatin. It is also advisable to carry out appropriate clinical monitoring of these patients.

It is not recommended to simultaneously appoint atorvastatin and fusidic acid, so it is worth temporarily cancel atorvastatin for the treatment period with fusidic acid.

Application to children.

The safety and efficacy of the drug in patients aged 10-17 years with heterozygous familial hypercholesterolemia were studied for 6 months in adolescent boys and girls after the onset of menstruation. Patients who received treatment with atorvastatin had an adverse reaction profile generally similar to those in placebo-treated patients. Infectious diseases were frequent undesirable events that were observed. Doses of large 20 mg have not been studied in this group of patients. The study did not reveal any significant effect of atorvastatin on growth or puberty of boys or on menstrual cycle length in girls. Adolescent girls should be advised on acceptable contraceptive methods during the period of treatment with atorvastatin.

Atorvastatin has not been studied in adolescent patients or patients under the age of 10 years.

Clinical efficacy of atorvastatin in doses up to 80 mg / day for 1 year was evaluated in patients with homozygous familial hypercholesterolemia, in which the group included 8 children of childhood.

Interstitial lung disease

During treatment, certain cases of development of interstitial lung disease were described by certain statins (especially during long-term treatment). The symptoms of this disease include shortness of breath, unproductive cough and general deterioration of well-being (fatigability, weight loss and fever). If there is a suspicion that the patient developed interstitial lung disease, statins should be discontinued.

Special warnings about auxiliary substances

Atrix contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose absorption should not take this medication. The therapy of lipid modifying drugs should be one of the components of complex therapy for patients with a significantly increased risk of developing atherosclerotic vascular disease through hypercholesterolemia. Drug therapy is recommended as a supplement to the diet, when the result of observing a diet restricting the consumption of saturated fats and cholesterol, as well as the use of other non-pharmacological measures was not enough. Patients with ischemic heart disease or with several risk factors for coronary heart disease may start taking the drug at the same time as observing the diet.

Use during pregnancy or breastfeeding.

Atorvastatin is not recommended for women of reproductive age who do not use a reliable contraceptive. If during the treatment with Atorisom the patient decides to become pregnant, she should stop taking the drug no later than a month before the planned pregnancy.

Statins can damage the fetus. Atrios can be used in women of childbearing age only if the probability of pregnancy is very low and the patient was informed about the potential risk. If a woman becomes pregnant during treatment, an immediate discontinuation of the drug should be repeated and the patient should be informed again of the potential risk to the fetus and there is no known clinical benefit from continued use of the drug during pregnancy. With normal pregnancy, levels of serum cholesterol and triglycerides increase. Admission of hypolipidemic drugs during pregnancy will not have a beneficial effect, because cholesterol and its derivatives are essential for the normal development of the fetus. Adequate and well-controlled studies of atorvastatin use during pregnancy were not performed. Rare reports of congenital anomalies after intrauterine exposure to statins.

Breast feeding period

It is not known that atorvastatin penetrates into female breast milk, but it is known that a small amount of another drug of this class penetrates into female breast milk. Since statins can cause serious adverse reactions in infants who are breastfed, women who require treatment with a dasg do not should breast-feed your babies (see section "Contraindications").

Ability to influence the reaction speed when driving or operating with other mechanisms.

There are no reports of the effect of Atrix on the ability to drive a car and use technical devices. But while using the drug, some patients may experience dizziness, muscle cramps. Therefore, caution should be exercised during carriage when driving or operating with other mechanisms.

Method of administration and dose

Hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia (Type IIa and IIb by Fredrickson classification)

Recommended initial dose of atorvastatin 10 mg or 20 mg once daily. For patients who require a significant reduction in the level of LDL cholesterol (more than 45%), therapy can be started with a dosage of 40 mg once a day. The dosing range of the drug is in the range of 10 to 80 mg once daily. The drug can be taken at a single dose at any time and regardless of food intake. Initial and maintenance doses are taken individually, depending on the purpose of the treatment and the response. After starting treatment and / or titrating the dose of the drug, lipid levels should be analyzed over a period of 2 to 4 weeks and appropriate dose adjustments.

Heterozygotic familial hypercholesterolemia in children of childhood (aged 10-17 years)

Recommended initial dose of atorvastatin 10 mg / day; The maximum recommended dose of 20 mg / day (doses exceeding 20 mg in this group of patients have not been studied). The doses of the drug should be selected individually.The dose adjustment should be done at intervals of 4 weeks or more.

Homozygous familial hypercholesterolemia

The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg per day. Atresis should be used as an adjunct to other hypolipidemic treatments (eg, apheresis LDL) or if hypolipidemic treatment is unavailable.

Simultaneous hypolipidemic therapy

The atyos can be used with BACTERIAL SECRETS. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should be used with caution in general (see sections "Peculiarities of use", "Interaction with other drugs").

Dosage for patients with impaired kidney function

Kidney diseases do not affect either the concentration in plasma or the decrease in the level of LDL cholesterol in the use of the drug, therefore, dose adjustment for patients with impaired renal function is not required (see sections "Peculiarities of use", "Pharmacokinetics").

Dosage for patients taking cyclosporine, clarithromycin, itraconazole or certain protease inhibitors

Patients taking cyclosporin or HIV protease inhibitors (tyrannavir + ritonavir) or a hepatitis C virus protease inhibitor (telaprevir) should be avoided. Caution should be exercised in HIV patients taking lopinavir + ritonavir and administered at the most appropriate dose. For patients taking clarithromycin, itraconazole, or for HIV patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir, the therapeutic dose should be limited to 20 mg, and it is recommended that clinical trials should be conducted to ensure that the smallest required dose of the drug.For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, treatment should be limited to a dose of 40 mg, and appropriate clinical trials are recommended to ensure the use of the smallest required dose of the drug (see section "Peculiarities of use" and "Interaction with other medicines and other types of interactions ").

Where are you.

The use of atorvastatin in patients with heterozygous familial hypercholesterolemia under the age of 10 years has not been studied.

Overdose

No specific treatment for overdose with atorvastatin exists. In cases of overdose, the drug is given symptomatic and supportive therapy if necessary. Functional liver tests should be performed and blood serum levels monitored. Since Atoris is extensively bound to blood plasma proteins, hemodialysis can not significantly increase the clearance of atorvastatin.

Adverse reactions

Side effects in most cases are of minor severity and are temporary.

From the psyche: nightmares, insomnia.

From the immune system: allergic reactions, anaphylactic shock.

On the part of metabolism and nutrition: hyperglycemia, hypoglycemia, weight gain, anorexia.

From the reproductive system and mammary glands: impotence, gynecomastia.

From the nervous system: headache, paresthesia, dizziness, hypoaesthesia, dysgeusia, amnesia, peripheral neuropathy.

On the part of the respiratory system, thoracic and mediastinum: sore throat and larynx, nasal bleeding.

Infections and infestations: nasopharyngitis.

From the side of the blood and lymphatic system: thrombocytopenia.

From the organ of vision: blurred vision, visual impairment.

On the part of the hearing and balance organs: ringing in the ears, loss of hearing.

On the part of metabolism and nutrition: increased transaminases, deviations from the norm of functional liver tests, elevation of alkaline phosphatase in the blood, increased activity of KFK, hyperglycemia;

From the digestive system: constipation, flatulence, dyspepsia, nausea, diarrhea, vomiting, pain in the upper and lower abdomen, lacrimation, pancreatitis.

Hepatobiliary system: hepatitis, cholestasis, hepatic insufficiency.

Skin and subcutaneous tissue: urticaria, skin rashes, itching, alopecia, angioedema, bullous dermatitis, including exudative erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

On the part of the musculoskeletal system: myalgia, arthralgia, limb pain, muscle spasm, joint swelling, back pain, neck pain, muscle weakness, myopathy, myositis, rhabdomyolysis, tendonopathy (sometimes difficult to break the tendon).

General disorders: malaise, pyrexia, asthenia, chest pain, peripheral edema, fatigue, fever.

Laboratory parameters: abnormal liver function tests, increase of the level of CFC in the blood, presence of leukocytes in the urine.

Increase in transaminases urovnja whey javljaetsja dozozavysymыm.

Increase urovnja CPK something more than 10 times the norm Above indicators was observed in 0.4% patsyentov.0,1% эtyh patsyentov ymely pain in the muscles, muscle weakness or chuvstvytelnost.

If nablyudayutsya Heavy Side эffektы, Treatment of drug sleduet prekratyt.

Dety (10-17 years)

In patsyentov, poluchavshyh atorvastatin nablyudalys Side reactions , podobnыe topics kotoryya nablyudalys in patsyentov, poluchavshyh placebo . Most rasprostranennыmy pobochnыmy effect, kotoryya nablyudalys a group obeyh not schytaya prychynnaya communication, bыly infection.

Storony nervous system Co: Headache pain.

Storony system pyschevarytelnoy Co: pain in vivo.

Laboratory indicators: povыshennыy Level ALT, povыshennыy Level of CPK in the blood.

Shelf life

2 years.

Storage conditions

Hranyt oryhynalnoy in packaging for protection from moisture Impact. Keep out of the reach of children.

Packaging

10 tablets in a blister, 3 or 6 or 9 blysterov in kartonnoy box.

Vacation category

By recipe


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