Etset 40 mg tablets № 28

Amount in a package -
Product form Pills
Manufacturer Kusum Healthcare (India)
Registration certificate UA/9658/01/03
The main medicament Etset
morion code 327211

ATSAT instructions for use

Composition

active ingredient: atorvastatin; 1 tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg, 20 mg, 40 mg or 80 mg;
auxiliary substances: lactose, microcrystalline cellulose, calcium carbonate, povidone KZ0, sodium croscarmellose, silicon dioxide colloid, magnesium stearate, Opadry 03F84827 pink *;

* Opadry 03F84827 pink: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red (E172).

Dosage form

The tablets covered with a cover.

Basic physical and chemical properties:

tablets, coated with 10 mg, 20 mg round biconvex tablets, covered with a pink coating with the inscription "10" or "20" on one side
tablets, coated with 40 mg, 80 mg round biconvex tablets, covered with a pink coating, smooth on both sides.

Pharmacological group

Drugs that lower the level of cholesterol and triglycerides in the blood serum. Inhibitors of HMG-CoA reductase.ATX Code C10A A05.

Pharmacological properties

Pharmacodynamics.

It is a synthetic lipid-lowering drug. Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA into mevalonate, the precursor substance of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream in a complex with lipoproteins. These complexes are separated by ultracentrifugation into high-density lipoprotein (HDL) fractions, intermediate density lipoproteins, LDL (low density lipoproteins) and VLDLP (very low density lipoproteins). Triglycerides (TG) and cholesterol in the liver are included in VLDL and released into plasma for transport to peripheral tissues. LDL are formed by VLDL and are catabolized by interaction with high-affinity LDL receptors. Clinical and pathoanatomical studies show that elevated levels of total cholesterol (LD), LDL cholesterol (LDL-C) and apolipoprotein B (apo B) in the blood plasma contribute to the development of atherosclerosis in humans and are risk factors for the development of cardiovascular diseases, at that time as elevated HDL cholesterol levels are associated with a reduced risk of cardiovascular disease.

Atorvastatin reduces cholesterol and lipoprotein levels in the blood plasma by inhibiting the HMG-CoA reductase in the liver and cholesterol synthesis and by increasing the number of liver LDL receptors on the cell surface to enhance absorption and catabolism of LDL. Atorvastatin also reduces the production of LDL and the amount of these particles.Atorvastatin lowers LDL cholesterol in some patients with homozygous familial hypercholesterolemia, that is, groups of people who rarely respond to treatment with other lipid-lowering drugs.

There is evidence that elevated levels of total cholesterol, LDL cholesterol and apo B (a membrane complex for LDL cholesterol) provoke the development of atherosclerosis. Reduced levels of HDL cholesterol (and its transport complex - a by A) are associated with the development of atherosclerosis. It is known that cardiovascular morbidity and lethality vary in direct proportion to the level of total cholesterol and LDL cholesterol and inversely proportional to the level of HDL cholesterol.

Atorvastatin reduces the level of total cholesterol, LDL cholesterol and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemia.Atorvastatin also lowers cholesterol levels in VLDL and TG, and also leads to an unstable increase in HDL cholesterol and apolipoprotein A-1. Atorvastatin reduces total cholesterol, LDL cholesterol, VLDLP cholesterol, apo B, triglycerides and cholesterol-lowering HDL-C, and also increases HDL cholesterol in patients with isolated hypertriglyceridemia.Atorvastatin reduces cholesterol lowering in patients with disbetalipoproteinemia.

Like LDL, lipoproteins enriched with cholesterol and triglycerides, including VLDL, LLP and residues, can also contribute to the development of atherosclerosis. Elevated levels of triglycerides in plasma often find themselves in a triad with low HDL cholesterol levels and small slices of LDL, as well as in combination with non-lipid metabolic risk factors for coronary heart disease. It has not been consistently proven that the total plasma triglyceride level as such is an independent risk factor for the development of coronary heart disease. In addition, an independent effect of increasing the level of HDL cholesterol or lowering the level of triglycerides on the risk of coronary and cardiovascular morbidity and mortality was established.

Atorvatsatin, like some of its metabolites, is pharmacologically active in humans. The main place of action of atorvastatin is the liver, which plays a major role in the synthesis of cholesterol and the clearance of LDL. The dose of the drug, in contrast to the systemic concentration of the drug, better correlates with a decrease in the level of LDL cholesterol.Individual dose selection should be performed depending on the therapeutic response (see Section "Method of administration and dose").

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

Pharmacokinetics.

Suction.

Atorvastatin is rapidly absorbed after oral administration and its maximum concentration in blood plasma is reached within 1-2 hours. The degree of absorption increases in proportion to the dose of atorvastatin. The bioavailability of atorvastatin (the starting drug) is approximately 14%, and the systemic bioavailability of the inhibitory activity against HMG-CoA reductase is approximately 30%. Low system availability of the drug is associated with pre-systemic clearance in the mucosa of the gastrointestinal tract and / or pre-system biotransformation in the liver. Although food reduces the rate and extent of drug absorption by about 25% and 9%, respectively, based on C max and AUC, lowering LDL cholesterol is similar regardless of whether atorvastatin is taken with food or separately. When using atorvastatin in the evening, its concentration in the blood plasma is lower (about 30% for C max and AUC) than in the morning reception. However, the decrease in LDL cholesterol is the same regardless of the time of taking the drug (see Section "Method of administration and dose").

Distribution.

The average volume of atorvastatin distribution is approximately 381 liters. More than 98% of the drug binds to blood plasma proteins. The blood / plasma concentration ratio is approximately 0.25, indicating a poor penetration of the drug into the erythrocytes. It is believed that atorvastatin is able to penetrate into breast milk (see Sections "Contraindications", "Use during pregnancy or lactation" and "Features of use").

Metabolism.

Atorvastatin is extensively metabolized in ortho and para-hydroxylated derivatives and various beta-oxidation products.In vitro studies of inhibition of ortho HMG-CoA reductase and parahydroxylated metabolites is equivalent to inhibition of atorvastatin. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with active metabolites. In vitro studies indicate the importance of atorvastatin cytochrome P450 3A4 metabolism, which is consistent with increased concentrations of atorvatatin in human blood plasma after concomitant use with erythromycin, a known inhibitor of this enzyme (see Section "Interaction with Other Drugs").

Excretion.

Atorvastatin and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism, but this substance obviously does not experience gastrohepatic recirculation. The half-life of atorvastatin from human plasma is approximately 14 hours, but the period of substitution of inhibitory activity against HMG-CoA reductase is from 20 to 30 hours through the contribution of active metabolites. After taking the drug with urine, less than 2% of the dose is released.

Patient populations

Patients of advanced age. Atorvastatin concentrations in the blood plasma are higher (about 40% for Cmax and 30% for AUC) in healthy elderly patients (65 years or older) than in young adults. Clinical evidence suggests a greater degree of lowering of LDL when using any dose of the drug in elderly patients compared with young people (see section "Features of application").

Children. Pharmacokinetic data for a group of patients of childhood are absent.

Paul. The concentrations of atorvastatin in women's blood plasma differ from those in blood plasma (about 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in the reduction of LDL cholesterol when using atorvastatin in both men and women.

Impaired renal function. Kidney disease does not affect the concentrations of atorvastatin in the plasma or decrease in LDL cholesterol, and, consequently, correction of the dose of the drug in patients with impaired renal function is not required (see Sections "Method of administration and dose", "Features of application").

Hemodialysis. It is believed that hemodialysis does not significantly increase the clearance of atorvastatin, since the drug binds intensely to plasma proteins.

Liver failure . The concentrations of atorvastatin in plasma are markedly increased in patients with chronic alcoholic liver disease. The values of Cmax and AUC are 4 times higher in patients with class A liver disease on the Child-Pugh scale.In patients with liver disease class on the Child-Pugh scale, the values of Cmax and AUC increase approximately 16-fold and 11-fold, respectively (see Section "Contraindications").

Transport protein polymorphism SLOC1B1.

Absorption by the liver of all HMG-CoA reductase inhibitors, including atorvastatin, occurs with the transport protein OATP1B1. Patients with polymorphism of transport protein SLCO1B1 are at risk of increasing the content of atorvastatin in the body, which may increase the risk of rhabdomyolysis. Polymorphism of the gene coding for the protein OATP1B1 (SLCO1B1 c.521CC) is associated with an increase in exposure (AUC) of atorvastatin by 2.4 times compared with the corresponding index in individuals for which the given genotype is absent (c.521TT). In such patients, a genetically determined violation of the absorption of atorvastatin by the liver can also be observed. The possible consequences of this phenomenon for the effectiveness of treatment are unknown.

Table 1. Effect of concurrently used drugs on the pharmacokinetics of atorvastatin.

Simultaneously used drugs and dosing regimen Atorvastatin
  Dose (mg) The change in AUC & Changing Cmax &
# Cyclosporine 5.2 mg / kg / day, stable dose 10 mg once a day for 28 days 8.7 times 10.7 times
# Tipranavir 500 mg twice daily / ritonavir 200 mg twice daily, 7 days 10 mg of RD 9.4 times 8.6 times
# Telaprevir 750 mg every 8:00, 10 days 20 mg of RD 7,88 times 10.6 times
#, ‡ Saquinavir 400 mg twice daily / ritonavir 400 mg twice daily, 15 days 40 mg once a day for 4 days 3.9 times 4.3 times
# Clarithromycin 500 mg twice daily, 9 days 80 mg once a day for 8 days 4.4 times 5,4 times
# Darunavir 300 mg twice daily / ritonavir 100 mg twice daily, 9 days 10 mg once a day for 4 days 3,4 times 2.25 times
# Itraconazole 200 mg once a day, 4 days 40 mg of RD 3.3 times 20%
# Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily, 14 days 10 mg once a day for 4 days 2.53 times 2.84 times
# Fosamprenavir 1400 mg 2 times a day, 14 days 10 mg once a day for 4 days 2.3 times 4.04 times
# Nelfinavir 1250 mg 2 times a day, 14 days 10 mg once a day for 28 days 74% 2.2 times
# Grapefruit juice, 240 ml 1 time per day * 40 mg once a day 37% 16%
Diltiazem 240 mg once a day, 28 days 40 mg once a day 51% without change
Erythromycin 500 mg 4 times a day, 7 days 10 mg once a day 33% 38%
Amlodipine 10 mg, single dose 80 mg once daily 15% 12%
Cimetidine 300 mg once a day, 4 weeks 10 mg once a day for 2 weeks ¯ Less than 1% eleven%
Colestipol 10 mg twice daily, 28 weeks 40 mg once a day for 28 weeks indefined ¯ 26% **
Maalox TC 30 ml once a day, 17 days 10 mg once a day for 15 days ¯ 33% ¯ 34%
Efavirenz 600 mg once a day, 14 days 10 mg for 3 days ¯ 41% 1%
# Rifampin 600 mg once a day, 7 days (with simultaneous administration) † 40 mg once a day thirty% 2.7 times
# Rifampin 600 mg once daily, 5 days (in separate doses) † 40 mg once a day ¯ 80% ¯ 40%
# Gemfibrozil 600 mg twice daily, 7 days 40 mg once a day 35% ¯ Less than 1%
# Fenofibrate 160 mg once a day, 7 days 40 mg once a day 3% 2%
# Boceprivir 800 mg 3 times a day, 7 days 40 mg once a day 2.3 times 2.66 times

The data indicated as a change of x times is a simple relationship between the simultaneous use of drugs and the use of atorvastatin alone (i.e., single = unchanged). The data indicated in the% change are% the difference in the ratio of the indices when using atorvastatin alone (i.e., 0% = unchanged).

# For information on clinical significance, see the sections on "Features of Use" and "Interaction with Other Drugs and Other Interactions".

* A large increase in AUC (up to 2.5 times) and / or C max (up to 71%) was reported with excessive consumption of grapefruit juice (750 ml - 1.2 liters per day or more).

** A single sample taken 8-16 hours after taking the drug.

† The simultaneous use of atorvastatin with rifampin is recommended through the mechanism of double interaction of rifampin, as it was shown that the delayed use of atorvastatin after rifampin is associated with a significant decrease in the concentrations of atorvastatin in the blood plasma.

‡ The dose of saquinavir + ritonavir combination in this study is not a clinically applicable dose. Increasing the exposure of atorvastatin when used in clinical settings is likely to be higher than that observed in this study. Therefore, it is necessary to use the drug with caution in a low required dose.

Table 2. Effect of atorvastatin on the pharmacokinetics of concomitantly used drugs.

Atorvastatin Simultaneously, the drug used and the dosing regimen
The drug / dose (mg) Change in AUC Changing Cmax
80 mg once a day for 15 days Antipyrine, 600 mg once a day 3% ↓ 11%
80 mg once a day for 14 days # Digoxin 0.25 mg once a day, 20 days 15% 20%
40 mg once a day for 22 days Oral contraceptives once a day, 2 months

    • norethisterone 1 mg
    • ethinylestradiol 35 μg

28%

19%

 

23%

thirty%

10 mg once daily Tipranavir 500 mg twice daily / ritonavir 200 mg 2 times a day, 7 days without change without change
10 mg once a day for 4 days Fosamprenavir 1400 mg 2 times a day, 14 days ¯ 27% 18%
10 mg once a day for 4 days Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily, 14 days without change without change

# For information on clinical significance, see "Interaction with Other Drugs and Other Interactions".

Indications

Prevention of cardiovascular disease

For adult patients without clinically severe coronary heart disease, but with several risk factors for developing coronary heart disease such as age, smoking, hypertension, low HDL cholesterol, or the presence of early coronary heart disease in a family history, Ettset is indicated for:

  • reduction in the risk of myocardial infarction
  • reducing the risk of stroke;
  • reducing the risk of revascularization procedures and angina pectoris.

For patients with type 2 diabetes mellitus and without clinically severe coronary heart disease, but with several risk factors for coronary heart disease such as retinopathy, albuminuria, smoking or hypertension, Ettset is indicated for:

  • reduction in the risk of myocardial infarction
  • reduction of the risk of stroke.

For patients with clinically severe coronary heart disease, Ettset is indicated for:

  • decrease in the risk of non-lethal myocardial infarction
  • reduction in the risk of lethal and non-lethal stroke;
  • reducing the risk of revascularization procedures;
  • reduction in the risk of hospitalization for congestive heart failure,
  • reducing the risk of angina.

Hyperlipidemia

In addition to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels, and to increase HDL cholesterol levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Types IIa and IIb Fredrickson classification ).
As an adjunct to diet for the treatment of patients with elevated levels of serum triglycerides (type IV Fredrickson classification).
For the treatment of patients with primary disbetalipoproteinemiey (type III Fredrickson classification) when dieting is not enough effective.
In order to reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg LDL apheresis) or if such treatments are unavailable.
As an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B in boys and girls after the onset of menstruation at the age of 10 to 17 years with heterozygous familial hypercholesterolemia if after an appropriate test results of diet therapy are as follows:

  1. a) ³ LDL cholesterol is 190 mg / dl or
  2. b) LDL cholesterol ³ 160 mg / dL: a family history are the early heart disease or two or more other risk factors for cardiovascular zabolevaniyprisutstvuyut in pediatric patients.

Contraindications

Liver disease in the acute phase, which can include sustained increase in liver transaminases of unknown etiology.
Hypersensitivity to any of the drug components.

The interaction with other drugs and other types of interactions

The risk of myopathy during treatment with statins is increased in the case of simultaneous use of fibric acid derivatives, lipidomodifikatsiynih doses of niacin, cyclosporin or potent inhibitors of CYP 3A4 (eg clarithromycin, HIV protease inhibitors and itraconazole) (see. Sections "Features of application "and" Pharmacological properties ").

Potent inhibitors of CYP 3A4. Atorvastatin is metabolized by cytochrome P450 3A4. Simultaneous application Etset drug with potent inhibitors of CYP 3A4 may increase atorvastatin plasma concentration (see. Table 1 and details bellow). The degree of interaction and potentiation of dependent variation effects on CYP 3A4. It is possible to avoid the simultaneous application of potent inhibitors of CYP3A4 (for example, cyclosporin, telithromycin, clarithromycin, delavirdine, stiripentolom, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir). If you can not avoid the simultaneous use of these medications with atorvastatin, should consider the possibility of using a lower initial and maximum doses of atorvastatin.Also recommended adequate clinical monitoring of the patient's condition (see. Table 1).

Moderate inhibitors of CYP3A4 (e.g. erythromycin, diltiazem, verapamil and fluconazole) can increase atorvastatin plasma concentration (see. Table 1). Concomitant use of erythromycin and statins is accompanied by an increased risk of myopathy. Investigation of the interaction of drugs to assess the influence of amiodarone or verapamil on atorvastatin not conducted. It is known that amiodarone, and verapamil inhibit CYP3A4 activity, and hence co-administration of these drugs with atorvastatin may result in increased exposure of atorvastatin. Thus, while the use of atorvastatin and these moderate CYP3A4 inhibitors should consider destination lower maximum doses of atorvastatin. Also clinical patient monitoring is recommended.After initiation of treatment or inhibitor after correction its dose recommended clinical patient monitoring.

Grapefruit juice. Comprises one or more components which inhibit CYP 3A4 and can increase the concentration of atorvastatin in plasma, especially when excessive consumption of grapefruit juice (more than 1.2 liters per day).

Clarithromycin. Meaning atorvastatin AUC increased significantly while applying atorvastatin 80 mg and clarithromycin (500 mg twice daily) compared with atorvastatin alone (see. Section "Pharmacological properties"). Thus, patients who take clarithromycin, should be used with caution Etset 20 mg (cm. Sections "Properties Applications" and "Instructions for use and dose").

A combination of protease inhibitors. Meaning atorvastatin AUC increased significantly, while the application of atorvastatin with several combinations of HIV protease inhibitors, as well as with an inhibitor of hepatitis C virus protease telaprevir compared with atorvastatin alone (see. Section "Pharmacological properties"). Therefore, in patients taking HIV protease inhibitor, tipranavir, ritonavir + or an inhibitor of hepatitis C virus protease telaprevir, avoid the simultaneous application of the drug Etset. The drug should be used with caution in patients who are taking an HIV protease inhibitor lopinavir + ritonavir and apply the most necessary dose. In patients receiving HIV protease inhibitors ritonavir + saquinavir, ritonavir + darunavir, fosamprenavir + ritonavir or fosamprenavir,Etset dose should not exceed 20 mg, and it should be used with caution (see. Sections "Features of application" and "Application dose"). When applied in patients taking HIV protease inhibitor nelfinavir or an inhibitor of hepatitis C virus protease boceprevir, Etset dose should not exceed 40 mg, and recommended careful clinical monitoring of patients.

Itraconazole.Meaning atorvastatin AUC increased significantly, while the application of atorvastatin 40 mg itraconazole and 200 mg (see. Section "Pharmacological properties"). Thus, patients taking itraconazole should be careful, if the dose exceeds 20 mg Etset (see. Sections "Properties Applications" and "Instructions for use and dose").

Cyclosporine. Atorvastatin and its metabolites are substrates of OATP1B1 transporter. OATP1B1 inhibitors (eg Ciclosporin) may increase the bioavailability of atorvastatin. Meaning atorvastatin AUC increased significantly, while the application of atorvastatin and 10 mg cyclosporin in a dose of 5.2 mg / kg / day as compared to using only atorvastatin (see. Section "Pharmacological properties"). Avoid the simultaneous application Etset and cyclosporine ( see. Section "Properties application").

Medical recommendations for the use of drugs interacting summarized in Table 3 (see. Also "Dosage and Administration" "Features of the application", "Pharmacological properties").

Gemfibrozil. Due to the increased risk of myopathy / rhabdomyolysis while taking inhibitors of HMG-CoA reductase inhibitor with gemfibrozil avoid joint use drug Etset with gemfibrozil (see. "Application Features" section).

Other fibrates. Since it is known that the risk of myopathy during treatment with HMG-CoA reductase increases while receiving other fibrates Etset should be used with caution when combined with other fibrates (see. Section "use of features).

Niacin. The risk of side effects from the skeletal muscle may be increased when used in combination with niacin, and hence under such conditions should consider a dose reduction Etset formulation (see. Section "Properties application").

Rifampicin or other inducers of cytochrome P450 3A4 . Simultaneous use of the drug with inducers of cytochrome P450 3A4 (eg efavirenz, rifampicin) can lead to an unstable reduction atorvastatin plasma concentration. Through the mechanism of interaction of rifampin dual simultaneous application Etset rifampin, since it has been shown that delayed administration of the preparation after administration of rifampin is associated with a significant reduction of atorvastatin concentrations in plasma.

diltiazem hydrochloride

Simultaneous treatment with atorvastatin (40 mg), and diltiazem (240 mg) was accompanied by increased concentrations of atorvastatin in the blood plasma.

cimetidine

As a result of evidence of studies of the interaction of cimetidine and atorvastatin was not revealed.

antacids

Simultaneous atorvastatin and oral antacid formulation a suspension containing magnesium and aluminum hydroxide, accompanied by a decrease in blood plasma concentration of atorvastatin for 35%. In this case, lipid-lowering effect of atorvastatin unchanged.

colestipol

plasma concentration of atorvastatin lower (approximately 25%), while taking atorvastatin and colestipol . Thus hypolipidemic effect of the combination of atorvastatin and colestipol exceed effect, which allows the reception of each of the drugs individually.

azithromycin

Simultaneous administration of atorvastatin (10 mg 1 time per day) and azithromycin (500 mg 1 time per day) was not accompanied by changes in the concentration of atorvastatin in plasma.

Inhibitors of transport proteins

Inhibitors of transport proteins (eg cyclosporin) can increase the systemic exposure level of atorvastatin (see. Table 1). The effect of suppressing accumulation of transport proteins on the concentration of atorvastatin in liver cells is unknown. If avoid simultaneous administration of these preparations impossible recommended dose reduction and clinical monitoring of the effectiveness of atorvastatin (see. Table 1).

ezetimibe

The use of ezetimibe as a monotherapy has been associated with effects from the musculoskeletal system, including rhabdomyolysis. Thus, while the use of ezetimibe and atorvastatin risk of these events is increased. It is recommended to carry out appropriate clinical monitoring of these patients.

fusidic acid

interaction and atorvastatin acid fuzidovoi study were not conducted. As is the case with other statins, a post-marketing period while taking atorvastatin and fuzidovoi acid phenomena observed by the muscular system (including rhabdomyolysis). The mechanism of this interaction is unknown. Patients need to be carefully monitored, may require the temporary suspension of treatment with atorvastatin.

Digoxin.With simultaneous use of multiple doses of atorvastatin and digoxin Digoxin equilibrium plasma concentrations increased by approximately 20%. It is necessary to properly monitor the status of patients taking digoxin.

Oral contraceptives.Simultaneous use of atorvastatin with oral contraceptives increased the AUC value for ethinylestradiol and norethisterone (see. Section "Pharmacological properties"). These increases should be considered when selecting an oral contraceptive for a woman who takes Etset.

Warfarin. Atorvastatin had no clinically significant effect on the prothrombin time in the application of patients who were treated with warfarin for a long period.

Colchicine. With simultaneous use of atorvastatin with colchicine reported cases of myopathy, including rhabdomyolysis, should therefore be used with caution atorvastatin with colchicine.

Table 3.

Drug interactions associated with an increased risk of myopathy / rhabdomyolysis
Drugs that interact Medical recommendations for application
Cyclosporin, HIV protease inhibitors (tipranavir + ritonavir), an inhibitor of hepatitis C virus protease (telaprevir) Avoid the use of atorvastatin
HIV protease inhibitor (lopinavir + ritonavir) Be used with caution and at the required dose

Clarithromycin, itraconazole,

HIV protease inhibitors (saquinavir, ritonavir + * + ritonavir, darunavir, fosamprenavir, ritonavir, fosamprenavir +)

Exceed the dose of 20 mg of atorvastatin per day

HIV protease inhibitor (nelfinavir)

Protease inhibitor of hepatitis C virus (boceprevir)

Exceed 40 mg atorvastatin dose per day

* Use with caution and at lower dose required.

Features of the application

Therapy lipidomodifikatsiynimy drugs should be one of the constituents of complex therapy for patients with significantly increased risk of atherosclerotic vascular disease through hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the result of dieting, limiting the intake of saturated fats and cholesterol, as well as the use of other non-drug measures were not enough. Patients with coronary heart disease or multiple risk factors for heart coronary disease taking the drug Etset can start simultaneously with dieting.

skeletal muscles

There are rare reports of rhabdomyolysis with acute renal failure due to myoglobinuria with use of atorvastatin and other drugs in this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients need closer monitoring to detect violations of the skeletal muscles.

Atorvastatin, like other drugs of the statin group sometimes cause myopathy, defined as muscle pain or weakness of muscles in conjunction with an increase in CPK indicators (CK) more than 10 times the upper limit of normal. The simultaneous use of high doses of atorvastatin with certain drugs such as cyclosporin and potent inhibitors of CYP3A4 (eg clarithromycin, itraconazole and HIV protease inhibitors) increases the risk of myopathy / rhabdomyolysis.

There are rare reports of immunologically mediated necrotising myopathy (IONM) - autoimmune myopathy associated with statin use. IONM is characterized by the following features: proximal muscle weakness and elevated levels of creatine kinase in the blood serum, which persist despite discontinuation of statin therapy; Muscle biopsy reveals necrotizing myopathy without significant inflammation; the application of immunosuppressive agents observed a positive trend.

The possibility of developing myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and / or a significant increase in CPK. Patients should be advised to immediately report cases of muscle pain, tenderness, or weakness of the muscles of unknown etiology, particularly if it is accompanied by a feeling of malaise or fever, or if signs and symptoms of muscle disease persist after discontinuation of the drug Etset. Treatment should be discontinued in case of increase of CPK, diagnosis or suspicion of myopathy.

The risk of myopathy during treatment with this class of drugs increases with simultaneous use of cyclosporine, fibroic acid derivatives, erythromycin, clarithromycin, hepatitis C virus protease inhibitor, telmappervirus protease inhibitor, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or antimycotics of the azole group.Doctors who are considering the combination of Ekset and derivatives of fibrotic acid, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, azole antimycotics or lipid modifying doses of niacin should carefully weigh the potential benefits and risks, and carefully monitor the condition of patients for any signs or symptoms of pain, tenderness, or weakness in the muscles, especially in the initial th months of therapy and during any of the titration periods of the dose in the direction of increasing any of the drugs. It should be considered the possibility of using low initial and maintenance doses of atorvastatin while taking with the above medicines (see Section "Interaction with other drugs"). In such situations, the possibility of periodic determination of CPF may be considered, but there is no guarantee that such monitoring will help prevent cases of severe myopathy.

There have been reports of cases of myopathy, including rhabdomyolysis with the simultaneous use of atorvastatin with colchicine, and therefore, atorvastatin with colchicine should be given to patients with caution (see Section "Interaction with Other Drugs").

The therapy should be temporarily discontinued or completely stopped in any patient with acute serious condition, indicates the development of myopathy, or if there is a risk factor for renal failure due to rhabdomyolysis (eg severe acute infection, arterial hypotension, surgical operation, trauma, severe metabolic, endocrine and electrolytic disorders, as well as uncontrolled convulsions).

Impaired liver function

It was shown that statins, like some other lipid-lowering therapeutic agents, are associated with a deviation from the norm of biochemical indicators of liver function. After dose reduction, interruption in the use of atorvastatin or discontinuation of its use, transaminase levels returned to pre-treatment levels or approximately these levels without residual effects.

Before starting therapy with Ettset, it is recommended to obtain the results of liver enzyme analysis and to re-test if necessary. There are rare reports of cases of lethal and non-lethal hepatic insufficiency in patients taking drugs of the statin group, including atorvastatin. In the case of severe liver damage with clinical symptoms and / or hyperbilirubinemia or jaundice with the drug, Etset should be discontinued immediately. If no other etiologic factors of liver damage are identified, do not re-initiate treatment with the drug.

There should be caution in prescribing to patients who take significant amounts of alcohol and / or have a history of liver disease. It is contraindicated in case of liver disease in the acute phase or persistent increase in activity of hepatic transaminases of unclear etiology (see Section "Contraindications").

Endocrine function

An increase in the level of HbA1c and glucose concentration in the fasting serum was reported with the use of HMG-CoA reductase inhibitors, including atorvastatin.

Statins interfere with the synthesis of cholesterol and theoretically can weaken the secretion of the adrenal glands and / or gonadnichnyh steroids. Atorvastatin does not reduce the basal concentration of plasma cortisol and does not damage the adrenal reserve. The effect of statins on the fertilizing capacity of sperm has not been studied in a sufficient number of patients. It is not known how the drug affects and generally affects the "sex glands-pituitary-hypothalamus" system in women in the pre-menopausal period. Caution should be exercised when using the drug group of statins simultaneously with drugs that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

Use in patients with recent cases of stroke or transient ischemic attack

There are clinical data that when using atorvastatin 80 mg in patients without ischemic heart disease who had a history of stroke or transient ischemic attack during the previous 6 months, there was a higher incidence of hemorrhagic stroke compared to the placebo group. The increased risk was particularly noticeable in patients who already had hemorrhagic stroke or lacunar infarction at the beginning of the study.

For patients with hemorrhagic stroke or lacunar infarction, the risk-benefit ratio of atorvastatin 80 mg is not determined, so the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment.

Patients older than 65 years of age

There was not a single general difference in the safety and efficacy of the drug in elderly patients and young patients, however, the sensitivity of some older patients can not be ruled out. Since the senior age (65 years) is a predisposition factor to myopathy, caution should be given to elderly people.

Liver failure

It is contraindicated in patients with active liver disease, including a steady increase in the activity of hepatic transaminases of unclear etiology (see Sections "Contraindications" and "Pharmacological properties").

Before treatment begins

Atorvastatin should be administered with caution to patients with a tendency to develop rhabdomyolysis. Prior to the initiation of statin therapy in patients prone to rhabdomyolysis, the level of CC should be determined when:

  • impaired renal function
  • hypothyroidism of the thyroid gland;
  • hereditary disorders of the muscular system in family or personal history
  • past cases of toxic effects of statins or fibrates on muscles;
  • suffered in the past liver diseases and / or the use of large amounts of alcohol.

For elderly patients (over 70 years of age), the need for these measures should be evaluated in view of the presence of other factors predisposing to the development of rhabdomyolysis.

An increase in the level of the drug in the blood plasma is possible, in particular, in the case of interaction and use of special populations of patients, including patients with hereditary diseases.

In such cases it is recommended to evaluate the ratio of risks and possible benefits from treatment and to conduct clinical monitoring of the patients' condition. If before the start of treatment the level of CC is significantly increased (exceeds BMT by more than 5 times), treatment should not be started.

Measurement of the level of CK

The level of CK should not be determined after intensive physical exertion or if there are any possible alternative reasons for raising the level of MC, as this may complicate the interpretation of the results. If at the initial level there is a significant increase in MC (exceeding the upper limit of the norm by more than 5 times), then after 5-7 days it is necessary to re-determine to confirm the result.

During treatment

Patients should be aware of the need to immediately report the development of muscle pain, judgment or weakness, especially if they are accompanied by a malaise or fever.

If these symptoms appear during treatment with atorvastatin, the level of QC in this patient should be determined. If the level of CC is significantly increased (exceeds the IMH more than 5 times), treatment should be discontinued.

The expediency of cessation of treatment should also be considered if the increase in the level of MC does not reach a fivefold excess of the IMH, but the symptoms from the muscles are severe and daily cause unpleasant sensations.

After the disappearance of symptoms and the normalization of the level of CC, it may be possible to consider the resumption of treatment with atorvastatin or the initiation of treatment with alternative statins, subject to the application of the minimum possible dose and careful monitoring of the patient's condition.

Treatment with atorvastatin should be discontinued if there is a clinically significant increase in the level of CC (exceeding the upper limit of the norm by more than 10 times) or in the case of establishing a diagnosis of rhabdomyolysis (or suspected development of rhabdomyolysis).

Simultaneous use with other medicinal products

The risk of rhabdomyolysis increases with simultaneous use of atorvastatin with certain medications that can increase the concentration of atorvastatin in the blood plasma. Examples of such drugs may be potent inhibitors of CYP3A4 or transport proteins, cyclosporine, telithromycin, clarithromycin, delavirdine, styipentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir.With simultaneous use with gemfibrozilom and other derivatives of fibrous acid, erythromycin, niacin and ezetimibe also the risk of myopathy. If possible, other medications should be used (do not interact with atorvastatin) instead of the above.

If simultaneous treatment with atorvastatin and the aforementioned drugs is necessary, the benefits and risks of simultaneous treatment should be carefully weighed. If patients take medications that increase the concentration of atorvastatin in blood plasma, it is recommended to reduce the dose of atorvastatin to a minimum. In addition, in the case of the use of potent inhibitors of CYP3A4, a lower initial dose of atorvastatin should be considered. It is also recommended that proper clinical monitoring of the condition of these patients be carried out.

It is not recommended at the same time to appoint atorvastatin and fusidic acid, so consider the possibility of temporary withdrawal of atorvastatin during treatment with fusidic acid.

Interstitial lung disease

During treatment with some statins (especially during long-term treatment), exceptional cases of interstitial lung disease development have been described. To manifestations of this disease include shortness of breath, unproductive cough and general deterioration of health (fatigue, weight loss and fever). In case of suspicion of interstitial lung disease, treatment with statins should be discontinued.

Restriction of use

Possible consequences of using atorvastatin under conditions when the main deviation from the norm from the side of lipoproteins is an increase in the level of chylomicrons (types I and V according to Fredrickson's classification) have not been investigated.

Excipients. The preparation contains lactose. Patients with rare hereditary diseases, such as galactose intolerance, Lappease lactase deficiency and glucose-galactose malabsorption, should not use this drug.

Use during pregnancy and lactation

It is contraindicated for pregnant women and women who can become pregnant. Statins can harm the fetus when used in pregnant women. It can be used for women of reproductive age only if it is very unlikely that such patients will become pregnant and have been informed of potential risk factors. If a woman becomes pregnant during the treatment period, immediately stop taking the medication and re-advise the patient on the potential risk factors for the fetus and the lack of known clinical benefit from continuing the drug during pregnancy.

With a normal course of pregnancy, serum cholesterol and triglyceride levels increase. Admission of lipid-lowering drugs during pregnancy will not have a beneficial effect, since cholesterol and its derivatives are necessary for normal fetal development. Atherosclerosis is a chronic process, and, consequently, a break in taking lipid-lowering drugs during pregnancy should not have a significant effect on the results of long-term treatment of primary hypercholesterolemia.

Adequate and well-controlled studies of the use of atorvastatin during pregnancy have not been conducted. There are rare reports of congenital anomalies after intrauterine exposure to statins

Breastfeeding period

It is not known whether atorvastatin penetrates into breast milk, but it is known that a small amount of another drug of this class penetrates into the human breast milk. Because statins are potentially capable of causing serious adverse reactions in infants who are breastfeeding, women who need treatment with Ettset should not breast-feed (see Section "Contraindications").

The ability to influence the reaction rate when driving vehicles or other mechanisms

Has very little effect on the reaction rate when driving vehicles or working with mechanisms.

Dosing and Administration

Hyperlipidemia (heterozygous family and non-family) and mixed dyslipidemia (type IIa and IIb according to Fredrickson classification)

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

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10-17 years)

The recommended initial dose of Eetset is 10 mg / day, the maximum recommended dose is 20 mg / day (doses exceeding 20 mg in this group of patients have not been studied). Doses of the drug should be selected individually in accordance with the recommended goal of treatment. The dose adjustment should be done at intervals of 4 weeks or more.

Homozygous familial hypercholesterolemia

The dose in patients with homozygous familial hypercholesterolemia is 10 to 80 mg per day. This should be used as an adjunct to other lipid-lowering treatments (eg, LDL apheresis), or if lipid-lowering treatments are not available.

Simultaneous lipid-lowering therapy

This can be used with SECTIONS of bile acids. The combination of inhibitors of HMG-CoA reductase (statins) and fibrates should generally be used with caution (see Sections "Features of use", "Interaction with other drugs").

Dosing for patients with impaired renal function

Kidney disease does not affect the concentration in the blood plasma, nor the lowering of LDL cholesterol when using Etset; consequently, correction of the dose of the drug in patients with impaired renal function is unnecessary (see the sections on "Features of application", "Pharmacokinetics").

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

Etset treatment should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitor (telaprevir). There should be caution in prescribing to patients with HIV who take lopinavir + ritonavir and apply it in the most appropriate dose. In patients taking clarithromycin, itraconazole, or in patients with HIV who are taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir in combination, the therapeutic dose of Etset should be limited to a 20 mg dose, and it is also recommended that the necessary clinical Ensuring the application of the slightest necessary dose. In patients taking the HIV protease inhibitor nelfinavir or hepatitis C protease inhibitor bocetreviros, treatment with Etes should be limited to a dose of up to 40 mg, and it is also recommended that appropriate clinical trials be performed to ensure that the smallest dose required is available (see "Features of Use" and "Interaction with other drugs ").

Children

Atorvastatin was not investigated in controlled clinical trials, which included adolescent patients or patients younger than 10 years.

It was shown that patients aged 10-17 years with heterozygous familial hypercholesterolemia treated with atorvastatin (20 mg dose), had a similar profile of adverse reactions in patients receiving placebo. There was no significant effect of the drug on the growth or puberty in boys or length of the menstrual cycle in women (see. Sections "Adverse Reactions", "Dosing and dose"). Teenage girls should be consulted for suitable methods of contraception during the treatment Etset (cm. "Applying during pregnancy and lactation" and "Application in certain patient groups").

Overdose

Specific treatment for an overdose of atorvastatin is not there. In cases of overdose, symptomatic and supportive therapy should be carried out if necessary. It is necessary to carry out functional tests of liver and follow the Criminal Code level in blood serum. Since Etset extensively bound to plasma proteins, hemodialysis is not significantly enhance clearance of atorvastatin.

Adverse reactions

Part of the On the psyche , depression, sleep disorders, including insomnia and nightmares.

The nervous system From : headache, peripheral neuropathy, paresthesia, hypoesthesia, dizziness, dysgeusia, cognitive disorders (such as memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin therapy, stroke.

On the part of the ear and labyrinth : tinnitus, ringing in the ears, hearing loss.

On the part of the organ of vision: blurred vision, blurred vision, blurred vision.

On the part of the digestive tract : dyspepsia, nausea, vomiting, belching, diarrhea, constipation, bloating, abdominal pain, pain in the upper and lower parts of the stomach, stomach pain, gastrointestinal discomfort, pancreatitis.

Of the liver and gall bladder : hepatitis, cholestasis, cholestatic jaundice, fatal and non-hepatic failure.

Metabolic disorders : hypoglycemia, hyperglycemia, anorexia, weight gain, diabetes.

On the part of the musculoskeletal system and connective tissue disorders: myalgia, myopathy, myositis, convulsions, muscle cramps, muscle weakness, rhabdomyolysis, arthralgia, joint pain, back pain, pain in the extremities, muscular skeletal pain, neck pain, joint swelling , tendinopathy (sometimes difficult tendon rupture)

Skin and subcutaneous tissue: alopecia, pruritus, skin rashes, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), urticaria, angioneurotic edema.

The respiratory system: nasopharyngitis, epistaxis, interstitial lung disease, sore throat and larynx.

With the genitourinary system: urinary tract infection, leykotsitouriya.

Reproductive system and breast: sexual dysfunction, impotence, gynecomastia.

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

On the part of the circulatory and lymphatic system: thrombocytopenia.

Immune system: allergic reactions, anaphylactic shock (including anaphylactic shock).

In shkodzhennya, poisoning and complications of procedures: tendon rupture.

Infections and infestations: infection.

Changes in laboratory test results: an increase in transaminase levels and liver enzymes, abnormal liver function tests, increased levels of alkaline phosphatase in the blood, increased blood creatine kinase activity.

Children (10-17 years)

The frequency and nature of adverse events and abnormal laboratory results are comparable to those in adults. Safety experience prolonged use of atorvastatin in children is currently limited.

Shelf life

film-coated tablets 10 mg, 20 mg of 3 years.
film-coated tablets 40 mg, 80 mg of 2 years.

Storage conditions

Stored in original package at a temperature not higher than 25 ° C. Keep out of reach of children.

Packaging

14 tablets in blisters; 2 or 4 or 6 blister packs in a cardboard box.

holiday category

On prescription.

 

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