Liprimard 10 mg tablet number 100

Liprimar (Atorvastatin) instructions for use

Composition

active ingredient: atorvastatin; 1 tablet contains atorvastatin calcium, equivalent to 10 mg or 20 mg, or 40 mg, or 80 mg atorvastatin;
auxiliary substances: calcium carbonate; cellulose microcrystalline lactose monohydrate, sodium croscarmellose;polysorbate 80 hydroxypropyl cellulose; magnesium stearate material for film coating (hydroxypropylmethylcellulose, polyethylene glycol 8000, titanium dioxide (E 171), talc) simethicone emulsion (simethicone, emulsify tensile stearate, thickener, benzoic acid, sorbic acid).

Dosage form

Film-coated tablets.

Basic physical and chemical properties:

white, round, film-coated tablets with engraving "10", "20", "40" or "80" on the one hand and "ATV", "ATV", "ATV", "ATV" - on the other, for tablets 10 mg, 20 mg, 40 mg and 80 mg, respectively.

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.

Liprimar is a synthetic lipid-lowering drug. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA into mevalonate, the early stage of cholesterol biosynthesis, which limits the rate of its formation.

Liprimar is a selective competitive inhibitor of HMG-CoA reductase, an enzyme on which the rate of conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, the precursor substance of sterols, including cholesterol, depends.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 blood 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.

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

Numerous clinical studies have shown that elevated levels of total cholesterol, LDL cholesterol and apo B (a membrane complex for LDL cholesterol) provoke the development of atherosclerosis. Likewise, the levels of HDL cholesterol (and its transport complex - a for A) are lowered due to the development of atherosclerosis. Epidemiological studies have established that cardiovascular morbidity and mortality change in direct proportion to the level of total cholesterol and LDL cholesterol and inversely proportional to the level of HDL cholesterol.

Liprimar 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.Liprimar also lowers cholesterol levels in VLDL and TG, and also leads to an unstable increase in HDL cholesterol and apolipoprotein A-1. Liprimar lowers total cholesterol, LDL cholesterol, VLDLP cholesterol, apo B, triglycerides and cholesterol-lowering HDL-C, and also increases HDL cholesterol in patients with isolated hypertriglyceridemia. Liprimar lowers cholesterol-lowering cholesterol in patients with disbetalipoproteinemia.

Like LDL, lipoproteins enriched with cholesterol and triglycerides, including VLDL, LTR and residues, can also contribute to the development of atherosclerosis. Elevated levels of triglycerides in the blood plasma are often found in a triad with low levels of HDL cholesterol and small slices of LDL, and in combination with non-lipid metabolic risk factors for coronary heart disease. It has not been consistently shown 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.

Liprimar, 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").

Pharmacokinetics.

Suction. Lipimar 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 the drug lypemar. 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 approximately 25% and 9%, respectively, based on C max and AUC, lowering LDL cholesterol is similar regardless of whether the lymar 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 distribution of the drug 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. On the basis of observations in rats, it is considered that the lymar is able to penetrate into breast milk (see Sections "Contraindications", "Use during pregnancy or lactation" and "Features of use").

Metabolism. Lipimar is extensively metabolized in ortho and parahydroxylated derivatives and various products of beta oxidation. In vitro studies of the inhibition of ortho HMG-CoA reductase and parahydroxylated metabolites is equivalent to inhibition by the drug of lymer. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with active metabolites. In vitro studies indicate the importance of the metabolism of the drug lypimar cytochrome P450 3A4, which is consistent with increased concentrations of the drug liprimar in human blood plasma after simultaneous use with erythromycin, a known inhibitor of this enzyme (see Section "Interaction with other drugs").

Excretion. Liprimar and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism, but this drug obviously does not experience gastrohepatic recirculation. The half-life of the lipipine 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. The concentration of the drug in the plasma is higher (about 40% for C max and 30% for AUC) in healthy elderly patients (over 65 years) 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.

Floor. The concentration of the drug lipipine in the blood plasma of women differs from that in blood plasma (about 20% higher for C max and 10% lower for AUC). However, there is no clinically significant difference in the lowering of LDL cholesterol when using the drug Liprimar in men and women.

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

Hemodialysis. Despite the fact that patients with terminal stage of kidney disease have not undergone studies, it is believed that hemodialysis does not significantly increase the clearance of lipipine, since the drug binds intensely to plasma proteins.

Liver failure. The concentration of the drug lipprimar in the blood plasma is markedly elevated in patients with chronic alcoholic liver disease. The values of C max 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 C max and AUC increase approximately 16-fold and 11-fold, respectively (see Section "Contraindications").

Table 1.

The effect of concurrently used drugs on the pharmacokinetics of atorvastatin

Simultaneously used drugs and dosing regimen	Atorvastatin
	Dose (mg)	The change in AUC &	The change in C max &
# Cyclosporine 5.2 mg / kg / day, stable dose	10 mg once daily 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 4 times a day, 2 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	2.30 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., 1-fold = 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.

The 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	Change C max
80 mg once a day for 15 days	Antipyrine, 600 mg once	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 adults 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 an early ischemic heart disease in a family history, the lymor 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 II diabetes mellitus and without clinically severe ischemic heart disease, but with several risk factors for coronary heart disease such as retinopathy, albuminuria, smoking or hypertension, the drug lymar is indicated for:

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

For patients with clinically severe ischemic heart disease, lypemar 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 due to congestive heart failure,
• reduction in the risk of angina pectoris.

Hyperlipidemia

In addition to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides, and also to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-family) and mixed dyslipidemia (type IIa and IIb according to Fredrickson classification) .
As a supplement to the diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV).
For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrikson's classification), in cases when diet compliance is not effective enough.
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 not available.
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:

a) ³ LDL cholesterol is 190 mg / dl or

b) ³ LDL cholesterol 160 mg / dl:

In the early family history of cardiovascular disease or two or more other risk factors for cardiovascular disease are present in childhood patients.

Contraindications

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

Interaction with other drugs and other 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. Lipitor is metabolized by cytochrome P450 3A4. Simultaneous use of the drug Lipitor 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 Lipitor 80 mg and clarithromycin (500 mg twice per day) as compared to using only the drug Lipitor (see. Section "Pharmacological properties"). Thus, patients who take clarithromycin, should be used with caution Lipitor 20 mg (cm. Sections "Properties Applications" and "Instructions for use and dose").

A combination of protease inhibitors. Meaning atorvastatin AUC increased significantly while applying Lipitor with several combinations of HIV protease inhibitors, as well as with an inhibitor of hepatitis C virus protease telaprevir as compared to using only the drug Lipitor (see. Section "Pharmacological properties"). Therefore, for patients taking HIV protease inhibitor ritonavir, tipranavir + or an inhibitor of hepatitis C virus protease telaprevir, avoid the simultaneous application of drug Lipitor. The drug should be used with caution in patients who are taking an HIV protease inhibitor lopinavir + ritonavir and apply the most necessary dose. For patients taking HIV protease inhibitors ritonavir + saquinavir, ritonavir + darunavir, fosamprenavir + ritonavir or fosamprenavir,Lipitor dose should not exceed 20 mg and apply them with caution (see. Sections "Properties Applications" and "Instructions for use and dose"). When applied in patients taking HIV protease inhibitor nelfinavir or an inhibitor of hepatitis C virus protease boceprevir, Lipitor dose should not exceed 40 mg, and recommends a thorough clinical patient monitoring.

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

Cyclosporine. Atorvastatin and its metabolites are substrates of OATP1B1 transporter. OATP1B1 inhibitors (e.g. Ciclosporin) may increase the bioavailability of atorvastatin. Meaning atorvastatin AUC increased significantly while applying Lipitor 10 mg dose of cyclosporine and 5.2 mg / kg / day as compared to using only the drug Lipitor (see. Section "Pharmacological properties"). Avoid the simultaneous application Lipitor 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").

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.

Gemfibrozil. Due to the increased risk of myopathy / rhabdomyolysis while taking inhibitors of HMG-CoA reductase inhibitor with gemfibrozil avoid concomitant use with gemfibrozil drug Lipitor (cm. "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, Lipitor 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 these conditions should be considered the possibility of reducing the dose of the drug Lipitor (see. Section "Properties application").

Rifampicin or other inducers of cytochrome P450 3A4. Simultaneous use of the drug with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin) can lead to an unstable reduction atorvastatin plasma concentration. Through the mechanism of interaction of rifampin dual simultaneous application Lipitor 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 (e.g. 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 digoxin and Lipitor equilibrium digoxin concentration in the blood plasma increased by approximately 20%. It is necessary to properly monitor the status of patients taking digoxin.

Oral contraceptives.

Simultaneous use of the drug Lipitor 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 women who take Lipitor.

Warfarin.

Lipitor had no clinically significant effect on prothrombin time when used in patients receiving long-term warfarin therapy.

Colchicine.

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

Other drugs

Clinical studies have shown that the concurrent use of atorvastatin and antihypertensive drugs and their use in the course of estrogen replacement therapy was not associated with clinically significant side effects. Interaction studies with other drugs have not been conducted.

Application features

Skeletal muscles

There have been rare reports of rhabdomyolysis with acute renal failure due to myoglobinuria when using the drug Lipitor 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 have been rare reports of an 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 Lipitor. 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 is increased while the use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, protease inhibitors of hepatitis C virus telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir, and fosamprenavir + ritonavir, and niacin or antimycotic azole group. Doctors who are considering combination therapy drug Lipitor and fibric acid derivatives, erythromycin, clarithromycin, combinations saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, antimycotics group azoles or lipidomodifitsiruyuschey doses of niacin should carefully weigh the potential benefits and risksand carefully monitor the condition of patients for any signs or symptoms of pain, tenderness, or weakness in the muscles, especially in the initial months of therapy and during any periods of dose titration in the direction of increase of any of the drugs. Should consider the use of low initial and maintenance doses of atorvastatin while taking the above drugs (see. Section "interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.especially in the initial months of therapy and during any periods of dose titration in the direction of increasing any of the drugs. Should consider the use of low initial and maintenance doses of atorvastatin while taking the above drugs (see. Section "interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.especially in the initial months of therapy and during any periods of dose titration in the direction of increasing any of the drugs. Should consider the use of low initial and maintenance doses of atorvastatin while taking the above drugs (see. Section "interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.CATEGORY "Interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.CATEGORY "Interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.

It reported cases of myopathy, including rhabdomyolysis, while the use of atorvastatin with colchicine, so atorvastatin with colchicine should be administered with caution to patients (see. Section "Interaction with other medicinal products and other forms of interaction").

Therapy Lipitor should be temporarily or permanently discontinued in any patient with an acute, serious condition, it indicates the development of myopathy, or if there is a risk factor for renal disease development due to rhabdomyolysis (eg severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

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. A steady increase (more than 3 times the upper limit of the normal range, which occurred 2 times or more) in serum transaminase levels was observed in 0.7% of patients who received lipprim during clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6% and 2.3% for doses of 10, 20, 40 and 80 mg, respectively.

During clinical trials of the drug, jaundice developed in one patient. Increased indicators of functional liver samples (PFR) in other patients were not associated with jaundice or other clinical signs and symptoms. After reducing the dose of interruption in taking the drug or stopping its use, transaminase levels returned to pre-treatment levels or approximately these levels without residual effects. 18 out of 30 patients with a sustained increase in liver function tests continued treatment with less doses of lipipine.

Before starting therapy with the drug, it is recommended that liver enzyme test results be obtained and tests should be re-submitted in case of clinical necessity. There were rare post-registration 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, when using the drug, lypemar should be discontinued immediately. If an alternative etiology is not defined, do not re-initiate treatment with the drug.

Liprimar should be administered with caution to patients who take significant amounts of alcohol and / or have a history of liver disease. Liprimar is contraindicated in case of active liver disease or persistent increase in hepatic transaminases activity of unclear etiology (see Section "Contraindications").

Endocrine function

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

Statins interfere with the synthesis of cholesterol and theoretically can weaken the secretion of adrenal and / or gonadal steroids. Clinical studies have shown that Liprimar 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 in general affects the "sex glands-pituitary-hypothalamus" system in women in the premenopausal 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

In the post-hoc analysis of the SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), during which 80-200 mg of lipprimer, in contrast to placebo, were administered to 4731 patients without ischemic heart disease who had a history of stroke or transient ischemic attack during the previous 6 months, there was a greater incidence of hemorrhagic stroke in the group of patients treated with a 80 mg lipprim compared with the placebo group (55 cases, 2.3% in the atorvastatin group compared to 33 cases, 1.4% in the placebo group; p: 1.68, 95% CI: 1,09, 2,59; p = 0,0168). The incidence of lethal hemorrhagic stroke was similar in all treatment groups (17 and 18 for atorvastatin and placebo, respectively). The incidence of non-lethal hemorrhagic stroke was significantly higher in the group of patients receiving atorvastatin (38, 1.6%) compared with the placebo group (16, 0.7%). Some initial characteristics, including the presence of cases of hemorrhagic and lacunar stroke during enrollment, were associated with a higher incidence of hemorrhagic stroke in the group of patients receiving atorvastatin (see Section "Adverse Reactions").

Among the 39,828 patients who received lipprimes in clinical trials, 15813 (40%) patients were aged 65 years and 2,800 (7%) patients were aged 75 years. There was no overall difference in the safety and efficacy of the drug between these patients and young patients, nor was there any difference in response to treatment in elderly patients and young patients according to other clinical experiences, but the sensitivity of some older patients . Since the senior age (65 years) is a factor of predisposition to myopathy, caution should be taken to prescribe the lypemar to elderly people.

Liver failure

Liprimar is contraindicated in patients with active liver disease, including persistent increases in 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, possibly, 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 cause unpleasant sensations every day.

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 to simultaneously appoint atorvastatin and fusidic acid, so it is worth considering the temporary withdrawal of atorvastatin during the 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.

Fillers

The composition of the drug lipid is lactose. This drug should not be taken to patients with rare hereditary diseases associated with galactose intolerance, Lappease lactase deficiency, or malabsorption of glucose-galactose. Therapy lipidomodifikatsiiimy drugs should be one of the components of complex therapy for patients with a significantly increased risk of atherosclerotic vascular disease through hypercholesterolemia. Drug therapy is recommended as an addition to a diet, when the result of adherence to a diet that restricts the intake of saturated fats and cholesterol, as well as from the use of other non-medicament measures was not enough. Patients with coronary heart disease or several risk factors for developing coronary heart disease can take lipprimar once the diet is observed.

Restriction of use

Liprimar was not studied under conditions when the main deviation from the norm from lipoproteins is an increase in the level of chylomicrons (types I and V according to Fredrikson's classification).

Use during pregnancy or lactation

Pregnancy.

Liprimar is contraindicated in pregnant women and women who may become pregnant. Statins can harm the fetus when administered to pregnant women. Liprimar can be used in 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 of lypemar, should immediately stop taking the drug and re-advise the patient on the potential risk factors for the fetus and the lack of a known clinical benefit of 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 were rare reports of congenital anomalies after intrauterine exposure to statins. In a prospective observation of approximately 100 pregnancies in women treated with other statin drugs, the incidence of congenital fetal abnormalities, miscarriages and fetal deaths / stillbirths did not exceed the frequency expected for the general population. However, this study could only rule out a 3-4 fold increase in the risk of congenital fetal anomalies compared to the background frequency. In 89% of these cases, treatment began before pregnancy and stopped at I trimester after pregnancy was detected.

Breastfeeding period

It is not known whether atorvastatin penetrates breast milk, but it is known that a small amount of another drug of this class penetrates into breast milk. Because statins are potentially capable of causing serious adverse reactions in infants who are breastfeeding, women who need treatment with the drug lypemar should not breastfeed their infants (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 other 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 the drug 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 between 10 and 80 mg once a day. The drug can be taken in a single dose at any time and regardless of food intake. The initial and maintenance doses of lypemar should be selected individually depending on the purpose of treatment and response. After the start of treatment and / or after titration of the dose of the drug, lipipine should be analyzed for lipid levels over a period of 2 to 4 weeks and the dosage adjusted accordingly.

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

The recommended initial dose of the drug is 10 mg / day maximum recommended dose of 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 of lipprimar in patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg per day.Liprimar 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

Liprimar can be used with bile acid sequestrants. 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 and Other Interactions").

Dosing for patients with impaired renal function

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

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

Lipromar treatment should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitor (telaprevir). Liprimar should be used with caution in patients with HIV who take lopinavir + ritonavir and apply 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 the drug liprimar should be limited to a dose of 20 mg, and it is also recommended that the necessary clinical ensuring the application of the slightest necessary dose of lime.In patients receiving HIV protease inhibitor nelfinavir or an inhibitor of HCV protease C boceprevir, treatment Lipitor should limit the dose to 40 mg, and also recommended to perform appropriate clinical examinations to ensure application of the least required dose Lipitor (see. Section "Features of application "and" Interaction with other drugs, and other kinds of interactions ").

Children

Safety and efficacy in patients aged 10-17 years with heterozygous familial hypercholesterolemia has been investigated in a controlled clinical trial of 6 months in adolescent boys and girls after the onset of menstruation. Patients who were treated with drug Lipitor, have a generally shaped profile of adverse reactions in patients receiving placebo. Infectious diseases were the adverse events most frequently observed in both groups, regardless of the assessment of the causal link. In this group of patients we studied doses 20 mg. In this narrow, controlled trial found no significant effect of the drug on growth or sexual maturation of boys or on menstrual cycle length in girls (see. Sections "Adverse Reactions""Dosage and Administration"). Teenage girls should be consulted for suitable methods of contraception during the treatment Lipitor (cm. "Applying during pregnancy and lactation" and "Application in certain patient groups").

Lipitor has not been studied in controlled clinical trials, which included adolescent patients or patients younger than 10 years.

The clinical efficacy of the drug in doses up to 80 mg / d for 1 year was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, in which 8 pediatric patients were included (see. Section "Homozygous familial hypercholesterolemia").

Overdose

Specific treatment for an overdose of the drug Lipitor no. In the case of an overdose the patient should be treated symptomatically and apply supportive measures if necessary. For a high degree of binding of drug with plasma proteins should not expect a significant increase in drug clearance Lipitor via hemodialysis.

Adverse Reactions

Due to the fact that clinical trials are conducted under conditions that vary widely, the frequency of adverse reactions observed during clinical trials of a drug can not be directly compared to those obtained in clinical trials of another drug and may not reflect the frequency indicators observed in clinical practice.

At the base of the placebo-controlled clinical trial of the drug Lipitor data among 16066 patients (8755 receiving Lipitor and 7311 received placebo; age range 10-93 years, 39% female, 91% Caucasian, 3% of blacks, 2% Asian race, 4% others), with a median of treatment was 53 weeks, 9.7% of patients receiving Lipitor, and 9, 5% of patients on placebo discontinued use of the drug through unwanted reactions, irrespective of causal relationship to the drug. The five most common adverse events in patients treated with the drug Lipitor, which led to discontinuation of the drug, and occurred at a frequency higher than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea ( 0.4%), increased levels of alanine aminotransferase (ALT) (0.4%) and liver enzymes (0.4%).

In patients treated with the drug Lipitor in the placebo-controlled trials (n = 8755) often observed such side reaction (the incidence of 2% or more and greater than placebo), regardless of causality: nasopharyngitis (8, 3%) , arthralgia (6.9%), diarrhea (6.8%), pain in the limbs (6.0%) and urinary tract infection (5.7%).

Table 4 summarizes the frequency of clinical adverse events, regardless of causality, for the 2% of patients or more and a frequency higher than the placebo in patients treated with the drug Lipitor (n = 8755), according to the 17 placebo-controlled research.

Table 4.

Clinical adverse reactions that occurred in 2% of patients and more treated with any dose of the drug Lipitor, and with a frequency higher than placebo, regardless of causality (% of patients).

Adverse Drug Reaction *	Any dose N = 8755	10 mg of N = 3908	20 mg N = 188	40 mg N = 604	80 mg of N = 4055	Placebo N = 7311
nasopharyngitis	8.3	12.9	5.3	7th	4.2	8.2
arthralgia	6.9	8.9	11.7	10.6	4.3	6.5
diarrhea	6.8	7.3	6.4	14.1	5.2	6.3
Pain in the extremities	6th	8.5	3.7	9.3	3.1	5.9
Urinary tract infection	5.7	6.9	6.4	8	4.1	5.6
dyspepsia	4.7	5.9	3.2	6th	3.3	4.3
nausea	4	3.7	3.7	7.1	3.8	3.5
Musculoskeletal pain	3.8	5.2	3.2	5.1	2.3	3.6
muscle spasms	3.6	4.6	4.8	5.1	2.4	3
myalgia	3.5	3.6	5.9	8.4	2.7	3.1
insomnia	3	2.8	1.1	5.3	2.8	2.9
faringolaringealnaya pain	2.3	3.9	1.6	2.8	0.7	2.1
* Adverse Drug Reaction> 2% at any dose over placebo

For other adverse reactions reported during the placebo-controlled studies, include:

general disorders: malaise, pyrexia;

From the digestive system: abdominal discomfort, belching, flatulence, hepatitis, cholestasis,

On the part of the musculoskeletal system: musculoskeletal pain, fatigue muscles, neck pain, joint swelling, tendinopathy (sometimes difficult tendon rupture)

on the part of metabolism and nutrition: increased transaminases, abnormal liver function tests, increased levels of alkaline phosphatase in the blood, increased CPK activity, hyperglycemia;

on the part of the nervous system: nightmares;

The respiratory system: nose bleeding;

of the skin and its appendages: urticaria

by the organs of vision: blurred vision, blurred vision;

by hearing and balance organs: tinnitus

genitourinary: leykotsitouriya;

Reproductive system and breast: Gynecomastia.

The incidence of adverse reactions was determined as follows: often (> 1/100 <1/10); infrequently

(> 1/1000, <1/100); Rare (> 1/10000, <1/1000); very rare (<1/10000).

Violation of the nervous system: frequent headache Uncommon: dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia rare: peripheral neuropathy.

Dysfunction of the gastrointestinal tract: constipation often infrequent pancreatitis, vomiting.

Impaired function of the musculoskeletal system and connective tissue: often joint pain, back pain uncommon: myopathy, myositis, rhabdomyolysis.

General disorders: Infrequent: asthenia, chest pain, peripheral edema, fatigue.

Metabolic disorders and nutritional: Infrequent hypoglycemia, weight gain, anorexia.

The liver and gall bladder: extremely rare: hepatic insufficiency.

On the part of the skin and connective tissue infrequently skin rash, pruritus, alopecia rare angioneurotic edema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders: common: pain in the throat and larynx.

Disorders of the blood system and lymphatic system: Infrequent: thrombocytopenia.

Immune system disorders: allergic reactions often; are extremely rare: anaphylaxis.

Disorders of organs of vision: rarely blurred vision.

Changes in laboratory results: often: deviation liver function tests results, elevated blood CK infrequently positive content analysis of leukocytes in urine.

As with other inhibitors of HMG-CoA reductase inhibitor, in patients taking atorvastatin, there was an increase of serum transaminase activity. These changes were usually mild, transient and did not require intervention or treatment. Clinically significant increase in serum transaminase activity blood (exceeding the upper limit of normal more than 3-fold) were observed in 0.8% of patients taking atorvastatin. This increase should be dose-dependent and was reversible in all patients.

In 2.5% of patients taking atorvastatin, we observed an increase in CPK serum activity that is more than 3 times the upper limit of normal. This coincides with observations when using other HMG-CoA reductase inhibitor in clinical trials. In 0.4% of patients receiving atorvastatin, we observed level exceeding the upper limit of normal in more than 10 times.

Adverse reactions that occurred during clinical trials: a urinary tract infection, diabetes, stroke.

The ASCOT study (Anglo-Scandinavian Cardiac Outcomes Trial), which included 10,305 participants (age range 40-80 years, 19% women; 94.6% white, 2.6% blacks, 1.5% South Asian origin and 1.3% of mixed origin / other) who received treatment Lipitor 10 mg daily (n = 5168) or placebo (n = 5137) the safety and tolerability profile of the drug group patients who received Lipitor was comparable to that of placebo group during follow-up period with a median duration 3.3 years.

The study CARDS (Collaborative Atorvastatin Diabetes Study), which included 2838 patients (age range 39-77 years, 32% of women, 94.3% Caucasians, 2.4% of South Asian origin, 2.3% Afro Caribbean origin and 1% others) with diabetes II type diabetes treated with drug Lipitor 10 mg per day (n = 1428) or placebo (n = 1410) was not observed any difference in the overall incidence of adverse reactions or serious adverse reactions between groups treatment during the period of follow-up for a median of and 3.9 years. No cases of rhabdomyolysis have been reported.

In a study of TNT (Treating to New Targets Study / Research), which included 10,001 patients (age range 29-78 years, 19% women; 94.1% white, 2.9% blacks, 1.0% of representatives Mongoloid races and 2,0% others) with clinically significant coronary artery disease who received Lipitor 10 mg per day (n = 5006) or Lipitor 80 mg per day (n = 4995) were observed more serious adverse reactions and cases of drug discontinuation due to adverse reactions in patients receiving high doses of atorvastatin (92, 1.8%, 4 97, 9.9% respectively) compared with the group of patients treated with low dose (69 1.4% 404 8.1%, respectively) during the period of follow-up with a median duration of 4.9 years .Sustained elevated levels of transaminase (3 times or more higher than the upper limit of normal range, twice 4-10 days) were observed in 62 (1.3%) patients who received atorvastatin 80 mg and 9 (0.2%) subjects receiving atorvastatin 10 mg. Increased CK were generally low, but were higher in patients treated with high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6 (10 times or more higher than the normal upper limit of the range), 0.1%). receiving high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6, 0.1%). receiving high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6, 0.1%).3%) compared with the group of patients treated with low doses of atorvastatin (6 (10 times or more higher than the normal upper limit of the range), 0.1%). Receiving high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6, 0.1%). receiving high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6, 0.1%).3%) compared with the group of patients treated with low doses of atorvastatin (6 (10 times or more higher than the normal upper limit of the range), 0.1%). Receiving high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6, 0.1%). receiving high doses of atorvastatin (13, 0.3%) compared with the group of patients treated with low doses of atorvastatin (6, 0.1%).

The study IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study), which included 8888 patients (age range 26-80 years, 19% of women, 99.3% Caucasians, 0.4% representatives Mongoloid races, 0, 3% blacks, and 0.04% other) who received Lipitor 80 mg / day (n = 4439) or simvastatin 20-40 mg daily (n = 4449), no differences were observed in the total frequency adverse events or serious adverse events between treatment groups during follow-up period with a median continue lnosti 4.8 years.

In SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), which included 4731 patients (age range 21-92 years, 40% of women, 93.3% Caucasians, 3.0% blacks, 0.6% representatives Mongoloid races and 3.1% others) without clinically manifest coronary heart disease, but with a history of stroke or transient ischemic attack (TIA) within the previous 6 months who received Lipitor 80 mg (n = 2365) or placebo (n = 2366) during the follow-up period with a median duration of 4.9 yes, there was a higher incidence of sustained increase in liver transaminases (3 times or more higher than the upper limit of normal range for two days 4-10) in patients treated with atorvastatin (0,9%) compared with the placebo group (0.1%). Cases raising CPK (10 times above the upper limit of normal) were rare but were more common in patients treated with atorvastatin (0.1%) than in the placebo group (0.0%). Diabetes was recorded as adverse reaction in 144 patients (6.1%) in the group receiving atorvastatin, and in 89 patients (3.8%) in the placebo group (see. "Application Features" section).

In post-hoc analysis demonstrated that Lipitor 80 mg reduced the incidence of ischemic stroke (218/2365, 274/2366 9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2, 3 33/2366% vs. 1.4%) compared with placebo. The incidence of fatal hemorrhagic stroke were similar between groups (17 cases in group drug Lipitor compared to 18 events in the placebo group). The incidence of non-fatal hemorrhagic stroke was significantly greater in patients treated with atorvastatin (38 cases lethal hemorrhagic stroke) as compared with the placebo group (16 cases lethal hemorrhagic stroke). It was found that patients who entered the study with hemorrhagic stroke in history,received increased risk of hemorrhagic stroke (7 (16%) Lipitor 2 (4%) placebo).

No significant differences between treatment groups in patient mortality was observed for all reasons: 216 (9.1%) in the group receiving Lipitor 80 mg / day versus 211 (8.9%) in the placebo group. Proportion of patients who have died due to cardiovascular disease, was numerically lower in patients treated with Lipitor 80 mg (3.3%) than in the placebo group (4.1%). Proportion of patients who did not die due to cardiovascular disease, was numerically greater in patients treated with Lipitor 80 mg (5.0%) than in the placebo group (4.0%).

The experience of the drug post-approval.

The following adverse reactions were observed during the post-registration application drug Lipitor. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the use of the drug.

By adverse reactions associated with treatment Lipitor registered after the preparation on the market, regardless of the evaluation causation include reactions: anaphylaxis, angioneurotic edema, bullous rashes (including exudative erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis) , rhabdomyolysis, myositis, fatigue, tendon rupture, non-lethal and lethal hepatic insufficiency, vertigo, depression, peripheral neuropathy and pancreatitis.

There have been rare reports of an immunologically mediated necrotizing myopathy associated with statin use (see. "Features of the application" section).

There have been rare post-marketing report of cognitive disorders (such as memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive disorders have been reported with the use of statins. The reports generally did not belong to the category of serious adverse reactions, and these symptoms were reversible after discontinuation of statin therapy in all the time to onset of symptoms (from 1 day to several years), and the disappearance of symptoms (median duration was 3 weeks).

With some statins have been described such undesirable effects: sexual dysfunction; exceptional cases of interstitial lung disease, especially during long term treatment.

During postmarketing observations reported below are adverse reactions.

Impaired function of the circulatory and lymphatic system: thrombocytopenia.

Violation of the immune system: allergic reactions, anaphylactic shock (including anaphylactic shock).

Violation of metabolism and nutrition: weight gain.

Violation of the nervous system: headache, hypoesthesia, dysgeusia.

Gastrointestinal: abdominal pain.

Dysfunction of hearing and balance: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Impaired function of the musculoskeletal system and connective tissue disorders: arthralgia, back pain.

General disorders: chest pain, peripheral edema, malaise, fatigue.

Changes in laboratory test results: increased activity of alanine aminotransferase, increased blood creatine kinase activity.

Children (10-17 years)

During the 26-week controlled study in men and women after the onset of menses (n = 140, 31% female, 92% white, 1.6% blacks, 1.6% of the representatives of the Mongoloid race and 4.8% of other ethnic groups) the safety and tolerability profile of the drug Lipitor at a dose of 10 mg to 20 mg per day was generally similar to placebo profile (see. the sections "dosage and Administration", "Children").

Shelf life

3 years.

Storage conditions

Special storage conditions are required. Keep out of the reach of children.

Packaging

10 tablets in a blister, 3 blisters in a cardboard box. For tablets of 10 mg and 20 mg of 10 tablets in a blister, the blister 3 or 10 blisters per box.

Category of leave

on prescription.