Liprimar - instructions for use, doses, side effects, contraindications

film sheath: opadrai white YS-1-7040 (contains hypromellose, polyethylene glycol, titanium dioxide, talc), simethicone emulsion (contains simethicone, stearin emulsifier, sorbic acid, water), candelilla wax (only for tablets with dosages of 10 mg, 20 mg and 40 mg).

Description:

Tablets with a dosage of 10 mg: white elliptical tablets, coated with a shell, engraved "10" on one side and "PD 155 "on the other side.

Tablets with a dosage of 20 mg: white elliptical tablets, coated, with engraving "20" on one side and "PD 156 "on the other side.

Tablets with a dosage of 40 mg: white elliptical tablets, coated with a shell, engraved "40" on one side and "PD 157 "on the other side.

Tablets with a dosage of 80 mg: white elliptical tablets, coated with a shell, engraved "80" on one side and "PD 158 "on the other side.

The core of the tablets of all dosages on the fracture is white.

Pharmacotherapeutic group:Hypolipidemic agent - inhibitor of HMG-CoA reductase

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.05 Atorvastatin

Pharmacodynamics:

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into a mevalonate precursor of steroids, including cholesterol.Synthetic lipid-lowering agent.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia and mixed dyslipidemia atorvastatin reduces the concentration in the blood plasma of total cholesterol (cholesterol), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo-B), and very low density lipoprotein cholesterol (XC-VLDLP) and triglycerides (TG), causes an increase in high-density lipoprotein cholesterol (HDL-C) cholesterol.

Atorvastatin reduces the concentration of cholesterol and LDL-C in blood plasma, inhibiting HMG-CoA reductase and the synthesis of cholesterol in the liver and increasing the number of "liver" LDL receptors on the cell surface, which leads to an increase in the capture and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles, causes a marked and persistent increase in the activity of LDL receptors in combination with favorable qualitative changes in LDL-particles, and also reduces the concentration of LDL-C in patients with homozygous hereditary familial hypercholesterolemia, resistant to therapy with other lipid-lowering means.

Atorvastatin in doses from 10 mg to 80 mg reduces the concentration of cholesterol by 30-46%, LDL-C by 41-61%, apo-B by 34-50% and TG by 14-33%. The results of therapy are similar in patients with heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia and mixed hyperlipidemia, including in patients with type 2 diabetes.

In patients with isolated hypertriglyceridemia atorvastatin reduces the concentration of total cholesterol, LDL-C, HDL-VLD, apo-B and TG and increases the concentration of cholesterol-HDL. In patients with disbetalipoproteinemia atorvastatin reduces the concentration of intermediate-density lipoprotein (cholesterol-LDL) cholesterol.

In patients with hyperlipoproteinemia of the type IIa and IIb according to Fredrickson classification, the average value of increasing the concentration of cholesterol-HDL in the treatment with atorvastatin (10-80 mg) compared with the initial index is 5.1-8.7% and dose-independent. There is a significant dose-dependent decrease in the ratio: the total cholesteroln /XC-LHD and LDL-C-HDL-C-cholesterol in 29-44% and 37-55%, respectively. Atorvastatin in a dose of 80 mg significantly reduces the risk of development of ischemic complications and mortality by 16% after a 16-week course, and the risk of re-hospitalization for angina pectoris accompanied by signs of myocardial ischemia,by 26% (study of a decrease in the severity of myocardial ischemia with intensive hypolipidemic therapy (MIRACL)). In patients with different baseline concentrations of LDL-C atorvastatin causes a reduction in the risk of ischemic complications and mortality (in patients with myocardial infarction without a tooth Q and unstable angina in men, women, and in patients younger than 65 years of age). Reducing the concentration in the blood plasma of LDL-C is better correlated with the dose of atorvastatin than with its concentration in the blood plasma. The dose is selected taking into account the therapeutic affect (see section "Method of administration and dose").

The therapeutic effect is achieved 2 weeks after the initiation of therapy, reaches a maximum after 4 weeks, and persists throughout the period of therapy.

Prevention of cardiovascular complications

Atorvastatin 10 mg reduces fatal and nonfatal infarctions in comparison with placebo in patients with hypertension and three or more risk factors

(Anglo-Scandinavian study evaluating the outcome of heart disease (ASCOT-LLA)). Atorvastatin 10 mg reduces the risk of developing the following complications:
	Decrease risk
Coronary complications (ischemic heart disease (CHD) with a fatal outcome and non-fatal myocardial infarction (MI))	36 %
General cardiovascular complications and revascularization procedures	20 %
Common cardiovascular complications	29 %
Stroke (fatal and nonfatal)	26 %

Diabetes

In patients with diabetes, atorvastatin therapy reduces the risk of developing the following cardiovascular complications, regardless of sex, patient age or baseline LDL cholesterol (a study of atorvastatin in type 2 diabetes mellitus (CARDS)):

	Risk reduction
Major cardiovascular complications (fatal and nonfatal myocardial infarction, painless myocardial ischemia, lethal outcome as a result of exacerbation of coronary artery disease, unstable angina, coronary artery bypass, percutaneous transluminal coronary angioplasty, revascularization procedures, stroke)	37 %
IM (fatal and nonfatal MI, painless myocardial ischemia)	42%
Stroke (fatal and nonfatal)	48%

Atherosclerosis

In patients with ischemic heart disease atorvastatin in a dose of 80 mg / day leads to a reduction in the total volume of atheroma by 0.4% for 1.8 months of therapy (an examination of the reverse development of coronary atherosclerosis in the background of intensive lipid lowering therapy (REVERSAL)).

Recurrent stroke

Atorvastatin at a dose of 80 mg per day reduces the risk of repeated fatal or nonfatal stroke in patients who underwent a stroke or transient ischemic attack (TIA) without history of coronary artery disease (a study on the prevention of stroke with intensive lowering of cholesterol concentration (SPARCL)), by 16% compared with placebo. This significantly reduces the risk of major cardiovascular complications and revascularization procedures. Reduction of the risk of cardiovascular disorders with atorvastatin therapy is noted in all patient groups, except for those with patients with primary or repeated hemorrhagic stroke.

Secondary prevention of cardiovascular complications

In patients with ischemic heart disease atorvastatin in a dose of 80 mg, but compared with 10 mg, significantly reduces the development of the following complications (according to the study TNTtreatment until new target concentrations of lipids are reached):

	Atorvastatin 80 mg
Cardiovascular complications (AND \| BR with a fatal outcome and non-fatal MI)	8.7 %
IM is non-fatal, not associated with the procedure	4,9 %
Stroke (fatal and nonfatal)	2,3 %
Hospitalization for congestive heart failure	2,4 %
Coronary artery bypass grafting or other revascularization procedures	13,4%
Documented Angina	10,9%

Pharmacokinetics:

Suction

Atorvastatin is rapidly absorbed after oral administration: the time to reach its maximum concentration (TC_max) in blood plasma is 1-2 hours. In women, the maximum concentration of atorvastatin (C_m_Oh) is 20% higher, and the area under the "concentration-time" curve (AUC) - 10% lower than that of men. The degree of absorption and concentration in the blood plasma increase in proportion to the dose. The bioavailability of atorvastatin in the form of tablets is 95 to 99% compared to atorvastatin in the form of a solution. Absolute bioavailability is about 14%, and systemic bioavailability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic metabolism in the mucosa of the gastrointestinal tract and / or during the "primary passage" through the liver. Eating somewhat reduces the speed and degree of absorption of the drug (by 25% and 9%, respectively, as evidenced by the results of the determination of C_m_Oh and AUC), but the decline XC-LLNP is similar to that when taking atorvastatin on an empty stomach.Despite the fact that after taking atorvastatin in the evening, its concentration in the blood plasma is lower (C_m_Oh and AUC, approximately 30%) than after taking in the morning, the decrease in the concentration of LDL-C is not dependent on the time of day in which the drug is taken.

Distribution

The average volume of atorvastatin distribution is about 381 liters. The connection with plasma proteins is not less than 98%. The ratio of the erythrocyte / plasma content is about 0.25, i.e. atorvastatin poorly penetrates into red blood cells.

Metabolism

Atorvastatin is largely metabolized with the formation of ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. Approximately 70% decrease in the activity of HMG-CoA reductase occurs due to the action of active circulating metabolites. Research results in vitro suggest that isoenzyme CYP3A4 The liver plays an important role in the metabolism of atorvastatin. In favor of this fact is an increase in the concentration of atorvastatin in blood plasma with the simultaneous administration of erythromycin, which is an inhibitor of this isoenzyme. Research in vitro They also showed that atorvastatin is a weak isoenzyme inhibitor CYP3A4. Atorvastatin does not have a clinically significant effect on the concentration in the blood plasma of terfenadine, which is metabolized mainly by isoenzyme CYP3A4, therefore, its significant effect on the pharmacokinetics of other isoenzyme substrates CYP3A4 unlikely (see "Interaction with other medicinal preparations ").

Excretion

Atorvastatin and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism (atorvastatin not subject to severe intestinal hepatic recirculation). The half-life period (T1 / 2) is about 14 hours, while the inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and lasts about 20-30 hours due to their presence. After ingestion, less than 2% of the accepted dose of the drug is found in the urine.

Special patient groups

Elderly patients

The concentrations of atorvastatin in blood plasma in patients older than 65 years are higher (C_max by about 40%, AUC approximately 30%) than in adult patients of a young age.Differences in the efficacy and safety of the drug, or the achievement of the goals of lipid-lowering therapy in elderly patients, as compared with the general population, have not been revealed.

Children

In an 8-week open study, children (aged 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL cholesterol concentration> 4 mmol / L received atorvastatin in the form of chewable tablets of 5 mg or 10 mg or tablets coated with a dose of 10 mg or 20 mg once daily, respectively. The only significant covariate in the pharmacokinetic model of the population receiving atorvastatin, was the mass of the body. The apparent clearance of atorvastatin in children did not differ from that in adult patients with an allometric measurement by body weight. In the range of action of atorvastatin and o-hydroxy-atorvastatin, there was a consistent decrease in LDL-C and cholesterol.

Lack of kidney function

Violation of the kidney function does not affect the concentration of atorvastatin in the blood plasma or its effect on lipid metabolism, so a dose change in patients with impaired renal function is not required (see the section "Method of administration and dose").Studies of the use of atorvastatin in patients with terminal stage of renal failure have not been conducted. Atorvastatin is not excreted during hemodialysis due to intensive binding to blood plasma proteins.

Lack of liver function

The concentration of the drug is significantly increased (C_m_Oh about 16 times, AUC approximately 11 times) in patients with alcoholic liver cirrhosis (class B on the Child-Pugh scale) (see "Contraindications").

Hepatic seizure of all HMG-CoA reductase inhibitors, including atorvastatin, occurs with the participation of the OATP1B1 transporter. In patients with genetic polymorphism SLCO1B1 there is a risk of increasing exposure to atorvastatin, which may lead to an increased risk of rhabdomyolysis. Polymorphism of the gene encoding OATP1B1 (SLCO1B1 p.521S) is associated with an increase in exposure (AUC) atorvastatin by 2.4 times compared with patients without such a genotypic change (p.521TT). Violation of atorvastatin capture by the liver associated with genetic disorders can also be observed in such patients. The possible consequences for effectiveness are unknown.

Interaction with other drugs

The effect of other drugs on the pharmacokinetics of atorvastatin

The drug, dosage	Atorvastatin
	Dose (mg)	Change AUC^&	Change FROM_m_Oh^&
Cyclosporine 5.2 mg / kg / day, a constant dose	10 mg once a day, for 28 days	↑ 8,7	↑ 10,7
Tipranavir 500 mg twice daily / ritonavir 200 mg 2 times a day for 7 days	10 mg, once	↑ 9,4	↑ 8,6
Telaprevir 750 mg every 8 hours, for 10 days	20 mg, once	↑ 7,88	↑10,6
Boceprevir 800 mg 3 times a day, for 7 days	40 mg, once	↑ 2,30	↑ 2,66
Lopinavir 400 mg 2 times per day / ritonavir 100 mg 2 times a day for 14 days	20 mg once daily, for 4 days	↑ 5,9	↑ 4,7
‡ Saquinavir 400 mg twice a day / ritonavir 400 mg twice a day, for 15 days	40 mg once a day, for 4 days	↑ 3,9	↑ 4,3
Clarithromycin 500 mg 2 times a day, for 9 days	80 mg once a day, for 8 days	↑ 4,4	↑ 5,4
Darunavir 300 mg twice daily / ritonavir 100 mg 2 times a day for 9 days	10 mg once a day, for 4 days	↑ 3,4	↑ 2,25
Itraconazole 200 mg once daily for 4 days	40 mg, once	↑ 3,3	↑ 20 %
Fosamprenavir 700 mg twice daily / ritonavir 100 mg 2 times a day, during 14 days	10 mg once a day, for 4 days	↑ 2,53	↑ 2,84
Fosamprenavir 1400 mg 2 times a day, at within 14 days	10 mg once a day, for 4 days	↑ 2,3	↑ 4,04
Nelfinavir 1250 mg 2 times a day, for 14 days	10 mg once a day, for 28 days	1 0,74	12,2
Grapefruit juice, 240 ml once a day *	40 mg, once	↑ 0,37	↑ 0,16
Diltiazem 240 mg once daily, at within 28 days	40 mg, once	↑ 0,51	0
Erythromycin 500 mg 4 times a day, for 7 days	10 mg, once	↑ 0,33	↑ 0,38
Amlodipine 10 mg, once	80 mg, once	↑ 0,15	↓ 0,12
Cimetidine 300 mg 4 times a day, for 2 weeks	10 mg once a day, for 2 weeks	↓ 0,001	↓ 0,11
Colestipol 10 mg twice daily for 28 weeks	40 mg once a day, for 28 weeks	Not is established	↓ 0,26 **
Maalox TC® 30 ml once a day, 13 for 17 days	10 mg once a day, for 15 days	↓ 0,33	↓ 0,34
Efavirenz 600 mg once daily for 14 days	10 mg, for 3 days	↓ 0,41	↓ 0,01
Rifampicin 600 mg once daily for 7 days (simultaneous use)^ẝ	40 mg, once	↑ 0,30	↑ 2,7
Rifampicin 600 mg once a day, for 5 days (separate intake)^ẝ	40 mg, once	↓ 0,80	↓ 0,40
Gemfibrozil 600 mg 2 times a day, for 7 days	40 mg, once	↑ 0,35	↓ less than 1%
Fenofibrate 160 mg once per day, for 7 days	40 mg, once	↑ 0,03	↑ 0,02

& change ratio [(I-B) / B], where I = pharmacokinetic values at time interactions and B = pharmacokinetic values are normal;

* With a significant intake of grapefruit juice (> 750 ml - 1.2 liters per day), a greater increase in AUC (up to 1.5 times) and / or C max (up to 0.71 times) was observed;

** The sample was taken once 8-16 hours after taking the drug;

ẝ Since rifampicin has a dual mechanism of interaction, it is recommended to introduce atorvastatin and rifampicin Simultaneously. A later use of atorvastatin after rifampicin is associated with a significant reduction in the concentration of atorvastatin in the blood plasma.

‡ The doses of saquinavir and ritonavir used in this study differ from the dosages that are used in clinical practice. It should be noted that the increase in exposure to atorvastatin in clinical use is likely to be higher than observed in this study. In this regard, the lowest dose of atorvastatin should be used.

The effect of atorvastatin on the pharmacokinetics of other drugs

Atorvastatin	The drug, used concomitantly with atorvastatin, dosage
	Preparation / Dose (mg)	Change AUC^&	Change FROM_m_Oh^&
80 mg once a day, for 15 days	Antipyrine, 600 mg, once	↑ 0,03	↓ 0,11
80 mg once daily, for 14 days	Digoxin 0.25 mg once daily for 20 days	↑ 0,15	↑ 0,20
40 mg once a day, for 22 days	Oral contraceptives once a day, for 2 months norethindrone 1 mg ethinylestradiol 35 μg	↑ 0,28 ↑ 0,19	↑ 0,23 ↑ 0,30
10 mg, once	Tipranavir 500 mg twice daily / ritonavir 200 mg 2 times a day for 7 days	Does not change	Does not change
10 mg once a day, for 4 days	Fosamprenavir 1400 mg 2 times a day, for 14 days	↓ 0,27	↓ 0,18
10 mg once a day, for 4 days	Fosamprenavir 700 mg twice daily / ritonavir 100 mg 2 times a day for 14 days	Does not change	He is changing

& change ratio [(I-B) / B], where I = pharmacokinetic values during the interaction and B = pharmacokinetic values are normal.

Indications:

Hypercholesterolemia:

- as a supplement to the diet to reduce elevated total cholesterol, LDL-C, apo-B and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (respectively, type IIa and IIb according to Fredrickson's classification), when the response to a diet and other non-pharmacological methods of treatment is insufficient.

- to reduce elevated total cholesterol, LDL cholesterol in adults with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatment methods (eg, LDL-apheresis) or if such treatments are not available.

Prevention of cardiovascular diseases:

- prevention of cardiovascular events in adult patients with a high risk of developing primary cardiovascular events, as a supplement to the correction of other risk factors;

- secondary prevention of cardiovascular complications in patients with ischemic heart disease in order to reduce mortality, myocardial infarction, strokes, repeated hospitalizations for angina pectoris and the need for revascularization.

Contraindications:

Hypersensitivity to any component of the drug.

Active liver disease or increased activity "liver" enzymes in the blood plasma of unclear origin by more than 3-fold compared with the upper limit of normal.

Pregnancy.

Breastfeeding period.

Women of childbearing age who do not use adequate methods of contraception.

Age to 18 years (not enough clinical data on the efficacy and safety of the drug in this age group),except for heterozygous familial hypercholesterolemia (use contraindicated in children under 10 years of age).

Simultaneous application with fusidic acid.

Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:In patients who abuse alcohol; in patients with a history of liver disease.

Patients with risk factors for rhabdomyolysis (renal dysfunction, hypothyroidism, hereditary muscle disorders in a patient in a history or family history, already suffered toxic effects of HMG-CoA reductase inhibitors (statins) or fibrates on muscle tissue, liver disease in the anamnesis and / or patients who consume alcohol in significant quantities, age over 70, situations in which an increase in the concentration of atorvastatin in the blood plasma is expected (for example, interactions with other drug means)).

Pregnancy and lactation:

Lipimar® is contraindicated in pregnancy.

Women of reproductive age during treatment should use adequate methods of contraception.The use of Lipimar® is contraindicated in women of childbearing age who do not use adequate methods of contraception.

There were rare cases of congenital anomalies after the effect of inhibitors of HMG-CoA reductase (statins) on the fetus in utero. In animal studies, a toxic effect on reproductive function was shown. Lipimar® is contraindicated during breastfeeding. It is not known whether atorvastatin with breast milk. If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped in order to avoid the risk of adverse events in infants.

Dosing and Administration:

Inside. Take at any time of the day, regardless of food intake.

Before starting treatment with Lipimar®, you should try to control hypercholesterolemia with diet, exercise and weight reduction in patients with obesity, as well as therapy for the underlying disease.

When appointing the drug, the patient should recommend a standard hypocholesterolemic diet, which he must adhere to throughout the period of therapy.

The dose of the drug varies from 10 mg to 80 mg once a day and titrated, taking into account the concentration of LDL-C, the purpose of therapy and individual response to the therapy.

The maximum daily dose of the drug is 80 mg.

At the beginning of treatment and / or while increasing the dose of Lipimar® it is necessary to monitor the concentration of plasma lipids every 2-4 weeks and adjust the dose accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

For most patients, the recommended dose of Lipimar® is 10 mg once a day; The therapeutic effect manifests itself within 2 weeks and usually reaches a maximum after 4 weeks. With prolonged treatment, the effect persists.

Homozygous familial hypercholesterolemia

In most cases, appoint 80 mg once a day (reducing the concentration of LDL-C in 18-45%).

Dechterozygous familial hypercholesterolemia

The initial dose is 10 mg per day. The dose should be selected individually and the dose should be assessed every 4 weeks, with a possible increase to 40 mg per day. Then either the dose can be increased to a maximum of 80 mg per day, or it is possible to combine bile acid sequestrants with atorvastatin at a dose of 40 mg per day.

Prevention of cardiovascular diseases

In studies of primary prevention, the dose of atorvastatin was 10 mg per day. It may be necessary to increase the dose in order to achieve the LDL cholesterol values, which correspond to the current recommendations.

Use in children from 10 to 18 years with heterozygous familial hypercholesterolemia

The recommended initial dose is 10 mg once a day. The dose can be increased to 20 mg per day depending on the clinical effect. The experience of using a dose of more than 20 mg (corresponding to a dose of 0.5 mg / kg) is limited.

The dose of the drug must be titrated depending on the purpose of lipid-lowering therapy. Correction of the dose should be carried out at intervals of 1 every 4 weeks or more.

Insufficiency of liver function

If liver function is insufficient, the dose of Lipimar® should be reduced, with the regular monitoring of the activity of "liver" transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (AL'G).

Lack of kidney function

Violation renal function does not affect the concentration of atorvastatin in the blood plasma or the degree of decrease in the concentration of LDL-C, so no dose adjustment is required.

Elderly patients

Differences in the therapeutic efficacy and safety of Lipimar® in elderly patients were not found in comparison with the general population, no dose adjustment is required (see the section "Pharmacokinetics").

Use in combination with other medicines

If necessary, combined with cyclosporine, telaprevir, or a combination of tipranavir / ritonavir, the dose of the drug Leethe mayor^® should not exceed 10 mg / day (see section "Special instructions").

Caution should be exercised and the lowest effective dose of atorvastatin should be used when combined with HIV protease inhibitors, hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole.

Side effects:

Lymaris^® usually well tolerated; adverse reactions are usually mild and transient.

Adverse reactions are distributed according to the following classification: often - ≥ 1/100 to <1/10, infrequently - ≥ 1/1000 to <1/100, rarely - ≥ 1/10000 to <1/1000, very rarely - <1/10000. unknown - can not be estimated based on available data.

Disorders of the psyche:

Infrequently - "nightmarish" dreams, insomnia.

Unknown - depression.

Impaired nervous system:

Often - headache.

Infrequently - dizziness, paresthesia, hypoesthesia, a violation of taste perception, amnesia.

Rarely - peripheral neuropathy.

Unknown - loss or loss of memory.

Disorders from the side of the organ of vision:

Infrequently - the appearance of "shroud" before the eyes.

Rarely - visual impairment.

Hearing disorders and labyrinthine disturbances:

Infrequently - noise in ears.

Rarely - loss of hearing.

Disturbances from the respiratory system, chest and mediastinal organs:

Often - Sore throat, nosebleed.

Unknown - single cases of interstitial lung disease (usually with prolonged use).

Disturbances from the digestive tract:

Often - constipation, flatulence, indigestion, nausea, diarrhea.

Infrequently - vomiting, abdominal pain, belching, pancreatitis, discomfort in the abdomen.

Disorders from the liver and bile ducts:

Infrequently - Hepatitis.

Rarely - cholestasis.

Rarely - secondary renal failure.

Disturbances from the skin and subcutaneous tissues:

It is unclean - urticaria, skin itching, rashes, alopecia.

Rarely - angioneurotic edema, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Disturbances from the musculoskeletal and connective tissue:

Often - myalgia, arthralgia, pain in the extremities, muscle cramps, swelling of the joints, back pain, musculoskeletal pain.

Infrequently - pain in the neck, muscle weakness.

Rarely - myopathy, myositis, rhabdomyolysis, tendopathy (in some cases with a rupture of the tendon).

Unknown - immuno-mediated necrotizing myopathy.

Violations of the genitals and breast:

Infrequently - impotence.

Rarely - gynecomastia.

General disorders and disorders at the site of administration:

Infrequently - malaise, asthenic syndrome, chest pain, peripheral edema, increased fatigue, fever.

Laboratory and instrumental data:

Often - deviation from the norm of the results of "liver" tests (ACT and ALT), an increase in the activity of serum creatine phosphokinase (CKF).

Infrequently - leukocyturia.

Unknown - increase in the concentration of glycosylated hemoglobin (HbAl).

Immune system disorders:

Often - allergic reactions.

Rarely - anaphylaxis.

Disorders from the metabolism and nutrition:

Often - hyperglycemia.

Infrequently - hypoglycemia, weight gain, anorexia.

Unknown - diabetes mellitus: the frequency of development depends on the presence or absence of risk factors (fasting blood glucose> 5.6 mmol / L, body mass index (BMI)> 30 kg / m, elevated triglyceride concentration, history of arterial hypertension).

Infringements from bodies of a hemopoiesis:

Rarely - thrombocytopenia.

Infections and infestations:

Often - Nasopharyngitis.

Children

Adverse reactions associated with the use of Liprimar® in the amount did not differ from the reactions on the background of taking placebo. The most frequent reactions, regardless of the frequency of the control, were infections.

Overdose:

Specific antidote for the treatment of overdose with Lipimar^® no. In case of overdose, symptomatic treatment should be performed as needed. It is necessary to conduct functional liver tests and monitor the activity of CK. Since the drug actively binds to blood plasma proteins, hemodialysis is ineffective.

Interaction:

During treatment with HMG-CoA reductase inhibitors, while using cyclosporine, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day) or inhibitors of the isoenzyme CYP3A4 (eg, erythromycin, clarithromycin, antifungal agents - azole derivatives) increases the risk of myopathy (see section "Special instructions").

Inhibitor inhibitors CYP3A4

Because the atorvastatin is metabolized by isoenzyme CYP3A4, combined use of atorvastatin with isozyme inhibitors CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of potentiation is determined by the variability of the effect on the isoenzyme CYP3A4.

It was found that potent inhibitors of isoenzyme CYP3A4 lead to a significant increase in the concentration of atorvastatin in blood plasma. If possible, simultaneous use of potent inhibitors of isoenzyme should be avoided CYP3A4 (eg, ciclosporin, telithromycin, clarithromycin, delavirdine, styipentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, and etc.). If simultaneous administration of these drugs is necessary, consideration should be given to initiating therapy with a minimal dose, and the possibility of reducing the maximum dose of atorvastatin should be evaluated.

Moderate inhibitors of isoenzyme CYP3A4 (eg, erythromycin, diltiazem, verapamil and fluconazole) can lead to an increase in the concentration of atorvastatin in the blood plasma. Against the background of simultaneous use of inhibitors of HMG-CoA reductase (statins) and erythromycin, there was an increased risk of myopathy. Studies of the interaction of amiodarone or verapamil and atorvastatin have not been conducted. It is known that u amiodarone and verapamil inhibit isoenzyme activity CYP3A4 and the simultaneous use of these drugs with atorvastatin may lead to an increased exposure to atorvastatin. In this regard, it is recommended to reduce the maximum dose of atorvastatin and to conduct appropriate monitoring of the patient's condition while using with moderate isoenzyme inhibitors CYP3A4. The control should be performed after the initiation of therapy and against the background of a change in the dose of the inhibitor.

Inhibitors of transport protein OATP1B1

Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. Inhibitors of OATP1B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin. Thus, the simultaneous use of atorvastatin 10 mg and cyclosporine at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in blood plasma by 7.7 times (see section "Method of administration and dose"). Effect of inhibition of hepatic transport function on the concentration of atorvastatin in hepatocytes is unknown. In the event that it is impossible to avoid the simultaneous use of such drugs, it is recommended to reduce the dose and control the effectiveness of therapy.

Gemfibrosil / Fibrates

Against the background of the use of fibrates in monotherapy, undesirable reactions, including rhabdomyolysis, concerning the musculoskeletal system were periodically noted. The risk of such reactions increases with the simultaneous use of fibrates and atorvastatin. If simultaneous application of these drugs can not be avoided, then a minimum effective dose of atorvastatin should be used, and regular monitoring of patients' condition should be carried out.

Ezetimibe

The use of ezetimibe is associated with the development of unwanted reactions, including rhabdomyolysis, from the musculoskeletal system. The risk of such reactions increases with simultaneous use of ezetimibe and atorvastatin. Careful observation is recommended for such patients.

Erythromycin / clarithromycin

With simultaneous use of atorvastatin and erythromycin (500 mg 4 times per day) or clarithromycin (500 mg twice a day), inhibitors of isoenzyme CYP3A4, an increase in the concentration of atorvastatin in the blood plasma was observed (see section "Special instructions").

Inhibitors of proteases

The simultaneous use of atorvastatin with protease inhibitors, known as isoenzyme inhibitors CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

Diltiazem

Joint use of atorvastatin in a dose of 40 mg with diltiazem at a dose of 240 mg, leads to an increase in the concentration of atorvastatin in blood plasma.

Cimetidine

Clinically significant interaction of atorvastatin with cimetidine was not detected.

Itraconazole

Simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole at a dose of 200 mg conducted to an increase in the value AUC atorvastatin.

Grapefruit juice

Because grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4, its excessive consumption (more than 1.2 liters per day) can cause an increase in the concentration of atorvastatin in the blood plasma.

Inductors of isoenzyme CYP3A4

Combined use of atorvastatin with isoenzyme inducers CYP3A4 (eg, efavirenz, rifampicin, or preparations of St. John's wort) can lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (isoenzyme inducer CYP3A4 and inhibitor of hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin results in a significant decrease in the concentration of atorvastatin in blood plasma. However, the effect of rifampin on atorvastatin concentrations in hepatocytes is unknown and if the simultaneous use can not be avoided, it is necessary to carefully monitor the effectiveness of this combination during therapy.

Antacids

Simultaneous ingestion of the suspension,containing magnesium hydroxide and aluminum hydroxide, reduced the concentration of atorvastatin in blood plasma by approximately 35%. but the degree of decrease in concentration XC-LLNP while not changing.

Fenazone

Atorvastatin does not affect the pharmacokinetics of phenazone, therefore interaction with other drugs metabolized by the same isoenzymes of cytochrome is not expected.

Kolestypol

With the simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased by about 25%; However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone. Digoxin

With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increased by about 20%. Patients receiving digoxin in combination with atorvastatin, require appropriate monitoring.

Azithromycin

With the simultaneous use of atorvastatin 10 mg once a day and azithromycin 500 mg once a day, the concentration of atorvastatin in the blood plasma did not change.

Oral contraceptives

With simultaneous use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, there was a significant increase AUC norethisterone and ethinyl estradiol by about 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

Terfenadine

With the simultaneous use of atorvastatin and terfenadine, clinically significant changes in the pharmacokinetics of terfenadine have not been identified.

Warfarin

In a clinical study in patients on regular treatment with warfarin while taking atorvastatin at a dose of 80 mg per day, a small prothrombin time increase of approximately 1.7 seconds during the first 4 days of therapy was observed. The indicator returned to normal within 15 days of therapy with atorvastatin. Despite the fact that only in rare cases there was a significant interaction affecting the anticoagulant function, prothrombin time should be determined before the initiation of therapy with atorvastatin in patients receiving coumarin anticoagulant therapy and often enough during therapy to prevent a significant change in prothrombin time.Once a stable prothrombin time is noted, it can be monitored as recommended for patients receiving coumarin anticoagulants. When changing the dose of atorvastatin or stopping therapy, prothrombin time should be monitored according to the same principles as described above. Therapy with atorvastatin was not associated with the development of bleeding or changes in prothrombin time in patients who did not receive anticoagulant treatment.

Colchicine

Despite the fact that no simultaneous application of colchicine and atorvastatin has been performed, there are reports of myopathy developing with this combination. Care should be taken when using atorvastatin and colchicine concomitantly.

Amlodipine

With simultaneous use of atorvastatin in a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin did not change in the equilibrium state.

Fusidic acid

During postmarketing studies, there have been cases of rhabdomyolysis in patients taking both fusidic acid and atorvastatin. Patients should be carefully monitored and accounted for, that temporary cancellation of atorvastatin may be advisable.

Other concomitant therapy

In clinical trials atorvastatin were used in combination with antihypertensive agents and estrogens within the framework of hormone replacement therapy. There were no signs of clinically significant undesirable interaction; studies of interaction with specific drugs have not been conducted.

In addition, there was an increase in the concentration of atorvastatin when used simultaneously with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole. Caution should be exercised when these drugs are used concomitantly, and the lowest effective dose of atorvastatin should be used.

Special instructions:

Effects on the liver

As with the use of other hypolipidemic drugs in this class, a moderate increase (more than 3 times the upper limit of the norm) of the activity of "liver" transaminases ACT and ALT.A persistent increase in serum activity of "liver" transaminases (more than 3 times compared with the upper limit of normal) was observed in 0.7% of patients receiving Lipimar^®. The frequency of such changes with the use of the drug in doses of 10 mg, 20 mg, 40 mg and 80 mg were 0.2%, 0.2%, 0.6% and 2.3%, respectively. Increased activity of "liver" transaminases usually was not accompanied by jaundice or other clinical manifestations. When the dose of Lipimar® was reduced, the activity of "hepatic" transaminases returned to the initial level temporarily or completely. Most patients continued to receive Lipimar^® in a reduced dose without any clinical consequences.

Before the start of therapy, after 6 weeks and 12 weeks after the start of Lipimar® or after increasing its dose, it is necessary to monitor the liver function parameters. The liver function should also be monitored when clinical signs of liver damage. In the case of increased activity of "liver" transaminases, ALT and ACT should be monitored until it is normalized. If the increase in activity ACT or ALT more than 3 times compared with the upper limit of the norm is maintained, it is recommended to reduce the dose or cancel the drug Lipimar® (see section "Side effect").

Lipromar® should be used with caution in patients who consume significant amounts of alcohol and / or have a history of liver disease. Active liver disease or constantly increased activity of "hepatic" transaminases of blood plasma of unknown origin is a contraindication to the use of the drug Lipimar^® (see section "Contraindications").

Action on skeletal muscles

In patients receiving Liprim®, myalgia was noted (see section "Side effect"). Myopathy should be diagnosed in patients with diffuse myalgia, muscle soreness or weakness, and / or a marked increase in CKK activity (more than 10 times the upper limit of normal). Therapy with Lipimar® should be discontinued in the event of a marked increase in the activity of CK in the presence of confirmed myopathy or suspected development. The risk of myopathy in the treatment with drugs of this class increased with the simultaneous use of potent inhibitors of the isoenzyme CYP3A4 (eg, cyclosporine, telithromycin, clarithromycin, delavirdine, styipentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir and others), gemfibrozil or other fibrates, bocetrevir, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g / day), ezetimibe, azole antifungal agents, colchicine, telaprevir, boceprevir or a combination of tipranavir / ritonavir. Many of these drugs inhibit isoenzyme mediated metabolism CYP3A4, and / or the transport of drugs. It is known that isoenzyme CYP3A4 - the main isoenzyme of the liver involved in the biotransformation of atorvastatin. Applying Lipimar® in combination with fibrates, erythromycin, immunosuppressants, azole antifungal agents or nicotinic acid in lipid-lowering doses (more than 1 g / day), the physician should carefully weigh the expected benefit of treatment and the possible risk. Patients should be observed regularly to identify pain or weakness in the muscles, especially during the first months of therapy and during the period of increasing the dose of any of these agents.If combination therapy is required, consideration should be given to the possibility of using lower initial and maintenance doses of the above means. Temporary cancellation of atorvastatin may be appropriate during treatment with fusidic acid. In such situations, periodic monitoring of the activity of CK can be recommended, although such monitoring does not prevent the development of severe myopathy (see section "Interaction with other drugs").

Before treatment begins

Atorvastatin should be administered with caution to patients with factors predisposing to the development of rhabdomyolysis. Control of the activity of CKF should be performed in the following cases prior to initiation of therapy with atorvastatin:

- impaired renal function,

- hypothyroidism,

- hereditary muscle disorders in a patient in an anamnesis or in a family anamnesis,

- already transferred toxic effect of inhibitors of HMG-CoA reductase (statins) or fibrates on muscle tissue,

- liver disease in the history and / or patients who consume alcohol in significant quantities,

- in patients over the age of 70 years should assess the need for control of CK, given that these patients already have factors predisposing to the development of rhabdomyolysis,

- situations in which an increase in the concentration of atorvastatin in the blood plasma, such as interactions with other drugs, is expected (see section "Interaction with Other Drugs").

In such situations, the risk / benefit ratio should be assessed and the patient's medical condition monitored.

In the case of a significant increase in the activity of CK (more than 5 times higher than the upper limit of the norm), do not start therapy with atorvastatin.

When using Lipimar preparation^® as well as other inhibitors of HMG-CoA reductase, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described. The risk factor for rhabdomyolysis may be a previous impairment of kidney function. Such patients should be provided with more careful monitoring of the condition of the musculoskeletal system. When symptoms of possible myopathy appear or if there are risk factors for developing renal failure against rhabdomyolysis (for example, severe acute infection, arterial hypotension, extensive surgery, trauma, metabolic, endocrine and water-electrolyte disorders, uncontrolled convulsions) therapy with Lipimar® should be temporarily discontinued or completely abolished.

Attention! Patients should be warned that they should seek medical attention immediately if unexplained pain or muscle weakness occurs, especially if they are accompanied by a malaise or fever.

Prevention of stroke by actively lowering cholesterol concentration (SPARCL)

In a retrospective analysis of the stroke subtypes in patients without ischemic heart disease who had recently undergone a stroke or transient ischemic attack in the initial stage who received atorvastatin at a dose of 80 mg, there was a higher incidence of hemorrhagic stroke, compared to patients receiving placebo. The increased risk was particularly noticeable in patients with a history of hemorrhagic stroke or lacunar infarction at the beginning of the study. In this group of patients, the benefit / risk ratio for atorvastatin at a dose of 80 mg it is not sufficiently defined, therefore, before starting therapy, the possible risk of hemorrhagic stroke in such patients should be carefully assessed.

After a special analysis of a clinical trial involving 4,731 patients without IHD who underwent a stroke or transient ischemic attack (TIA) during the previous 6 months that were assigned atorvastatin 80 mg / day, revealed a higher incidence of hemorrhagic strokes in the atorvastatin 80 mg group compared with the placebo group (55 in the atorvastatin group versus 33 in the placebo group). Patients with hemorrhagic stroke at the time of enrollment had a higher risk for recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group). However, in patients who received atorvastatin 80 mg / day was less than any type of stroke (265 vs. 311) and fewer cardiovascular events (123 vs. 204).

Diabetes

Some data confirm that inhibitors of HMG-CoA reductase (statins), as a class, can lead to an increase in the concentration of glucose in the blood plasma, and in some patients with a high risk of developing diabetes can develop a state of hyperglycemia, requiring correction as in diabetes mellitus. However, this risk does not exceed the benefit of therapy with HMG-CoA reductase inhibitors (statins) in terms of vascular risks, so this can not be the reason for the abolition of therapy.Patients at risk (glucose concentration in of fasting blood from 5.6 to 6.9 mmol / l, BMI> 30 kg / m², elevated plasma triglyceride concentration, hypertension) should be under medical supervision, including monitoring of biochemical blood parameters, in accordance with local recommendations.

Interstitial lung disease

On the background of therapy with some inhibitors of HMG-CoA reductase (statins), especially in the foyer of long-term therapy, single cases of interstitial lung disease were noted. There may be shortness of breath, an unproductive cough, and a deterioration in overall health (fatigue, weight loss and fever). In case the patient is suspected of interstitial lung disease, it should be canceled therapy atorvastatin.

Endocrine function

When using inhibitors of HMG-CoA reductase (statins), including atorvastatin, there were cases of increased glycosylated hemoglobin (HbAl) and fasting plasma glucose concentration. However, the risk of hyperglycemia is lower than the degree of reduction in the risk of vascular complications when taking HMG-CoA reductase inhibitors (statins).

Effect on the ability to drive transp. cf. and fur:Data on the effect of Lipimar® on the ability to drive vehicles and engage in potentially hazardous activities that require increased concentration and speed of psychomotor reactions are not. However, given the possibility of developing dizziness, care should be taken when performing the listed activities.

Form release / dosage:

Tablets, film-coated 10 mg, 20 mg, 40 mg and 80 mg.

Packaging:

7 or 10 tablets in a blister of opaque polypropylene / PVC and aluminum foil.

2, 4, 5 or 8 blisters for 7 tablets;

3, 5 or 10 blisters of 10 tablets in a cardboard box, together with instructions for use.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 of the year.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014014 / 01

Date of registration:02.06.2009

The owner of the registration certificate:Pfizer Manufakchuring Deutschland GmbH Pfizer Manufakchuring Deutschland GmbH Germany

Manufacturer: & nbsp

PFIZER PHARMACEUTICALS, LLC Puerto Rico

PFIZER IRELAND PHARMACEUTICALS Ireland

Representation: & nbspPfizer LtdPfizer LtdUSA

Information update date: & nbsp27.12.2015

Illustrated instructions

Instructions

Lipimar® (Liprimar®)