Atorvastatin - instructions for use, dose, side effects, contraindications

Excipients (core): lactose monohydrate (sugar milk) - 43.71 mg, microcrystalline cellulose - 15.00 mg, sodium lauryl sulfate - 0.50 mg, povidone-K25 - 2.50 mg, calcium carbonate - 17.50 mg, sodium carboxymethyl starch - 4, 00 mg, magnesium stearate - 0.95 mg.

Auxiliary substances (shell): hypromellose - 1.71 mg, macrogol-4000 - 0.45 mg, titanium dioxide - 0.84 mg.

Tablet 20.0 mg:

Active substance: atorvastatin calcium trihydrate 21.69 mg, calculated as atorvastatin 20.00 mg.

Excipients (core): lactose monohydrate (milk sugar) - 87.41 mg, microcrystalline cellulose - 30.00 mg, sodium lauryl sulfate - 1.00 mg, povidone-K25 - 5.00 mg, calcium carbonate 35.00 mg, sodium carboxymethyl starch 8, 00 mg, magnesium stearate - 1.90 mg.

Auxiliary substances (shell): hypromellose - 3,42 mg, macrogol-4000 - 0,90 mg, titanium dioxide - 1,68 mg.

Tablet 40.0 mg:

Active substance: Atorvastatin calcium trihydrate 43.37 mg, calculated as atorvastatin 40.00 mg.

Excipients (core): lactose monohydrate (sugar milk) - 174.83 mg, microcrystalline cellulose - 60.00 mg, sodium lauryl sulfate - 2.00 mg, povidone-K25 - 10.00 mg, calcium carbonate - 70.00 mg, sodium carboxymethyl starch - 16.00 mg, magnesium stearate - 3.80 mg.

Auxiliary substances (shell): hypromellose - 6.84 mg, macrogol-4000 - 1.80 mg of titanium dioxide - 3.36 mg.

Tablet 80.0 mg:

Active substance: Atorvastatin calcium trihydrate 86.74 mg, calculated as atorvastatin 80.00 mg.

Excipients (core): lactose monohydrate (sugar milk) - 131.46 mg, microcrystalline cellulose - 60.00 mg, sodium lauryl sulfate - 2.00 mg, povidone-K25 - 10.00 mg, calcium carbonate - 70.00 mg, sodium carboxymethyl starch - 16, 00 mg, magnesium stearate - 3.80 mg.

Auxiliary substances (shell): hypromellose - 6.84 mg, macrogol-4000 - 1.80 mg, titanium dioxide - 3.24 mg, ferric oxide red oxide - 0.120 mg.

Description:Tablets with a dosage of 10 mg, 20 mg, 40 mg round biconvex, covered with a film coat of white or almost white color. Tablets with a dosage of 80 mg round biconvex, covered with a film coat from pink to light pink. At the break the core is white.

Pharmacotherapeutic group:Lipid-lowering agent - inhibitor of GM G-CoA reductase

ATX: & nbsp

Atorvastatin

Pharmacodynamics:

Synthetic lipid-lowering agent. Atorvastatin - a selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase (HMG-CoA reductase), a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into the mevalonate precursor of sterols, including cholesterol.

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 (cholesterol-VLDL) and triglycerides (TG), causes an unstable increase concentration of high-density lipoprotein cholesterol (HDL-C).

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the 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 increased 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 total cholesterol by 30-46%, LDL-cholesterol 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 mellitus.

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. In patients with type IIa and IIb hyperlipoproteinemia according to Fredrickson, the average increase in 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 reduction in the ratio: total cholesterol / HDL-C and LDL-C-HDL-C cholesterol by 29-44% and 37-55%, respectively.

Atorvastatin 80 mg significantly reduces the risk 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 is 26%. In patients with different baseline concentrations of LDL-C atorvastatin reduces the risk of ischemic complications and mortality (in patients with myocardial infarction without a tooth and unstable angina, as well as in men and 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 the drug than with its concentration in the blood plasma. The dose is selected taking into account the therapeutic effect (see section "Method of administration and dose"). Therapeutic effect is achieved after 2 week after initiation of therapy, reaches a maximum after 4 weeks and persists during the entire period of therapy.

Atorvastatin 10 mg reduces the fatal and nonfatal outcome of coronary heart disease (CHD) compared with placebo in patients with hypertension with three or more risk factors.

Pharmacokinetics:

Suction

Atorvastatin is rapidly absorbed after oral administration: the time to reach it maximum concentration (TC_max) in blood plasma - 1-2 hours In women, the maximum concentration of atorvastatin (C_max) is 20% higher, and the area under the concentration-time curve (AUC) is 10% lower than that of men. The degree of absorption and concentration in the blood plasma increase in proportion to the dose. Absolute bioavailability is about 14%, and the 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_max and AUC), however, a decrease in LDL-C is similar to that of fasting atorvastatin. Despite the fact that after taking atorvastatin in the evening, its concentration in the blood plasma is lower (C_max and AUC, approximately 30%) than after taking in the morning, the decrease in the concentration of LDL-C is independent of 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 products β-oxidation. 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 the isoenzyme CYP3A4 of 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 inhibitor of the isoenzyme CYP3A4. Atorvastatin does not have a clinically significant effect on the concentration in the blood plasma of terfenadine, which is metabolized mainly by the isoenzyme CYP3A4, so its significant effect on the pharmacokinetics of other substrates of the CYP3A4 isoenzyme is unlikely (see "Interactions with Other Drugs").

Excretion

Atorvastatin and its metabolites are excreted mainly through the intestines with bile after hepatic and / or extrahepatic metabolism (atorvastatin not subject to severe intestinal hepatic recirculation). The half-life (T_1/2) is about 14 hours, while the inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of the circulating metabolites and remains about 20-30 hours due to their presence.After ingestion, less than 2% of the dose is detected in urine.

Special patient groups

Elderly patients

The concentrations of atorvastatin in the blood plasma of patients older than 65 years are higher (C_max approximately 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 to the general population, have not been revealed.

Children

Studies of the pharmacokinetics of the drug in children have not been conducted.

Lack of kidney function

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

Lack of liver function

The concentration of atorvastatin is significantly increased (C_max approximately 16 times, AUC approximately 11 times) in patients with alcoholic cirrhosis of the liver (class B according to the Child-Pugh classification) (see the section "Contraindications").

Indications:

Primary hypercholesterolemia (heterozygous family and non-family hypercholesterolemia (type IIa according to Fredrickson classification);
combined (mixed) hyperlipidemia (type IIa and IIb according to Fredrickson classification);
dysetalopoproteinemia (type III according to Fredrickson's classification) (as a supplement to the hypocholesterol diet);
family endogenous hypertriglyceridemia (type IV according to Fredrickson classification), resistant to hypocholesterol diet;
homozygous familial hypercholesterolemia with insufficient effectiveness of diet therapy and other non-pharmacological methods of treatment; Primary prophylaxis of cardiovascular complications in patients without clinical signs of coronary heart disease, but having several risk factors for its development: age over 55, nicotine dependence, arterial hypertension, diabetes mellitus, low concentrations of HDL-C in blood plasma, genetic predisposition, in including dyslipidemia;
secondary prevention of cardiovascular complications in patients with coronary heart disease in order to reduce the overall mortality rate, myocardial infarction, stroke,repeated hospitalization for angina pectoris and the need for revascularization procedures.

Contraindications:

Hypersensitivity to any component of the drug.

Active liver disease or increased activity of "hepatic" transaminases in blood plasma of unknown origin more than 3 times compared with the upper limit of the norm (VGN).

Age to 18 years (not enough clinical data on the efficacy and safety of the drug in this age group).

The use in women of reproductive age, not using adequate methods of contraception.

Pregnancy, the period of breastfeeding.

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:

Alcohol abuse, liver disease in history, severe water-electrolyte balance disorders, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgical interventions, injuries, skeletal muscle diseases, diabetes mellitus.

Pregnancy and lactation:

Atorvastatin is contraindicated in pregnancy and during breastfeeding.

Women of reproductive age during treatment should use adequate means of contraception. Atorvastatin can be prescribed to women of reproductive age only if the probability of pregnancy is very low, and the patient is informed of the possible risk of treatment for the fetus. Because cholesterol and substances synthesized from cholesterol are important for the development of the fetus, the potential risk of inhibiting HMG-CoA reductase exceeds the use of atorvastatin during pregnancy. In the case of pregnancy diagnosis, the drug should be discontinued as soon as possible, and the patient is warned about the potential risk to the fetus.

It is not known whether atorvastatin with breast milk. Given the potential for adverse effects in infants, if necessary, use during lactation should decide the issue of termination of breastfeeding.

Dosing and Administration:

Inside. Take at any time of the day, regardless of food intake. Before starting treatment, the drug should try to achieve control of hypercholesterolemia with diet, exercise and weight loss in obese patients, 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 is titrated taking into account the initial concentration of LDL-C, the purpose of therapy and the individual effect on the therapy.

The maximum daily dose of the drug for a single dose is 80 mg.

At the beginning of treatment and / or during a dose increase, every 2-4 week to control the concentration of lipids in the blood plasma and the corresponding adjust the dose of the drug.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

For the majority of patients - 10 mg once a day; The therapeutic effect is manifested during 2 weeks of therapy and usually reaches a maximum within 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%).

Lack of liver function

If liver function is insufficient, the dose of the drug should be reduced, with the regular monitoring of the activity of "liver" transaminases: aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

Lack of kidney function

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

Elderly patients

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

Use in combination with other medicines

If a simultaneous application with cyclosporine is required, the dose of the drug should not exceed 10 mg per day (see section "Special instructions").

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

Side effects:

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0,01%,but less than 0.1%; very rarely (including individual messages) - less than 0.01%, frequency unknown - can not be calculated from available data.

From the side of the blood and lymphatic system: rarely - Thrombocytopenia.

From the immune system: often - allergic reactions; rarely - angioedema; anaphylactic shock.

From the nervous system: often - headache; infrequently - dizziness, paresthesia, hypesthesia, amnesia, a violation of taste sensations, insomnia, "nightmarish" dreams; rarely - peripheral neuropathy; frequency unknown - Depression.

From the side of the organ of vision: infrequently - decreased vision clarity; rarely - impaired visual perception.

From the side of the hearing organ and labyrinthine disorders: infrequently - "noise in ears, rarely - loss of hearing.

From the respiratory system, chest and mediastinum: often - Nasopharyngitis, epistaxis, pain in the pharyngeal region; frequency unknown - interstitial lung disease.

From the digestive tract: often - Nausea, flatulence, constipation, indigestion, diarrhea; infrequently - belching, vomiting, abdominal pain, pancreatitis.

From the liver and bile ducts: infrequently - Hepatitis; rarely - cholestasis; rarely - hepatic insufficiency, cholestatic jaundice.

From the skin and subcutaneous tissues: infrequently - Alopecia, skin rash, itching, hives; rarely - bullous dermatitis, erythema multiforme; rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

From the musculoskeletal system and connective tissue: often - myalgia, arthralgia, pain in the limbs, muscle spasm, back pain, "swelling" of the joints; infrequently - pain in the neck, muscle weakness; rarely - myopathy, myositis, rhabdomyolysis, tendonopathy, complicated by a rupture of the tendon; frequency unknown - immuno-mediated necrotizing myopathy.

From the side of the reproductive system: very rarely - gynecomastia; frequency unknown - impotence.

Common violations: infrequently - asthenia, weakness, chest pain, peripheral edema, fever, increased fatigue, weight gain, anorexia.

Laboratory indicators: often - hyperglycemia, increased activity of creatine phosphokinase in the blood serum; infrequently - leukocyturia, hypoglycemia, increased activity of "liver" transaminases.

When using inhibitors of HMG-CoA reductase (statins), including atorvastatin, there were cases of increased glycosylated hemoglobin

Overdose:

There is no specific antidote for overdose treatment with the drug.

In case of an overdose, symptomatic treatment should be performed as soon as possible. necessity. Control of liver function and activity of creatine phosphokinase (CK) in the blood serum. Since the drug actively binds to plasma proteins hemodialysis is ineffective.

Interaction:

The risk of myopathy during treatment with HMG-CoA reductase inhibitors increases with simultaneous use of cyclosporine, fibrates, erythromycin, clarithromycin, antifungal agents - azole derivatives, - and nicotinic acid in lipid-lowering doses (see section "Special instructions").

Inhibitors of the isoenzyme CYP3A4

Because the atorvastatin is metabolized by the isoenzyme CYP3A4, the simultaneous use of atorvastatin with inhibitors of the isoenzyme CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of potentiation are determined by the variability of the effect on the isoenzyme CYP3A4.The simultaneous use of atorvastatin with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reducing endogenous steroid hormones.

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, simultaneous use of atorvastatin in a dose of 10 mg and cyclosporine in 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"). The 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.When, If the simultaneous use of these drugs can not be avoided, then use a minimally effective dose of atorvastatin, and regular monitoring of patients' condition.

Erythromycin / clarithromycin

With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times daily) or clarithromycin (500 mg twice daily) that inhibit the isozyme CYP3A4, an increase in the concentration of atorvastatin in the blood plasma was observed (see section "Special instructions").

Diltiazem

Simultaneous use of atorvastatin in a dose of 40 mg with diltiazem in 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 of 20 mg to 40 mg and itraconazole at a dose of 200 mg resulted in an increase in the value of Atorvastatin AUC.

Grapefruit juice

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

Inductors of the cytochrome isoenzyme CYP3A4

Combined use with atorvastatin isoenzyme inducers of CYP3A4 (e.g., efavirenz, rifampicin, phenytoin, Hypericum perforatum drugs) may lead to a reduction of atorvastatin plasma concentration. Because of the dual mechanisms of interaction with rifampicin (isoenzyme CYP3A4 inducer and an inhibitor of the transport protein OATR1V1 hepatocytes), the simultaneous application of atorvastatin and rifampicin as atorvastatin delayed after receiving rifampicin significantly reduces the concentration of atorvastatin in 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 a suspension containing magnesium hydroxide and aluminum hydroxide, reduced the concentration of atorvastatin in the blood plasma by approximately 35%, but the degree of decrease in the concentration of LDL-C was not changed.

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 in 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 at a dose of 10 mg 1 time per day and azithromycin at a dose of 500 mg per day, the concentration of atorvastatin in the blood plasma did not change.

Oral contraceptives

With simultaneous use of atorvastatin and oral contraceptive containing norethisterone and ethinyl estradiol, there was a significant increase in the AUC of norethisterone and ethinyl estradiol by approximately 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

There were no signs of a clinically significant interaction of atorvastatin with warfarin.

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, cases of rhabdomyolysis in patients taking statins were reported, including atorvastatin and fizundic acid. In patients for whom the use of fusidic acid is considered necessary, treatment with statins should be discontinued during the entire period of application of fusidic acid. Therapy with statins can be resumed 7 days after the last intake of fusidic acid. In exceptional cases where prolonged systemic therapy with fusidic acid is necessary, for example,for the treatment of severe infections, the need for simultaneous use of atorvastatin and fusidic acid should be considered in each case and under the strict supervision of a physician. The patient should immediately consult a doctor if symptoms of muscle weakness, sensitivity, or pain appear.

Colchicine

Caution should be exercised with the simultaneous use of atorvastatin with colchicine, since cases of myopathy have been described.

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 atorvastatin and ezetimibe. Careful observation is recommended for such patients.

Other concomitant therapy

In clinical trials atorvastatin were applied simultaneously with antihypertensive drugs 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 with simultaneous use with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprivir, fosamprivir with ritonavir and nelfinavir), hepatitis C protease inhibitorsboceprevir), clarithromycin and itraconazole. Caution should be exercised when these drugs are used concomitantly, and the lowest effective dose of atorvastatin should be used.

The effect of other drugs on the pharmacokinetics of atorvastatin

The drug, dosage	Atorvastatin
	Dose (mg)	Change AuC £	Change Сmах £
Cyclosporin 5.2 mg / kg / day fixed dose	10 mg once a day, 28 days	↑ 7,7	↑ 9,7
Tiprinavir 500 mg 2 times / day / within 7 days	10 mg once	↑ 8,4	↑ 7,6
Telaprevir 750 mg every 8 hours, for 10 days	20 mg once	↑ 6,9	↑ 9,6
Bocepprivir 800 mg 3 times a day for 7 days	40 mg once	↑ 2,30	↑ 2,66
Lopinavir 400 mg twice daily / ritonavir 100 mg 2 times a day, for 14 days	20 mg once a day, in	↑ 5,9	↑ 1,7
££Saquinavir 400 mg twice a day / ritonavir 400 mg twice a day, for 15 days	40 mg 1 time / day	↑ 2,9	↑ 3,3
Clarithromycin 500 mg twice a day for 9 days	80 mg once a day for 8 days	↑ 3,4	↑ 4,4
Darunavir 300 mg twice daily / ritonavir 100 mg 2 per day, for 9 days	10 mg 1 time / day for 4 days	↑ 2,4	↑ 1,3
Itraconazole 200 mg once a day, for 4 days	40 mg, once	↑ 2,3	↑ 0,2
Fosamprevir 700 mg twice daily / ritonavir 100 mg 2 per day for 14 days	10 mg once daily for 4 days	↑ 1,5	↑ 1,8
Fosaprevir 1400 mg twice a day for 14 days	10 mg once daily for 4 days	↑ 1,3	↑ 3,0
Nelfinavir 1250 mg 2 times a day for 14 days	10 mg once daily for 28 days	↑ 0,74	↑ 1,2
Grapefruit juice 240 ml once a day *	40 mg once	↑ 0,37	↑ 0,16
Diltiazem 240 mg once a day for 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 day for 2 weeks	↓ 0,001	↓ 0,11
Kolestypol 10 mg 2 times for 28 weeks	40 mg once daily in within 28 weeks	not installed	↑ 0,26**
Maalox TC® 30 ml once a day for 17 days	10 mg once daily within 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 a day for 7 days (simultaneous use)	40 mg once	↑ 0,30	↑ 1,72
Rifampicin 600 mg once a day for 5 days (separate intake)	40 mg once	↓ 0,80	↓ 0,40
Gemfibrozil 600 mg twice a day for 7 days	40 mg once	↑ 0,35	↓ 0,004
Fenofibrate 160 mg once daily for 7 days	40 mg once	↑ 0,03	↑ 0,02

£ is the coefficient of variation of [(I-B) / B], where I - pharmacokinetic values during the interaction and B = pharmacokinetic values in the norm;

* With a significant consumption of grapefruit juice (more than 750 ml - 1.2 liters per day) noted a large increase AUC (up to 1.5 times) and / or Cmah (up to 0.71 times);

** The sample was taken once 8-17 hours after taking the drug;

The doses of saquinavir and ritonavir used in the study differ from the dosages that are used in clinical practice. It should be borne in mind that increasing the exposure of atorvastatin in clinical use is likely to be higher than observed in the 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
	The drug / dose (mg)	Change AUS *	Change Сmах *
80 mg once every 15 days	Antipyrine, 600 mg once	↑ 0,03	↑ 0,11
80 mg once every 14 days	Digoxin 0.25 mg once daily for 20 days	↑ 0,15	↑ 0,20
40 mg once daily for 22 days	Oral contraceptives once a day for 2 months	↑ 0,28	↑ 0,23
40 mg once daily for 22 days	- norethindrone 1 mg - ethinyl estradiol 35 μg	↑ 0,19	↑ 0,30
10 mg once	Tipranavir 500 mg twice a day / ritonavir 200 mg twice a day for 7 days	does not change	does not change
10 mg once every 4 days	Fosamprevir 1400 mg 2 times a day for 14 days	↓ 0,27	↓ 0,18
10 mg once daily for 4 days	Fosamprevir 700 mg twice daily / ritonavir 100 mg twice daily for 14 days	does not change	does not change

* coefficient of change [(I-B) / B], where I - pharmacokinetic values during the interaction and B = pharmacokinetic values in the norm;

Special instructions:

Before starting therapy with the drug Atorvastatin the patient should be assigned a standard hypocholesterol diet, which he must observe during the entire treatment period.

The use of HMG-CoA reductase inhibitors to reduce lipid levels in the blood can lead to a change in biochemical parameters that reflect the function of the liver. The liver function should be monitored before the start of therapy, 6 weeks, 12 weeks after the initiation of atorvastatin and after each dose increase, and periodically, for example, every 6 months. An increase in the activity of "hepatic" enzymes in the serum can be observed during therapy with Atorvastatin.Patients who have an increase in enzyme activity should be monitored before the enzyme activity returns to normal. In the case of a persistent increase in the activity of ALT or ACT to a level exceeding more than 3 times the IGN, it is recommended to reduce the dose of atorvastatin or to stop treatment.

Atorvastatin should be used with caution in patients who abuse alcohol and / or have liver disease. Active liver disease or persistent increase in aminotransferase activity of unknown origin is a contraindication to the appointment of atorvastatin.

Treatment with atorvastatin, like other inhibitors of HMG-CoA reductase, can cause myopathy. The diagnosis of myopathy (pain and weakness in muscles combined with an increase in CKK activity by more than 10 times compared to IGN) should be discussed in patients with advanced myalgia, tenderness or weakness of the muscles and / or a marked increase in CKK activity. Patients should be warned that they should immediately inform the doctor of unexplained pain or weakness in the muscles if they are accompanied by a malaise or fever.Therapy with Atorvastatin should be discontinued in the event of a marked increase in the activity of CKK or in the presence of confirmed or suspected myopathy. The risk of myopathy in treatment with other drugs of this class increased with simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g / day) or azole antifungal agents. Many of these drugs inhibit the metabolism mediated by cytochrome P4503A4 and / or transport medicines. Atorvastatin biotransformed by isoenzyme CYP3A4.

Assigning Atorvastatin in combination with fibrates, erythromycin, immunosuppressive agents, azole antifungal agents or nicotinic acid in lipid-lowering doses (more than 1 g / day), the expected benefit and risk of treatment should be carefully weighed and patients monitored regularly to identify pain or weakness in the muscles, especially during the first months of treatment and during the period increase the dose of any drug. In such situations, periodic determination of activity CKF, although such control does not allow prevent the development of severe myopathy.

When using Atorvastatin, as well as other drugs of this class, cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. Atorvastatin should be temporarily discontinued or completely discontinued if there is evidence of possible myopathy or the presence of a risk factor for renal failure against rhabdomyolysis (eg, severe acute infection, arterial hypotension, severe surgery, trauma, severe metabolic, endocrine and water-electrolyte disorders and uncontrolled convulsions ).

Before starting therapy with the drug Atorvastatin it is necessary to try to achieve control of hypercholesterolemia by adequate dietotherapy, increased physical activity, weight loss in obese patients and treatment of other conditions. Patients should be warned that they should immediately consult a doctor if unexplained pain or weakness in the muscles occurs, especially if they are accompanied by a malaise or fever.

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

Patients belonging to the risk group (fasting blood glucose concentration from 5.6 to 6.9 mmol / L, body mass index more than 30 kg / m², increased concentration of thyroid-stimulating hormone, arterial hypertension) should be under medical control, including control of biochemical parameters of blood.

Against the background of therapy with some inhibitors of HMG-CoA reductase (statins), especially against the backdrop of prolonged therapy, there were isolated cases of interstitial lung disease. There may be shortness of breath, an unproductive cough and worsening of the general condition of the patient (increased fatigue, weight loss and fever). If the patient is suspected of interstitial lung disease, atorvastatin should be withdrawn.

Prevention of stroke by actively lowering cholesterol concentration

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 especially noticeable in patients with hemorrhagic stroke or lacunar myocardial infarction in the anamnesis at the beginning of the study. In this group of patients, the benefit / risk ratio for taking atorvastatin 80 mg is rather vague, so before starting therapy, the possible risk of hemorrhagic stroke in these patients should be carefully assessed.

Effect on the ability to drive transp. cf. and fur:The adverse effect of atorvastatin on the ability to drive vehicles and engage in potential hazardous activities requiring increased concentration and speed of psychomotor reactions was not reported. 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:

For 10, 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 10, 20, 30, 40, 50, 90 or 100 tablets in cans of polymer or cans of polyethylene terephthalate.

One jar or 1, 2, 3, 4, 9 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:3 years. Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003533

Date of registration:29.03.2016

Expiration Date:29.03.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp08.10.2017

Illustrated instructions

Instructions

Atorvastatin (Atorvastatin)