ATORVASTATIN-NANOLEC - instructions for use, doses, side effects, contraindications

	Amount, mg
	(10,0)	(20,0)	(40,0)	(80,0)
Active substance: Atorvastatin calcium trihydrate (in terms of atorvastatin)	10,85 (10,0)	21,7 (20,0)	43,4 (40,0)	86,75 (80,0)
Excipients: Corn starch	53,15	52,9	70,71	82,0
Lactose Monohydrate	57,0	55,89	74,74	86,49
Microcrystalline cellulose	40,0	39,79	53,3	61,71
Silica colloidal dioxide	1,0	0,99	1	1,54
Magnesium stearate	1,0	1,8	2,5	3,0
Talc	4,0	3,98	5,32	6,17
Croscarmellose sodium	8,0	7,95	10,7	12,34
Tablet casing: Coating "Instacoat universal white":	5,0	5,0	8,0	10,0
Hypromellose	65%	65%	65%	65%
Macrogol	13%	13%	13%	13%
Talc	2%	2%	2%	2%
Titanium dioxide	20%	20%	20%	20%

Description:

Dosage of 10 mg: Round, biconvex tablets, covered with a film coat of white color.

Dosage of 20 mg: Round, biconvex tablets, covered with a film shell of white color, with a risk on one side.

Dosage of 40 mg: Round, biconvex tablets, covered with a film shell of white color, with a risk on one side.

Dosage of 80 mg: Round, biconvex tablets, covered with a film shell of white color, with a risk on one side.

Pharmacotherapeutic group:Hypolipidaemic agent - HMG-CoA-reductase inhibitor

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 hydroxymethylglutaryl coenzyme A-reductase (HMG-CoA reductase), a key enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonate, the precursor of steroids, including cholesterol; synthetic hypolipidemic agent.

Cholesterol and triglycerides circulate in the vascular bed of lipoprotein molecules. From triglycerides and cholesterol in the liver are synthesized lipoproteins of very low density (VLDL).From the liver they enter the blood plasma and are delivered to the peripheral tissues. Lipoproteins of low density (LDL) are formed from VLDL, catabolism is carried out, mainly through interaction with LDL receptors. 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, LDL cholesterol and apolipoprotein B (apo-B), as well as concentration cholesterol VLDL and triglycerides (TG), causes an unstable increase in the concentration of high-density lipoprotein cholesterol (HDL). 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 increases the number of LDL receptors in the liver on the cell surface, thereby increasing the uptake and catabolism of LDL.

Atorvastatin reduces the formation of LDL and the number of particles of LDL, causes a pronounced and persistent increase in the activity of LDL receptors, combined with favorable qualitative changes in LDL-particles.Reduces the concentration of LDL in patients with homozygous familial hypercholesterolemia, resistant to therapy with lipid-lowering drugs. Atorvastatin in doses from 10 mg to 80 mg per day 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-familial 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 cholesterol, VLDL, apo-B and TG and increases the concentration of HDL cholesterol. In patients with disbetalipoproteinemia, the concentration of intermediate-density lipoprotein (LDL) cholesterol is lowered.

In patients with hyperlipoproteinemia IIa and IIb type in the classification of Fredrickson average value of increasing the concentration of HDL cholesterol in the treatment with atorvastatin (in doses of 10-80 mg) compared with the initial index is 5.1-8.7% and is dose-independent. There is a significant dose-dependent reduction in the ratio: total cholesterol / HDL cholesterol and LDL cholesterol / HDL 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 LDL cholesterol concentrations (with myocardial infarction without a tooth Q and unstable angina, men and women, in patients younger and older than 65 years) atorvastatin reduces the risk of ischemic complications and mortality.

Reduced plasma concentrations of LDL cholesterol are better correlated with the dose of atorvastatin 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").

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.

Does not have a carcinogenic and mutagenic effect.

Pharmacokinetics:

Suction: atorvastatin quickly absorbed after ingestion, approximately 80% is absorbed from the gastrointestinal tract. Maximum concentration in blood plasma (FROM_m_Oh) is achieved through 1-2 hours after ingestion. Eating slightly reduces the rate and extent of atorvastatin (by 25% and 9%, respectively), however, the reduction in LDL cholesterol is similar to that of fasting atorvastatin. The degree of absorption increases in proportion to the dose of atorvastatin.

After taking atorvastatin in the evening, its concentration in the blood plasma is lower by approximately 30% than after taking in the morning.

The total bioavailability of atorvastatin is approximately 12%, and the systemic bioavailability of the activity of HMG-CoA reductase inhibitors is approximately 30%. Low systemic bioavailability is associated with presystemic metabolism in the mucous membrane of the gastrointestinal tract and with "primary passage" through the liver.

Distribution. The average volume of atorvastatin distribution is approximately 381 liters, atorvastatin 98% bind to blood plasma proteins.

Metabolism. Atorvastatin metabolism occurs predominantly in the liver, with the participation of isoenzyme CYP3A4 cytochrome P450 with the formation of pharmacologically active metabolites (ortho- and para-hydroxylated derivatives and various beta-oxidation products). In conditions in vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% decrease in the activity of HMG-CoA reductase occurs due to active metabolites.

Excretion. Atorvastatin is excreted mainly with bile after hepatic and / or extrahepatic metabolism (does not undergo significant enterohepatic recirculation). The half-life (T ₁/₂) atorvastatin is approximately 14 hours. The inhibitory activity against HMG-CoA reductase remains about 20 to 30 hours due to the presence of active metabolites. Less than 2% of the dose taken internally is determined in the urine. It is not excreted in the course of hemodialysis, as atorvastatin is largely associated with plasma proteins.

Special groups of patients.

Patients of older age. The concentration of atorvastatin in blood plasma in elderly volunteers (65 years and older) is higher (C_ma_x - by about 40%, AUC (area under the concentration-time curve) by approximately 30%) than in young volunteers, while the effect on lipid concentration is comparable to that of patients from younger age groups.

Patients of childhood. Data on pharmacokinetics in patients of childhood are absent.

Patients are female and male. The concentration of atorvastatin and its active metabolites in women differs from that of men (value of C_m_Oh approximately 20% higher, and the value AUC approximately 10% lower). These differences are clinically insignificant, as a whole there are no clinically significant differences between men and women in the impact on lipid metabolism.

Patients with impaired renal function. Violation of the kidney function does not affect the concentration of atorvastatin in the blood plasma or its effect on lipid metabolism, therefore, a dose change in patients with impaired renal function is not required (see section "Method of administration and dose").

Patients with impaired liver function. The concentration of atorvastatin in blood plasma is markedly increased (the value of C_ma_x approximately 16 times, and the value AUC approximately 11 times) in patients with chronic alcoholic cirrhosis of the liver (class B according to the Child-Pugh classification) (see the section "Contraindications").

Genetic polymorphism

Polymorphism of the gene SLC01B1, coding OATP1B1, affects the pharmacokinetics of drugs metabolized in the liver. Inhibitors of HMG-CoA reductase, including, atorvastatin, binds to the transport protein OATP1B1 involved in the capture of HMG-CoA reductase (statin) inhibitors by hepatocytes. In carriers of the genotype SLC01B1 С.521СС concentration of atorvastatin in blood plasma (AUC) increased 2.4 times in comparison with the carriers of the genotype SLC01B1 p.52ITT, which can increase the risk of myopathy, including rhabdomyolysis.

Indications:

Hypercholesterolemia:

at an elevated concentration in the blood plasma of total cholesterol, low density lipoprotein (LDL), apo-B, TG and an increase in high-density lipoprotein (HDL) in patients with the following conditions:

- primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia (IIand the type according to Fredrickson));

- heterozygous familial hypercholesterolemia in patients 10-17 years old with insufficient response of the body to the diet and other non-pharmacological measures taken;

- combined (mixed) hyperlipidemia (types IIa and IIb by Fredrickson);

- disbetalipoproteinemia (III type by Fredrickson), as a supplement to the diet;

- family endogenous hypertriglyceridemia (type IV according to Fredrickson), resistant to diet;

- homozygous familial hypercholesterolemia in case of insufficient reaction of the body to a diet and other non-pharmacological measures taken;

- primary prevention of cardiovascular complications in patients without clinical signs of coronary heart disease (CHD), but having several risk factors for its development - age over 55, nicotine dependence, arterial hypertension, diabetes, genetic predisposition, incl. against dyslipidemia in addition to the effects on other risk factors;

- secondary prevention of cardiovascular complications in patients with ischemic heart disease in order to reduce the overall mortality rate, non-fatal myocardial infarction, stroke, and re-hospitalization for angina and the need for revascularization.

Contraindications:

- Hypersensitivity to atorvastatin or to any of the components of the drug;

- active liver disease or increased activity of "liver" transaminases in blood plasma of unknown origin more than three times compared with the upper limit of the norm;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose!);

- age up to 10 years - for patients with heterozygous familial hypercholesterolemia;

- age to 18 years - when applied for other indications (efficacy and safety not established);

- pregnancy, the period of breastfeeding, the lack of adequate methods of contraception in women of reproductive age (see the section "Use during pregnancy and during breastfeeding).

If you have any of these diseases, consult a doctor before taking the drug.

Carefully:

- Alcohol abuse;

- liver disease in anamnesis.

If you have any of these diseases, consult a doctor before taking the drug.

Pregnancy and lactation:

Atorvastatin is contraindicated in pregnancy and lactation.

Women of reproductive age during treatment should take appropriate measures of contraception. The use of the drug in women of reproductive age is possible only if the probability of pregnancy is very low and the patient is informed about the possible risk for the development of the fetus.When planning pregnancy, you should wait 1 month after the end of treatment with atorvastatin.

Due to the lack of data on the release of the drug or its metabolites with breast milk, and also considering the possibility of unwanted reactions in infants, if it is necessary to use the drug during lactation, breastfeeding should be stopped in order to avoid the risk of adverse events in infants.

Dosing and Administration:

Before starting therapy with ATORVASTATIN-NANOLEC, try to achieve control of hypercholesterolemia with diet, exercise and weight loss in obese patients, as well as treatment of 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. Atorvastatin-Nanolole is taken orally, at any time of the day, regardless of the time of ingestion.

Usually the initial dose is 10 mg per day. Dose atorvastatin NANOLEK range from 10 to 80 mg once a day. The dose of the drug should be selected individually depending on the initial concentration of LDL, the goals of therapy and the therapeutic response to treatment,taking into account current recommendations for target lipid concentrations. At the beginning of treatment and / or during an increase in the dose of the drug, it is necessary to monitor the concentration of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

The maximum dose of the drug ATORVASTATIN-NANOLEC is 80 mg per day.

Primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia) and combined (mixed) hyperlipidemia

Treatment begins with the recommended initial dose of the drug Atorvastatin-Nanolek 10 mg once a day, which is increased after four weeks of treatment, depending on the purpose of treatment and the patient's response. The maximum daily dose is 80 mg (once).

Heterozygous familial hypercholesterolemia in patients 10-17 years old

The recommended initial dose of ATORVASTATIN-NANOLEC is 10 mg per day. The maximum daily dose is 20 mg (once). The dose should be selected individually and adjusted at intervals of 4 weeks.

Homozygous familial hypercholesterolemia

Recommended dosages of the drug ATORVASTATIN-NANOLEC - from 10 to 80 mg per day.The initial dose is selected individually depending on the severity of the disease. In most patients with homozygous hereditary hypercholesterolemia, the optimal effect is observed when the drug is administered in a daily dose of 80 mg once. Atorvastatin-Nanolek is used as an adjunct therapy for other treatment methods (LDL apheresis) or in the case of inaccessibility of other methods of treatment.

Application the patients with kidney failure

Impaired renal function does not affect the concentration in the blood plasma or the therapeutic effect of atorvastatin, therefore no dosage adjustment of the drug Atorvastatin-Nanolech is required.

Application the patients with insufficient liver function

Use with caution in connection with the delay in removing atorvastatin from the body. Clinical and laboratory indicators should be closely monitored (regular monitoring of the activity of "hepatic" transaminases aspartate aminotransferase and alanine aminotransferase (ACT and ALT)). With a significant increase in the activity of "hepatic" transaminases, the dose of ATORVASTATIN-NANOLEC should be reduced or treatedbe discontinued, (see the sections "Contraindications", "Special instructions").

Application the elderly patients

Correction of the dose of the drug ATORVASTATIN-NANOLEC is not required (see section "Pharmacokinetics" - "Special patient groups").

Use in combination with other medicines (LS)

If a combination with cyclosporine, telaprevir, or a combination of tipranavir / ritonavir is required, the dose of ATORVASTATIN-NANOLECE should not exceed 10 mg (see section "Specific guidance"). Caution should be used and the lowest effective dose of ATORVASTATIN-NANOLEC when used simultaneously with HIV protease inhibitors, hepatitis C protease inhibitors, clarithromycin and intraconazole should be used.

Side effects:

The incidence of adverse reactions that were observed either during the clinical trials of the original drug, or were obtained from spontaneous reports on the development of adverse reactions, is classified according to the recommendations of the World Health Organization: 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%; rarely (including isolated cases) - less than 0.01%, frequency unknown - can not be calculated from available data.

Infectious and parasitic diseases: often - Nasopharyngitis.

Violations of the blood and lymphatic system: rarely - Thrombocytopenia.

Immune system disorders: often - allergic reactions; rarely - anaphylactic shock.

Disorders from the metabolism and nutrition: often - hyperglycemia, infrequently - hypoglycemia, weight gain, anorexia.

Disorders of the psyche: infrequently - insomnia, "nightmarish" dreams

Disturbances from the nervous system: often - headache; infrequently - dizziness, paresthesia, hypoesthesia, amnesia, a violation of taste sensations; rarely - peripheral neuropathy;

Disturbances on the part of the organ of sight: infrequently - decreased vision clarity; rarely - Visual impairment.

Hearing disorders and labyrinthine disorders: infrequently - "noise in ears; rarely - loss of hearing.

Disturbances from the respiratory system, chest and mediastinal organs: often - nosebleeds, pain in the pharyngeal region; frequency unknown - interstitial lung disease (especially with prolonged therapy).

Disorders from the digestive system: often - constipation, flatulence, indigestion, nausea, diarrhea; infrequently - vomiting, belching, abdominal pain, pancreatitis.

Disturbances from the liver and bile ducts: infrequently - Hepatitis; rarely - cholestasis; rarely - liver failure.

Disturbances from the skin and subcutaneous tissues: infrequently - alopecia, skin rash, itching, hives; rarely - angioedema, bullous dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disturbances from musculoskeletal system and connective tissue: often - myalgia, arthralgia, pain in the extremities, muscle spasms, back pain, swelling in the joints; infrequently - pain in the neck, muscle weakness; rarely - myopathy, myositis, rhabdomyolysis, tendinopathy, sometimes complicated by a rupture of the tendon; frequency unknown - immuno-mediated necrotizing myopathy.

Violations of the genitals and mammary gland: rarely - gynecomastia.

General disorders-, infrequently - asthenia, weakness, chest pain, peripheral edema, fever, increased fatigue.

Laboratory and instrumental data: often - Increased activity of "liver" transaminases, increased activity of creatine phosphokinase in blood serum; infrequently - leukocyturia.

When using inhibitors of HMG-CoA reductase (statins), including atorvastatin, there were cases of an increase in the concentration of glycosylated hemoglobin.

The following adverse reactions have been reported with the use of some statins: frequency unknown - Sexual dysfunction, depression. Single cases of development.

If any of the side effects indicated in the manual are aggravated or you notice any other side effects not listed in the instructions, inform your doctor.

Overdose:

There is no specific antidote. In case of an overdose, the necessary symptomatic and supportive therapy is performed. It is necessary to monitor liver function and determine the activity of serum creatine phosphokinase (CK). Hemodialysis is ineffective.

Interaction:

The effect of concomitant medications on atorvastatin.

The results of the most specific studies in vitro when using human cells, and liver microsomes, cytochrome P450 isoenzymes representing confirm that the metabolism of atorvastatin, as well as other HMG-CoA reductase inhibitors, is due to the cytochrome P450 ZA4, which indicates the possibility of interaction with drugs whose metabolism also occurs due to this isoenzyme. With simultaneous use of atorvastatin with other drugs that are substrates of this isoenzyme (eg., Immunomodulators, many antiarrhythmic agents, some blockers "slow" calcium channels, and certain derivatives of benzodiazepines) should take into account the possibility of changing the level of any of the drugs in the blood plasma. In clinical studies in which the use of atorvastatin was combined with reception antihypertensives (including angiotensin converting enzyme (ACE) inhibitors, beta-blockers, blockers "slow" calcium channels and diuretics) or hypoglycemic drugs, clinically significant interactions were observed.

On the basis of the results of studies on the intake of HMG-CoA reductase inhibitors, care should also be taken when using atorvastatin with cytochrome P450-ZA4 inhibitors (eg, certain macrolide antibiotics and azole derivatives). The results of studies confirming the increase and decrease in the level of phenytoin in the blood plasma were presented, but the character of interactions with atorvastatin is unknown.

Inhibitor inhibitors CYP3A4

It has been shown that strong inhibitors of isoenzyme CYP3A4 (eg, ciclosporin, clarithromycin, delavirdine, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir and others) cause a significant increase in the concentration of atorvastatin, therefore, their combined use with atorvastatin should be avoided. In cases of need for combination therapy, consideration should be given to the possibility of using lower initial and maintenance doses of the above-mentioned agents in combination with regular observation of the patient.

Moderate inhibitors of isoenzyme CYP3A4 (eg, erythromycin, diltiazem, verapamil and fluconazole) can increase the concentration of atorvastatin in the blood plasma. An increased risk of myopathy was observed with the use of erythromycin in combination with statins. Studies to assess the effects of amiodarone and verapamil on atorvastatin not conducted. It is known that amiodarone and verapamil inhibit isoenzyme CYP3A4, therefore, their combination with atorvastatin may lead to an increase in the concentration of atorvastatin. Therefore, the possibility of using lower maintenance doses of the aforementioned agents should be considered in combination with regular observation of the patient.

Clarithromycin: with the simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P450 3A4, an increase in the concentration of atorvastatin in blood plasma by 4.4 times was observed. In cases of need for combination therapy with a dose of atorvastatin greater than 20 mg / day is required by regular observation of the patient.

Erythromycin: with the simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day), an increase in the concentration of atorvastatin in blood plasma by 33% was observed.

Azithromycin: simultaneous use of atorvastatin and azithromycin (500 mg once a day) does not affect the concentration of atorvastatin in the blood plasma.

Inhibitors of proteases: Simultaneous use of atorvastatin 10 mg / sug and a combination of tipranavir / ritonavir in a daily dose of 1000 mg / 400 mg leads to an increase in the concentration of atorvastatin in blood plasma by 9.4 times, and simultaneous use of atorvastatin at a dose of 20 mg / day and telaprevir at a dose of 2250 mg / day leads to an increase in the concentration of atorvastatin in blood plasma by 7.9 times (see section "Method of administration and dose"). If a joint use with cyclosporine is required, the dose of atorvastatin should not exceed 10 mg / day, patients need regular monitoring.

Simultaneous use of atorvastatin and other protease inhibitors, known as cytochrome P450 inhibitors of ZA4, leads to an increase in the concentration of atorvastatin in blood plasma approximately 2-fold. When used simultaneously with protease inhibitors, a reduced dose of atorvastatin should be given.

Diltiazem: The combined use of atorvastatin 40 mg with diltiazem in a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma.

Itraconazole: Simultaneous use of atorvastatin in doses of 20 to 40 mg and itraconazole at a dose of 200 mg led to an increase in the concentration of atorvastatin in blood plasma. In cases of need for combination therapy with a dose of atorvastatin more than 40 mg / day requires regular observation of the patient.

GrEyepfruit juice: contains one or more isozyme inhibitory components CYP3A4, and can increase the concentration in the blood plasma of drugs, the metabolism of which occurs due to CYP3A4. Receiving 240 ml of grapefruit juice led to an increase in the value AUC by 37% and a decrease in the value AUC by 20.4% for the active orthohydroxy metabolite. However, the intake of grapefruit juice in large quantities (more than 1.2 liters per day for 5 days) led to an increase in the value AUC atorvastatin 2.5 times, and the values AUC active inhibitors of HMG-CoA reductase (atorvastatin and metabolites) - in 1,3 times. Therefore, the simultaneous intake of grapefruit juice in large quantities and atorvastatin is not recommended.

Inductors CYP3A4

Joint application with inducers of cytochrome P450 OA (such as efavirenz, rifampicin, St. John's wort perforated) 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 the inhibitor of the hepatocyte transport protein OATP1B1), simultaneous administration of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin results in a significant reduction in the concentration of atorvastatin in the blood plasma. Combined use with rifampicin is possible, but requires careful monitoring with respect to efficacy.

Inhibitors of transport proteins

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 8.7 times (see the section "Method of administration and dose"). If a joint use with cyclosporine is required, the dose of atorvastatin should not exceed 10 mg / day, patients need regular monitoring.

Gemfibrozil / derivatives of fibroic acid: When treating fibrates, sometimes there are muscle unwanted effects, including rhabdomyolysis. The risk of developing these phenomena can be increased by combining the derivatives of fibrolic acid and atorvastatin. Pre-clinical data also confirm the possibility of the interaction of gemfibrozil with atorvastatin by inhibiting the process of glucuronization of atorvastatin. In cases where combination therapy is required (especially with gemfibrozil), consideration should be given to the possibility of using lower initial and maintenance doses of the aforementioned agents in combination with regular observation of the patient.

Ezetimibe: With the treatment with ezetimibe, sometimes there are muscular undesirable phenomena, including rhabdomyolysis. The risk of developing these phenomena may increase with the combination of ezetimibe and atorvastatin. Regular monitoring of the patient is recommended.

Colestipol: With the simultaneous use of atorvastatin and colestipol, a decrease in the concentration of atorvastatin in the blood plasma (approximately 25%) was observed. However, with the combined use of atorvastatin and colestipol, the hypolipidemic effect was more pronounced than with each of these drugs alone.

Fusidic acid: Clinical studies on the interaction of atorvastatin and fusidic acid have not been conducted. There are spontaneous reports of the occurrence of muscle undesirable effects in the combined use of atorvastatin and fusidic acid. The mechanism of interaction is unknown. Patients receiving combined treatment need to be monitored by a physician. It may be advisable to temporarily stop taking atorvastatin if necessary with fusidic acid.

Cimetidine: The study of simultaneous use of cimetidine and atorvastatin did not reveal a significant interaction between these drugs.

Amlodipine: simultaneous use of atorvastatin and amlodipine 10 mg in a stable state did not change the pharmacokinetics of atorvastatin.

Antacids: simultaneous use of atorvastatin and ingestion of an antacid suspension containing magnesium and aluminum hydroxides, reduces the concentration of atorvastatin in the blood plasma approximately 35%; but the effect of lowering LDL cholesterol remained unchanged.

The effects of atorvastatin on co-administered drugs

Phenazone (antipyrine): is a nonspecific model for evaluating the metabolism of a drug with a system of microsomal liver enzymes. Taking high doses of atorvastatin phenazone has no or insignificant influence on the pharmacokinetics of phenazone in healthy patients (changes in the clearance of phenazone absent, the formation of 4-gidroksifenazona clearance is increased by 20% and formation of clearance normalized phenazone is increased by 8%).

Digoxin: with repeated administration of digoxin and 10 mg of atorvastatin, there was no effect on the equilibrium state of digoxin concentrations in the blood plasma. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration was increased by about 20%. Appropriate monitoring of patients taking digoxin.

Oral contraceptives: use of atorvastatin with an oral contraceptive containing norethisterone and ethinyl estradiol, leads to an increase in the concentration of norethisterone and ethinyl estradiol in blood plasma by approximately 30% and 20%, respectively. This increase in concentration should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

Warfarin: the use of atorvastatin with warfarin led to a minimum decrease in prothrombin time by about 1.7 seconds during the first 4 days of taking 80 mg of atorvastatin. Admission of this dose lasted for 15 days, and prothrombin time returned to normal by the end of treatment with atorvastatin. Nevertheless, patients receiving warfarin, should be carefully monitored when atorvastatin is added to the course of treatment.

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

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

Other concomitant therapy: In clinical trials atorvastatin used in combination with antihypertensive agents and estrogens within the framework of substitution treatment; Signs of clinically significant undesirable interaction were not observed; studies of interaction with other specific drugs have not been conducted.

Special instructions:

Before starting therapy with ATORVASTATIN-NANOLEC, the patient should begin to follow the standard hypocholesterolemic diet and continue to observe it throughout the treatment period.

Effects on the liver. 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 functional state of the liver. The liver function should be monitored before the start of therapy, 6 weeks, 12 weeks after the initiation of Atorvastatin-Nanolole and after each dose increase, and periodically, for example, every 6 months. Patients with signs or symptoms of liver dysfunction should undergo additional liver function tests. Patients with an increased activity of "liver" transaminases should be monitored until their activity decreases. In the case of a persistent increase in the activity of "hepatic" transaminases ACT and ALT more than 3 times compared with the upper limit of the norm, it is recommended to reduce the dose of the drug or stop treatment (see the section "Side effect").

Atorvastatin-Nanolek should be used with caution in patients who consume significant quantities of alcohol and / or have a history of liver disease. Active liver disease or persistent increase in the activity of "hepatic" transaminases of unknown origin are contraindications to the use of the drug Atorvastar-Nanolek (see section "Contraindications").

Influence on cerebral circulation. When analyzing the results of a clinical study, it was found that among patients included in the study with a diagnosis of "Ischemic heart disease" who had recently suffered a stroke or transient impairment of cerebral circulation, a high incidence of hemorrhagic stroke was observed against atorvastatin at a dose of 80 mg / in those receiving placebo. The greatest risk was observed in patients who had previously had hemorrhagic stroke or lacunar infarction of the brain. In patients who have experienced hemorrhagic stroke or lacunar cerebral infarction, treatment with atorvastatin may increase the risk of hemorrhagic stroke,the physician should carefully weigh the expected benefit of treatment and the possible risk in deciding whether to prescribe the drug Atorvastatin-Nanolole.

Influence on skeletal muscles. Atorvastatin as well as other inhibitors of HMG-CoA reductase, can cause the appearance of muscle pain, myositis and myopathy, which in rare cases can progress with the development of rhabdomyolysis, a potentially life-threatening condition characterized by a significant increase in the activity of creatine phosphokinase (CK) more than 10 times the normal limit, myoglobinemia and myoglobinuria, which can lead to kidney failure. The diagnosis of "Myopathy" should be assumed in all patients undergoing statin treatment and exhibiting such unexplained muscle symptoms as pain or soreness, muscle weakness, or muscle cramps. In such cases, the activity of creatine phosphokinase (CKF) should be determined.

If symptoms of possible myopathy appear or if there is a risk factor for developing renal failure with rhabdomyolysis (for example, severe acute infection, arterial hypotension, extensive surgical intervention,trauma, metabolic, endocrine and water-electrolyte disorders and uncontrolled convulsions) therapy with ATORVASTATIN-NANOLEC should be temporarily discontinued or completely abolished.

Attention! Patients should be warned that they should immediately inform the doctor of unexplained pain, seizures, or weakness in the muscles, especially if they are accompanied by a malaise or fever.

Measurement of the level of creatine phosphokinase. CKK activity should not be determined after intensive physical exertion or in the presence of any other possible causes of increased activity of CK, as this makes it difficult to explain the value obtained. If the activity of CK is significantly increased in the initial state (more than 5 times as compared with the upper limit of the norm), it is necessary to re-conduct the measurements within 5-7 days to confirm the results.

Before starting therapy. Like other statins, the drug Atorvastatin-Nanolek should be administered with caution to patients with a predisposition to rhabdomyolysis. The activity of CK should be measured before starting treatment in the following situations:

- kidney failure;

- hypothyroidism of the thyroid gland;

- individual or hereditary congenital musculoskeletal disorders;

- muscular intoxication with statins or fibrates in the anamnesis;

- liver disease and / or consumption of significant amounts of alcohol in history;

- older age (> 70 years), the decision to perform these measurements should be made in accordance with the presence of other predispositions to rhabdomyolysis;

In such cases, the risk-to-treatment ratio and possible positive effects should be considered, and monitoring in clinical settings is recommended. If the activity of CK is significantly increased in the initial state by more than 5 times relative to the upper limit value, treatment should not be started.

During therapy. In the case of muscle pain, weakness, or seizures, when the patient undergoes treatment with statin, it is necessary to determine the activity of CKK. If this level is significantly increased (more than 5 times the upper limit value), treatment should be stopped. If muscle symptoms become severe and cause daily discomfort,even if the activity of CK does not exceed a 5-fold increase with respect to the upper limit, the treatment should be stopped. In case of resolving the symptoms and returning the activity of CFC to normal, you can prescribe a second dose of ATORVASTATIN-NANOLEC, or take a similar statin with a minimal dosage and under close supervision. Increased activity of CK should be considered when assessing the possibility of myocardial infarction in the differential diagnosis of chest pain.

Joint use of atorvastatin with other drugs. Combined use of atorvastatin with inhibitors of the cytochrome isoenzyme CYP3A4 and substrates of transport proteins (such as cyclosporin, clarithromycin, delavirdine, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir , etc.) can lead to an increase in the concentration of atorvastatin in the blood plasma and increase the risk of myopathy. This risk may also increase with the simultaneous use of the drug Atorvastatin-Nanolek with other medications that can cause myopathy, such as gemfibrozil and other fibrates, ezetimibe, as well as with erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g / day).

In some rare cases, these combinations can cause rhabdomyolysis accompanied by renal insufficiency due to myoglobinuria.

In this regard, a careful evaluation of the relationship between the possible risk and the expected benefit of the combined treatment is necessary (see section "Special instructions" - "Influence on skeletal muscles", "Before the start of therapy"). 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. In such situations, periodic monitoring of the activity of CKF can be recommended (see section "Interaction with other drugs").

It is recommended to temporarily stop taking ATORVASTATIN-NANOLEC if necessary to treat fusidic acid (see section "Interaction with other drugs").

Interstitial lung disease. Single cases of interstitial lung disease, especially long-term therapy, have been reported. The disease is characterized by shortness of breath, unproductive cough and worsening of the general condition (fatigue, weight loss and fever). If the development of interstitial lung disease is suspected, treatment with ATORVASTATIN-NANOLEC should be stopped.

Effect on the ability to drive transp. cf. and fur:

Data on the effect of ATORVASTATIN-NANOLEC on the ability to drive a vehicle and to engage in potentially hazardous activities requiring increased concentration of attention are not available, but, given the potential for dizziness, care should be taken when carrying out the above activities.

Form release / dosage:

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

Packaging:

For 10 tablets in a contour mesh package made of a combined material of polyamide / aluminum / PVC and aluminum foil.

For 3 or 9 contour squares with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of ns above 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002901

Date of registration:10.03.2015

Expiration Date:10.03.2020

The owner of the registration certificate:NANOLEC, LTD. NANOLEC, LTD. Russia

Manufacturer: & nbsp

ZIM LABORATORIES, Ltd India

Information update date: & nbsp05.10.2017

Illustrated instructions

Instructions

ATORVASTATIN-NANOLEC (ATORVASTATIN-NANOLEK)