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

auxiliary substances (core): calcium carbonate 33 mg or 66 mg or 132 mg, microcrystalline cellulose 60 mg or 120 mg or 240 mg, lactose monohydrate 32.05 mg or 64.11 mg or 128.22 mg, croscarmellose sodium 9 mg or 18 mg or 36 mg,sodium lauryl sulfate 0.6 mg or 1.2 mg or 2.4 mg, hypromellose 3 mg or 6 mg or 12 mg, calcium stearate 1.5 mg or 3 mg or 6 mg,

auxiliary substances (shell): hypromellose - 3.3 mg or 6.6 mg or 13.2 mg, macrogol 0.95 mg or 1.9 mg or 3.8 mg, titanium dioxide 0.65 mg or 1.3 mg or 2.6 mg, talc 0.1 mg or 0.2 mg or 0.4 mg.

Description:

Tablets 10 mg: White or almost white, round, biconvex tablets with film coating.

Tablets of 20 mg: White or almost white, round, biconvex tablets with film coating.

Tablets 40 mg: White or almost white, round, biconvex tablets with film coating.

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 lipid-lowering drug from the group of statins. A selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A into mevalonic acid, a precursor of steroids, including cholesterol. Atorvastatin suppression of cholesterol synthesis (Xc) leads to an increased reactivity of low-density lipoprotein (LDL) receptors in the liver and extrahepatic tissues.These receptors bind LDL particles and remove them from the blood plasma, which leads to a decrease in the concentration of LDL cholesterol (LDL-C) in the blood.

The antisclerotic effect of the drug is manifested by the effect of atorvastatin on the walls of blood vessels and blood components. Atorvastatin Suppresses the synthesis of isoprenoids, which are factors of growth of the inner shell of the vessels. Under the influence of atorvastatin improves endothelium-dependent expansion of blood vessels. Atorvastatin reduces the concentration of total cholesterol, Xc-LDL, apolipoprotein B, triglycerides (TG), causes an increase in the concentration of high-density lipoprotein cholesterol (Xc-HDL) and apolipoprotein A.

Atorvastatin reduces the viscosity of the blood plasma and the activity of certain clotting factors and platelet aggregation. Due to this, it improves hemodynamics and normalizes the state of the coagulation system. Inhibitors of HMG-CoA reductase also have an effect on the metabolism of macrophages, block their activation and prevent the rupture of atherosclerotic plaque.

As a rule, the therapeutic effect of atorvastatin develops 2 weeks after the start of the drug,and the maximum effect is achieved after 4 weeks.

Reliably reduces the risk of developing ischemic complications (including death from myocardial infarction) by 16%; the risk of re-hospitalization for angina, accompanied by signs of myocardial ischemia - by 26%.

Pharmacokinetics:

Suction

Ingestion atorvastatin quickly absorbed in the gastrointestinal tract (GIT), the degree of absorption and concentration in the blood plasma increase in proportion to the dose. Time to reach the maximum concentration (TC_mOh) in blood plasma is 1-2 hours. The absolute bioavailability of atorvastatin is about 12%, and the systemic bioavailability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to, pre-systemic metabolism in the mucosa of the gastrointestinal tract and the effect of "primary transmission" through the liver.

Simultaneous intake of food slightly reduces the rate and duration of absorption of atorvastatin (by 25% and 9%, respectively), as evidenced by the results of determining the maximum concentration (C_mOh) atorvastatin and the area under the concentration-time curve (AUC), however, a decrease in LDL cholesterol is similar to that of fasting atorvastatin.

Distribution

Average volume of distribution (V_d) is about 381 liters, binding to plasma proteins is not less than 98%. Atorvastatin does not penetrate the blood-brain barrier (BBB).

Metabolism

Metabolized mainly in the liver under the action of the isoenzyme CYP3A4 systems of cytochrome P₄₅₀ with the formation of pharmacologically active metabolites: ortho- and para-hydroxylated derivatives, beta-oxidation products. Metabolites account for approximately 70% of the inhibitory activity against HMG-CoA reductase. The inhibitory activity persists for 20-30 hours.

Excretion

Atorvastatin is excreted mainly with bile, is not subjected to severe enterohepatic recirculation. The half-life (T_1/2) - about 14 hours After ingestion in the urine is detected less than 2% dose of this drug.

Special patient groups

Floor

The concentration of atorvastatin and its active metabolites in women differs from that of men. In women C_mOh higher by 20%, a AUC - lower by 10% than men. These the differences are not clinically significant and do not require dose adjustment (see the section "Dosing and Administration").

Patents of the elderly

FROM_mOh and AUC (older than 65 years) by 40% and 30% (respectively) higher than in adult patients of young age, which does not require dose adjustment (see the section "Dosing and Administration"), since the results of hypolipidemic therapy are comparable with those in adult patients of a young age.

Children

The study of pharmacokinetics of atorvastatin in children was not conducted.

Genetic polymorphism

Hepatic seizure of all HMG-CoA reductase inhibitors, including atorvastatin, occurs with the participation of the transporter OATP1B1. Patients with genetic polymorphism SLC01B1 have a risk of exposure increase (AUC) atorvastatin a, which may lead to an increased risk of rhabdomyolysis. The polymorphism of the gene coding for OATP1B1 (SLC01B1 p.521S) is associated with an increase in atorvastatin AUC 2.4-fold compared to patients without such 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.

Table 1. Effect of other drugs on the pharmacokinetics of atorvastatin

The drug, dosage	Atorvastatin
The drug, dosage	Dose (mg)	Change AUC¹	The change in C_m_Oh¹
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 twice daily / ritonavir 100 mg 2 times a day for 14 days	20 mg once a day, for 4 days	↑ 5,9	↑ 4,7
Saquinavir 400 mg twice daily / ritonavir 400 mg twice daily 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 for 14 days	10 mg once a day, for 4 days	↑ 2,53	↑ 2,84
Fosamprenavir 1400 mg 2 times a day, for 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	↑ 0,74	↑ 2,2
Grapefruit juice, 240 ml once a day²	40 mg, once	↑ 0,37	↑ 0,16
Diltiazem 240 mg once daily 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, for 2 weeks	↓ 0,001	↓ 0,11
Colestipol 10 mg twice daily for 28 weeks	40 mg once a day, for 28 weeks	Not installed	↓ 0,26³
Maalox TC® 30 ml once daily 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 once a day, for 3 days	↓ 0,41	↓ 0,01
Rifampicin 600 mg once daily for 7 days (simultaneous use)⁴	40 mg once	↑ 0,30	↑ 2,7
Rifampicin 600 mg once daily for 5 days (separate application)⁴	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 a day, for 7 days	40 mg, once	↑ 0,03	↑ 0,02

¹coefficient of change [(I - B) / B], where I = pharmacokinetic values during the interaction and B = pharmacokinetic values are normal;

²with a significant intake of grapefruit juice (> 750 ml - 1.2 liters per day), there was a greater increase AUC (up to 1.5 times) and / or C_m_Oh (up to 0.71 times);

³the sample was taken once 8-16 hours after taking the drug;

⁴as 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.

Pharmacokinetics in special clinical cases

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 the dose change in patients with impaired renal function is not required.

Lack of liver function

The concentration of atorvastatin is significantly increased (C_mOh about 16 times, AUC in 11 times) in patients with alcoholic liver cirrhosis (class B according to the Child-Pugh classification).

Indications:

- Hypercholesterolemia:

as an adjunct to the diet to reduce elevated cholesterol, LDL-C, apo-B and triglyceride levels in adults, including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (type IIa and IIb according to Fredrickson classification), when the response to diet and other non-pharmacological methods of treatment are 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;

- 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 mellitus, low concentration of HDL-C in the blood plasma, genetic predisposition, including against the background of dyslipidemia;

- secondary prevention of cardiovascular complications in patients with IHD in order to reduce mortality, myocardial infarction, stroke, re-hospitalization for angina pectoris and the need for revascularization procedures.

Contraindications:

- Hypersensitivity to atorvastatin or any other component of the drug;

- liver disease in the active phase (including active chronic hepatitis, chronic alcoholic hepatitis);

- an increase in the activity of "hepatic" transaminases of unknown origin more than 3-fold compared with the upper limit of the norm;

- simultaneous application with fusidic acid;

- use in women of childbearing age who do not use adequate methods of contraception;

- pregnancy;

- the period of breastfeeding;

- age under 18 years (effectiveness and safety not established);

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome.

Carefully:

With caution should be appointed for severe violations of water-electrolyte balance, endocrine and metabolic disorders, diabetes, alcohol abuse, liver diseases in history, arterial hypotension, severe acute infections, uncontrolled convulsions, cerebral circulation disorders, extensive surgical interventions and injuries.

Caution should be exercised in patients with risk factors for rhabdomyolysis (renal dysfunction, hypothyroidism, hereditary muscle disorders in a patient in the anamnesis or family history, already suffered toxic effects of HMG-CoA reductase inhibitors (statins) or fibrates on muscle tissue, diseases a history of liver 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, such as interactions with other drugs, is expected (see section "Interaction with Other Drugs").

Pregnancy and lactation:

The use of the drug during pregnancy is contraindicated. Women of reproductive age should be treated with reliable contraceptive methods when taking atorvastatin. If the patient is planning a pregnancy, she should stop taking the drug at least 1 month before the planned pregnancy.

Application of the drug atorvastatin contraindicated during lactation. It is not known whether atorvastatin in breast milk. However, if it is necessary to use the drug during lactation in order to avoid the risk of developing unwanted reactions in infants, breastfeeding should be stopped.

Dosing and Administration:

The drug is taken orally, regardless of the time of ingestion.

Before starting therapy, try to control hypercholesterolemia with using physical exercises and weight loss in obese patients, as well as therapy for the underlying disease.When using the drug, the patient should be recommended a standard hypocholesterolemic diet, which the patient must adhere to during the entire period of therapy.

The dose of the drug varies from 10 mg to 80 mg once a day. The dose is selected taking into account the initial level of Xc-LDL, the purpose and effectiveness of the therapy.

The maximum daily dose is 80 mg.

Atorvastatin is taken once at any time of the day, but at the same time every day.

At the beginning of therapy and / or during a dose increase, it is necessary to monitor the concentration of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

Primary (heterozygous hereditary and polygenic) hypercholesterolemia (type IIa) and mixed hyperlipidemia (type IIb)

For the majority of patients - 10 mg once a day; The therapeutic effect develops within 2 weeks and usually reaches a maximum within 4 weeks. With prolonged treatment, the effect persists.

Homozygous hereditary hypercholesterolemia

The initial dose is selected individually depending on the severity of the disease.In most cases, appoint 80 mg once a day.

Prevention of cardiovascular diseases

The recommended initial dose of the drug is 10 mg per day. Further dose titration is performed until the target concentration of LDL-C is reached in the blood plasma.

Elderly patients

The difference in the efficacy, safety or therapeutic effect of the drug in elderly patients is not found in comparison with the general population, and dose adjustment is not required.

Lack of kidney function

Lack of liver function

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

Use in combination with other medicines

If a simultaneous use with cyclosporine, telaprevir or a combination of tipranavir / ritonavir is required, the dose of the drug should not exceed 10 mg / day (see section "Special instructions").

Caution should be exercised and the lowest effective dose of the drug should be used when used simultaneously with HIV protease inhibitorssaquinavir, indinavir, ritonavir, nelfinavir, darunavir, fosamprenavir), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole.

Side effects:

Classification of the frequency of development of side effects of the World Health Organization (WHO):

Very often> 1/10

Frequently from> 1/100 to <1/10

Infrequently from> 1/1000 to <1/100

Rarely from> 1/10000 to <1/1000

Very rarely to <1/10000, including individual messages

Frequency is unknown - can not be calculated from available data.

Co the sides of the blood and lymphatic system: rarely - thrombocytopenia.

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

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

From the side of the organ of vision: infrequent - reduced clearness of vision; rarely - impaired visual perception.

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

On the part of the respiratory system, the organs of the thorax and the mediastinum: often - nasopharyngitis, epistaxis, pain in the pharyngeal region; frequency unknown - interstitial lung disease.

From the side of the digestive tract: often - nausea, flatulence, constipation, dyspepsia, diarrhea; infrequently - belching, vomiting, abdominal pain, pancreatitis.

From the liver and biliary tract: infrequently - hepatitis; rarely - cholestasis; very rarely - liver failure, cholestatic jaundice.

From the skin and subcutaneous tissues: infrequently - alopecia, skin rash, itching, hives; rarely - bullous dermatitis, erythema multiforme; very 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.

Laboratory indicators: often - hyperglycemia, increased activity of CK 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.

Other: infrequently - asthenia, weakness, chest pain, peripheral edema, fever, secondary renal failure, increased fatigue, weight gain, anorexia; very rarely - diabetes.

Overdose:

Cases of overdose are not described.

Treatment: Specific antidote for the treatment of drug overdose atorvastatin - no. In case of an overdose, the following general measures are necessary: monitoring and maintaining the vital functions of the body, as well as preventing further absorption of the drug (gastric lavage, intake of activated carbon or laxatives).

With the development of myopathy followed by rhabdomyolysis and acute renal failure (a rare but severe side effect), the drug should be immediately discontinued.The introduction of a diuretic and sodium bicarbonate solution is shown. Rhabdomyolysis can lead to hyperkalemia, which requires the intravenous administration of calcium chloride solution or calcium gluconate solution, the infusion of 5% dextrose (glucose) solution with insulin, the use of potassium-exchange resins.

Because the atorvastatin is largely associated with blood proteins, hemodialysis is an ineffective way of removing this substance from the body.

Interaction:

With simultaneous use of atorvastatin with cyclosporine, antibiotics (erythromycin, clarithromycin, quinupristine / delfopristin), HIV protease inhibitors (indinavir, ritonavir), antifungal agents from the azole group (fluconazole, itraconazole, ketoconazole), or with nefazadone the concentration of atorvastatin in the blood plasma increases, which increases the risk of myopathy with rhabdomyolysis and renal insufficiency. All these drugs inhibit the isoenzyme CYP3A4, which takes part in the metabolism of atorvastatin in the liver. Because the atorvastatin is metabolized by isoenzyme CYP3A4, simultaneous use of atorvastatin with isoenzyme inhibitors CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and potentiation effect is determined by the variability of the interaction with the isoenzyme CYP3A4. Thus, with simultaneous reception with erythromycin FROM_mOh Atorvastatin is increased by 40%.

A similar interaction is possible with simultaneous use of atorvastatin with fibrates and nicotinic acid in lipid-lowering doses (more than 1 g per day).

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

The simultaneous use of atorvastatin with phenytoin, rifampicin, which are inducers of isoenzyme CYP3A4, 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 inhibitors of the hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is not recommended, since delayed administration of atorvastatin after taking rifampicin results in a significant reduction in the concentration of atorvastatin in the blood plasma.

Inhibitors of transport protein OAT31B1 (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").

When combined with antacids (a suspension of magnesium hydroxide and aluminum hydroxide) reduces the content of atorvastatin in the blood plasma by about 35%, however, the degree of decrease in the concentration of LDL-C is not changed.

With simultaneous use of atorvastatin with colestipol the concentration of atorvastatin in the plasma is reduced by 25%, but the hypolipidemic effect of the combination of atorvastatin and colestipol exceeds that of each drug alone.

With simultaneous use of atorvastatin with drugs that reduce the concentration of endogenous steroid hormones (incl. cimetidine, ketoconazole, spironolactone), the risk of reducing endogenous steroid hormones increases (caution should be exercised).

When reapplying digoxin and atorvastatin at a dose of 10 mg per day, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when atorvastatin is used at a dose of 80 mg per day concomitantly with digoxin, the digoxin concentration is increased by 20% (patients taking this combination of drugs should be monitored).

With the 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.

The simultaneous use of atorvastatin with warfarin may in the first days increase the effect of warfarin on the parameters of blood coagulation (reduction of prothrombin time). This effect disappears after 15 days of simultaneous application of these drugs.

With the simultaneous use of atorvastatin and terfenadine there were no clinically significant changes in the pharmacokinetics of terfenadine.

Atorvastatin does not affect the pharmacokinetics phenazone, therefore, interaction with other drugs metabolized by the same isoenzymes of cytochrome P₄₅₀, is not expected.

Inhibitors of proteases

Value AUC for atorvastatin significantly increases with the simultaneous use of atorvastatin and certain combinations of HIV protease inhibitors, as well as atorvastatin and a protease inhibitor of hepatitis C virus of telaprevir. Therefore, simultaneous use of the drug should be avoided atorvastatin in patients taking a combination of HIV protease inhibitors tipranavir and ritonavir or protease inhibitor of viral hepatitis C telaprevir. Care should be taken with simultaneous application of the drug atorvastatin and combinations of HIV protease inhibitors lopinavir and ritonavir, it is also necessary to prescribe a reduced dose of atorvastatin. Care should be taken when using the drug simultaneously atorvastatin and combinations of HIV protease inhibitors saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir and ritonavir or fosamprenavir, while the dose of the drug atorvastatin should not exceed 20 mg.In patients taking an HIV protease inhibitor nelfinavir or a protease inhibitor of viral hepatitis C boceprevir, the dose of the drug atorvastatin should not exceed 40 mg, patients are recommended medical supervision.

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.

If the application fusidic acid consider 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 systemic therapy requires prolonged fusidic acid, for example, for the treatment of serious infections, the necessity of simultaneous application of atorvastatin and fusidic acid should be considered in each specific case and under strict medical supervision. The patient should immediately seek medical help if symptoms of muscle weakness, sensitivity, or pain appear.

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

When combined use of atorvastatin at a dose of 10 mg per day and azithromycin at a dose of 500 mg once a day, the concentration of atorvastatin in the blood plasma did not change.

Concomitant therapy

Clinically significant undesirable interactions with atorvastatin with antihypertensive drugs and estrogens in the framework of substitution therapy was not noted.

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

Ezetimibe

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

Colchicine

Caution should be exercised with the simultaneous use of atorvastatin with colchicine, in connection with an increased risk of myopathy.

Grapefruit juice

The consumption of grapefruit juice during the period of application of the drug may lead to an increase in the concentration of atorvastatin in the blood plasma, since grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4. In this regard, patients receiving atorvastatin, should avoid the use of grapefruit juice more than 1.2 liters per day.

Special instructions:

Before starting therapy with the drug atorvastatin the patient should be assigned a standard hypocholesterolemic diet, which must be observed during the entire treatment period.

When using atorvastatin, there may be an increase in the activity of CK and aminotransferases. This increase, as a rule, is small and has no clinical significance. However, it is recommended to monitor the level of activity of "liver" enzymes before treatment, 6 weeks, 12 weeks after the start of the drug and after increasing the dose, and periodically during the entire period of use. If there is a threefold increase in activity ACT and / or ALT as compared with the upper limit of the norm, the drug treatment should be discontinued. The increase in serum aminotransferase activity depends on the dose of the drug and is reversible in all patients.

Perhaps the excess of the upper limit of the activity rate of CK about 10 times.

Against the background of taking the drug, myalgia is possible.

The diagnosis of myopathy (muscle pain or muscle weakness, combined with an increase in CKK activity) is likely in patients with diffuse myalgia, muscle soreness or weakness, and / or a marked increase in CKK activity. When treating the drug atorvastatin, as with the use of other statins, it is rare, but possible development of rhabdomyolysis, leading to acute renal failure due to myoglobinuria. The risk of this complication increases with simultaneous administration with atorvastatin one or more of the following drugs: fibrates, nicotinic acid in lipid-lowering doses (more than 1 g per day), cyclosporine (daily dose of atorvastatin should not exceed 10 mg), nefazadone, certain antibioticserythromycin, clarithromycin, quinupristine / delfopristin), antifungal agents from the azole group (fluconazole, itraconazole, ketoconazole), HIV protease inhibitors (indinavir, ritonavir).

It is not recommended simultaneous use of atorvastatin and fusidic acid. Therapy with statins can be resumed 7 days after the last intake of fusidic acid. In exceptional cases where systemic therapy requires prolonged fusidic acid, for example, for the treatment of serious infections, the necessity of simultaneous application of atorvastatin and fusidic acid should be considered in each specific case and under strict medical supervision. The patient should immediately seek medical help if symptoms of muscle weakness, sensitivity, or pain appear.

When there are symptoms of myopathy or the presence of risk factors for the development of renal failure, it is recommended to determine the serum activity of CK. If the activity of CK exceeds the upper limit of the norm by more than 10 times, treatment should be discontinued. In the differential diagnosis of chest pain, consideration should be given to the possibility of an increase in serum CPK activity when taking the drug.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 the above.

Patients should be warned that they should immediately consult a doctor if unexplained pain or muscle weakness occurs, especially if they are accompanied by ailments or fever.

The drug contains lactose monohydrate, and therefore its use by patients with lactase deficiency, lactose intolerance and glucose-galactose malabsorption syndrome is contraindicated.

Effect on cerebral circulation (prevention of stroke by intensive lipid-lowering therapy)

In a retrospective analysis of the various subspecies of stroke in people without ischemic heart disease who recently (within 6 months) suffered a stroke or transient ischemic attack, a higher risk of hemorrhagic stroke in patients taking atorvastatin in a dose of 80 to, compared with placebo. Especially high risk was observed in patients who had hemorrhagic stroke or lacunar infarction at the time of the beginning of the study.For patients who have had hemorrhagic stroke or lacunar infarction and are receiving atorvastatin in a dose of 80 mg, the risk / benefit ratio is ambiguous, and the potential risk of developing a hemorrhagic stroke should be carefully assessed before starting treatment.

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 (fasting blood glucose from 5.6 to 6.9 mmol / L, BMI> 30 mg / 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

Against the background of therapy with some inhibitors of HMG-CoA reductase (statins), especially against the background of prolonged therapy, there were isolated cases of interstitial lung disease. 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, atorvastatin should be withdrawn.

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

Data on the effect of atorvastatin on the ability to drive a car and engage in potentially dangerous activities that require increased concentration and speed of psychomotor reactions are not. However, taking into account the possibility of developing dizziness, care should be taken when driving vehicles and other technical devices that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

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

For 30 tablets in a jar of polymer materials.

For 3, 6 contour squares or 1 can of polymeric materials, together with instructions for medical use, put in a pack of cardboard.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003843

Date of registration:19.09.2016 / 29.09.2017

Expiration Date:19.09.2021

The owner of the registration certificate:IRBITSK HFZ, OJSC IRBITSK HFZ, OJSC Russia

Manufacturer: & nbsp

IRBITSK HFZ, OJSC Russia

Information update date: & nbsp21.03.2018

Illustrated instructions

Instructions

Atorvastatin Avexime (Atorvastatin Avexima)