Rosuvastatin-SZ Tablets, box, 60 pcs., 10 mg, for oral administration, film-coated

Nosological classification (ICD-10)

• E78.0 Pure hypercholesterolemia
• E78.1 Pure hyperglyceridemia
• E78.2 Mixed hyperlipidemia
• E78.5 Hyperlipidemia, unspecified
• I10 Essential (primary) hypertension
• I15 Secondary hypertension
• I21 Acute myocardial infarction
• I25.9 Chronic ischemic heart disease, unspecified
• I64 Stroke not specified as hemorrhage or infarction
• I70 Atherosclerosis
• Z72.0 Tobacco use
• Z82.4 Family history of coronary heart disease and other diseases of the cardiovascular system

Compound

Pharmacodynamics

Mechanism of action. Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl CoA into mevalonic acid, a precursor of cholesterol (CH). The main target of action of rosuvastatin is the liver, where cholesterol synthesis and LDL catabolism occur. Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of VLDL synthesis, thereby reducing the total number of LDL and VLDL.

Rosuvastatin-SZ reduces elevated concentrations of LDL-C, total cholesterol, triglycerides (TG), increases the concentration of HDL-C, and also reduces the concentrations of apolipoprotein B (ApoB), non-HDL-C, VLDL-C, VLDL-TG and increases the concentration of apolipoprotein A -I (ApoA-I), reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C and non-HDL-C/HDL-C ratio and the ApoB/ApoA-I ratio.

The therapeutic effect develops within 1 week after the start of therapy with Rosuvastatin-SZ; after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular use of the drug.

Rosuvastatin-SZ is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, gender or age, incl. in patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with Fredrickson type IIa and IIb hypercholesterolemia (average initial LDL-C concentration of about 4.8 mmol/l), while taking the drug at a dose of 10 mg, the LDL-C concentration reaches values ​​of less than 3 mmol/L.

In patients with heterozygous familial hypercholesterolemia receiving Rosuvastatin-SZ at a dose of 20–80 mg, positive dynamics of lipid profile indicators are noted. After titration to a daily dose of 40 mg (12 weeks of therapy), a decrease in LDL-C concentrations by 53% was observed. In 33% of patients, an LDL-C concentration of less than 3 mmol/l is achieved.

In patients with homozygous familial hypercholesterolemia taking Rosuvastatin-SZ at a dose of 20 and 40 mg, the average reduction in LDL-C concentration is 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL who received Rosuvastatin-SZ at a dose of 5 to 40 mg once daily for 6 weeks, the concentration of TG in the blood plasma significantly decreased.

An additive effect is observed in combination with fenofibrate in relation to TG content and nicotinic acid in lipid-lowering doses in relation to HDL-C content (see “Special Instructions”).

According to the results of clinical studies, patients with severe hypercholesterolemia and a high risk of cardiovascular diseases should be prescribed a dose of Rosuvastatin-SZ 40 mg.

Results from a clinical trial (Rationale for Statins in Primary Prevention: An Intervention Study Evaluating Rosuvastatin) showed that rosuvastatin significantly reduced the risk of cardiovascular events.

Rosuvastatin-SZ

The effect of the use of other drugs on rosuvastatin

Transport protein inhibitors:

Rosuvastatin binds to some transport proteins, in particular OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in plasma concentrations of rosuvastatin and an increased risk of developing myopathy (see Table 1 and sections “Dosage and Administration” and “Special Instructions”).

Cyclosporine:

with simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 1). Does not affect plasma concentrations of cyclosporine. Rosuvastatin-SZ is contraindicated in patients taking cyclosporine (see section "Contraindications").

Viral protease inhibitors

human immunodeficiency (HIV):

Although the exact mechanism of interaction is unknown, coadministration of HIV protease inhibitors may result in a significant increase in rosuvastatin exposure (see Table 1). A pharmacokinetic study of co-administration of 20 mg rosuvastatin with a combination drug containing two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers resulted in approximately two-fold and five-fold increases in AUC(0-24) and Cmax of rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and Administration”, “Contraindications” and “Special Instructions”, Table 1).

Gemfibrozil and other lipid-lowering drugs:

The combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in the maximum concentration of rosuvastatin in the blood plasma and the AUC of rosuvastatin (see section "Special Instructions"). Based on specific interaction data, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section "Special Instructions") . When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), an initial dose of the drug of 5 mg is recommended for patients; taking a dose of 40 mg is contraindicated when co-administered with fibrates (see sections “Contraindications”, “ Method of administration and dosage", "Special instructions").

Ezetimibe:

simultaneous use of the drug Rosuvastatin-SZ at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). An increased risk of side effects due to the pharmacodynamic interaction between Rosuvastatin-SZ and ezetimibe cannot be excluded.

Antacids:

simultaneous use of rosuvastatin and antacid suspensions containing magnesium and aluminum hydroxide leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin:

simultaneous use of rosuvastatin and erythromycin leads to a decrease in AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by erythromycin.

Cytochrome P450 isoenzymes:

in vivo
and
in vitro
studies showed that rosuvastatin is neither an inhibitor nor an inducer

cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level involving cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction between rosuvastatin and fluconazole (an inhibitor

isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4).

Drug interactions that require rosuvastatin dose adjustment (see Table 1)

The dose of Rosuvastatin-SZ should be adjusted if it is necessary to use it together with drugs that increase exposure to rosuvastatin. If exposure is expected to increase by 2 times or more, the initial dose of Rosuvastatin-SZ should be 5 mg once daily. The maximum daily dose of Rosuvastatin-SZ should also be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of Rosuvastatin-SZ when used simultaneously with gemfibrozil is 20 mg (increased exposure by 1.9 times), with ritonavir/atazanavir - 10 mg (increased exposure by 3.1 times).

Table 1.

Effect of concomitant therapy on exposure to rosuvastatin
( AUC , data are given in descending order) - results of published clinical studies descending) - results of published clinical studies

The effect of rosuvastatin on other drugs

Vitamin K antagonists:

Initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (for example, warfarin) may lead to an increase in International

Normalized Attitude (MHO). Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in MHO. In such cases, monitoring of MHO is recommended.

Oral contraceptives/
hormone replacement therapy:
Concomitant use of rosuvastatin and oral contraceptives increases ethinyl estradiol AUC and norgestrel AUC by 26% and 34%, respectively. This increase in plasma concentration should be taken into account when selecting the dose of oral

contraceptives.

There are no pharmacokinetic data on the simultaneous use of Rosuvastatin-SZ and hormone replacement therapy,

therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other medicines:

No clinically significant interaction between rosuvastatin and digoxin is expected.

Pharmacokinetics

Absorption and distribution. Tmax of rosuvastatin in blood plasma is approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%. Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and LDL-C metabolism. Vd of rosuvastatin is approximately 134 l. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism. Subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. Isoenzymes CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism to a lesser extent.

The main identified metabolites of rosuvastatin are N-desmethyl rosuvastatin and lactone metabolites. N-desmethyl rosuvastatin is approximately 50% less active than rosuvastatin; the lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest is provided by its metabolites.

Excretion. About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remaining part is excreted by the kidneys. Plasma T1/2 is approximately 19 hours. T1/2 does not change with increasing doses of the drug. The geometric mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the process of hepatic uptake of rosuvastatin involves a membrane cholesterol transporter, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily use.

Special patient groups

Age and gender. Gender and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups. Pharmacokinetic studies have shown an approximately twofold increase in the median AUC and Cmax of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Caucasians; Indians showed a 1.3-fold increase in median AUC and Cmax. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasians and representatives of the Negroid race.

Renal dysfunction. In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethylrosuvastatin does not change significantly. In patients with severe renal failure (Cl creatinine less than 30 ml/min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration of N-desmethyl rosuvastatin is 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in hemodialysis patients were approximately 50% higher than in healthy volunteers.

Liver dysfunction. In patients with various stages of liver failure (7 points and below on the Child-Pugh scale), an increase in T1/2 of rosuvastatin was not detected. In two patients with 8 and 9 points on the Child-Pugh scale, an increase in T1/2 was noted by at least 2 times. There is no experience with the use of rosuvastatin in patients with a Child-Pugh score of more than 9.

Genetic polymorphism. HMG-CoA reductase inhibitors, incl. rosuvastatin bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in the uptake of statins by hepatocytes) and BCRP (efflux transporter). Carriers of the SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes had an increase in rosuvastatin exposure (AUC) by 1.6 and 2.4 times, respectively, compared with carriers of the SLCO1B1 c.521TT and ABCG2 c.421CC genotypes.

ROSUVASTATIN-SZ film-coated tablets 5 mg No. 30

Pharmacotherapeutic group of the drug: hypolipidemic agent - HMG-CoA reductase inhibitor ATC code: [C10AA07] Pharmacological properties Pharmacodynamics Mechanism of action Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, a cholesterol precursor. The main target of action of rosuvastatin is the liver, where the synthesis of cholesterol (C) and the catabolism of low-density lipoproteins (LDL) take place. Rosuvastatin increases the number of "liver" LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of very low-density lipoprotein (VLDL) synthesis, thereby reducing the total amount of LDL and VLDL. Pharmacodynamics Rosuvastatin-SZ reduces elevated concentrations of LDL-cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoB), non-HDL-C , VLDL-C, VLDL-TG and increases the concentration of apolipoprotein A-I (ApoA-I), reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA ratio -I. The therapeutic effect develops within one week after the start of therapy with Rosuvastatin-SZ; after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular use of the drug. Rosuvastatin-SZ is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, gender or age, including patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with Fredrickson type IIa and IIb hypercholesterolemia (average initial LDL-C concentration of about 4.8 mmol/l), while taking the drug at a dose of 10 mg, the LDL-C concentration reaches values ​​of less than 3 mmol/L. In patients with heterozygous familial hypercholesterolemia receiving Rosuvastatin-SZ at a dose of 20-80 mg, positive dynamics of lipid profile indicators are noted. After titration to a daily dose of 40 mg (12 weeks of therapy), a decrease in LDL-C concentrations by 53% was observed. In 33% of patients, an LDL-C concentration of less than 3 mmol/l is achieved. In patients with homozygous familial hypercholesterolemia taking Rosuvastatin-SZ at doses of 20 mg and 40 mg, the average reduction in LDL-C concentration is 22%. In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL who received Rosuvastatin-SZ at a dose of 5 mg to 40 mg once daily for 6 weeks, the concentration of TG in the blood plasma significantly decreased. An additive effect is observed in combination with fenofibrate in relation to the content of triglycerides and with nicotinic acid in lipid-lowering doses in relation to the content of HDL-C (see also section “Special instructions”). According to the results of clinical studies, patients with severe hypercholesterolemia and a high risk of cardiovascular diseases (CVD) should be prescribed a dose of Rosuvastatin-SZ 40 mg. Results from a clinical trial (Rationale for Statins in Primary Prevention: An Intervention Study Evaluating Rosuvastatin) showed that rosuvastatin significantly reduced the risk of cardiovascular events. Pharmacokinetics Absorption and distribution The maximum concentration of rosuvastatin in blood plasma is achieved approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%. Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and LDL-C metabolism. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin. Metabolism Subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. The isoenzymes CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism to a lesser extent. The main identified metabolites of rosuvastatin are N-desmethylrosuvastatin and lactone metabolites. N-desmethyl rosuvastatin is approximately 50% less active than rosuvastatin; the lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest is provided by its metabolites. Excretion About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remaining part is excreted by the kidneys. The plasma half-life (T1/2) is approximately 19 hours. The half-life does not change with increasing dosage of the drug. The geometric mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the process of “hepatic” uptake of rosuvastatin involves a membrane cholesterol transporter, which plays an important role in the hepatic elimination of rosuvastatin. Linearity Systemic exposure of rosuvastatin increases proportionally to the dose. Pharmacokinetic parameters do not change with daily use. Special populations of patients. Age and gender Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin. Ethnic groups Pharmacokinetic studies have shown an approximately twofold increase in the median AUC (area under the concentration-time curve) and Cmax (maximum plasma concentration) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Caucasians; Indians showed an increase in median AUC and Cmax by 1.3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasians and representatives of the Negroid race. Renal failure In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethylrose-vastatin does not change significantly. In patients with severe renal failure (creatinine clearance (CC) less than 30 ml/min.), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration of N-desmethylrosuvastatin is 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in hemodialysis patients were approximately 50% higher than in healthy volunteers. Liver failure In patients with various stages of liver failure, there was no increase in the half-life of rosuvastatin in patients with a Child-Pugh score of 7 or lower. In two patients with Child-Pugh scores of 8 and 9, an increase in the half-life of at least 2 times was noted. There is no experience with the use of rosuvastatin in patients with a Child-Pugh score of more than 9.

Indications of the drug Rosuvastatin-SZ

primary hypercholesterolemia according to the Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an addition to diet when diet and other non-drug treatments (eg exercise, weight loss) are insufficient;

familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (eg LDL apheresis) or in cases where such therapy is not sufficiently effective;

hypertriglyceridemia (type IV according to the Fredrickson classification) as an addition to the diet;

slowing the progression of atherosclerosis as an addition to diet in patients who are indicated for therapy to reduce the concentration of total cholesterol and LDL-C;

primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of coronary heart disease, but with an increased risk of its development (age over 50 years for men and over 60 years for women, increased concentration of C-reactive protein (≥2 mg/l) in the presence of at least one of the additional risk factors, such as arterial hypertension, low HDL-C concentration, smoking, family history of early onset coronary heart disease).

Rosuvastatin-SZ tablets 40 mg 30 pcs. in Orenburg

Inside,

without chewing or crushing, swallow whole, wash down with water. The drug can be prescribed at any time of the day, regardless of meals.

Before starting therapy with Rosuvastatin-SZ, the patient should begin to follow a standard cholesterol-lowering diet and continue to follow it during treatment. The dose of the drug should be selected individually, depending on the goals of therapy and the therapeutic response to treatment, taking into account current recommendations for target lipid concentrations.

The recommended initial dose for patients starting to take the drug or transferred from taking other HMG-CoA reductase inhibitors should be 5 or 10 mg of Rosuvastatin-SZ 1 time per day. When choosing an initial dose, one should be guided by the individual cholesterol level and take into account the possible risk of cardiovascular complications, and it is also necessary to assess the potential risk of side effects. If necessary, the dose can be increased to a higher dose after 4 weeks (see “Pharmacodynamics”).

Due to the possible development of side effects when taking a dose of 40 mg compared to lower doses of the drug (see “Side effects”), increasing the dose to 40 mg (after an additional dose above the recommended initial dose within 4 weeks of therapy) can only be carried out in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), who have not achieved the desired result of therapy when taking a dose of 20 mg, and who will be under the supervision of a specialist (see "Special Instructions" ). Particularly careful monitoring of patients receiving the drug at a dose of 40 mg is recommended.

It is not recommended to prescribe a dose of 40 mg to patients who have not previously consulted a doctor. After 2–4 weeks of therapy and/or when increasing the dose of Rosuvastatin-SZ, monitoring of lipid metabolism parameters is necessary (dose adjustment is required if necessary).

Special patient groups

Elderly patients.

No dose adjustment required.

Renal dysfunction.

No dosage adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal failure (creatinine clearance less than 30 ml/min), the use of Rosuvastatin-SZ is contraindicated. The use of the drug at a dose of 40 mg is contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 ml/min) (see “Pharmacodynamics” and “Special Instructions”). For patients with moderate renal impairment, an initial dose of 5 mg is recommended.

Liver dysfunction.

Rosuvastatin-SZ is contraindicated in patients with active liver disease (see “Contraindications”).

Ethnic groups.

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in the systemic concentration of rosuvastatin was noted in the Japanese and Chinese (see “Special Instructions”). This fact should be taken into account when prescribing Rosuvastatin-SZ to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended starting dose for patients of the Mongoloid race is 5 mg. The administration of the drug at a dose of 40 mg is contraindicated to patients of the Mongoloid race (see “Contraindications”).

Genetic polymorphism.

Carriers of the SLCO1B1 (OATP1B1) c.521CC and ABCG2 (
BCRP
) c.421AA genotypes showed an increase in exposure (AUC) to rosuvastatin compared to carriers of the SLCO1B1 c.521TT and ABCG2 c.421CC genotypes. For patients carrying genotypes c.521CC or c.421AA, the recommended maximum dose of Rosuvastatin-SZ is 20 mg once a day (see “Pharmacokinetics”, “Interaction” and “Special instructions”).

Patients predisposed to myopathy.

Prescribing the drug at a dose of 40 mg is contraindicated in patients with factors that may indicate a predisposition to the development of myopathy (see “Contraindications”). When prescribing doses of 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg (see “Contraindications”).

Concomitant therapy.

Rosuvastatin binds to various transport proteins (in particular OATP1B1 and
BCRP
). When co-administering Rosuvastatin-SZ with drugs (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy may increase ( including rhabdomyolysis) (see “Interaction” and “Special instructions”). In such cases, the possibility of prescribing alternative therapy or temporarily stopping the use of Rosuvastatin-SZ should be assessed. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosuvastatin-SZ should be assessed and the possibility of reducing its dose should be considered (see “Interactions”).

Contraindications

For all daily doses

hypersensitivity to rosuvastatin or any of the components of the drug;

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

simultaneous use of cyclosporine;

an increase in the concentration of CPK in the blood by more than 5 times compared to the ULN;

combined use with HIV protease inhibitors;

myopathy;

lack of adequate contraceptive methods;

pregnancy;

breastfeeding period;

children under 18 years of age.

Additionally for the drug Rosuvastatin-SZ in a daily dose of 5, 10, and 20 mg

liver diseases in the active phase, including a persistent increase in serum transaminase activity and any increase in transaminase activity in the blood serum (more than 3 times compared to ULN);

severe renal failure (creatinine Cl less than 30 ml/min);

patients predisposed to the development of myotoxic complications.

Additionally for the drug Rosuvastatin-SZ at a daily dose of 40 mg

moderate to severe renal failure (creatinine Cl less than 60 ml/min);

liver disease in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (more than 3 times compared to ULN) in patients with risk factors for the development of myopathy/rhabdomyolysis, namely:

- hypothyroidism;

— myotoxicity due to a history of taking other HMG-CoA reductase inhibitors or fibrates;

- excessive alcohol consumption;

- conditions that can lead to increased plasma concentrations of rosuvastatin;

- simultaneous use of fibrates;

personal or family history of muscle diseases;

patients of the Mongoloid race.

Carefully

For all daily doses: patients over 65 years of age; history of liver disease; sepsis; arterial hypotension; major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances, or uncontrolled seizures; simultaneous use with colchicine and ezetimibe.

Additionally, for the drug Rosuvastatin-SZ at a daily dose of 5, 10, and 20 mg: there is a risk of developing myopathy/rhabdomyolysis - renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; conditions in which an increase in plasma concentration of rosuvastatin is noted; race (Mongoloid race); simultaneous administration with fibrates (see “Pharmacokinetics”).

Additionally, for the drug Rosuvastatin-SZ at a daily dose of 40 mg: mild renal failure (creatinine Cl more than 60 ml/min).

Patients with liver failure

There are no data or experience with the use of the drug in patients with more than 9 points on the Child-Pugh scale (see “Pharmacodynamics” and “Special Instructions”).

Rosuvastatin-SZ, tablets coated. captivity. about. 20 mg, 30 pcs.

Renal effects

In patients receiving high doses of Rosuvastatin-SZ (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. This proteinuria did not indicate acute illness or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

From the musculoskeletal system

When using the drug Rosuvastatin-SZ in all doses, and especially when taking doses of the drug exceeding 20 mg, the following reactions from the musculoskeletal system were reported: myalgia, myopathy; in rare cases - rhabdomyolysis.

Determination of CPK

Determination of CPK activity should not be carried out after intense physical activity or in the presence of other possible reasons for increased CPK activity, which may lead to incorrect interpretation of the results obtained. If the initial CPK activity is significantly increased (5 times higher than ULN), a repeat measurement should be taken after 5–7 days. Therapy should not be started if a repeat test confirms the initial CPK activity (more than 5 times higher than the ULN).

Before starting therapy

When prescribing Rosuvastatin-SZ, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see Caution

), it is necessary to consider the balance of risk and possible benefit of therapy and conduct clinical observation.

During therapy

The patient should be informed to immediately notify the doctor if there is a sudden onset of muscle pain, muscle weakness or spasms, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (more than 5 times compared to ULN) or muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times less than ULN). If symptoms disappear and CPK activity returns to normal, re-prescribing Rosuvastatin-SZ or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient.

Routine monitoring of CPK activity in the absence of symptoms is impractical.

Very rare cases of immune-mediated necrotizing myopathy have been reported with clinical manifestations in the form of persistent weakness of the proximal muscles and an increase in serum CPK levels during treatment or upon discontinuation of statins, incl. rosuvastatin. Additional studies of the muscular and nervous system, serological studies, and therapy with immunosuppressive drugs may be required.

There were no signs of increased effects on skeletal muscles when taking the drug Rosuvastatin-SZ and concomitant therapy. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used together with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of Rosuvastatin-SZ and gemfibrozil is not recommended. The risk/benefit ratio should be carefully weighed when using Rosuvastatin-SZ together with fibrates or lipid-lowering doses of nicotinic acid. Taking the drug Rosuvastatin-SZ at a dose of 40 mg together with fibrates is contraindicated (see “Contraindications” and “Interaction”).

2–4 weeks after the start of treatment and/or when the dose of Rosuvastatin-SZ is increased, monitoring of lipid metabolism parameters is necessary (dose adjustment is required if necessary).

Liver

It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. Taking Rosuvastatin-SZ should be stopped or the dose reduced if the activity of transaminases in the blood serum is 3 times higher than the ULN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment for underlying diseases should be carried out before starting treatment with Rosuvastatin-SZ.

Ethnic groups

In pharmacokinetic studies, an increase in systemic concentrations of rosuvastatin was noted in Chinese and Japanese patients compared to Caucasian patients (see “Pharmacokinetics” and “Dosage and Administration”).

HIV protease inhibitors

Concomitant use of the drug with HIV protease inhibitors is not recommended (see “Contraindications” and “Interaction”).

Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, non-productive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus type 2

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, treatment with Rosuvastatin-SZ was associated with an increased risk of developing type 2 diabetes mellitus.

Impact on the ability to drive vehicles and operate machinery.

No studies have been conducted to study the effect of the drug Rosuvastatin-SZ on the ability to drive a vehicle and use machinery. Caution should be exercised when driving vehicles or doing work that requires increased concentration and speed of psychomotor reactions (dizziness may occur during therapy).

Use during pregnancy and breastfeeding

Rosuvastatin-SZ is contraindicated during pregnancy and breastfeeding.

Women of reproductive age should use adequate methods of contraception.

Since cholesterol and cholesterol biosynthesis products are important for fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefit of using the drug in pregnant women.

If pregnancy occurs during therapy, the drug should be discontinued immediately.

There are no data regarding the excretion of rosuvastatin in breast milk, therefore, during breastfeeding, the drug should be discontinued (see “Contraindications”).

Side effects

Side effects observed when taking the drug Rosuvastatin-SZ are usually mild and go away on their own. As with other HMG-CoA reductase inhibitors, the incidence of side effects is mainly dose-dependent.

The incidence of undesirable effects is presented as follows: often - ≥1/100, <1/10; uncommon - ≥1/1000, <1/100; rarely - ≥1/10000, <1/1000; very rarely - <1/10000; unspecified frequency (cannot be calculated from available data).

From the immune system: rarely - hypersensitivity reactions, including angioedema.

From the endocrine system: often - diabetes mellitus type 2.

From the side of the central nervous system: often - headache, dizziness.

From the digestive tract: often - constipation, nausea, abdominal pain; rarely - pancreatitis.

From the skin: infrequently - itching, rash, urticaria.

From the musculoskeletal system: often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis.

Other: often - asthenic syndrome.

From the urinary system: in patients receiving Rosuvastatin-SZ, proteinuria may be detected. Changes in the amount of protein in the urine (from none or trace amounts to "++" or more) are observed in less than 1% of patients receiving 10-20 mg of the drug and in approximately 3% of patients receiving 40 mg of the drug. A slight change in the amount of protein in the urine was noted when taking a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset of acute or progression of existing kidney disease.

From the musculoskeletal system: when using the drug Rosuvastatin-SZ in all doses, and especially when taking doses of the drug exceeding 20 mg, the following reactions from the musculoskeletal system were reported - myalgia, myopathy (including myositis); rarely - rhabdomyolysis with or without acute renal failure. A dose-dependent increase in CPK activity is observed in a small number of patients taking rosuvastatin. In most cases it was minor, asymptomatic and temporary. If CPK activity increases (more than 5 times compared to ULN), therapy should be suspended (see “Special Instructions”).

From the liver: when using rosuvastatin, a dose-dependent increase in the activity of hepatic transaminases is observed in a small number of patients. In most cases it is minor, asymptomatic and temporary.

Laboratory indicators: increased concentrations of glucose, bilirubin, GGTP activity, alkaline phosphatase, dysfunction of the thyroid gland.

Post-marketing use

From the hematopoietic system: unspecified frequency - thrombocytopenia.

From the digestive tract: very rarely - jaundice, hepatitis; rarely - increased activity of liver transaminases; unspecified frequency - diarrhea.

From the musculoskeletal system: very rarely - arthralgia; unspecified frequency - immune-mediated necrotizing myopathy.

From the side of the central nervous system: very rarely - polyneuropathy, memory loss.

From the respiratory system: unspecified frequency - cough, shortness of breath.

From the urinary system: very rarely - hematuria.

On the part of the skin and subcutaneous fat: unspecified frequency - Stevens-Johnson syndrome.

From the reproductive system and mammary gland: unspecified frequency - gynecomastia.

Other: unspecified frequency - peripheral edema.

The following side effects have been reported with some statins: depression, sleep disturbances including insomnia and nightmares, and sexual dysfunction. Isolated cases of interstitial lung disease have been reported, especially with long-term use of drugs (see "Special Instructions").

Rosuvastatin-SZ, 60 pcs., 20 mg, film-coated tablets

Renal effects

In patients receiving high doses of Rosuvastatin-SZ (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. This proteinuria did not indicate acute illness or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

From the musculoskeletal system

When using the drug Rosuvastatin-SZ in all doses, and especially when taking doses of the drug exceeding 20 mg, the following reactions from the musculoskeletal system were reported: myalgia, myopathy; in rare cases - rhabdomyolysis.

Determination of CPK

Determination of CPK activity should not be carried out after intense physical activity or in the presence of other possible reasons for increased CPK activity, which may lead to incorrect interpretation of the results obtained. If the initial CPK activity is significantly increased (5 times higher than ULN), a repeat measurement should be taken after 5–7 days. Therapy should not be started if a repeat test confirms the initial CPK activity (more than 5 times higher than the ULN).

Before starting therapy

When prescribing Rosuvastatin-SZ, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see Caution

), it is necessary to consider the balance of risk and possible benefit of therapy and conduct clinical observation.

During therapy

The patient should be informed to immediately notify the doctor if there is a sudden onset of muscle pain, muscle weakness or spasms, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (more than 5 times compared to ULN) or muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times less than ULN). If symptoms disappear and CPK activity returns to normal, re-prescribing Rosuvastatin-SZ or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient.

Routine monitoring of CPK activity in the absence of symptoms is impractical.

Very rare cases of immune-mediated necrotizing myopathy have been reported with clinical manifestations in the form of persistent weakness of the proximal muscles and an increase in serum CPK levels during treatment or upon discontinuation of statins, incl. rosuvastatin. Additional studies of the muscular and nervous system, serological studies, and therapy with immunosuppressive drugs may be required.

There were no signs of increased effects on skeletal muscles when taking the drug Rosuvastatin-SZ and concomitant therapy. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used together with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of Rosuvastatin-SZ and gemfibrozil is not recommended. The risk/benefit ratio should be carefully weighed when using Rosuvastatin-SZ together with fibrates or lipid-lowering doses of nicotinic acid. Taking the drug Rosuvastatin-SZ at a dose of 40 mg together with fibrates is contraindicated (see “Contraindications” and “Interaction”).

2–4 weeks after the start of treatment and/or when the dose of Rosuvastatin-SZ is increased, monitoring of lipid metabolism parameters is necessary (dose adjustment is required if necessary).

Liver

It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. Taking Rosuvastatin-SZ should be stopped or the dose reduced if the activity of transaminases in the blood serum is 3 times higher than the ULN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment for underlying diseases should be carried out before starting treatment with Rosuvastatin-SZ.

Ethnic groups

In pharmacokinetic studies, an increase in systemic concentrations of rosuvastatin was noted in Chinese and Japanese patients compared to Caucasian patients (see “Pharmacokinetics” and “Dosage and Administration”).

HIV protease inhibitors

Concomitant use of the drug with HIV protease inhibitors is not recommended (see “Contraindications” and “Interaction”).

Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, non-productive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus type 2

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, treatment with Rosuvastatin-SZ was associated with an increased risk of developing type 2 diabetes mellitus.

Impact on the ability to drive vehicles and operate machinery.

No studies have been conducted to study the effect of the drug Rosuvastatin-SZ on the ability to drive a vehicle and use machinery. Caution should be exercised when driving vehicles or doing work that requires increased concentration and speed of psychomotor reactions (dizziness may occur during therapy).

Interaction

The effect of the use of other drugs on rosuvastatin

Transport protein inhibitors: rosuvastatin binds to some transport proteins, in particular OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in plasma concentrations of rosuvastatin and an increased risk of developing myopathy (see Table 1, “Dosage and Administration” and “Special Instructions”).

Cyclosporine: with simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 1). Does not affect plasma concentrations of cyclosporine. Rosuvastatin-SZ is contraindicated in patients taking cyclosporine (see "Contraindications").

HIV protease inhibitors: Although the exact mechanism of interaction is unknown, coadministration of HIV protease inhibitors may result in a significant increase in rosuvastatin exposure (see Table 1). A pharmacokinetic study of the simultaneous use of 20 mg rosuvastatin with a combination drug containing two HIV protease inhibitors (lopinavir, 400 mg + ritonavir, 100 mg) in healthy volunteers resulted in an approximately two-fold and five-fold increase in AUC0-24 and Cmax of rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see “Contraindications”, “Dosage and Administration” and “Special Instructions”, Table 1).

Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax of rosuvastatin in blood plasma and AUC of rosuvastatin (see “Special Instructions”). Based on specific interaction data, PEF is not expected with fenofibrate, but FDV is possible.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see "Special Instructions"). When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), an initial dose of the drug of 5 mg is recommended for patients; taking a dose of 40 mg is contraindicated when co-administered with fibrates (see “Contraindications”, “Method of administration”) and doses", "Special instructions").

Ezetimibe: simultaneous use of Rosuvastatin-SZ at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). An increase in the risk of side effects due to FDV between Rosuvastatin-SZ and ezetimibe cannot be excluded.

Antacids: simultaneous use of rosuvastatin and antacid suspensions containing magnesium and aluminum hydroxide leads to a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin: simultaneous use of rosuvastatin and erythromycin leads to a decrease in AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by erythromycin.

Cytochrome P450 isoenzymes: results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these enzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level involving cytochrome P450 isoenzymes is not expected.

There was no clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes).

Interaction with drugs that requires dose adjustment of rosuvastatin (see Table 1)

The dose of Rosuvastatin-SZ should be adjusted if it is necessary to use it together with drugs that increase the exposure of rosuvastatin. If exposure is expected to increase by 2 times or more, the initial dose of Rosuvastatin-SZ should be 5 mg once a day. You should also adjust the maximum daily dose of Rosuvastatin-SZ so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of Rosuvastatin-SZ when used simultaneously with gemfibrozil is 20 mg (increased exposure by 1.9 times), with ritonavir/atazanavir - 10 mg (increased exposure by 3.1 times).

Table 1

Effect of concomitant therapy on rosuvastatin exposure (AUC, data in descending order) - results of published clinical studies

Effect of rosuvastatin on other drugs

Vitamin K antagonists: Initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (eg warfarin) may lead to an increase in INR. Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in MHO. In such cases, monitoring of MHO is recommended.

Oral contraceptives/hormone replacement therapy: Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUC of norgestrel by 26 and 34%, respectively. This increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives. There are no pharmacokinetic data on the simultaneous use of Rosuvastatin-SZ and hormone replacement therapy; therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other drugs: A clinically significant interaction between rosuvastatin and digoxin is not expected.

Rosuvastatin-SZ Tablets, box, 60 pcs., 10 mg, for oral administration, film-coated

Interaction with other drugs

Effect of the use of other drugs on rosuvastatin Transport protein inhibitors: rosuvastatin binds to some transport proteins, in particular OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in plasma and an increased risk of developing myopathy (see table 1, “Dosage and Administration” and “Special instructions”). Cyclosporine: with simultaneous use of rosuvastatin and cyclosporine The AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 1). Does not affect plasma concentrations of cyclosporine. Rosuvastatin-SZ is contraindicated in patients taking cyclosporine (see Contraindications). HIV protease inhibitors: Although the exact mechanism of interaction is unknown, coadministration of HIV protease inhibitors may result in a significant increase in rosuvastatin exposure (see Table 1). A pharmacokinetic study of the simultaneous use of 20 mg rosuvastatin with a combination drug containing two HIV protease inhibitors (lopinavir, 400 mg + ritonavir, 100 mg) in healthy volunteers resulted in an approximately two-fold and five-fold increase in AUC0-24 and Cmax of rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see “Contraindications”, “Method of administration and dosage” and “Special instructions”, table 1). Gemfibrozil and other lipid-lowering drugs: combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax of rosuvastatin in blood plasma and AUC of rosuvastatin (see “Special Instructions”). Based on specific interaction data, FFI is not expected to occur with fenofibrate, but FDV is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they may cause myopathy when used in monotherapy (see "Special Instructions"). When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), an initial dose of the drug of 5 mg is recommended for patients; taking a dose of 40 mg is contraindicated when co-administered with fibrates (see “Contraindications”, “Method of administration”) and doses", "Special instructions") Ezetimibe: simultaneous use of the drug Rosuvastatin-SZ at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). An increase in the risk of side effects due to FDV between the drug Rosuvastatin-SZ and ezetimibe cannot be excluded. Antacids: simultaneous use of rosuvastatin and antacid suspensions containing magnesium and aluminum hydroxide leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied. Erythromycin: simultaneous use of rosuvastatin and erythromycin leads to a decrease in rosuvastatin AUC by 20% and rosuvastatin Cmax by 30%. Such an interaction may occur as a result of increased intestinal motility caused by erythromycin. Cytochrome P450 isoenzymes: the results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these enzymes. Therefore, interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is not expected. There is no clinically significant interaction of rosuvastatin with fluconazole (inhibitor of the CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (inhibitor of the CYP2A6 and CYP3A4 isoenzymes). Interaction with drugs that requires dose adjustment rosuvastatin (see Table 1) The dose of Rosuvastatin-SZ should be adjusted if it is necessary to use it together with drugs that increase the exposure of rosuvastatin. If exposure is expected to increase by 2 times or more, the initial dose of Rosuvastatin-SZ should be 5 mg once a day. You should also adjust the maximum daily dose of Rosuvastatin-SZ so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of Rosuvastatin-SZ when used simultaneously with gemfibrozil is 20 mg (increased exposure by 1.9 times), with ritonavir/atazanavir - 10 mg (increased exposure by 3.1 times). Table 1 Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are given in descending order) - results of published clinical studies Concomitant therapy regimen Rosuvastatin regimen Change in rosuvastatin AUC Cyclosporine, 75–200 mg twice daily, 6 months 10 mg once daily, 10 days Increase by 7.1 times Atazanavir, 300 mg + ritonavir, 100 mg, once a day, 8 days 10 mg once Increase by 3.1 times Lopinavir, 400 mg + ritonavir, 100 mg, 2 times a day, 17 days 20 mg once a day , 7 days Increase by 2.1 times Gemfibrozil, 600 mg 2 times a day, 7 days 80 mg once Increase by 1.9 times Eltrombopag, 75 mg once a day, 10 days 10 mg once Increase by 1.6 times Darunavir , 600 mg + ritonavir, 100 mg, 2 times a day, 7 days 10 mg 1 time a day, 7 days Increase by 1.5 times Tipranavir, 500 g + ritonavir, 200 mg, 2 times a day, 11 days 10 mg once Increase by 1.4 times Dronedarone, 400 mg 2 times a day No data Increase by 1.4 times Itraconazole, 200 mg once a day, 5 days 10 or 80 mg once Increase by 1.4 times Ezetimibe, 10 mg 1 once a day, 14 days 10 mg once a day, 14 days Increase 1.2 times Fosamprenavir, 700 mg + ritonavir, 100 mg, 2 times a day, 8 days 10 mg once No change Aleglitazar, 0.3 mg, 7 days 40 mg, 7 days No changes Silymarin, 140 mg 3 times a day, 5 days 10 mg once No changes Fenofibrate,