Rosuvastatin-SZ - instructions for use, doses, side effects, contraindications

core - lactose monohydrate (sugar milk) - 32.9 mg; calcium hydrophosphate dihydrate 5.0 mg; povidone (medium-molecular weight polyvinylpyrrolidone) 3.0 mg; croscarmellose sodium (impellose) - 3.0 mg; sodium stearyl fumarate 0.8 mg; silicon dioxide colloid (aerosil) - 0.3 mg; microcrystalline cellulose - 30.0 mg;

shell - Opadrai II (alcohol polyvinyl, partially hydrolysed - 0.88 mg, macrogol (polyethylene glycol) 3350 - 0.247 mg, talc - 0.4 mg, titanium dioxide E 171 - 0.3384 mg, lecithin soybean E 322 - 0.07 mg; aluminum lacquer based on indigo carmine dye - 0,0012 mg, aluminum varnish based on azorubin dye - 0.0102 mg, aluminum varnish based on the dye crimson [Ponso 4R] 0.0082 mg).

Dosage of 10 mg

Active substance: rosuvastatin calcium in terms of rosuvastatin - 10 mg.

Excipients:

core - lactose monohydrate (sugar milk) - 44.3 mg; calcium hydrophosphate dihydrate - 10.0 mg; povidone (medium molecular weight polyvinylpyrrolidone) 6.0 mg; croscarmellose sodium (impellosis) - 4.0 mg; sodium stearyl fumarate - 1.2 mg; silicon dioxide colloid (aerosil) - 0.5 mg; cellulose microcrystalline - 44.0 mg;

sheath - Opadrai II (polyvinyl alcohol, partially hydrolyzed - 1.76 mg, macrogol (polyethylene glycol) 3350 - 0.494 mg, talc 0.8 mg, titanium dioxide E 171 0.7668 mg, soy lecithin E 322 0.14 mg Aluminum lacquer based on indigo carmine dye 0.0024 mg Aluminum lacquer based on azorubin dye 0.0204 mg Aluminum lacquer based on dye crimson [Ponso 4R] - 0.0164 mg).

Dosage of 20 mg

Active substance: rosuvastatin calcium in terms of rosuvastatin - 20 mg.

Excipients:

core - lactose monohydrate (sugar milk) - 67.6 mg; calcium hydrophosphate dihydrate - 20.0 mg; povidone (medium-molecular weight polyvinylpyrrolidone) - 9.0 mg; croscarmellose sodium (impellosis) - 6.6 mg; sodium stearyl fumarate 2.0 mg; silicon dioxide colloid (aerosil) - 0.8 mg; cellulose microcrystalline - 74.0 mg;

shell - Opadrai II (polyvinyl alcohol, partially hydrolyzed - 2.64 mg, macrogol (polyethylene glycol) 3350 - 0.741 mg;talc - 1.2 mg; titanium dioxide E 171 - 1,1502 mg; soy lecithin E 322 - 0.21 mg; Aluminum lacquer based on indigo carmine dye - 0,0036 mg; aluminum varnish based on dye azorubin - 0.0306 mg; Aluminum lacquer based on dye crimson [Ponso 4R] 0.0246 mg).

The dosage of 40 mg

Active substance: rosuvastatin calcium in terms of rosuvastatin - 40 mg.

Excipients:

core - lactose monohydrate (sugar milk) - 55.2 mg; calcium hydrophosphate dihydrate - 40.0 mg; povidone (medium-molecular weight polyvinylpyrrolidone) - 13.0 mg; croscarmellose sodium (impellosis) - 8.3 mg; sodium stearyl fumarate 2.5 mg; silicon dioxide colloid (aerosil) - 1.0 mg; cellulose microcrystalline - 90.0 mg;

sheath - Opadrai II (polyvinyl alcohol, partially hydrolysed - 3.52 mg, macrogol (polyethylene glycol) 3350 - 0.988 mg, talc 1.6 mg, titanium dioxide E 171 - 1.5336 mg, soy lecithin E 322 - 0.28 mg Aluminum lacquer based on indigo carmine dye 0.0048 mg Aluminum lacquer based on azorubin dye 0.0408 mg Aluminum lacquer based on dye Cranberry [Ponso 4R] 0.0328 mg).

Description:The tablets covered with a film cover of pink color, round, biconcave. On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:lipid-lowering agent - HMG-CoA reductase inhibitor

ATX: & nbsp

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

C.10.A.A.07 Rosuvastatin

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 precursor to cholesterol. The main target of the action of rosuvastatin is the liver, where the synthesis of cholesterol (cholesterol) and catabolism of low-density lipoprotein (LDL) is carried out.

Rosuvastatin increases the number of "liver" LDL receptors on the cell surface, increasing the catabolism of LDL and grip, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total amount of VLDL and LDL.

Pharmacodynamics

Rosuvastatin-SZ reduces the elevated concentrations of cholesterol-LDL cholesterol, triglycerides (TG), increases the concentration of high-density cholesterol (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoV), CS-non-HDL, X-VLDL, T-VLDL and increases the concentration of apolipoprotein A-I (ApoA-1), reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol and non-HDL-C-HDL cholesterol and the ApoB / ApoA-1 ratio.

The therapeutic effect develops within one week after the beginning of therapy with the drug 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 intake of the drug.

Rosuvastatin-C3 is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex or age, including patients with diabetes mellitus and familial hypercholesterolemia.

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

In patients with heterozygous familial hypercholesterolemia who receive Rosuvastatin-SZ at a dose of 20-80 mg, the dynamics of lipid profile indicators is positive. After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is reduced by 53%. In 33% of patients the concentration of LDL-C is less than 3 mmol / l.In patients with homozygous familial hypercholesterolemia taking Rosuvastatin-SZ at a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C 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 a day for 6 weeks, the concentration of TG in plasma was significantly reduced.

The additive effect is noted in combination with fenofibrate for triglycerides and with nicotinic acid in lipid-lowering doses for the content of cholesterol-lowering cholesterol (see also the "Specific guidance" section).

According to the results of clinical studies, patients with severe hypercholesterolemia and high risk of cardiovascular disease (CVD) should receive a dose of Rosuvastatin-C3 40 mg. The results of the clinical trial (Rationale for the use of statins for primary prevention: an interventional study evaluating rosuvastatin) showed that rosuvastatin significantly reduced the risk of cardiovascular complications.

Pharmacokinetics:

Absorption and distribution

The maximum concentration of rosuvastatin in the blood plasma is reached approximately 5 hours after ingestion. Absolute bioavailability is approximately 20%.

Rosuvastatin metabolite is mainly produced by the liver, which is the main site for the synthesis of cholesterol and the metabolism of LDL-C. The volume distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism

It is 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 isoenzyme CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main revealed metabolites of rosuvastatin are N-detemethyl-zouvastatin and lactone metabolites. Nis less than 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting the circulating HMG-CoA reductase is provided by rosuvastatin, the rest - by its metabolites.

Excretion

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including the absorbed and unabsorbed rosuvastatin).

The rest is excreted by the kidneys. The plasma half-life (T1 / 2) is approximately 19 hours. The half-life does not change with an increase in the dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As with other inhibitors of HMG-CoA reductase, a membrane cholesterol transporter involved in the hepatic elimination of rosuvastatin plays an important role in the hepatic elimination of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

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 showed approximately a twofold increase in the median AUC (area under the concentration-time curve) and Cm(maximum concentration in the blood plasma) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Caucasians; Hindus show an increase in median AUC and Cmah 1.3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Caucasians and representatives of the Negroid race.

Renal insufficiency

In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethyl-rosuvastatin does not change significantly. In patients with severe renal failure (creatinine clearance (CK) less than 30 ml / min.), The concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration N-desmethylrozuvastatin is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

Liver failure

Patients with different stages of hepatic insufficiency did not have an increase in the half-life of rosuvastatin in patients with 7 points or lower on the Child-Pugh scale. Two patients with the 8th and 9th points on the Child-Pugh scale had an increase in the half-life period, at least 2-fold. The experience with rosuvastatin in patients with more than 9 points on the Child-Pugh scale is not available. Genetic polymorphism

Inhibitors of HMG-CoA reductase, including, rosuvastatin, bind to transport proteins OATP1B1 (the polypeptide of organic anion transport, involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLC01B1 (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genotypes SLC01B1 p.521TT and ABCG2 p.421S.

Indications:- Primary hypercholesterolemia according to Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-pharmacological methods of treatment (for example, physical exercises, weight loss) are insufficient.

- Family room homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (eg, LDL-apheresis), or in cases where such therapy is not effective enough.

- Hypertriglyceridemia (type IV according to Fredrickson classification) as a supplement to the diet.

- To slow the progression of atherosclerosis as a supplement to the diet in patients,which shows the therapy to reduce the concentration of total cholesterol and LDL-C.

- Primary prevention of major cardiovascular diseases complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of coronary artery disease, but with an increased risk of its development (age over 50 for men and over 60 for women, increased concentration of C-reactive protein (more than 2 mg / L) if there is at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early onset of CHD).

Contraindications:

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

- increased sensitivity to rosuvastatin or any of the components of the drug

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

- children under 18 years of age

- liver diseases in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of the norm)

- severe renal failure (CC less than 30 ml / min.)

- myopathy

- simultaneous administration of cyclosporine

- in women: pregnancy; the period of breastfeeding, the lack of adequate methods of contraception

- increase in the concentration of creatine phosphokinase (CK) in the blood more than 5 times compared with the upper limit of the norm

- joint application with HIV protease inhibitors

- patients who are predisposed to the development of myotoxic complications

For the drug Rosuvastatin-SZ in a daily dose of 40 mg:

- increased sensitivity to rosuvastatin or any of the components of the drug

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

- children under 18 years of age

- simultaneous administration of cyclosporine

- in women: pregnancy, the period of breastfeeding, the lack of adequate methods of contraception

- increase in the concentration of creatine phosphokinase (CK) in the blood more than 5 times compared with the upper limit of the norm

- joint application with HIV protease inhibitors

- renal failure of moderate and severe degree (CC less than 60 ml / min.)

- liver disease in the active phase, including persistent increase in serum transaminase activity and any increase in serum transaminase activity (morethan in 3 times in comparison with the top border of norm or rate) to patients with risk factors of development of a myopathy / rhabdomyolysis, namely:

- hypothyroidism

- myotoxicity on the background of taking other inhibitors of HMG-CoA reductase or fibrates in anamnesis

- excessive drinking

- conditions that can lead to an increase in the plasma concentration of rosuvastatin

- simultaneous reception of fibrates

- myopathy

- personal or family anamnesis of muscular diseases

- patients of the Mongoloid race

Carefully:

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

The presence of a risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other inhibitors of HMG-CoA reductase or fibrates; excessive use of alcohol; age over 65; conditions in which there was an increase in the plasma concentration of rosuvastatin; race (Mongoloid race); simultaneous appointment with fibrates (see section "Pharmacokinetics"); liver disease in history; sepsis; arterial hypotension; extensive surgical interventions,trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled convulsive seizures. Simultaneous use with colchicine and with ezetimibe (see section "Interaction with other medicinal products").

For the drug Rosuvastatin-SZ in a daily dose of 40 mg:

Renal insufficiency of mild severity (QC more than 60 ml / min); age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled convulsive seizures.

Simultaneous use with colchicine and with ezetimibe (see section "Interaction with other medicinal products").

Patients with hepatic insufficiency

Data or experience of the drug in patients with more than 9 points on the Child-Pugh scale is not available (see the sections "Pharmacodynamics" and "Special instructions").

Pregnancy and lactation:

Rosuvastatin-SZ is contraindicated in pregnancy and during breastfeeding.

Women of reproductive age should apply adequate methods of contraception.

Because cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of inhibiting HMG-CoA reductase exceeds the benefit of using the drug in pregnant women. In case of pregnancy in the process of therapy, taking the drug should be stopped immediately.

Data on the allocation of rosuvastatin to breast milk are not available, so during breast-feeding, the drug should be discontinued (see section "Contraindications").

Dosing and Administration:

Inside, do not chew and do not grind the tablet, swallow whole, squeezed water. The drug can be administered at any time of the day, regardless of the intake of the substance. Before starting therapy with Rosuvastatin-SZ the patient should start to observe the standard hypocholesterolemic diet and continue to observe it during treatment. The dose of the drug should be selected individually, depending on the purpose 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 for patients,translated from the administration of other inhibitors of HMG-CoA reductase, should be 5 mg or 10 mg of the drug Rosuvastatin-SZ 1 time per day. When choosing the initial dose should be guided by individual cholesterol and take into account the possible risk of cardiovascular complications, as well as assess the potential risk of side effects. If necessary, the dose may be increased to greater after 4 weeks (see the section "Pharmacodynamics").

In connection with the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug (see the section "Side effect"), increasing the dose to 40 mg, after additional doses above the recommended initial dose for 4 weeks therapy, can only be performed in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who did not achieve the desired result of therapy when taking a dose of 20 mg and which will be monitored by a specialist (see section "Special instructions"). It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg.

Do not administer a dose of 40 mg to patients who have not previously consulted a doctor.After 2-4 weeks of therapy and / or with an increase in the dose of the drug Rosuvastatin-SZ, it is necessary to monitor the lipid metabolism (if necessary, dose adjustment is required).

Elderly patients

No dose adjustment is required.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not required. In patients with severe renal failure (CC less than 30 ml / min.), The use of the drug Rosuvastatin-SZ is contraindicated. Contraindicated use of the drug in a dose of 40 mg to patients with moderate impaired renal function (CK 30-60 ml / min.) (See the sections "Special instructions" and "Pharmacodynamics"). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency Rosuvastatin-SZ is contraindicated in patients with liver diseases in the active phase (see section "Contraindications").

Special populations.

Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, there was an increase in the systemic concentration of rosuvastatin among Japanese and Chinese (see section "Special instructions").This fact should be taken into account when prescribing Rosuvastatin-C3 to these patient groups. When appointing doses of 10 mg and 20 mg, the recommended initial dose for patients of the Mongoloid race is 5 mg. Contraindicated appointment of the drug in a dose of 40 mg to patients of the Mongoloid race (see the section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLC01B1 (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin but compared with carriers of genotypes SLCOIBI p.521TT and ABCG2 p.421S. For patients carrying genotypes с.521СС or с.421АА the recommended maximum dose of the drug Rosuvastatin-SZ is 20 mg once a day (see the sections "Pharmacokinetics", "Special instructions" and "Interaction with other medicinal products ").

Patients predisposed to myopathy Contraindicated the appointment of the drug in a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy (see section "Contraindications"). When appointing doses of 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg (see the section "Contraindications").

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). With the joint application of the drug Rosuvastatin-SZ with medicines (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopiavir and / or tipranavir), which increase the concentration of rosuvastatin in plasma through interaction with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see "Specific guidance" and "Interaction with other medicinal products "). In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of Rosuvastatin-SZ should be assessed. If the use of the above drugs is necessary, the ratio of benefit and risk of concomitant therapy with Rosuvastatin-C3 should be assessed and the possibility of reducing its dose should be considered (see "Interaction with other medicinal products ").

Side effects:

Side effects observed with the use of the drug Rosuvastatin-SZ, usually expressed slightly and pass independently.As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly dose-dependent.

The frequency of undesirable effects is as follows: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000), frequency, unspecified (can not be calculated from available data).

The immune system

Rarely: hypersensitivity reactions, including angioedema.

Endocrine system

Often: diabetes mellitus type 2

From the central nervous system

Often: headache, dizziness

From the side of the digestive tract

Often: constipation, nausea, abdominal pain

Rarely: pancreatitis

From the skin

Infrequently: itching, rash, urticaria

From the side of the locomotor system

Rarely: pancreatitis

From the skin

Infrequently: itching, rash, urticaria

From the side of the musculoskeletal system

With the use of the drug Rosuvastatin-SZ in all doses, and especially when taking doses of the drug in excess of 20 mg, the following effects on the musculoskeletal system have been reported: myalgia, myopathy (including myositis), in rare cases rhabdomyolysis with acute renal insufficiency or without her.A dose-related increase in activity of creatine phosphokinase (CK) is observed in a small number of patients taking rosuvastatin. In most cases, it was insignificant, asymptomatic and temporary. In the case of increased activity of CK (more than 5 times compared with the upper limit of the norm) therapy should be suspended (see section "Special instructions").

From the side of the liver

With the use of rosuvastatin, a dose-dependent increase in the activity of "hepatic" transaminases in a small number of patients is observed. In most cases, it is insignificant, asymptomatic and temporary.

Laboratory indicators

With the use of the drug Rosuvastatin-SZ, the following changes in laboratory parameters were also observed: an increase in the concentration of glucose, bilirubin, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, thyroid dysfunction.

Postmarketing application

The following side effects have been reported in post-marketing application of the drug Rosuvastatin-SZ:

On the part of the hematopoiesis system

Unspecified frequency: thrombocytopenia

From the side of the digestive tract

Very rarely: jaundice, hepatitis

Rarely: increased activity of "liver" transaminases

Unspecified frequency: diarrhea

From the side of the musculoskeletal system

Very rarely: arthralgia

Unspecified frequency: immuno-mediated necrotizing myopathy

From the central nervous system

Very rarely: polyneuropathy, memory loss

From the respiratory system

Unspecified frequency: cough, dyspnea

From the side of the urinary system

Very rare: hematuria

From the skin and subcutaneous fat

Unspecified frequency: Stevens-Johnson syndrome

From the reproductive system and breast

Unspecified frequency: gynecomastia

Other

Unspecified frequency: peripheral edema.

Some statins reported the following side effects: depression, sleep disturbances, including insomnia and nightmarish dreams, sexual dysfunction. Single cases have been reported interstitial lung disease, especially with prolonged use of drugs (see section "Special instructions").

Overdose:

With the simultaneous administration of several daily doses, the pharmacokinetic parameters of rosuvastatin do not change.

There is no specific treatment for an overdose of rosuvastatin. In case of an overdose, it is recommended to carry out symptomatic treatment and measures aimed at maintaining the functions of vital organs and systems. It is necessary to monitor liver function and the level of CK. It is unlikely that hemodialysis will be effective.

Interaction:

Effect of the use of other drugs on rosuvastatin

Inhibitors of transport proteins: Rosuvastatin binds to some transport proteins, in particular, to OATP1B1 and BCRP. The 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 myopathy (see Table 1 and the sections on "Dosage and Administration" and "Special instructions").

Cyclosporine: with simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin was an average of 7 times higher than that seen in healthy volunteers (see Table 1). Does not affect the plasma concentration of cyclosporine. Rosuvastatin-SZ is contraindicated in patients taking cyclosporine (see section "Contraindications").

Inhibitors of the protease of the virus

human immunodeficiency virus (HIV): despite the fact that the exact mechanism of interaction is unknown, joint intake of HIV protease inhibitors can lead to a significant increase in the exposure of rosuvastatin (see Table 1). A pharmacokinetic study but simultaneous use of 20 mg rosuvastatin with a combined preparation containing two HIV protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers resulted in approximately a two- and five-fold increase AUC_(0-24) and Cmrosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see "Dosing and Administration", "Contraindications" and "Special instructions", Table 1).

Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil leads to an increase in 2 times the maximum concentration of rosuvastatin in blood plasma and AUC rosuvastatin (see section "Special instructions"). Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrate is expected, possibly pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy with concomitant use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section "Special instructions"). With simultaneous administration of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), the initial dose of 5 mg is recommended for patients, the dose of 40 mg is contraindicated in a joint appointment with fibrates (see "Contraindications", " Method of administration and dose "," Special instructions ").

Ezetimibe: simultaneous application of the drug Rosuvastatin-SZ in a dose of 10 mg and ezetimibe in a dose of 10 mg was accompanied by an increase AUC rosuvastatin in patients with hypercholesterolemia (see Table 1). It is not possible to exclude an increased risk of side effects due to the pharmacodynamic interaction between the drug Rosuvastatin-SZ and ezetimibe.

Antacids: simultaneous application of rosuvastatin and suspensions of antacids 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 administered 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: simultaneous application of rosuvastatin and erythromycin leads to a decrease AUC rosuvastatin by 20% and Cmrosuvastatin rose by 30%. Such interaction can arise as a result of increased intestinal motility caused by the intake of erythromycin.

Isozymes of cytochrome P450: research results in vivo and in vitro showed that rosuvastatin is neither an inhibitor, nor an inducer

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

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

Interaction with drugs, which requires correction of the dose of rosuvastatin (see Table 1)

The dose of Rosuvastatia-SZ should be adjusted if necessary for its joint application with drugs that increase exposure to rosuvastatin. If the exposure is expected to increase 2 times or more, the initial dose of the drug Rosuvastatin-SZ should be 5 mg once a day. Also, the maximum daily dose of Rosuvastatin-C3 should 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 medications interacting with rosuvastatin. For example, the maximum daily dose of the drug Rosuvastatin-SZ with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

Table 1.

The effect of concomitant therapy on exposure to rosuvastatin (AUC, data are shown in order decrease) - the results of published clinical studies decrease) - the results of published clinical studies

Complementary therapy regimen	Mode of taking rosuvastatin	Change AUC rosuvastatin
Cyclosporine 75-200 mg 2 times a day, 6 months.	10 mg 1 time per day, 10 days	An increase of 7.1 times
Atazanavir 300 mg / ritonavir 100 mg 1 time per day, 8 days	10 mg once	Increase 3.1-fold
Lopinavir 400 mg / ritonavir 100 mg 2 times per day, 17 days	20 mg 1 time per day, 7 days	An increase of 2.1 times
Gemfibrozil 600 mg 2 times a day, 7 days.	80 mg once	Increase 1.9 times
Eltrombopag 75 mg 1 time per day, 10 days	10 mg once	Increase 1.6 times
Darunavir 600 mg / ritonavir 100 mg 2 times per day, 7 days	10 mg 1 time per day, 7 days	Increase by 1.5 times
Tipranavir 500 mg / 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 1 time per day, 5 days	10 mg or 80 mg once	Increase by 1.4 times
Ezetimibe 10 mg 1 time per day, 14 days	10 mg once a day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg 2 times per day, 8 days	10 mg once	Without changes
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 times a day, 5 days	10 mg once	Without changes
Fenofibrate 67 mg 3 times a day, 7 days	10 mg, 7 days	Without changes
Rifampin 450 mg 1 time per day, 7 days	20 mg once	Without changes
Ketoconazole 200 mg 2 times per day, 7 days	80 mg once	Without changes
Fluconazole 200 mg 1 time per day, 11 days	80 mg once	Without changes
Erythromycin 500 mg 4 times per day, 7 days	80 mg once	Decrease by 28%
Baikalin 50 mg 3 times per day, 14 days	20 mg once	Decrease in 47%

Effect of rosuvastatin on other drugs

Antagonists of vitamin K: the initiation of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both vitamin K antagonists (for example, warfarin), may lead to an increase in the International

Normalized Relationships (MHO). The cancellation of rosuvastatin or a decrease in the dose of the drug may lead to a decrease MHO. In such cases, control is recommended MHO.

Oral contraceptives / hormone replacement therapy:

simultaneous use of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when choosing a dose of oral

of contraceptives.

Pharmacokinetic data on the simultaneous use of the drug Rosuvastatin-SZ and hormone replacement therapy are not available,

therefore, it is impossible to exclude a similar effect 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.

Special instructions:

Renal Effects

In patients who received high doses of the drug Rosuvastatin-SZ (mostly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate an acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor the performance of kidneys during treatment.

From the side of the musculoskeletal system

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

Determination of creatine phosphokinase

Determination of CKK activity should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK, which may lead to incorrect interpretation of the results.If the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the baseline CK activity (more than 5 times higher than the upper limit of the norm).

Before the start of therapy

Caution should be exercised in patients with risk factors for myopathy / rhabdomyolysis (see "With caution") when prescribing Rosuvastatin-C3, as well as when prescribing other HMG-CoA reductase inhibitors, it is necessary to consider the relationship between risk and possible benefit of therapy and to conduct clinical observation.

During therapy

The patient should be informed of the need to report immediately to the doctor about cases of sudden onset of muscle pain, muscle weakness, or spasms, especially in combination with malaise and fever. In such patients, the activity of CK should be determined. Therapy should be discontinued if the activity of CK is significantly increased (more than 5 times compared with the upper limit of the norm) or if the symptoms from the muscles are sharply expressed and cause daily discomfort (even if the activity of CK is 5 times lower compared to the upper boundary of the norm).If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering RosUVASTatin-C3 or other HMG-CoA reductase inhibitors in smaller doses with close monitoring of the patient. Routine monitoring of the activity of CKK in the absence of symptoms is inappropriate.

Very rare cases of immuno-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of proximal muscles and an increase in the level of CK in the blood serum during treatment or with stopping the intake of statins, including rosuvastatin, have been noted. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive drugs.

There were no signs of an increase in the effect on skeletal musculature when taking Rosuvastatin-SZ and concomitant therapy. However, an increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid, azole antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous use of the drug Rosuvastatin-C3 and gemfibrozil is not recommended. The risk-benefit ratio should be carefully weighed in conjunction with the use of Rosuvastatin-C3 and fibrates or lipid-lowering doses of nicotinic acid. Contraindicated taking Rosovastatin-SZ in a dose of 40 mg in conjunction with fibrates (see the sections "Interaction with other medicines" and "Contraindications").

After 2-4 weeks after the start of treatment and / or with an increase in the dose of the drug Rosuvastatin-SZ, it is necessary to monitor the lipid metabolism (if necessary, dose adjustment is required).

Liver

It is recommended to carry out the determination of liver function indices before the start of therapy and 3 months after the start of therapy. Taking the drug Rosuvastatin-SZ should stop or reduce the dose of the drug if the activity of transaminases in the serum is 3 times higher than the upper limit of the norm.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of underlying diseases should be performed prior to the initiation of Rosuvastatin-C3 treatment.

Special populations. Ethnic groups

In the course of pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin was noted among Chinese and Japanese patients compared to those obtained among patients - Caucasoids (see the sections "Dosage and Administration" and "Pharmacokinetics").

HIV protease inhibitors

It is not recommended to use the drug jointly with HIV protease inhibitors (see "Interactions with other drugs" and "Contraindications").

Lactose

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

Interstitial lung disease

With the use of some statins, especially for a long time, there have been reports of single cases of interstitial lung disease. Manifestations of the disease may be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever).If suspicion of interstitial lung disease should be stopped by statin therapy.

Diabetes mellitus type 2

In patients with a glucose concentration of 5.6 to 6.9 mmol / L, therapy with Rosuvastatin-SZ was associated with an increased risk of developing type 2 diabetes mellitus.

Effect on the ability to drive transp. cf. and fur:There have been no studies on the effect of Rosuvastatin-C3 on the ability to drive a vehicle and use mechanisms. Care should be taken when driving a motor vehicle or work that requires a high concentration of attention and speed of psychomotor reactions (dizziness may occur during therapy).

Form release / dosage:

Film-coated tablets, 5 mg, 10 mg, 20 mg and 40 mg.

Packaging:

For 10, 14 or 30 tablets per contour cell package.

For 20 or 90 tablets in cans of polymeric or in polymeric bottles. Each bank or vial, 3, 6 contour cell packs of 10 tablets, 2, 4 contour packs of 14 tablets or 2, 3, 4 contour packs of 30 tablets together with the instructions for use are placed in a cardboard box.

Storage conditions:In a dry, the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002471

Date of registration:21.05.2014/19.02.2016

Date of cancellation:2019-05-21

The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia

Manufacturer: & nbsp

NORTH STAR, CJSC Russia

Information update date: & nbsp30.05.2016

Illustrated instructions

Instructions

Rosuvastatin-SZ (Rosuvastatin-SZ)