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

core: lactose monohydrate - 60,000 mg, microcrystalline cellulose - 45,400 mg, croscarmellose sodium - 1,200 mg, silicon colloidal dioxide - 0,600 mg, magnesium stearate - 2,400 mg;

film sheath: hypromellose 2910/5 - 2,500 mg, macrogol 6000 - 0.400 mg, titanium dioxide - 0.325 mg, talcum - 0.475 mg, iron oxide red oxide - 0.013 mg.

Each tablet coated with a film coating of 20 mg contains:

active substance:

rosuvastatin - 20,000 mg (in the form of rosuvastatin calcium - 20,800 mg);

Excipients:

core: lactose monohydrate - 120,000 mg, microcrystalline cellulose - 90,800 mg, croscarmellose sodium - 2,400 mg, silicon colloid dioxide - 1,200 mg, magnesium stearate - 4,800 mg;

film sheath: hypromellose 2910/5 - 5,000 mg, macrogol 6000 - 0,800 mg, titanium dioxide - 0,650 mg, talc - 0,950 mg, ferric oxide red oxide - 0.065 mg.

Each 40 mg film-coated tablet contains:

active substance:

rosuvastatin - 40,000 mg (in the form of rosuvastatin calcium - 41,600 mg);

Excipients:

core: lactose monohydrate 240,000 mg, microcrystalline cellulose 181,600 mg, croscarmellose sodium 4,800 mg, silicon dioxide colloid 2,400 mg, magnesium stearate 9,600 mg;

film sheath: hypromellose 2910/5 - 10,000 mg, macrogol 6000 - 1,600 mg, titanium dioxide 1,300 mg, talc 1,900 mg, iron oxide red oxide 0.200 mg.

Description:

Tablets of 10 mg: oblong, biconcave tablets with a risk, covered with a film membrane of light pink color.

Tablets of 20 mg: oblong, biconvex tablets, covered with a pink film membrane.

Tablets of 40 mg: oblong, biconvex tablets, covered with a film membrane * of a dark pink 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:

Gipolipidemicheskom remedy from the group of statins. Selective competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that converts HMG-CoA to mevalonate. the precursor of cholesterol (cholesterol). Increases the number of low-density lipoprotein receptors (LINI) on the surface of hepatocytes,which leads to increased seizure and catabolism of LINI, inhibition of the synthesis of very low density lipoproteins (VLDL). reducing the overall concentration of LINI and VLDL. Reduces the concentrations of LDL-C, high-density cholesterol-non-lipoproteins (CS-non-HDL), cholesterol-VLDL, total cholesterol, triglycerides (TG), TG-VLDL, apolipoprogine B (ApoB), reduces the ratio of LDL-C, HDL-C Cholesterol / HDL cholesterol, cholesterol-HDL / HDL cholesterol, Apov / apolipoprotein A1 (AOA1), increases the concentration of HDL-C and HDAO. The hypolipidemic effect is directly proportional to the magnitude of the prescribed dose. The therapeutic effect appears within 1 week after the initiation of therapy, after 2 weeks reaches 90% of the maximum, reaches a maximum at 4 weeks, and then remains constant. Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type Ha and lib according to the classification of Fredriksoia) (the average corrected percentage change in comparison with the initial value).

Dose	Number of patspin	LDL cholesterol	General HS	Cholesterol-HDL	TG	HS-nsLVP	LCO B	Lpo L-1
Placebo	13	-7	-5	3	-3	-7	-3	0
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (type IIb and IV according to the Fredrickson classification) (mean percentage change compared to the original value).

Dose	QTY patient ETON	TG	xs- LPP	General HS	xs- lbv P	XS-NLP VP	ХС-л лпо NP	TG- LHPO NP
Placebo	26	1	5	1	-3	2	2	6
10 mg	23	-37	-45	-40	8	-49	-48	-39
20 mg	27	-37	-31	-34	22	-43	-49	-40
40 Mi-	25	-43	-43	-40	17	-51	-56	-48

Clinical efficacy

Effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia (regardless of race, sex or age), including in patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with hypercholesterolemia IIa and IIb type (according to Fredrickson classification) with an 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 receiving rosuvastatin in a dose of 20-80 mg per day, there is a positive dynamics of lipid profile. After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C was reduced by 53%. In 33% of patients the concentration of LDL-C was less than 3 mmol / l.

In patients with homozygous familial hypercholesterolemia, taking the drug at a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C was 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dL, rosuvastatin in a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in blood plasma decreased significantly (see Table 2).

The additive effect is noted in combination with fenofibrate (in terms of reducing TG concentration and with nicotinic acid in lipid-lowering doses (more than 1 g / day) (in terms of reducing the concentration of cholesterol-HDL) (see "Specific guidance"). METEOR therapy with rosuvastatin significantly slowed the progression of the maximum thickness of the intima-media complex (TKIM) for 12 segments of the carotid artery compared with placebo. Compared to baseline values in the rosuvastatin group, a decrease in the maximum TKIM value by 0.0014 mm / year was observed compared to an increase of 0.0131 mm / year in the placebo group. To date, there has been no direct relationship between a decrease in TKIM and a reduction in the risk of cardiovascular events. Results of the study JUPITER They showed, what rosuvastatin significantly reduced the risk of developing cardiovascular complications with a relative risk reduction of 44%.The effectiveness of therapy was noted in the first 6 months of the drug. There was a statistically significant 48% reduction in the combined criteria, including death from cardiovascular causes, stroke and myocardial infarction, a 54% decrease in the incidence of fatal or nonfatal myocardial infarction and a 48% increase in fatal or nonfatal stroke. Total mortality decreased by 20% in the rosuvastatin group. The safety profile of patients taking rosuvastatin in a dose of 20 mg, was. in general, is similar to the safety profile in the placebo group.

Pharmacokinetics:

Suction

The maximum concentration (C_ma_x) rosuvastatin in the blood plasma is reached approximately 5 hours after taking the drug. Absolute bioavailability is approximately 20%.

Distribution

Penetrates through the placental barrier. Rosuvastatin is absorbed mainly by the liver, which is the main site for the synthesis of cholesterol and the metabolism of LDL-C. The volume of distribution is 134 liters. Binding to blood plasma proteins (predominantly with albumin) is approximately 90%.

Metabolism

Biotransformiruetsya in the liver to a small extent (about 10%).being a non-core substrate for cytochrome P450 isoenzymes. The main isoenzyme involved in the metabolism of rosuvastatin is isoenzyme CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main metabolites of rosuvastatin are N- dismethyl-rosvastatin and lactone metabolites. Nis approximately 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting 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, the rest - by the kidneys. The half-life (T1 / 2) is approximately 19 hours, does not change with increasing dose of the drug. The average value of geometric plasma clearance is approximately 50 l / h (coefficient of variation of 21.7%). As with other HMG-CoA reductase inhibitors, a specific membrane transporter-a polypeptide transporting the organic anion of OATP1B1-is involved in the hepatic capture of the drug.performing an important role in its hepatic elimination. Linearity

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

Special populations of patients

Renal insufficiency

In patients with mild to moderate renal insufficiency, plasma concentrations of rosuvastatin or N-dis-methyl-isosvastatin did not change significantly. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and N-dis-methyl-rosvastatin - 9 times that of healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis is approximately 50% higher than in healthy volunteers.

Liver failure

Patients with a score of 7 or lower on the Child-Pugh scale there was no increase T_1/2rosuvastatin; In patients with scores of 8 and 9 on the Child-Pugh scale, lengthening T_1/2 in 2 times. The experience of using the drug in patients with more severe violations of liver function is absent.

Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups

The pharmacokinetic parameters of rosuvastatin depend on race: the area under the concentration-time curve (AUC) the representatives of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) are 2 times higher than the representatives of the European race. The Hindu mean AUC and C_m_Ohincreased by 1.3 times.

Genetic polymorphism

Inhibitors of HMG-CoA reductase, including rosuvastatin bind to transport proteins OATP1B1 (a polypeptide transporting organic anions involved in the capture of statins by hepatocytes) and BCRP (efflujusyy transporter). In carriers of genotypes SLC01B1 (OATP1B1) p.521N and ABCG2 (BCRP) c.421AA increase in exposure was noted (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genotypes SLC01B1 c.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-medicamentous therapies (for example, physical exercises, weight loss) are insufficient.

- Family homozygous hypercholesterolemia as a supplement to a diet and other lipid-lowering therapy (eg, LDL-apheresis), or in cases when such therapy is not effective enough.

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

- To slow the progression of atherosclerosis as an adjunct to the diet in patients who are shown therapy to reduce the concentration of total cholesterol and LDL-cholesterol.

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

Contraindications:

Contraindications for tablets 10 and 20 mg

- Hypersensitivity to rosuvastatin or other components of the drug;

- Liver disease in the active phase, or a steady increase in the serum activity of "liver" transaminases (more than 3 times the upper limit of the norm) of unclear genesis, liver failure (severity from 7 to 9 on the Child-Pugh scale);

- Increase in the concentration of creatinine phosphokinase (CK) in the blood more than 5 times. compared with the upper limit of the norm (VGN);

- Hereditary diseases, such as lactose intolerance, lactase deficiency or glkozo-galactose malabsorption (due to the presence of lactose in the composition);

- The expressed disturbances of function of kidneys (KK less than 30 ml / mines);

- Myopathy;

- Patients who are predisposed to the development of myotoxic complications;

- Simultaneous administration of cyclosporine;

- Joint use with HIV protease inhibitors;

- Women of reproductive age who do not use adequate methods of contraception;

- Pregnancy and lactation;

- Age to 18 years (effectiveness and safety not established).

Contraindications for tablets 40 mg (supplement to the contraindications for tablets 10 and 20 mg)

- The presence of the following risk factors for the development of myopathy / rhabdomyolysis:

1. Myotoxicity on the background of taking other inhibitors of HMG-CoA reductase or fibrates in anamnesis;

2. Hypothyroidism;

3. Renal failure of moderate severity (CK 30-60 ml / min);

4. Excessive use of alcohol;

5. Conditions that may lead to an increase in the plasma concentration of rosuvastatin;

6. Simultaneous reception of fibrates;

- Patients of the Mongoloid race;

- Family history of muscular diseases.

Carefully:

For dosages of 10 and 20 mg:

with liver diseases in the anamnesis; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or water-electrolyte disturbances; uncontrolled convulsions; with renal insufficiency of mild and moderate severity; hypothyroidism; data on muscle toxicity in history with the use of other inhibitors of HMG-CoA reductase or fibrates; hereditary muscle diseases in the anamnesis; age over 65; Conditions in which there was an increase in the concentration of rosuvastatin in the blood plasma; use in patients of the Mongoloid race; with simultaneous appointment with fibrates; at excessive use of alcohol.

For a dosage of 40 mg:

with renal insufficiency of mild severity (SC more than 60 ml / min); age over 65; liver diseases in anamnesis; sepsis; arterial hypotension; extensive surgical interventions: trauma; severe metabolic, endocrine or water-electrolyte disturbances; uncontrolled cramps.

Pregnancy and lactation:

The use of ROSUKARD® in women of reproductive age is possible only if reliable methods of contraception are used and if the patient is informed of the possible risk of treatment for the fetus.

Because cholesterol and substances synthesized from cholesterol are important for the development of the fetus, the potential risk of inhibiting HMG-CoA reductase exceeds the benefit of using the drug during pregnancy. ROSUKARD® is contraindicated in pregnancy and lactation. If pregnancy is diagnosed during therapy with the drug, ROSUKARDA® should be immediately discontinued and the patient warned of the potential risk to the fetus.

If it is necessary to use the drug during lactation, taking into account the possibility of undesirable phenomena in infants, it is necessary to solve the problem of stopping breastfeeding.

Dosing and Administration:

Inside, without chewing and chopping, swallow whole, with water, at any time of the day, regardless of the time of food intake.

Before starting therapy with ROSUKARD®, the patient should begin to follow the standard lipid-lowering diet and continue to observe it during treatment. The dose of the drug should be selected individually depending on the indications and therapeutic response, taking into account the current generally accepted recommendations for target lipid concentrations. If you need to take the drug ROSUKARD® at a dose of 5 mg, you should divide the 10 mg tablet into two parts according to the risk.

The recommended initial dose of ROSUKARD® for patients starting to take the drug, or for patients transferred from other HMG-CoA reductase inhibitors, is 5 or 10 mg once daily. When choosing the initial dose should be guided by the concentration of cholesterol in the blood plasma and taken in attention to the risk of the patient developing cardiovascular complications, and also to assess the potential risk of side effects. If necessary, after 4 weeks, the dose of the drug may be increased.In connection with the possible development of side effects (see the "Side effect" section), the final titration to a maximum daily dose of 40 mg should be performed only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia), which, when taking a dose of 20 mg, did not achieve the target concentration of cholesterol. Such patients should be under medical supervision. 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 ROSUKARD®, it is necessary to monitor lipid metabolism (if necessary, dose adjustment is required).

Elderly patients

In patients older than 65 years, no dose adjustment is required.

Patients with hepatic insufficiency

In patients with hepatic insufficiency with values of the Child-Pugh scale below 7, the dose adjustment of ROSUKARD® is not required. The drug ROSUKARD® is contraindicated in patients with active liver disease,a stable increase in the serum activity of "hepatic" transaminases (more than 3 times higher than the upper limit of the norm (VGN)) of an unknown genesis and patients with hepatic insufficiency (severity from 7 to 9 on the Child-Pugh scale) (see " Contraindications ").

Patients with renal insufficiency

In patients with mild renal insufficiency, no dose adjustment is required. The initial dose of ROSUKARD® is 5 mg per day. In patients with severe renal insufficiency (KC less than 30 ml / min), the use of ROSUKARD ® is contraindicated.

In patients with moderate renal insufficiency of moderate severity (CK 30-60 ml / min), the use of ROSUKARD ® in a dose of 40 mg per day is contraindicated (see the section "Contraindications").

Special populations.

Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin, there was an increase in its systemic concentration in representatives of the Mongoloid race (see the section "Pharmacokinetics"). This fact should be taken into account when prescribing ROSUKARD® to patients of the Mongoloid race.When appointing doses of 10 and 20 mg, the recommended initial dose of ROSUKARD® for this group of patients is 5 mg per day. The use of ROSUKARD® in a dose of 40 mg per day in representatives of the Mongoloid race is contraindicated (see section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLCO1B1 (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLC01B1 C.521TT and ABCG2 C.421SS. For patients carrying genotypes p.521SS or p.421AA, the recommended maximum dose of ROSUKARD® is 20 mg per day (see the sections "Pharmacokinetics", "Special instructions" and "Interaction with other drugs").

Patients with predisposition to myopathy

The use of the drug ROZUKARD® at a dose of 40 mg per day is contraindicated in patients with a predisposition to myopathy (see the section "Contraindications.") In prescribing doses of 10 mg and 20 mg per day, the recommended initial dose of ROSUKARD® for this group of patients is 5 mg per day .

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). With the joint application of ROSUKARD® with medicines (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir) that increase the concentration

rosuvastatin in blood plasma due to interaction with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see sections "Special instructions" and "Interaction with other drugs"). In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of ROSUKARD® should be evaluated. If the use of the above drugs is necessary, you should read the instruction on the use of drugs before they are prescribed simultaneously with the drug ROSUKARD®, assess the benefit-risk ratio of concomitant therapy and consider the possibility of reducing the dose of ROSUKARD® (see "Interaction with other drugs" ).

Side effects:

Side effects. Observed with the use of rosuvastatin, usually expressed slightly and pass independently.As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly dose-dependent. Below is a profile of unwanted reactions for rosuvastatin, based on data from clinical trials and extensive post-registration experience.

The frequency of adverse reactions was determined according to the following gradation (classification of the World Health Organization):

- very often - more than 1/10,

- often from more than 1/100 to less than 1/10.

- infrequently - from more than 1/1000 to less than 1/100,

- rarely from more than 1 / 10,000 to less than 1/1000,

- very rarely - from less than 1/10000. including individual messages,

- frequency is unknown. It is not possible to set the frequency according to available data.

Violations from the blood and lymphatic system: rarely - thrombocytopenia.

Impaired nervous system: often - headache, dizziness; very rarely - peripheral peyropatiya. loss or loss of memory; frequency is unknown - sleep disturbances, including insomnia and nightmarish dreams.

Disorders of the psyche: frequency is unknown - depression.

Disorders from the digestive system: often - nausea, constipation, abdominal pain; infrequently - vomiting; rarely - pancreatitis; frequency is unknown - diarrhea.

Disorders from the liver and bile ducts: rarely - a dose-dependent transient increase in activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT); very rarely - hepatitis, jaundice.

Disturbances from the respiratory system: frequency unknown - cough, dyspnea.

Immune system disorders: rarely - hypersensitivity reactions, including angioedema.

Disturbances from the musculoskeletal and connective tissue: often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis with acute renal failure and without it (in patients treated at doses> 20 mg per day); very rarely - arthralgia; frequency unknown - immuno-mediated necrotizing myopathy.

Disturbances from the skin and subcutaneous tissues: infrequently - skin itching, hives, skin rash; frequency is unknown - Stevens-Johnson syndrome.

Disorders from the kidneys and urinary tract: often - proteinuria. Changes in the amount of protein in the urine (from absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving a dose of 10-20 mg per day and about 3% of patients receiving 40 mg per day.Proteinuria decreases during therapy and is not associated with the onset of kidney disease or urinary tract infection; very rarely - hematuria.

Violations of the genitals and breast: very rarely - gynecomastia.

Influence on indicators of laboratory and instrumental research: infrequently - a dose-dependent increase in serum creatine phosphokinase (CKF) activity. In most cases, it was insignificant, asymptomatic and temporary. When the activity is increased more than 5 times in comparison with VGN, therapy with ROSUKARD® should be temporarily suspended. Increase in the concentration of glycosylated hemoglobin in blood plasma.

Other: often - asthenic syndrome, frequency unknown - peripheral edema.

When using the drug ROSUKARD ®, the following laboratory parameters were noted: an increase in the concentration of glucose, bilirubin, activity of alkaline phosphatase, gamma-glutamyl-transferase (GGT). The development of the following adverse events was reported during the administration of some statins:

- erectile disfunction:

- single cases of иистистилиялыго lung disease (especially with prolonged use);

- type 2 diabetes mellitus: frequency depends on the presence or absence of risk factors (fasting blood glucose concentration 5.6-6.9 mmol / L, body mass index (IMG)> 30 kg / m², hypertriglyceridemia, arterial hypertension in the anamnesis).

Overdose:

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

Treatment: There is no specific treatment, symptomatic therapy is performed to maintain the functions of vital organs and systems. It is necessary to monitor the parameters of liver function and the activity of CK. Hemodialysis is ineffective.

Interaction:

Effect 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 the blood plasma and an increased risk of myopathy (see Table 3 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 3). Does not affect the plasma concentration of cyclosporine. The drug ROSUKARD® is contraindicated in patients taking ciclosporin (see section "Contraindications").

Inhibitors of human immunodeficiency virus protease (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 3). A pharmacokinetic study on 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 C_m_Oh rosuvastatin, respectively. Therefore, simultaneous use of the drug ROSUKARD® and HIV protease inhibitors is not recommended (see sections "Dosing and Administration", "Special instructions", table 3).

Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil leads to an increase in 2 times C_m_Oh and AUC rosuvastatin (see Fig.section "Special instructions"). Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrate is expected, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g per day) increased the risk of myopathy with simultaneous use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myoia in monotherapy (see " Special instructions"). If the drug is simultaneously administered with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses, the initial dose of ROSUKARD® 5 mg is recommended for patients, the dose of 40 mg is contraindicated in a joint appointment with fibrates (see "Contraindications", "Dosing and Administration", " "Special instructions").

Fusidic acid: specific studies on the drug interaction between fusidic acid and rosuvastatin have not been carried out, but separate reports have been noted about cases of rhabdomyolysis.

Ezetimibe: simultaneous application of the drug ROSUKARD ® at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase AUC rosuvastatin in patients with hypercholesterolemia (see Table 3). It is not possible to exclude an increased risk of side effects due to the pharmacodynamic interaction between the drug ROSUKARD® 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 about 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 FROMmax rosuvastatin by 30%. Such interaction can arise as a result of increased intestinal motility caused by the administration of erythromycin.

Isozymes of the cytochrome 1450 system: research results in vivo and in vitro showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a weak substrate for these isoenzymes. Therefore, rosuvastatin is not expected to interact with other drugs at the metabolic level with the participation of cytochrome P450 isoenzymes.There was no clinically significant interaction between rosuvastatin and fluconazole (isozyme inhibitor CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4).

Interaction with drugs, which requires correction of the dose of rosuvastatin (see Table 3)

The dose of ROSUKARD® should be adjusted when it is necessary to use it together with drugs that increase the exposure of rosuvastatin. If an increase in exposure is expected to be 2 times or more, the initial dose of ROSUKARD® should be 5 mg once daily. Also, adjust the maximum daily dose of ROSUKARD® so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without concomitant prescribing. interacting with rosuvastatin. For example, the maximum daily dose of ROSUKARD® with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (an increase in exposure by 3.1 times).

Table 3. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order) - the results of published clinical studies.

Complementary therapy regimen	The mode of reception of rosuvastatin on	Change AUC rosuvastatin
Cyclosporine 75-200 mg 2 times a day .. 6 months.	10 mg once a 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 times
Symeprevir 150 mg 1 time per day, 7 days	10 mg, once	An increase of 2.8 times
Lopinavir 400 mg / ritonavir 100 mg 2 times a day, 17 days	20 mg 1 time per day, 7 days	Increase 2.1 times
Clopidogrel 300 mg. then 75 mg within 24 hours	20 mg, once	2 times increase
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 a day .. 7 days	10 mg 1 time in a 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
Ezetimib 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 a day, 8 days	10 mg, once	Bcd 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 once a day, 7 days	20 mg, once	Without changes
Ketoconazole 200 mg 2 times a 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 a day, 7 days	80 mg, once	Decrease by 28%
Baikalin 50 mg 3 times a day, 14 days	20 mg, once	Decrease by 47%

Effect of rosuvastatin on other drugs.

Antagonists of vitamin K: initiation of therapy or an increase in the dose of ROSUKRLD ® in patients receiving simultaneously vitamin K antagonists (for example, warfarin), can lead to an increase in the International Normalized Relationship (MHO). The cancellation or reduction of the dose of ROSUKARD® can lead to a decrease MHO. In such cases, control is recommended M1IO.

Oral contraceptives / hormone replacement therapy: simultaneous use of rosuvastatin and oral contraceptives increases AUFROM 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 contraceptives.

Pharmacokinetic data on the simultaneous use of the drug ROSUKARD® and hormone replacement therapy are absent, 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 receiving high doses of rosuvastatin (and 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.

Effects on the musculoskeletal system

When rosuvastatin is used in all doses and. especially when taking doses of the drug, exceeding 20 mg.the following effects on the locomotor system were reported: myalgia. Myopathy, in rare cases rhabdomyolysis.

Determination of the activity of creatine phosphokinase (CK) 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. In the event that the initial activity of CK is significantly increased (5 times higher than VGN), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the initial activity of CK (more than 5 times higher than UGN).

Before the start of therapy

When using ROSUKARD®, as with other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis (see "With caution"). It is necessary to assess the risk-benefit ratio and, if necessary, to conduct clinical observation of the patient during treatment.

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 higher than ULN) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CK is increased by less than 5 times compared to VGN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering ROSUKARD® or other HMG-CoA reductase inhibitors in smaller doses with careful 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 increased activity of CKK in blood serum during treatment or with stopping of taking 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 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 as lipid-lowering doses (more than I g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy with joint application with some inhibitors GMG-CoA reductase, thus is not suitable for the simultaneous administration of the preparation ROZUKARD® and gemfibrozil. It must be carefully weighed ratio of risk and potential benefit in the combined use of the drug and ROZUKARD® fibrates or lipid-lowering doses of nicotinic acid. Medication contraindicated reception ROZUKARD® 40mg conjunction with fibrate (see. The sections "interaction with other drugs," "Contra"). After 2-4 weeks after the start of treatment and / or when the dose of ROSUKARD® is increased, it is necessary to monitor the lipid metabolism parameters (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 ROSUKARD® should stop or reduce the dose of the drug if the activity of "hepatic" transaminases in the blood plasma is 3 times higher than VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of underlying diseases should be performed prior to the initiation of treatment with ROSUKARD®. 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 with those obtained among patients - Caucasoids (see the sections "Dosage and Administration" and "Pharmacokinetics"). Protease Inhibitors HIV

It is not recommended to use ROSUKARD® together with HIV protease inhibitors together (see "Interaction with Other Drugs"). Lactose

The drug ROZUKARD® should not be used in patients with lactase deficiency, galactose intolerance 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 can be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever). If suspected of interstitial lung disease, therapy with ROSUKARD® should be discontinued.

Diabetes mellitus type 2

Preparations of the class of statins can cause an increase in the concentration of glucose in the blood. In some patients at high risk of developing diabetes, such changes can lead to its manifestation, which is an indication for the appointment of hypoglycemic therapy. However, a reduction in the risk of vascular disease with statins is greater than the risk of developing diabetes, so this factor should not serve as a basis for the abolition of statin treatment. For patients at risk (fasting blood glucose concentration 5.6 to 6.9 mmol / L, body mass index (BMI)> 30 kg / m², hypertriglyceridemia, arterial hypertension in anamnesis) should be established by medical supervision and regularly monitor biochemical parameters.

Effect on the ability to drive transp.cf. and fur:Care should be taken when driving vehicles and occupations that require a high concentration of attention and speed of psychomotor reactions (dizziness may occur during therapy).

Form release / dosage:

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

Packaging:For 10 tablets in a blister of A1 / A1. For 3, 6 or 9 blisters (for dosages of 10 mg, 20 mg) and 3 or 9 blisters (for a dosage of 40 mg) are placed in a cardboard pack together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C in the original packaging. Keep out of the reach of children!

Shelf life:2 years. The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001704

Date of registration:18.05.2012/29.01.2016

Date of cancellation:2017-05-18

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Representation: & nbspZENTIVA PHARMA, LLCZENTIVA PHARMA, LLC

Information update date: & nbsp02.06.2016

Illustrated instructions

Instructions

Rosacard® (Rozucard®)