Rosart - instructions for use, doses, side effects, contraindications

Excipients: cellulose microcrystalline, type 102 11.55 mg, crospovidone, type A 3.5 mg, calcium hydrophosphate dihydrate 17.15 mg, lactose monohydrate 31.71 mg, magnesium stearate 0.88 mg;

film coating: Opaprai white II 33G28435 ~ 2.1 mg (hypromellose-2910 0.84 mg, titanium dioxide 0.525 mg, lactose monohydrate 0.441 mg, macrogol-3350 0.168 mg, triacetin 0.126 mg).

1 tablet, film-coated, 10 mg contains:

active substance: rosuvastatin 10 mg (in the form of rosuvastatin calcium 10.42 mg);

Excipients: cellulose microcrystalline, type 102 23.1 mg, crospovidone, type A 7 mg, calcium hydrophosphate dihydrate 34.3 mg, lactose monohydrate 63.42 mg, magnesium stearate 1.76 mg;

film coating: Opaprai pink II 33G240007 ~ 4.2 mg (hypromellose-2910 1.68 mg, titanium dioxide 1.0441 mg, lactose monohydrate 0.882 mg, macrogol-3350 0.336 mg, triacetin 0.252 mg, carmine red dye 0.0059 mg).

1 tablet, film-coated, 20 mg contains:

active substance: rosuvastatin 20 mg (in the form of rosuvastatin calcium - 20.84 mg);

Excipients: cellulose microcrystalline, type 102 46.2 mg, crospovidone, type A 14 mg, calcium hydrophosphate dihydrate 68.6 mg, lactose monohydrate 126.84 mg, magnesium stearate 3.52 mg;

film coating: Opaprai pink II 33G240007 ~ 8.4 mg (hypromellose-2910 3.36 mg, titanium dioxide 2.0882 mg, lactose monohydrate 1,764 mg, macrogol-3350 0.672 mg, triacetin 0.504 mg, carmine red dye 0.0118 mg).

1 tablet, film-coated, 40 mg contains:

active substance: rosuvastatin 40 mg (in the form of rosuvastatin calcium 41.68 mg);

Excipients: cellulose microcrystalline, type 102 92.4 mg, crospovidone, type A 28 mg, calcium hydrophosphate dihydrate 137.2 mg, lactose monohydrate 253.68 mg, magnesium stearate 7.04 mg;

film coating: Opaprai pink II 33G240007 ~ 16.8 mg (hypromellose-2910 6.72 mg, titanium dioxide 4.1765 mg, lactose monohydrate 3.528 mg, macrogol-3350 1.344 mg, triacetin 1,008 mg, carmine red dye 0.0235 mg).

Description:

Tablets 5 mg

Round, biconvex tablets, covered with a film membrane of white color with engraving "ST 1 "on one side of the tablet.

Tablets 10 mg

Round, biconvex tablets, covered with a pink film membrane with an engraving "ST 2 "on one side of the tablet.

Tablets 20 mg

Round, biconvex tablets, covered with a pink film membrane with an engraving "ST 3 "on one side of the tablet.

Tablets 40 mg

Oval, biconvex tablets, covered with a pink film membrane with an engraving "ST 4 "on one side of the tablet.

Pharmacotherapeutic group:Hypolipidaemic agent - HMG-CoA reductase inhibitor

ATX: & nbsp

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

C.10.A.A.07 Rosuvastatin

Pharmacodynamics:

A hypolipidemic agent from the group of statins. A 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. Increases the number of low-density lipoprotein (LDL) receptors on the surface of hepatocytes, which leads to increased capture and catabolism of LDL, inhibition of the synthesis of very low density lipoproteins (VLDL), reducing the total number of LDL and VLDL. Reduces the increased concentration of LDL cholesterol, low-density lipoprotein cholesterol (non-HDL), cholesterol-VLDL, total cholesterol, triglycerides (TG), TG-VLDL, apolipoprotein B (ApoV),reduces the ratio of cholesterol-LDL / cholesterol-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol, non-HDL / cholesterol-HDL cholesterol, ApoB / apolipoprotein A-I (ApoA-1), increases the concentration of cholesterol-HDL and ApoA-1.

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. 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 (Fredrickson classification) with an average baseline of cholesterol-LDL of about 4.8 mmol / l, when taking the drug at a dose of 10 mg, the concentration of cholesterol-LDL reaches values below 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 cholesterol-LDL is 22%.

Additive effect is noted in combination with fenofibrate (inreduction of TG concentration) and with nicotinic acid in lipid-lowering doses> 1 g / day (Concerning the increase in cholesterol-HDL concentration).

Pharmacokinetics:

Suction

The maximum concentration (C_m_Oh) rosuvastatin in the blood plasma is reached approximately 5 hours after taking the drug. Absolute bioavailability is approximately 20%. The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

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 plasma proteins (predominantly with albumin) is approximately 90%.

Metabolism

Biotransformed in the liver to a small extent (about 10%), being a non-core substrate for cytochrome P450 isoenzymes. As in the case of other HMG-CoA reductase inhibitors, a specific membrane transporter-a polypeptide transporting an organic anion (AAPP) 1B1, is involved in the hepatic capture of the drug,performing an important role in its hepatic elimination. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.

The main metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N- desmethyl is about 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, the rest - by the kidneys. The half-life (T_1/2) - approximately 19 hours, does not change with increasing dose of the drug. The average value of plasma clearance is approximately 50 l / h (coefficient of variation of 21.7%).

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

In patients with different stages of liver failure with a score of 7 or lower on the Child-Pugh scale, there was no increase in T_1/2 rosuvastatin; in patients with scores of 8 and 9 on the Child-Pugh scale, an elongation of 2 times was observed. 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. Pharmacokinetic parameters depend on race: the area under the curve "concentration-time" (AUC) the Japanese and Chinese are two times higher than those of Europeans and North Americans. In representatives of the Mongoloid race and Indians, the mean AUC and C_m_Oh increases by 1.3 times.

Indications:

- Primary hypercholesterolemia (type IIa according to Fredrickson classification), including heterozygous hereditary hypercholesterolemia or mixed (combined) hyperlipidemia (type IIb according to Fredrickson classification), as a supplement to the diet and other

Non-medicamentous measures (physical activity and weight loss).

- Homozygous form of hereditary hypercholesterolemia with insufficient effectiveness of diet therapy and other treatments aimed at reducing lipid concentrations (eg, LDL-apheresis) or if such treatments are not suitable for the patient.

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

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

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

Contraindications:

Contraindications for the drug Rosart in a daily dose of 5, 10 and 20 mg:

- Hypersensitivity to rosuvastatin or other components of the drug;

- Liver diseases in the active phase, including persistent increase in serum activity of "liver" transaminases (more than 3 times compared with the upper limit of the norm (VGN));

- Severe renal dysfunction (CC less than 30 ml / min);

- Myopathy;

- Simultaneous reception of cyclosporine;

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

- Pregnancy and the period of breastfeeding;

- Age under 18 years (efficiency and safety not established);

- Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the preparation contains lactose monohydrate).

Contraindications for the drug Rosart in a daily dose of 40 mg:

- Hypersensitivity to rosuvastatin or other components of the drug;

- Diseases of the liver in the active phase, including persistent increase in serum activity of "liver" transaminases (more than 3 times in comparison with VGN);

- Myopathy;

- Simultaneous reception of cyclosporine;

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

- Pregnancy and the period of breastfeeding;

- Age under 18 years (efficiency and safety not established);

- Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the preparation contains lactose monohydrate);

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

- Hypothyroidism;

- Renal failure of severe and moderate severity (CC less than 60 ml / min);

- Excessive use of alcohol;

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

- Simultaneous reception of fibrates;

- Use in patients of the Mongoloid race;

- Family or personal history of hereditary muscle diseases.

Carefully:

For the preparation Rosart in a daily dose of 5, 10 and 20 mg:

Presence of risk factors for myopathy and / or rhabdomyolysis - renal failure (QC more than 30 ml / min), hypothyroidism, personal or family history of hereditary muscle diseases and previous history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption, age over 70; state,at which there was an increase in the plasma concentration of rosuvastatin; racial affiliation (Mongoloid race), concomitant use with fibrates, history of liver disease, sepsis, arterial hypotension, extensive surgical interventions, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled epilepsy.

For the preparation Rosart in a daily dose of 40 mg:

The presence of risk factors for the development of myopathy and / or rhabdomyolysis - renal failure (CC greater than 60 ml / min), age over 70 years, history of liver disease, sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled epilepsy.

Pregnancy and lactation:

The drug Rosart is contraindicated in pregnancy and lactation.

The use of Rosart 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.

Since 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. In the case of diagnosing pregnancy during the treatment with Rosart, the drug should be stopped immediately, and the patients are warned about the potential risk to the fetus.

Data on the allocation of rosuvastatin to breast milk are not available, therefore, when it is necessary to use the drug during lactation, taking into account the possibility of undesirable phenomena in infants, the question of stopping breastfeeding should be addressed.

Dosing and Administration:

Inside, not liquid, not crushing, swallowing whole, washing down with water, regardless of time of day and food intake. Before starting therapy with Rosart, 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. The recommended initial dose of Rosart for patients who start taking the drug, or for patients,translated from the administration of other inhibitors of HMG-CoA reductase, is 5 or 10 mg 1 time / day. When choosing the initial dose should be guided by the concentration of cholesterol in the patient and take into account the risk of cardiovascular complications, as well as the potential risk of adverse reactions. If necessary, after 4 weeks, the dose of the drug may be increased. Due to the possible development of side effects when taking a dose of 40 mg compared with lower doses of the drug (see the "Side effect" section), the final titration to a maximum dose of 40 mg should be performed only in patients with severe hypercholesterolemia and a high risk of cardiovascular disease, (especially in patients with hereditary hypercholesterolemia) who, when taking a dose of 20 mg, did not achieve the target cholesterol concentration and who will be under medical supervision.

It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg. After 2-4 weeks of therapy and / or increasing the dose of the drug, control of lipid metabolism parameters is necessary.

In elderly patients older than 70 years, the recommended initial dose of Rosart is 5 mg, no other dose adjustment is required.

Have patients with hepatic Insufficiency on the Child-Pugh scale below 7 points dosage adjustment is not required. Have patients with values of 8 and 9 on the Child-Pugh scale a preliminary assessment of renal function should be performed. Experience with rosuvastatin in patients with hepatic insufficiency above 9 points on the Child-Pugh scale is not available. Rosuvastatin contraindicated in patients with liver disease in the active phase.

With renal insufficiency of mild or moderate severity correction of the dose is not required. The initial dose of 5 mg is recommended for patients with moderate renal insufficiency (CC less than 60 ml / min). Patients with renal insufficiency of moderate severity (CK less than 30-60 ml / min) administration of the drug in a dose of 40 mg is contraindicated. Taking Rosalt is contraindicated in any dose to patients with severe renal failure (QC less than 30 mL / min).

Ethnic groups

In patients of the Mongoloid race, an increase in the systemic concentration of rosuvastatin is possible.The initial recommended dose of the drug for patients of the Mongoloid race is 5 mg. The use of the drug in a dose of 40 mg in such patients is contraindicated.

Genetic polymorphism

There are known varieties of genetic polymorphism, which can lead to an increase in the systemic concentration of rosuvastatin. In patients with identified specific polymorphism, lower daily doses of rosuvastatin are recommended.

Patients who are predisposed to the development of myopathy

The initial recommended dose for such patients is 5 mg. The use of the drug in a dose of 40 mg in such patients is contraindicated.

Combination Therapy

Rosuvastatin is a substrate for various transport proteins (eg, OATP1B1 and BCRP). Increased risk of myopathy, including rhabdomyolysis, while taking rosuvastatin with medications that increase the concentration of rosuvastatin in blood plasma due to their interaction with transport proteins. To this group of substances belong ciclosporin, HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir, and / or tipranavir; see section special instructions and Interaction with other medicinal products). If this is possible, a decision should be made on the appointment of alternative therapy and, if necessary, temporarily stop taking rosuvastatin. In the case when simultaneous administration can not be avoided, the possible risk of interaction and the potential benefit of co-treatment should be carefully assessed (see section Interaction with other medicinal products).

Side effects:

According to clinical studies of rosuvastatin, as well as data from its post-marketing application, the following adverse reactions were observed in patients.

The frequency of adverse reactions is distributed as follows: 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 1/10000 to less than 1/1000; very rarely - from less than 1/10000; the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

From the side of the blood and lymphatic system: rarely - thrombocytopenia.

From the nervous system: often - headache, dizziness, asthenic syndrome; very rarely - polyneuropathy,decreased memory; frequency is unknown - depression, peripheral neuropathy, sleep disturbances, including insomnia and nightmares.

From the digestive system: often - constipation, nausea, abdominal pain; rarely - pancreatitis; very rarely - hepatitis, jaundice; frequency is unknown - diarrhea.

From the respiratory system: frequency unknown - cough, shortness of breath, interstitial lung disease.

From the endocrine system: often - diabetes mellitus¹.

From the musculoskeletal system: often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis; very rarely arthralgia; frequency unknown immuno-mediated necrotizing myopathy; lesions of tendons, sometimes with ruptures.

Allergic reactions: infrequently - itchy skin, rash, hives; rarely - reactions of hypersensitivity, including angioedema.

From the skin and subcutaneous tissues: frequency is unknown - Stevens-Johnson syndrome.

From the urinary system: very rarely - hematuria.

From the genitals and the breast: very rarely - gynecomastia.

Laboratory indicators: rarely transient increase in activity of aspartate aminotransferase and alanine aminotransferase.

Other: frequency unknown - peripheral edema.

1 - The frequency depends on the presence of risk factors (fasting blood glucose >5.6 mmol / l, body mass index> 30 kg / m², increased concentration of TG, arterial hypertension in history).

As with the use of other inhibitors of HMG-CoA reductase, the incidence of adverse reactions is dose-dependent, side effects are usually not very significant and pass independently.

Effect on kidney function

In patients who received rosuvastatin, during the analysis of urine test strips revealed proteinuria, mainly tubular. Changes in the amount of protein in the urine (from absence or trace amounts to ++ or more) were observed in less than 1% of patients receiving 10-20 mg of rosuvastatin and about 3% of patients receiving 40 mg of rosuvastatin. A slight change in the amount of protein in the urine (from absence or trace amounts to +) was noted with a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset or progression of an existing kidney disease.

In patients receiving rosuvastatinhematuria was observed, the available data showed a low incidence of this undesirable reaction.

Influence on the musculoskeletal system

With the use of all doses of rosuvastatin and, in particular, when doses exceeding 20 mg were reported, the development of myalgia, myopathy, including myositis, in rare cases, rhabdomyolysis with or without acute renal failure. When taking rosuvastatin, a dose-dependent increase in activity of creatine phosphokinase (CKF) was observed. In most cases, it was insignificant, asymptomatic and temporary. In the case of an increase in the activity of CKK (more than 5 times compared with IGN) therapy should be suspended (see section Special instructions).

Effects on liver function

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

When some inhibitors of HMG-CoA reductase were used, sexual dysfunction was observed, and single cases of interstitial lung disease were noted (see section Special instructions). The frequency of reports on the development of rhabdomyolysis, serious violations of kidney and liver function (expressed mainly in increasing the activity of "liver" transaminases) is higher when taking a dose of rosuvastatin 40 mg.

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 and activities aimed at maintaining the function of vital organs and systems under the control of liver function and activity of CFC are carried out. It is unlikely that hemodialysis will be effective.

Interaction:

Inhibitors of transport proteins

Rosuvastatin is a substrate for some transport proteins, including the membrane transporter OATP1B1 involved in the hepatic capture process, and transport protein BCRP. The simultaneous administration of rosuvastatin with drugs that inhibit these transport proteins can lead to an increase in the concentration of rosuvastatin in the blood plasma and increase the risk of myopathy.

The simultaneous use of rosuvastatin and cyclosporine does not affect the plasma concentration of cyclosporine, but increases the effect of rosuvastatin (slowing its excretion, increases AUC 7 times, C_m_Oh - 11 times).Simultaneous administration of cyclosporine and rosuvastatin is contraindicated.

Simultaneous reception erythromycin and rosuvastatin leads to a decrease AUC rosuvastatin by 20% and increases C_m_Oh by 30%. Such interaction can arise as a result of increased intestinal motility caused by the intake of erythromycin.

In patients receiving indirect anticoagulants (eg, warfarin) it is recommended to monitor the international normalized ratio (MHO), Since the initiation of therapy with rosuvastatin or an increase in its dose may lead to an increase MHO, and the withdrawal of rosuvastatin or a decrease in its dose may lead to its reduction.

Gemfibrozil and other lipid-lowering drugs: simultaneous reception Gemfibrozil and rosuvastatin increases C_m_Oh and AUC rosuvastatin in 2 times (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 hypolipidemic doses of nicotinic acid (not less than 1 g / day) increased the risk of myopathy with simultaneous application with other HMG-CoA reductase inhibitors, possibly due to the fact,that they can cause myopathy and when used as monotherapy. With simultaneous administration of rosuvastatin with one of the drugs in this group, patients are advised to take an initial dose of rosuvastatin 5 mg, a daily dose of rosuvastatin 40 mg is contraindicated in this case.

The simultaneous use of rosuvastatin and antacids, containing aluminum and magnesium 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.

The simultaneous use of rosuvastatin and oral contraceptives increases the AUC ethinylestradiol and AUC norgestrel by 26% and 34% respectively, which should be taken into account when selecting a dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy are absent, therefore, it is impossible to exclude a similar effect when they are used together. However, a similar combination was widely used during clinical trials of rosuvastatin and was well tolerated by patients.

Research results in vivo and in vitro showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Rosuvastatin is a non-core substrate for these isoenzymes. There was no clinically significant interaction with such drugs as fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4), ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4), related metabolism with the cytochrome P450 system. Co-administration of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia led to an increase AUC rosuvastatin in 1,2 times. However, it is impossible exclude pharmacodynamic interactingctvia between rosuvastatin and ezetimibe in relation to the appearance of undesirable phenomena.

Despite the fact that the exact mechanism of interaction is unknown, the application of inhibitors of HIV proteases with rosuvastatin may lead to a pronounced increase in the exposure of rosuvastatin.

A pharmacokinetic study of concomitant 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_Ohrosuvastatin, respectively.Thus, the combined use of rosuvastatin with HIV-protease inhibitors in HIV-infected patients is not recommended.

There was no clinically significant interaction of rosuvastatin with digoxin. Table 1 lists various types of interactions, including interactions requiring dose adjustment for rosuvastatin. It is necessary to adjust the dose of rosuvastatin if it is necessary to use simultaneously with other medicinal products that increase the systemic concentration of rosuvastatin. If the expected increase AUC is approximately 2 times or more, the initial dose of rosuvastatin should be 5 mg once a day. Rosuvastatin daily dose should be adjusted so that its systemic concentration, taking into account its increase is not greater than that when taking rosuvastatin dose of 40 mg monotherapy. For example, when taking gemfibrozil, the dose of rosuvastatin should not exceed 20 mg (increase AUC in 1.9 times) and 10 mg with the combination atazanavir / ritonavir (increase AUC in 3.1 times).

Table 1. Effect of simultaneous administration of drugs on the exposure of rosuvastatin (AUC, in order of decreasing importance)

Dosage regimen of the interacting drug	The dosage regimen of rosuvastatin	Changing the value AUC rosuvastatin
Cyclosporine 75-200 mg 2 r / day, 6 months	10 mg 1 r / day, 10 days	An increase of 7.1 times
Atazanavir 300 mg / ritonavir 100 mg 1 r / day, 8 days	10 mg, single dose	Increase 3.1-fold
Lopinavir 400 mg / ritonavir 100 mg 2 r / day, 17 days	20 mg 1 r / day, 7 days	An increase of 2.1 times
Gemfibrozil 600 mg 2 r / day, 7 days	80 mg, single dose	Increase 1.9 times
Eltrombopag 75 mg 1 r / day, 10 days	10 mg, single dose	Increase 1.6 times
Darunavir 600 mg / ritonavir 100 mg 2 r / day, 7 days	10 mg 1 r / day, 7 days	Increase by 1.5 times
Tipranavir 500 mg / ritonavir 200 mg 2 r / day. 11 days	10 mg, single dose	Increase by 1.4 times
Dronedarone 400 mg 2 r / day	Not applicable	Increase by 1.4 times
Itraconazole 200 mg 1 r / day, 5 days	10 mg, single dose	Increase by 1.4 times
Ezetimibe 10 mg 1 r / day, 14 days	10 mg 1 r / day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg 2 r / day, 8 days	10 mg, single dose	Without changes
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 r / day, 5 days	10 mg, single dose	Without changes
Fenofibrate 67 mg 3 r / day. 7 days	10 mg, 7 days	Without changes
Rifampin 450 mg 1 r / day, 7 days	20 mg, single dose	Without changes
Ketoconazole 200 mg 2 r / day, 7 days	80 mg, single dose	Without changes
Fluconazole 200 mg 1 r / day. 11 days	80 mg, single dose	Without changes
Erythromycin 500 mg 4 r / day, 7 days	80 mg, single dose	Decrease by 28%
Baikalin 50 mg 3 r / day, 14 days	20 mg, single dose	Decrease by 47%

Special instructions:

Effect on kidney function

In patients who received high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed in the urine test strip, which in most cases was transient. Such proteinuria did not indicate an acute kidney disease or progression of kidney disease. The frequency of reports on the development of serious adverse reactions from the kidneys in the postmarketing period was higher in patients taking rosuvastatin in a dose of 40 mg.

When using the drug Rosart at a dose of 40 mg, it is recommended to monitor the indices of kidney function during treatment.

Influence on the musculoskeletal system

With the use of all doses of rosuvastatin and, in particular, when doses exceeding 20 mg were reported, the development of myalgia, myopathy and, in rare cases, rhabdomyolysis. In very rare cases, the development of rhabdomyolysis with simultaneous administration of inhibitors of HMG-CoA reductase and ezetimibe has been reported.In this case, pharmacodynamic interaction can not be ruled out, so caution should be exercised when they are taken together. As with the administration of other inhibitors of HMG-CoA reductase, the frequency of postmarketing observation about the development of rhabdomyolysis associated with rosuvastatin was higher with a dose of 40 mg.

Determination of creatine phosphokinase

Determination of the activity of CKK should not be performed after intensive physical exertion or in the presence of other possible causes of an increase in its activity, which may lead to incorrect interpretation of the results. In case the initial activity of CK is significantly increased, after 5-7 days a repeated measurement should be performed - do not start therapy if the repeated test confirms the initial activity of CK (5 times higher than normal).

Before the start of therapy

Caution should be exercised when prescribing Rosart, as well as with the administration of other HMG-CoA reductase inhibitors, to patients with existing risk factors for myopathy / rhabdomyolysis (see section Carefully). It is necessary to consider the ratio of expected benefits from therapy and potential risk and to conduct clinical follow-up throughout the course of treatment.In the event that the initial activity of CK is significantly increased (5 times higher than ULN), then do not start treatment with the drug.

During treatment

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 the CK is significantly increased (more than 5 times compared with the IGN) or if the muscular symptoms are pronounced and cause daily discomfort (even if the CKK activity is 5 times less than the VLN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering Rosart 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 inexpedient. 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 discontinuation of statins, including rosuvastatin, have been noted.There were no signs of an increase in the effect on skeletal musculature when taking rosuvastatin and concomitant therapy. However, there have been reports of 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 in lipid-lowering doses > 1 g / day, azole antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy with simultaneous administration with certain HMG-CoA reductase inhibitors, so the simultaneous use of gemfibrozil and rosuvastatin is not recommended. The ratio of expected benefit and potential risk should be carefully weighed in the combined use of Rosart and fibrates or nicotinic acid in lipid-lowering doses > 1 g / day. Contraindicated taking RosArt 40 mg at a time with fibrates (see sections Interaction with other medicines and contraindications). During treatment, especially during the dosage adjustment period of Rosart, every 2-4 weeks you should monitor the lipid profile and, if necessary, change the dose of the drug.Rosart should not be taken to patients with acute or severe myopathy or risk factors predisposing to the development of renal dysfunction and secondary rhabdomyolysis (eg, sepsis, arterial hypotension, extensive surgery, trauma, severe metabolic disorders, severe endocrine disorders, and severe violations of water-electrolyte balance, uncontrolled convulsions).

Effects on liver function

Like other inhibitors of HMG-CoA reductase rosuvastatin should be used with caution in patients who abuse alcohol and / or have a history of liver disease. 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 Roswart should stop or reduce the dose of the drug if the level of activity of "hepatic" transaminases in the serum is 3 times higher than VGN. In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the treatment of underlying diseases should be performed prior to treatment with Rosart.In post-marketing surveillance of rosuvastatin, the frequency of reports on the development of serious violations of liver function (expressed primarily in an increase in the activity of "liver" transaminases) was higher with a dose of 40 mg.

Ethnic groups

In the course of pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin was noted among patients of the Mongoloid race in comparison with the european race (see section Dosage and Administration and Pharmacokinetics).

HIV protease inhibitors

During the joint administration of rosuvastatin and a combination of different inhibitors of HIV proteases with ritonavir, an increase in the systemic concentration of rosuvastatin is observed. Careful evaluation should be made of a reduction in blood lipid concentrations, and also consider a possible increase in rosuvastatin in blood plasma at the beginning of treatment and during the period of increasing the dose of Rosart in patients with HIV taking HIV protease inhibitors. Simultaneous administration of HIV protease inhibitors is not recommended without dose adjustment for rosuvastatin (see section Dosing and Administration and Interaction with Other Drugs).

Interstitial lung disease

Some inhibitors of HMG-CoA reductase, especially for a long time, reported 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 discontinued therapy with HMG-CoA reductase inhibitors.

Diabetes mellitus type II

Some data confirm that HMG-CoA reductase inhibitors increase blood glucose concentration and increase the likelihood of developing type 2 diabetes in some patients. However, this risk is outweighed by the ability of HMG-CoA reductase inhibitors to reduce the risk of vascular complications, so this fact is not a reason to interrupt the treatment with rosuvastatin. It is necessary to establish a clinical observation and conduct a biochemical blood test according to national standards in patients at risk of developing hyperglycemia (blood glucose concentration 5.6-6.9 mmol / L, body mass index> 30 kg / m², triglyceridemia, arterial hypertension).In one study of rosuvastatin, the overall incidence of diabetes mellitus was reported: 2.8% in the rosuvastatin group and 2.3% in the placebo group, mainly in patients with fasting glucose 5.6 - 6.9 mmol / l.

Lactose intolerance

The drug Rosart should not be taken to patients with lactose intolerance, lactase deficiency and glucose-galactose malabsorption, since it contains lactose monohydrate.

Effect on the ability to drive transp. cf. and fur:There have been no studies to study the effect of rosuvastatin on the ability to drive vehicles and mechanisms. When driving vehicles and engaging in potentially hazardous activities, patients should be careful, as dizziness may occur during therapy.

Form release / dosage:The film-coated tablets are 5 mg, 10 mg, 20 mg and 40 mg.

Packaging:By 7, 10 or 14 tablets in the blister PVC / PVDC / Aluminum foil or blister Aluminum foil / Aluminum foil. For 4 blisters for 7 tablets, 3 or 9 blisters for 10 tablets and 2 or 6 blisters for 14 tablets with instructions for use in a cardboard pack.

Storage conditions:At a temperature of no higher than 30 ° C.Keep out of the reach of children!

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002213

Date of registration:02.09.2013 / 07.03.2017

Expiration Date:02.09.2018

The owner of the registration certificate:Actavis PTS ehf GroupActavis PTS ehf Group Iceland

Manufacturer: & nbsp

ACTAVIS, Ltd. Iceland

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp08.11.2017

Illustrated instructions

Instructions

Rosart (Rosart)