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

Excipients: lactose monohydrate - 89,6400 / 179,2800 / 229,6450 mg, microcrystalline cellulose - 42,6850 / 85,3700 / 109,3550 mg, crospovidone - 6,0000 / 12,0000 / 16,0000 mg, magnesium stearate - 1.2750 / 2.5500 / 3.4000 mg; shell tablets: lactose monohydrate - 1,8000 / 3,6000 / 4,8000 mg, hypromellose - 1,2600 / 2,5200 / 3,3600 mg, titanium dioxide - 1,0778 / 2,1555 / 2,8740 mg, triacetin - 0,3600 / 0,7200 / 0,9600 mg, quinoline yellow - 0,0022 / 0,0045 / 0,0060 mg.

Description:

10 mg: Round, biconvex tablets, film-coated, from light yellow to yellow, engraved "10" on one side and "15" on the other side.

20 mg: Round, biconvex tablets, film-coated, from light yellow to yellow, engraved "20" on one side and "15" on the other side.

40 mg: Round, biconvex tablets, film-coated, from light yellow to yellow, engraved "40" on one side and "15" on the other side.

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, which is 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 uptake and catabolism of LDL, which leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total number of LDL and VLDL.

Pharmacodynamics

Rosuvastatin reduces the high content of cholesterol-LDL (cholesterol-LDL-C), total cholesterol and triglycerides (TG),increases the concentration of high-density cholesterol-lipoproteins (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoB), cholesterol-non-HDL, cholesterol-VLDL, TG-VLDL and increases the concentration of apolipoprotein A-I (ApoA-1), reduces the ratio of LDL-C-HDL cholesterol, total 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, after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved after 4 weeks of treatment and is maintained with further regular intake of the drug.

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia, regardless of race, sex or age, or in the treatment of patients with diabetes mellitus and hereditary family hypercholesterolemia.

Rosuvatatin is effective in patients with hypercholesterolemia IIa and IIb type by Fredrickson (mean baseline concentration of LDL-C is about 4.8 mmol / L). In 80% of these patients who received 10 mg of rosuvastatin,concentration reaches the target values of the level of LDL-C, established by the European Community for the study of atherosclerosis - less than 3 mmol / l. In patients with heterozygous familial hypercholesteridemia who took rosuvastatin in doses from 20 to 80 mg, there is a positive dynamics of the lipid profile.

As a result of titration of doses up to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is decreased by 53%. In 33% of patients, an LDL cholesterol concentration of less than 3 mmol / L is achieved, consistent with the European Community guidelines for the study of atherosclerosis.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 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, rosuvastatin in a dose of 5 mg to 40 mg once a day for six weeks, the concentration of TG in blood plasma decreased significantly.

Additive effect is noted in combination with fenofibrate for TG and nicotinic acid (more than 1 g per day) for the content of cholesterol-HDL.In patients with a low risk of developing coronary heart disease (CHD) (a 10-year risk for the Framingham scale is less than 10%), with an average LDL-C concentration of 4.0 mmol / L (154.5 mg / dL) and subclinical atherosclerosis was estimated by the thickness of the complex "intima-media" of carotid arteries - TKIM, rosuvastatin in a dose of 40 mg / day significantly slowed the progression of the maximum TKIM for 12 segments of the carotid artery compared with placebo with a difference of 0.0145 mm / year (95% confidence interval (CI): from -0.0196 to -0.0093; p <0.001). The study was conducted in patients with a low risk of coronary heart disease, for whom a dose of 40 mg is not recommended. A dose of 40 mg should be given only to patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD).

The results of a study on the use of statins for primary prevention showed that rosuvastatin significantly reduced the risk of cardiovascular complications with a relative risk reduction of 44%. The effectiveness of therapy was noted after 6 months of the drug. A statistically significant 48% reduction in the combined test was noted,including death from cardiovascular diseases, stroke and myocardial infarction, a 54% reduction in the occurrence of fatal or nonfatal myocardial infarction and a 48% 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 similar to the safety profile in the placebo group.

Pharmacokinetics:

Absorption and distribution

The maximum concentration of rosuvastatin in blood plasma is reached after 5 hours after ingestion. Absolute bioavailability is approximately 20%. Rosuvastatin is metabolized primarily 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. About 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a rather non-core substrate for metabolism by isoenzymes of the P450 system. CYP2C9 is the main isoenzyme involved in the metabolism of rosuvastatin, while isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.The main revealed metabolites of rosuvastatin are N-desmethylrozvastatin, which is 50% less active than rosuvastatin. and lactone metabolites, which are pharmacologically inactive. More than 90% of pharmacological activity but inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest - by its metabolites.

Excretion

Approximately 90% of the administered dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and nonabsorbed rosuvastatin), the rest is excreted by the kidneys. The half-life (T1 / 2) is approximately 19 hours. The half-life does not change with increasing dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation of 21.7%). As with other inhibitors of HMG-CoA reductase, a membrane cholesterol transporter is involved in the process of hepatic engagement of rosuvatatin, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose.Changes in pharmacokinetic parameters are not observed several times a day when taking the drug.

Age and gender

Sex and age have no clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Ethnic groups

Comparative studies of pharmacokinetics showed approximately a twofold increase in the mean AUC (area under the curve "concentration-time") and Cm(the time to reach the maximum concentration of the drug in the blood plasma) in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with those of the Caucasoid race. The increase in the average value was observed in Indians AUC and Cmah approximately in 1,3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among representatives of the Caucasoid and Negroid race.

Renal insufficiency

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

Liver failure

In patients with various stages of liver failure with 7 points or lower in the Child-Pugh scale, the half-life of rosuvastatin was not increased. However, in 2 patients with the 8th and 9th points on the Child-Pugh scale, the half-life was approximately halved. The experience with rosuvastatin in patients with more than 9 points on the Child-Pugh scale is not available.

Genetic polymorphism

HMG-CoA reductase inhibitors, including RosistarC®, bind to transport proteins OATP1B1 (a polypeptide for the transport of organic anions involved in the capture of statins by gayatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLCOIBI (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA notesincreased exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genotypes SLCO1B1 p.521TT and ABCG2 p.421S.

Indications:

- Primary hypercholesterolemia according to Fredrickson classification (type Ha.including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIB) as a supplement to the diet, when diet and other non-drug treatments (eg exercise, weight loss) are insufficient.

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

- Hypertriglyceridemia (Tin 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 who are shown therapy to reduce the concentration of total cholesterol and LDL-C.

- Primary prevention of major cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adult patients without clinical signs of IHD, at 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) with at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early development of coronary artery disease).

Contraindications:

For tablets 10 and 20 mg

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

- liver disease in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity by more than 3 times, but in comparison with the upper limit of the norm;

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

- myopathy;

- simultaneous administration of cyclosporine;

- in patients predisposed to the development of myotoxic complications:

- pregnancy and the period of breastfeeding;

- in women of childbearing age who do not use reliable means 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;

- co-administration with HIV protease inhibitors;

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

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption

(since the preparation contains lactose).

For tablets 40 mg

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

- liver disease in the active phase,including persistent increase in serum activity of transaminases and any increase in serum transaminase activity in more than 3 patients with an upper limit of normal;

- renal failure of moderate severity (CC less than 60 ml / min);

- myopathy;

- simultaneous administration of cyclosporine;

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

- hypothyroidism;

- personal or family anamnesis of muscular diseases;

- excessive use of alcohol;

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

- simultaneous reception of fibrates;

- pregnancy and the period of breastfeeding;

- in women of childbearing age who do not use case contraceptives;

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

- co-administration with HIV protease inhibitors;

- patient of the Mongoloid race;

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

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

Carefully:

For tablets 10 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 with other HMG-CoA reductase inhibitors or fibrates; excessive use of alcohol; conditions in which there was an increase in the plasma concentration of rosuvastatin; age over 70 years; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions: trauma; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; race (Mongoloid race); simultaneous reception of fibrates; simultaneous use with colchicine and ezetimibe.

For tablets 40 mg

Renal failure of moderate severity (CC greater than 60 ml / min); age over 70 years; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; one-time and its use with colchicine and ezetimibe.

Patients with hepatic insufficiency Data on the use of the drug in patients with more than 9 points on the scale Child-11y are absent.

Dosing and Administration:

Inside, do not chew and do not grind the tablet, swallow whole, squeezed water. The drug can be used at any time of the day, regardless of food intake. Before starting treatment, the patient should begin to follow a diet with the use of foods with a low cholesterol content, which should be continued throughout the treatment period. The dose of the drug should be selected individually, depending on the purpose of therapy and the therapeutic response to treatment, taking into account modern generally accepted recommendations for target lipid concentrations. If you need to take the drug at a dose of 5 mg, you can use the drug rosuvastatin in another dosage form or dosage, for example 5 mg tablets or 10 mg tablets with a risk (10 mg tablet should be divided into two parts at risk).

The recommended initial dose of the drug is 5 mg or 10 mg once a day for patients who have not previously taken statins, and for patients transferred to the drug after treatment with other HMG-CoA reductase inhibitors.When choosing the initial dose, you should take into account the cholesterol level in each individual patient and take into account the possible risk of cardiovascular complications, and also to assess the potential risk of side effects. If necessary, after 4 weeks, the dose may be increased. In connection with the possible development of side effects when taking a dose of 40 mg compared with lower doses of the drug (see section "Side effect"), increasing the dose to 40 mg, after additional doses above the recommended initial dose for 4 weeks of therapy , can be performed only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia) who, when taking a dose of 20 mg, did not achieve the desired result pi, and which will be under the supervision of a physician (see section "Special instructions"). When administering a dose of 40 mg, careful monitoring of the patient is recommended. Not recommended dose 40 mg patients who had not previously consulted a doctor. After 2-4 weeks of therapy and / or with an increase in the dose of the drug, it is necessary to monitor the lipid metabolism parameters, if necessary, the dose should be adjusted.The dose of the drug should be adjusted when it is necessary to use it together with drugs that increase the exposure to rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of the drug should be 5 mg once a day. Also, the maximum daily dose of the drug 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 that interact with rosuvastatin (see "Interactions with Other Drugs" in Table 1).

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 (QC less than 30 ml / min), the use of the drug is contraindicated. The drug in a dose of 40 mg is contraindicated in patients with moderate renal dysfunction (CK 30-60 ml / mi). Patients with moderate renal impairment are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency The drug is contraindicated in patients with liver disease in the active phase (see section "Contraindications").

Ethnic groups

In patients of the Mongoloid race, an increase in the systemic concentration of rosuvastatin is possible. This fact should be taken into account when prescribing the drug to these patient groups. When appointing doses of 10 mg and 20 mg, the recommended initial dose of the drug for patients of the Mongoloid race is 5 mg. The use of the drug in a dose of 40 mg to such patients is contraindicated (see section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLC01B1 (OATP1B1) p.521SS and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCOIBI p.521TT and ABCG2 p.421S. For patients - carriers of genotypes с.521СС or with.42IAA the recommended maximum dose of Rosestar® is 20 mg once a day (see the sections "Pharmacokinetics", "Special instructions" and "Interaction with other medicinal products").

Patients who are predisposed to myopathy When appointing doses of 10 mg and 20 mg, the recommended initial dose of the drug for patients with a predisposition to myopathy is 5 mg. The use of the drug in a dose of 40 mg in such patients is contraindicated.

Concomitant therapy

Rosuvastatin binds to various transport proteins, in particular to OATP1B1 and BCRP. When combined with use of the drug Rozistark® drugs (such as cyclosporin, some HIV protease inhibitors including ritonavir combination with atazanavir, lopinavir and / or tipranavir) that increase in concentration in the plasma rozuvasgati- due to interaction with transport proteins, may increase the risk of myopathy including rhabdomyolysis (see. Forums "Cautions" and "Interaction with other medicinal products") In such cases, you should evaluate the possibility of appointing an alternate treatment sludge and temporary discontinuation of Rosestar®. If the application of the above preparations necessary should assess the risk-benefit ratio and the concomitant drug therapy and Rozistark® consider reducing the dose (see. The "interaction with other medicinal products ").

Side effects:

The side effects associated with the use of Rosestar® are usually mild and pass on their own.The incidence of side effects is mainly dose-dependent, as with other inhibitors of HMG-CoA reductase.

To indicate the frequency of side effects, the following classification is used: often (> 1/100 and < 1/10), infrequently (> 1/1000 and < 1/100). rarely (> 1/10000 and < 1/1000), rarely (< 1/10000), unspecified frequency (can not be calculated from available data).

From the skin: infrequently: itching, rash, hives; Unspecified Frequency: Stevens-Johnson Syndrome.

From the digestive tract: often: constipation, nausea, abdominal pain; rarely: pancreatitis; very rarely: jaundice, hepatitis; frequency of disorder: diarrhea.

From the central nervous system: often: headache, dizziness; very rarely: polyneuropathy, memory loss.

From the immune system: rarely: toheightened sensitivity, including angioedema.

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

Other: often: asthenic syndrome; unspecified frequency: peripheral edema.

From the musculoskeletal system: often: myalgia; rarely: myopathy (including myositis), rhabdomyolysis; very rarely: arthralgia; Unspecified frequency: immuno-mediated necrotizing myopathy.Actions on skeletal muscles that cause myalgia, myopathy (including myositis) and, in rare cases, rhabdomyolysis with or without development of acute renal failure, have been observed in patients taking any dose of rosuvastatin, especially when taking doses. exceeding 20 mg. The dose-dependent increase in activity of creatine phosphokinase (CK) was revealed in patients taking rosuvastatin, but in most cases these manifestations were insignificant, asymptomatic and temporary. In the case of an increase in 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 urinary system

When taking rosuvastatin, proteinuria can be observed. Changes in the protein content in the urine (from lack or presence of trace amounts to the level of ++ and above) are observed in less than 1% of patients taking rosuvasgatin 10 mg and 20 mg and approximately 3% of patients taking the drug at a dose of 40 mg . A slight change in the amount of protein in the urine, expressed in a change from zero level or the presence of traces to the level of +, was observed when taking the drug at a dose of 20 mg.In most cases, proteinuria decreased and passed independently during the treatment. When analyzing the data of clinical studies, there is no causal relationship between proteinuria and acute or progressive kidney disease. Very rarely: hematuria, microhematuria.

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, this increase is slight, asymptomatic and temporary.

Laboratory indicators

When rosuvastatin was used, the following changes in laboratory parameters were observed: an increase in the concentration of glucose, bilirubin, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, thyroid dysfunction.

On the part of the hematopoiesis system: Unspecified frequency: thrombocytopenia.

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

From the reproductive system and the breast: unspecified frequency: gynecomastia.

Some statins reported the following side effects: depression, sleep disturbances, including insomnia and nightmarish dreams, sexual dysfunction.

With prolonged use of rosuvastatin, single cases of interstitial lung disease were reported.

Overdose:There is no specific treatment for an overdose of rosuvastatin. In case of overdose, it is recommended to carry out symptomatic treatment and supporting functions of vital organs and systems of the event. It is necessary to monitor the liver function and the activity of CK. Hemodialysis in this case is probably ineffective.

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 increased in 7 times in comparison with the values obtained in healthy volunteers (see the section "Contraindications").Joint application leads to an increase in the concentration of rosuvastatin in blood plasma by 11 times. Simultaneous use of drugs does not affect the concentration of cyclosporine in the blood plasma.

Ezetimibe: with simultaneous application of rosuvastatin and ezetimibe there is no change AUC or withmax both preparations. However, the risk of side effects due to pharmacodynamic interaction between rosuvastatin and ezetimibe can not be ruled out.

Gemfibrozil and other lipid-lowering drugs: simultaneous application of rosuvastatin and gemfibrozil leads to an increase in 2 times Cmax and AUC rosuvastatin (see section "Special instructions"). Based on the data of the study of specific interactions, no pharmacokinetically significant interaction with fenofibrate is expected, but pharmacodynamic interaction is possible. Gemfibrozil. fenofibrate, other fibrates and nicotinic acid in lipid-lowering doses (1 g or more per day) with simultaneous with the HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can cause myoia and when used as monotherapy.Simultaneous administration of 40 mg rosuvastatin and fibrates is contraindicated (see section "Special instructions" and "Contraindications"). At simultaneous reception of a preparation with gemfibrozilom and other lipid-lowering agents in a dose more than 1 g / day the initial dose of preparation Rosistark® should not exceed 5 mg.

HIV protease inhibitors: despite the fact that the exact mechanism of interaction is unknown, simultaneous administration of rosuvastatin with HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin. In a pharmacokinetic study with simultaneous administration of 20 mg rosuvastatin and a combined preparation containing two HIV protease inhibitors (400 mg lopivavir / 100 mg ritonavir) in healthy volunteers, a 2-fold increase was observed AUC_(0-24) and 5 times the Cmax rosuvastatin. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors in the treatment of patients with HIV is not recommended.

Antacids: simultaneous administration of rosuvastatin and suspensions of antacids, containing aluminum or magnesium hydroxide, can lead to a decrease in the concentration of rosuvastatin in the blood plasma 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 administration of rosuvastatin and erythromycin may lead to a decrease AUC_(0-24) rosuvastatin by 20% and Cmrosuvastatin - by 30%. Such interaction can be caused by increased intestinal motility caused by the administration of erythromycin.

Isozymes of cytochrome P450: results of studies in vitro and in vivo showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a rather weak substrate for these isoenzymes. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4). Modern use of rosuvastatin and itracoazole (inhibitor of isoenzyme CYP3A4) increases the AUC rosuvastatin by 28% (clinically significant). Therefore, any interaction of drugs associated with the metabolism of cytochrome P450. does not expect gt;

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with simultaneous use of HMG-CoA reductase inhibitors, including rosuvastatin. and colchicine.

Effect of rosuvastatin on other drugs

Antagonists of vitamin K: as in the case of other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or an increase in the dose of the drug in patients receiving concomitantly indirect anticoagulants (for example, warfarin or other coumarin anticoagulants) can lead to an increase in prothrombin time (an international normalized relationship - MHO). Removing rosuvastatin or lowering the dose may cause a decrease MHO. In such cases, monitoring MHO.

Oral contraceptives / hormone replacement therapy: simultaneous administration of rosuvastatin and hiereradic contraceptives may increase AUC ethinylestradiol and porgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be considered when choosing a dose of oral contraceptives. Pharmacokinetic data on simultaneous application of a rose Vastatin and hormone replacement therapy are not available, therefore, it is impossible to exclude a similar action when using this combination. However, this combination of drugs was widely used during clinical trials and was well tolerated by patients.

Other medicines: no clinically significant interaction is expected with simultaneous application of rosuvastatin and digoxin.

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

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

Table 1. Effect of concomitant therapy on exposure to rosuvastapa (AUC, data are listed in descending order) - the results of published clinical studies.

Complementary therapy regimen

Mode of rosuva-statin administration

Change AUC rosewood

Cyclosporine 75-200 mg 2 times a day, 6 months

10mg 1 once a day, 10 days

An increase of 7.1 times

Atazanavir

300 mg / ritonavir

100 mg 1 once a day, 8 days

10 mg once

Increase in 3,1 times

Lopinavir

400 mg / ritonavir

100 mg 2 times a day, 17 days

20 mg 1 once a day, 7 days

Increase in 2.1 times

Gemfibrozil 600 mg 2 times a day, 7 days

80 mg once

The increase in 1, 9 times

Eltrombopag 75 mg 1 time per day, 10 days

10 mg once

The increase in 1.6 times

Darunavir

600 mg /

ritonavir 100 mg

2 times a day,

7 days

10 mg 1 time per

day, 7 days

Increase

in 1,5 times

Tipranavir

500 mg /

ritonavir 200 mg

2 times a day,

11 days

10 mg one

multiple

Increase

in 1,4 times

Dronedaron

400 mg

2 times a day.

No data

Increase

in 1,4 times

Itraconazole

200 mg

1 time per day,

5 days

10 mg or 80

mg one

multiple

Increase

in 1,4 times

Ezetimibe

10 mg

1 time per day ..

14 days

10 mg 1 time per

day, 14 days

Increase

1,2 times

Fosamprenavir

700 mg /

ritonavir 100 mg

2 times a day,

8 days

10 mg one

multiple

Without treason

the

Aleglitazar

0.3 mg,

7 days

40 mg, 7

days

Without treason

the

Silymarin

140 mg

3 times per day,

5 days

10 mg one

multiple

Without treason

the

Fenofibrate

67 mg

3 times per day,

7 days

10 mg. 7th

days

Without treason

the

Rifampin

450 mg

1 time per day

ki. 7 days

20 mg one

multiple

Without treason

the

Ketoconazole

200 mg

2 times a day ..

7 days

80 mg one

multiple

without treason

the

Fluconazole

200 mg

1 time per day,

11 days

80 mg one

multiple

Without treason

the

Erythromy

zinc 500 mg

4 times per

day .. 7 days

80 mg one

multiple

Decrease

by 28%

Baikalin

50 mg

3 times per day,

14 days

20 mg one

multiple

Decrease

na 47%

Special instructions:

Renal Effects

Proteinuria, mainly of tubular origin, was noted in patients receiving high doses of rosuvastatin, in particular 40 mg, which in most cases was periodic or transient. Such proteinuria does not mean the occurrence of acute or progressive kidney disease. The frequency of serious impairment of kidney function is increased by taking 40 mg rosuvastatin.In such patients during the treatment with Rosestar® it is recommended to monitor the parameters of kidney function.

From the side of the musculoskeletal system

When using the drug Rosistarka in all dosages, and, especially when taking the drug at a dose exceeding 20 mg, myalgia, myopathy and. in rare cases, rhabdomyolysis.

Determination of creatine phosphokiose (CK) Determination of the activity of CKK should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK. which can lead to incorrect interpretation of the results. If the initial level of CK is significantly increased (more than 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 repeat measurement confirms the baseline level of CK (5 times higher than the upper limit of the norm).

Before the start of therapy

Rosistarc®, like other HMG-CoA reductase inhibitors, should be administered with caution to patients with existing risk factors for myopathy / rhabdomyolysis (see "With caution.") The risk-to-benefit ratio of therapy should be assessed and clinical observation performed throughout the course treatment.

During therapy

It is recommended that patients be informed of the need to immediately notify the doctor of cases of unexpectedness muscular pain, muscle weakness, or spasms, especially in combination with malaise or fever. In such patients, it is necessary to monitor the activity of CK. Treatment should be discontinued if the activity of CK is more than 5 times higher than the upper limit of the norm or if the symptoms from the muscles are pronounced and cause daily discomfort. even if the activity of CK is 5 times lower than the upper limit of the norm. If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering Rosestar® or other HMG-CoA reductase inhibitors in smaller doses with careful monitoring of the patient. Regular 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 immunosuppressive therapy. No signs of increased exposure on skeletal musculature with rosuvastatin and concomitant therapy. However, there have been reports of an increase in cases of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors together with fibrin acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid, antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Therefore, simultaneous administration of rosuvastatin and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully evaluated when rosuvastatin is combined with fibrates or nicotinic acid in laxifacting doses (> 1 g / day). Contraindicated simultaneous administration of rosuvastatin in a dose of 40 mg and fibrates (see the sections "Interaction with other drugs" and "Side effect").In 2-4 pedules after the start of treatment and / or with an increase in the dose of Rosestar®, control of lipid metabolism parameters is necessary, if necessary, dose correction is required.

Liver

Like other HMG-CoA-Reducers basins. Rosistarc® should be used with extreme caution in patients who have abused alcohol 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. If the activity of "hepatic" transaminases in the serum is 3 times higher than the upper limit of the norm, you should stop taking the drug Rosistark® or reduce the dose of the drug (see the section "Method of administration and dose"), in patients with secondary hypercholesterolemia due to hypothyroidism or nephrologic syndrome therapy the main disease should be performed before the treatment with rosuvastatin.

Ethnic groups

In the course of pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin among patients of Chinese and Japanese origin was found in comparison with the indices obtained among patients - representatives of the Caucasoid race (cf.section "Method of administration and dose" and "Pharmacokipetka").

HIV protease inhibitors

Simultaneous use of rosuvastatin with HIV protease inhibitors is not recommended (see section "Interaction with other drugs").

Lactose

Do not use the drug in patients with lactase deficiency, intolerance to galactose and glucose-galactose malabsorption.

Interstitial lung disease

Some statins, especially for a long time, reported single cases of interstitial lung disease. Manifestations of the disease may include shortness of breath, dry cough and deterioration in overall health (weakness, weight loss and fever). If there is a suspicion of interstitial lung disease, you should stop the therapy for us and.

Diabetes mellitus type 2

For patients with a glucose concentration of 5.6 to 6.9 mmol / L, the use of rosuvastatin leads to an increased risk of developing type 2 diabetes.

Effect on the ability to drive transp. cf. and fur:Studies to study the effect of rosuvastatin on the ability to drive vehicles and mechanisms were not conducted.Based on the pharmacodynamic properties of the drug, it can be assumed that rosuvastatin should not exert such effects, however, it must be taken into account that dizziness may occur during treatment.

Form release / dosage:

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

Packaging:

10 mg: For 14 tablets, film-coated, in PA / Al / PVC blister; 1. 2 or 4 blisters together with instructions for use are placed in a cardboard box.

20 mg and 40 mg: 7 tablets, film-coated, in PA / Al / PVC blister; 2. 4 or 8 blisters together with instructions for use are placed in a cardboard box.

10 mg. 20 mg and 40 mg: 10 tablets coated with a film coating in PA / Al / PVC blister; 3 blisters together with the instruction but are placed in a cardboard box.

Storage conditions:Store at a temperature not exceeding 25 ° C. Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002346

Date of registration:16.01.2014/22.04.2015

Date of cancellation:2019-01-16

The owner of the registration certificate:Beluga, medicines and cosmetics.Beluga, medicines and cosmetics. Croatia

Manufacturer: & nbsp

BELUPO, Pharmaceuticals & Cosmetics, d.d. Croatia

Representation: & nbspBeluga, medicines and cosmetics. Beluga, medicines and cosmetics. Croatia

Information update date: & nbsp30.05.2016

Illustrated instructions

Instructions

RosystarK® (Rozistark® )