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

Excipients: calcium hydrogen phosphate dihydrate 16.3 mg / 14.0 mg / 28.0 mg / 56.0 mg, giprolose (hydroxypropylcellulose) 2.385 mg / 2.2 mg / 4.4 mg / 8.8 mg, crospovidone 3.5 mg / 3.5 mg / 7.0 mg / 14.0 mg, lactose monohydrate 59.0 mg / 56.17 mg / 112.34 mg / 224.68 mg, microcrystalline cellulose 12.5 mg / 12.5 mg / 25.0 mg / 50.0 mg, magnesium stearate 1.0 mg / 1.0 mg / 2.0 mg / 4.0 mg;

excipients for the shell: Opadry II [alcohol polyvinyl 1,2 mg / 1,2 mg / 2,4 mg / 4,8 mg, macrogol 0,606 mg / 0,606 mg / 1,212 mg / 2,424 mg, talc 0,444 mg / 0,444 mg / 0,888 mg / 1,776 mg, titanium dioxide 0.702 mg / 0.702 mg / 1.404 mg / 2.808 mg, an aluminum lacquer based on a dye of charming red 0.017 mg / 0.017 mg / 0.034 mg / 0.068 mg, an aluminum lacquer based on azorubin dye 0.014 mg / 0.014 mg / 0.028 mg / 0.056 mg, aluminum dye-based dye sunset yellow 0.017 mg / 0.017 mg / 0.034 mg / 0.068 mg].

Description:The tablets covered with a film covering of pink color, round, biconcave form (dosages of 5 mg and 20 mg) or biconvex, oblong with rounded ends, with a risk (dosages of 10 mg and 40 mg). On the cross section, the nucleus is white or almost white in color.

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

ATX: & nbsp

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

C.10.A.A.07 Rosuvastatin

Pharmacodynamics:

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, the precursor of cholesterol. The main target of the action of rosuvastatin is the liver, where the synthesis of cholesterol (cholesterol) and catabolism of low-density lipoprotein (LDL) is carried out.

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

Rosuvastatin reduces elevated concentrations of cholesterol-LDL (cholesterol-LDL-C), total cholesterol,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, and VGLP and increases the concentration of apolipoprotein AI (ApoA-I), reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol, and non-HDL / CS-HDL cholesterol and the ApoB / ApoA-1 ratio. The therapeutic effect is within one week after initiation of treatment with rosuvastatin, after 2 weeks of treatment up to 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular intake of the drug.

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex or age, including patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with Fredrickson IIa and IIb type cholesterolinemia (average baseline LDL-C concentration of about 4.8 mmol / L), the concentration of LDL-C is lower than 3 mmol / L in the case of rosuvastatin 10 mg.In patients with heterozygous familial hypercholesterolemia receiving rosuvastatin in a dose of 20-80 mg, there is a positive dynamics of lipid profile (a study involving 435 patients). After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is reduced by 53%. In 33% of patients the concentration of LDL-C is less than 3 mmol / l.

In patients with homozygous familial hypercholesterolemia receiving rosuvastatin in a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C is 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dL, 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.

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

In a clinical study involving 984 patients aged 45 to 70 years with a low risk of developing coronary heart disease (CHD) (a 10-year risk for the Framingham scale of less than 10%),an average concentration of LDL cholesterol 4.0 mmol / L (154.5 mg / dl) and subclinical atherosclerosis (which is estimated from the thickness of the complex "intima-media" carotid - IMT) studied the effect of the thickness of rosuvastatin complex "intima-media." Patients received rosuvastatin in a dose of 40 mg / day or placebo for 2 years. Rosuvastatin therapy 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 from -0.0196 to -0.0093; p <0.001]. Compared with the baseline values in comparison with the increase of this figure to 0.0131 mm / year (1.12 rosuvastatin group was observed a decrease in the maximum value of IMT 0.0014 mm / year (0.12% / year (nonsignificant difference)) % / year (p <0.001)) in the placebo group. To date, there has been no direct correlation between a decrease in TKIM and a reduction in the risk of cardiovascular events. This study was conducted in patients with a low risk of coronary heart disease (CHD), for whom a dose of rosuvastatin 40 mg is not recommended. A dose of rosuvastatin 40 mg should be given to patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD).

The results of another clinical study in 17802 patients showed that rosuvastatin significantly reduced the risk of cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p <0.001) with a relative risk reduction of 44%. The effectiveness of therapy was noted in the first 6 months of rosuvastatin. There was a statistically significant 48% reduction in the combined criteria, including cardiovascular mortality, stroke and myocardial infarction (risk ratio: 0.52, 95%, confidence interval 0.40-0.68, p <0.001), a decrease in 54% of fatal or nonfatal myocardial infarction (risk ratio: 0.46, 95%, confidence interval 0.30-0.70) and 48% fatal or nonfatal stroke. Overall mortality decreased by 20% in the rosuvastatin group (risk ratio: 0.80, 95%, confidence interval 0.67-0.97, p = 0.02). The safety profile of patients taking rosuvastatin in a dose of 20 mg, was, in general, similar to the safety profile in the placebo group.

Pharmacokinetics:

Absorption and distribution. The maximum concentration of rosuvastatin in the blood plasma is reached approximately 5 hours after ingestion. Absolute bioavailability is approximately 20%.The volume distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism. Rosuvastatin is subject to limited metabolism (about 10%) in the liver. Rosuvastatin is a non-core substrate for metabolism by isoenzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is isoenzyme CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.

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

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

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

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

Ethnic groups. Pharmacokinetic studies showed approximately a twofold increase in the median AUC (the area under the concentration-time curve) and Stach (the maximum concentration in blood plasma) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Europeans. Indian patients showed an increase in the median AUC and C_m_Oh in 1,3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race.

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

Liver failure. Patients with different stages of hepatic insufficiency did not have an increase in T1 / 2 rosuvastatin in patients with 7 points or lower on the Child-Pugh scale. Two patients with the 8th and 9th points on the Child-Pugh scale had an increase in T1 / 2 by at least 2-fold. The experience with rosuvastatin in patients with more than 9 points on the Child-Pugh scale is not available.

Genetic polymorphism. Inhibitors of HMG-CoA reductase (statins), including, rosuvastatin, bind to OAT31B1 transport proteins (the polypeptide of organic anion transport, involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLC01B1 (OATP1B1) C.521CC and ABCG2 (BCRP) C.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2.4 times, respectively, compared with the carriers of genotypes SLC01B1 p.521TT and ABCG2 p.421S.

Indications:

- Primary hypercholesterolemia according to Fredrickson (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 by Fredrickson) 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, heart attack, arterial revascularization) in adult patients without clinical signs of coronary heart disease,but with an increased risk of its development (age over 50 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:

For the drug Rustor in a daily dose of 5 mg, 10 mg and 20 mg:

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

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

- age to 18 years;

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

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

- myopathy;

- simultaneous administration of cyclosporine;

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

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

For the drug Rustor in a daily dose of 40 mg:

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

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption;

- age to 18 years;

- simultaneous administration of cyclosporine;

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

- patients with risk factors for myopathy / rhabdomyolysis, namely:

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

- hypothyroidism;

- personal or family anamnesis of muscular diseases;

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

- excessive use of alcohol;

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

- simultaneous reception of fibrates;

- patients of the Mongoloid race.

Carefully:

For the drug Rustor in a daily dose of 5 mg, 10 mg and 20 mg: the risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other inhibitors of HMG-CoA reductase or fibrates; excessive use of alcohol; age over 65; conditions in which there was an increase in the plasma concentration of rosuvastatin; race (Mongoloid race); simultaneous appointment with fibrates; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled convulsive seizures.

For the drug Rustor in a daily dose of 40 mg: renal failure of mild severity (CC greater than 60 ml / min); age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled convulsive seizures.

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

Pregnancy and lactation:

Pregnancy

The drug Rustor is contraindicated in pregnancy.

Women of reproductive age should apply adequate methods of contraception.

Because cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of rosuvastatin in pregnancy.

In the case of diagnosing pregnancy during therapy, taking the drug should be stopped immediately.

Breastfeeding period

Data on the allocation of rosuvastatin to breast milk are not available, therefore, during the period of breastfeeding, its use is contraindicated. If you need to use the drug during lactation, breast-feeding should be discontinued.

Dosing and Administration:

Inside, do not chew and do not grind the tablet, swallow whole, squeezed water. The drug can be administered at any time of the day, regardless of food intake.Before starting therapy, the patient should begin to follow the standard hypocholesterolemic diet and continue to observe it during treatment. The dose of the drug should be selected individually, depending on the purpose of therapy and the therapeutic response to treatment, taking into account current recommendations for target lipid concentrations.

The recommended initial dose for patients starting to take the drug, or for patients transferred from other HMG-CoA reductase inhibitors, should be 5 mg or 10 mg of the drug Rustor 1 time per day. When choosing the initial dose should be guided by individual concentration of cholesterol and taken in attention to the possible risk of cardiovascular complications, as well as the potential risk of side effects. If necessary, the dose may be increased to greater after 4 weeks.

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 therapy,It can be performed only in patients with severe hypercholesterolaemia and at high risk for cardiovascular complications (especially in patients with familial hypercholesterolaemia), who do not have the desired result of therapy was achieved when receiving doses of 20 mg, and which will be under the supervision of a physician. 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 dose needed Rustor control lipid metabolism (dose required correction if necessary).

Patients of advanced age. No dose adjustment is required.

Patients with renal insufficiency. In patients with mild or moderate renal insufficiency, dose adjustment is not required. In patients with severe renal failure (CC less than 30 ml / min.), The use of the drug Rustor is contraindicated. Do not use this rosuvastatin 40mg patients with moderate renal impairment (creatinine clearance of 30-60 ml / min.). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency. The drug Rustor is contraindicated in patients with liver disease in the active phase.

Ethnic groups. When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, there was an increase in the systemic concentration of rosuvastatin among Japanese and Chinese. This fact should be taken into account when prescribing Rustor to these groups of patients. When appointing doses of 10 mg and 20 mg, the recommended initial dose for patients of the Mongoloid race is 5 mg. Contraindicated the appointment of the drug in a dose of 40 mg to patients of the Mongoloid race.

Genetic polymorphism. In carriers SLCOIBI (OATP1B1) p.521N and ABCG2 (BCRP) from. 421 AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCOIBI P.521TT and ABCG2 from. 421SS. For patient carriers of genotypes с.521СС or С.421АА the recommended maximum dose of the drug Rustor is 20 mg once a day.

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

Concomitant therapy. Rosuvastatin binds to various transport proteins (in particular, to OAT31B1 and BCRP). With the simultaneous application of the drug Rustor with medications (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir, and / or tipranavir) that increase the concentration of rosuvastatin in blood plasma by interacting with transport proteins may increase the risk of myopathy, including rhabdomyolysis (see "Specific guidance" and "Interaction with other medicinal products "), In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of Rustor should be assessed. If the use of the above mentioned drugs is necessary, the relationship between the benefit and the risk of concomitant therapy with Rustor should be evaluated and the possibility of reducing its dose should be considered (see the section on "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 adverse reactions is mainly dose-dependent.

The frequency of unwanted reactions is as follows: very often (>1/10 cases), often (>1/100 and <1/10 cases), infrequently (>1/1000 and <1/100 cases), rarely (>1/10000 and <1/1000 cases) and very rarely (<1/10000 cases, including individual messages). Undesirable reactions, the frequency of development of which can not be estimated from available data, have the designation "frequency is unknown".

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

From the endocrine system: often - type 2 diabetes.

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

and

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

From the skin and subcutaneous tissues: infrequently - itchy skin, rash, hives.

From the side of the musculoskeletal and connective tissue: often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis.

When rosuvastatin is used in all doses, especially at doses exceeding 20 mg,the following effects on the musculoskeletal system were reported: myalgia, myopathy (including myositis), in rare cases - rhabdomyolysis with or without acute renal failure.

A dose-related increase in activity of creatine phosphokinase (CK) is observed in a small number of patients taking rosuvastatin (in most cases it was insignificant, asymptomatic and temporary). In case of increased activity of CK (more than 5 times compared with the upper limit of the norm) therapy should be suspended.

From the side of the kidneys and urinary tract:

In patients who received rosuvastatin, proteinuria can be detected; 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 rosuvastatin in a dose of 10-20 mg, and about 3% of patients receiving rosuvastatin in a dose of 40 mg. A slight change in the amount of protein in the urine 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.

From the liver and bile ducts: rarely - a dose-dependent increase in the activity of "liver" transaminases (in a small number of patients, in most cases it is insignificant, asymptomatic and temporary).

Laboratory indicators: frequency unknown - increase in glucose concentration, bilirubin, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, thyroid dysfunction.

Other: often - asthenic syndrome.

In the postmarketing period reported the following adverse reactions with rosuvastatin:

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

From the side of the musculoskeletal and connective tissue: very rarely - arthralgia; frequency unknown - immuno-mediated necrotizing myopathy.

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

From the respiratory system, chest and mediastinum: frequency unknown - cough, dyspnea.

From the side of the kidneys and urinary tract: very rarely - hematuria.

From the skin and subcutaneous fat: frequency unknown - syndrome

Stevens-Johnson.

From the genitals and the breast: frequency unknown - gynecomastia.

On the part of the hematopoiesis system: frequency unknown - thrombocytopenia.

Other: frequency unknown - peripheral edema.

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

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

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

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

Interaction:

Inhibitors of transport proteins. Rosuvastatin binds to some transport proteins, in particular, to OAT31B1 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.

Cyclosporine. With simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin was an average of 7 times higher than that seen in healthy volunteers. Simultaneous application leads to an increase in the concentration of rosuvastatin in blood plasma by 11 times. Rosuvastatin does not affect the plasma concentration of cyclosporine. The simultaneous use of rosuvastatin and cyclosporine is contraindicated.

Indirect anticoagulants. The beginning of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both indirect anticoagulants (for example, warfarin), can lead to an increase in prothrombin time (an international normalized relationship - MHO). The cancellation of rosuvastatin or a decrease in the dose of the drug may lead to a decrease MHO. In such cases, control is recommended MHO.

Gemfibrozil and other lipid-lowering drugs. The simultaneous use of rosuvastatin and gemfibrozil leads to an increase in 2 times the maximum concentration of rosuvastatin in blood plasma and AUC rosuvastatin. Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrates is expected, possibly pharmacodynamic interaction.

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g / day) increased the risk of myopathy with simultaneous use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used in monotherapy. With the simultaneous use of rosuvastatin with gemfibrozil, fibrates, nicotinic acid at a dose of more than 1 g / day, patients are advised to take an initial dose of rosuvastatin 5 mg.

Ezettshib. The simultaneous use of rosuvastatin 10 mg and ezetimibe at a dose of 10 mg was not accompanied by a change AUC and C_m_Oh both drugs in patients with hypercholesterolemia.

HIV protease inhibitors. Despite the fact that the exact mechanism of interaction is unknown, simultaneous intake of HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin. 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 AUCo-24 and C_m_Oh rosuvastatin, respectively. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors in the treatment of patients with the human immunodeficiency virus (HIV) is not recommended.

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

Erythromycin. The simultaneous use of rosuvastatin and erythromycin leads to a decrease AUC rosuvastatin by 20% and C_m_Oh rosuvastatin by 30%. Such interaction can arise as a result of increased intestinal motility caused by the administration of erythromycin.

Oral contraceptives / hormone replacement therapy. The simultaneous use of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when choosing a dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy are not available, therefore, it is impossible to exclude a similar effect when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Isozymes of cytochrome P450. 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. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4). The simultaneous use of rosuvastatin and itraconazole (inhibitor of isoenzyme CYP3A4) increases the AUC rosuvastatin by 28% (it is clinically insignificant). Thus, the interaction associated with cytochrome P450 metabolism is not expected.

Digoxin. No clinically significant interaction between rosuvastatin and digoxin is expected.

Interaction with medicinal products, which requires correction of the dose of rosuvastatin. The dose of the drug Rustor should be adjusted when it is necessary to simultaneously use with medicinal products that increase the exposure to rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of Rustor 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 simultaneous administration of medications interacting with rosuvastatin. For example, the maximum daily dose of the drug with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

Special instructions:

urinary system

In patients receiving high doses of rosuvastatin (mainly 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 Rustor in a dose of 40 mg, it is recommended to monitor the indicators of kidney function during treatment.

Musculoskeletal system

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

Determination 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.If the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the baseline CK activity (more than 5 times higher than the upper limit of the norm).

Before the start of therapy

When prescribing Rustor, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised for patients with existing risk factors for myopathy / rhabdomyolysis, the risk-to-benefit ratio should be considered and clinical observation performed.

During therapy

The patient should be informed of the need to report immediately to the doctor about cases of sudden onset of muscle pain, muscle weakness, or spasms, especially in combination with malaise and fever. In such patients, the activity of CK should be determined. Therapy should be discontinued if the activity of CK is significantly increased (more than 5 times compared with the upper limit of the norm) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CK is 5 times lower compared to the upper limit norms).If symptoms disappear and CPK activity returns to normal, re-administration of Rustor or other HMG-CoA reductase inhibitors in smaller doses should be considered 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 system 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 in lipid-lowering doses, azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Gemfibrosil increases the risk of myopathy with simultaneous use with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of the drug Rustor and gemfibrozil is not recommended. The balance of risk and possible benefit should be carefully weighed while using the drug Rustor and fibrates or lipid-lowering doses of nicotinic acid. Contraindicated simultaneous use of fibrates and the drug Rustor in a dose of 40 mg. In 2-4 weeks after the start of treatment and / or with an increase in the dose of Rustor, control of lipid metabolism parameters is necessary (if necessary, dose correction 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. You should stop taking the drug Rustor or reduce its dose, if the activity of "liver" transaminases in the serum is 3 times higher than the upper limit of the norm.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapyThe main diseases should be performed before starting treatment with the drug Rustor. Ethnic groups

During pharmacokinetic studies among Chinese and Japanese patients, an increase in the systemic concentration of rosuvastatin was noted in comparison with the indices obtained among patients - Europeans. This fact should be taken into account when prescribing Rustor to these patient groups (see the sections "Pharmacokinetics", "Method of administration and dose"). HIV protease inhibitors

It is not recommended simultaneous application of rosuvastatin with HIV protease inhibitors (see section "Interaction with other drugs").

Interstitial lung disease

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

Diabetes mellitus type 2

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

Lactose

The composition of the drug includes lactose monohydrate, so the drug should not be taken in patients with lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Effect on the ability to drive transp. cf. and fur:

Studies on the effect of rosuvastatin on the ability to drive vehicles and mechanisms have not been conducted.

Since during the treatment with Rustor, dizziness may occur, care should be taken when driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

By 7, 10, 14, 15, 20, 30 tablets in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

By 1, 2, 4 contour squares with instructions for use in a pack of cardboard.

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

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002736

Date of registration:28.11.2014/04.05.2016

Date of cancellation:2019-11-28

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp29.05.2016

Illustrated instructions

Instructions

Rustor (Rustor)