Active substanceRosuvastatinRosuvastatin
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  • Dosage form: & nbspfilm-coated tablets
    Composition:

    One tablet, film-coated, contains:

    Dosage 5 mg

    active substance: rosuvastatin calcium - 5.2 mg (in terms of rosuvastatin - 5.0 mg);

    Excipients: lactose monohydrate 54.9 mg, microcrystalline cellulose 18.0 mg, calcium hydrogen phosphate dihydrate 6.5 mg, crospovidone 4.5 mg, magnesium stearate 0.9 mg;

    film sheath: [hypromellose 1.6200 mg, talc 0.5400 mg, titanium dioxide 0.2862 mg, macrogol 4000 (polyethylene glycol 4000) 0.22430 mg, iron oxide red (iron oxide) 0.0108 mg] or [ dry film-coating mixture containing hypromellose (60%), talc (20%), titanium dioxide (10.6%), macrogol 4000 (polyethylene glycol 4000) (9%), iron oxide red (iron oxide) (0.4 %)] - 2,700 mg.

    Dosage of 10 mg

    active substance: rosuvastatin calcium - 10,4 mg (in terms of rosuvastatin - 10.0 mg);

    Excipients: lactose monohydrate 109.8 mg, microcrystalline cellulose 36.0 mg, calcium hydrophosphate dihydrate 13.0 mg, crospovidone 9.0 mg, magnesium stearate 1.8 mg;

    film sheath: [hypromellose - 3,2400 mg, talc - 1,0800 mg, titanium dioxide - 0.5724 mg, macrogol 4000 (polyethylene glycol 4000) - 0.4860 mg, iron oxide red (iron oxide) - 0.0216 mg] or [ dry film-coating mixture containing hypromellose (60%), talc (20%), titanium dioxide (10.6%), macrogol 4000 (polyethylene glycol 4000) (9%), iron oxide red (iron oxide) (0.4 %)] - 5,400 mg.

    Dosage of 20 mg

    active substance: rosuvastatin calcium - 20.8 mg (in terms of rosuvastatin - 20.0 mg);

    Excipients: lactose monohydrate 219.6 mg, microcrystalline cellulose 72.0 mg, calcium hydrophosphate dihydrate 26.0 mg, crospovidone 18.0 mg, magnesium stearate 3.6 mg;

    film sheath: [hypromellose - 6,4800 mg, talc - 2,1600 mg, titanium dioxide - 1,1448 mg, macrogol 4000 (polyethylene glycol 4000) - 0.9720 mg, iron oxide red (iron oxide) - 0.0432 mg] or [ dry film-coating mixture containing hypromellose (60%), talc (20%), titanium dioxide (10.6%), macrogol 4000 (polyethylene glycol 4000) (9%), iron oxide red (iron oxide) (0.4 %)] - 10.8000 mg.

    The dosage of 40 mg

    active substance: rosuvastatin calcium - 41.6 mg (in terms of rosuvastatin - 40.0 mg);

    Excipients: lactose monohydrate 439.2 mg, microcrystalline cellulose 144.0 mg, calcium hydrophosphate dihydrate 52.0 mg, crospovidone 36.0 mg, magnesium stearate 7.2 mg;

    film sheath: [hypromellose - 12.9600 mg, talc - 4.3200 mg, titanium dioxide - 2.2896 mg, macrogol 4000 (polyethylene glycol 4000) - 1.9440 mg, iron oxide red (iron oxide) - 0.0864 mg] or [ dry film-coating mixture containing hypromellose (60%), talc (20%), titanium dioxide (10.6%), macrogol 4000 (polyethylene glycol 4000) (9%), iron oxide red (iron oxide) (0.4 %)] -21.6000 mg.

    Description:

    Round, biconvex tablets (doses of 5 mg and 20 mg) or oblong biconvex tablets with a risk on each side (doses of 10 mg and 40 mg), covered with a film coating of pink color. On the cross section, the nucleus is white or almost white in color.

    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:

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

    Rosuvastatin increases the number of LDL-C receptors on the surface of liver cells, increasing the uptake and catabolism of Xc-LDL, which in turn leads to inhibition of the synthesis of very low-density lipoprotein cholesterol (X-VLDL), thereby reducing the total amount of Xc-LDL and Xc- VLDLE.

    Rosuvastatin reduces the elevated concentrations of LDL-C, total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (Xc-HDL), and also reduces the concentration of apolipoprotein B (ApoB), high density non-lipoprotein cholesterol (Xc-non-HDL), Xc- VLDL, TG, and increases the concentration of apolipoprotein A I (ApoA-I), reduces the ratio of LDL-C-HDL-cholesterol, total cholesterol / X-HDL and Xc-non-LDL / XPS-HDL and apoB / apoA-I 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.

    Rosuvastatin is effective in adult patients with hypercholesterolemia, with or without hypertriglyceridemia, including patients with diabetes mellitus and familial hypercholesterolemia.

    The additive effect is noted in combination with fenofibrate (in terms of TG concentration) and with nicotinic acid in lipid-lowering doses (for the concentration of X-HDL), but the possibility of such combinations should be evaluated by the attending physician in view of possible risks (see section "Special instructions"). .

    Pharmacokinetics:

    Absorption and distribution

    The maximum concentration (CmOh) 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 metabolized primarily by the liver, which is the main site for the synthesis of cholesterol and the metabolism of HDL-C.

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

    The main revealed metabolites of rosuvastatin are N-desmethyl-rosuvastatin and lactone metabolites. N-desmethylrozvastatin is approximately 50% less active than rosuvastatin; lactone metabolites are not pharmacologically active. More than 90% of the pharmacological activity of inhibiting circulating GMC-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 (T1/2) is approximately 19 hours. T1/2 does not change with increasing dose of rosuvastatin. 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 effect of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

    Pharmacokinetics in specific patient groups

    Age and gender

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

    Ethnic groups

    Pharmacokinetic studies showed approximately a twofold increase in the median AUC (area under the concentration-time curve) and CmOh 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 CmOh in 1,3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race.

    Renal insufficiency

    In patients with mild or moderate renal failure, the plasma concentration of rosuvastatin or N-desmethyl-rosuvastatin 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 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 with a score of 7 or lower on the Child-Pugh scale did not show an increase in T1/2 rosuvastatin. In two patients with scores of 8 and 9 on the Child-Pugh scale, an increase in T1/2, at least in 2 times. The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available.

    Genetic polymorphism

    Inhibitors of G'MG-CoA reductase, including rosuvastatin. bind to transport proteins OATP1B1 (a polypeptide transporting organic anions involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLCO1B1 (OATP1B1) p.521NC and ABCG2 (BCRP) p.421AA there was an increase AUC rosuvastatin 1.6 and 2.4 times, respectively, compared with carriers of genotypes SLCO1B1 p.521TT and ABCG2 p.421S.

    Indications:

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

    - family homozygous hypercholesterolemia as an adjunct to diet and other lipid-containing therapy (eg, LDL-apheresis), or in cases where such therapy is not sufficiently effective;

    - 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 Xc and Xc-LDL;

    - Primary prevention of major cardiovascular complications (stroke, myocardial infarction, 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 (more than 2 mg / L) in the presence of at least one of additional risk factors such as hypertension, low concentration of X-HDL, smoking, family history of early onset of CHD).

    Contraindications:

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

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

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

    - children's age till 18 years;

    - liver diseases in the active phase, including a persistent increase in serum transaminase activity and any increase in transaminase activity in the blood plasma (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 preparation Rosuvastatin in a daily dose of 40 mg:

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

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

    - children's age till 18 years;

    - simultaneous administration of cyclosporine;

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

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

    - 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 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 preparation Rosuvastatin 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 (statins) or fibrates;

    - excessive use of alcohol;

    - age over 65;

    - conditions in which there was an increase in the plasma concentration of rosuvastatin;

    - race (Mongoloid race);

    - simultaneous appointment with fibrates (see sections "Pharmacokinetics" and "Interaction with other drugs");

    - liver disease in history;

    - sepsis;

    - arterial hypotension;

    - extensive surgical interventions;

    - injuries;

    - severe metabolic, endocrine or electrolyte disturbances or uncontrolled convulsive seizures.

    For the preparation Rosuvastatin 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;

    - injuries;

    - severe metabolic, endocrine or water-electrolyte disorders or uncontrolled convulsive seizures.

    Patients with hepatic insufficiency

    Data or experience of the drug in patients with severe impairment of liver function (more than 9 on the Child-Pugh scale) are not available (see section "Pharmacological properties").

    Pregnancy and lactation:

    Pregnancy

    A drug Rosuvastatin 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 inhibiting HMG-CoA reductase exceeds the benefit of using the drug in pregnant women.

    In case of pregnancy in the process of therapy, the drug should be discontinued immediately.

    Breastfeeding period

    A drug Rosuvastatin contraindicated during breastfeeding. Data on the allocation of rosuvastatin to breast milk are not available, so during breastfeeding, the drug should be discontinued.

    Dosing and Administration:

    Inside, without chewing and not crushing the tablet, swallow whole, squeezed water. The drug can be taken at any time of the day, regardless of food intake.

    Before starting therapy with the drug Rosuvastatin the patient should begin to observe the standard hypocholesterolemic diet and continue to observe it during treatment.

    The dose of the drug should be selected individually depending on the purpose of therapy and the therapeutic response to treatment, taking into account current recommendations but the target concentration of lipids.

    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 Rosuvastatin once a day.When choosing the initial dose should be guided by the individual concentration of cholesterol in the blood plasma and take into account the possible risk of cardiovascular complications, as well as to assess the potential risk of side effects. If necessary, after 4 weeks, the doctor may increase the dose (see the section "Pharmacodynamics").

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

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

    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 KK 30-60 ml / min the recommended initial dose of the drug is 5 mg, the use of the drug in a dose of 40 mg is contraindicated (see sections "Special instructions" and "Pharmacological properties").

    In patients with severe renal failure (CC less than 30 ml / min), the drug Rosuvastatin it is contraindicated.

    Patients with hepatic insufficiency

    A drug Rosuvastatin is contraindicated in patients with active liver disease (see "Contraindications").

    Ethnic groups

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

    Genetic polymorphism

    In carriers of genotypes SLCOIBI (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase AUC rosuvastatin compared with carriers of genotypes SLCO1B1 p.521TT and ABCG2 p.421S. For patients carrying genotypes p.521SS or p.421AA, the recommended maximum dose of the drug Rosuvastatin is 20 mg once a day (see the sections "Pharmacokinetics", "Special instructions" and "Interaction with other drugs").

    Patients who are predisposed to myopathy

    Contraindicated the purpose of the drug Rosuvastatin in a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy (see section "Contraindications"). When prescribing the drug at doses of 10 mg and 20 mg, the recommended initial dose for this group of patients is 5 mg (see the section "With caution").

    Concomitant therapy

    Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). When the drug is used together Rosuvastatin with medicines (such as ciclosporinSome inhibitors of HIV protease, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir), increase the concentration of rosuvastatin in plasma due to the interaction with the transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see. The "Special instructions" "Interaction with other drugs"). It is necessary to familiarize with the instruction on the use of these preparations before their appointment together with the drug Rosuvastatin. In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of the drug should be evaluated Rosuvastatin. If the use of the above drugs is necessary, the relationship between the benefit and the risk of concomitant drug therapy Rosuvastatin and consider the possibility of reducing its dose (see section "Interaction with other drugs").

    Side effects:

    As with other inhibitors of HMG-CoA reductase. the incidence of side effects is mainly dose-dependent.

    Classification of the incidence of adverse events according to the recommendations of the World Health Organization (WHO):

    very often ≥1 / 10;

    often from ≥ 1/100 to <1/10;

    infrequently from ≥ 1/1000 to <1/100;

    rarely from ≥ 1/10000 to <1/1000;

    very rarely <1/10000. including individual messages;

    the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

    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;

    very rarely - loss or loss of memory;

    frequency unknown - peripheral neuropathy.

    From the respiratory system:

    frequency unknown - cough, dyspnea.

    From the digestive system:

    often - constipation, nausea, abdominal pain;

    rarely - pancreatitis;

    frequency is unknown - diarrhea.

    From the skin:

    infrequently - itchy skin, skin rash, hives;

    frequency is unknown - Stevens-Johnson syndrome.

    On the part of the organs of hematopoiesis:

    frequency unknown - thrombocytopenia.

    From the side of the musculoskeletal system:

    often - myalgia;

    rarely - myopathy (including myositis), rhabdomyolysis;

    very rarely - arthralgia;

    frequency unknown - immuno-mediated necrotizing myopathy.

    When rosuvastatin was used in all doses and, in particular, when doses exceeding 20 mg were given, the following effects on the musculoskeletal system were reported: myalgia, myopathy (including myositis), in rare cases rhabdomyolysis with or without acute renal insufficiency.

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

    From the urinary system:

    very rarely - hematuria;

    often - proteinuria.

    Changes in the amount of protein in the urine (from absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving rosuvastatin in a dose of 10-20 mg, and approximately 3% of patients receiving 40 mg of rosuvastatin.A slight change in the amount of protein in the urine was noted with the use of rosuvastatin in 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 side of the liver:

    rarely - increased activity of "liver" transaminases;

    very rarely - jaundice, hepatitis.

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

    From the reproductive system and breast:

    frequency unknown - gynecomastia.

    Laboratory indicators:

    the frequency is unknown - an increase in the concentration of glucose, bilirubin, the activity of gamma-glutamintranspeptidase, alkaline phosphatase, thyroid dysfunction.

    Other:

    often - asthenic syndrome;

    frequency unknown - peripheral edema.

    With the use of some statins, the following side effects have been reported: depression, sleep disturbances, including insomnia and nightmarish dreams, sexual dysfunction, hyperglycemia, increased concentrations of glycosylated hemoglobin.

    Single cases of interstitial lung disease have been reported (especially with prolonged use of statins).

    Overdose:

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

    Symptoms

    Symptoms are effects that are reinforced and similar to those described in the "Side effect" section. Characteristic for rosuvastatin symptoms are not observed.

    Treatment

    There is no specific treatment or specific antidote for an overdose of rosuvastatin. It is recommended timely gastric lavage and symptomatic treatment, it is necessary to monitor liver function and activity of CK, as well as activities aimed at maintaining the functions of vital organs and systems. Hemodialysis is 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. Concomitant use of drugs that are inhibitors of these transport proteins,may be accompanied by an increase in the concentration of rosuvastatin in the blood plasma and an increased risk of myopathy (see table and sections "Dosing and Administration" and "Special instructions").

    Cyclosporine: with simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin was an average of 7 times higher than that seen in healthy volunteers. Rosuvastatin does not affect the plasma concentration of cyclosporine. A drug Rosuvastatin contraindicated in patients receiving ciclosporin (see section "Contraindications").

    Inhibitors of the human immunodeficiency virus (HIV) protease: despite the fact that the exact mechanism of interaction is unknown, joint intake of HIV protease inhibitors and rosuvastatin can lead to a significant increase AUC rosuvastatin. Pharmacokinetic study but simultaneous use of 20 mg rosuvastatin with a combined preparation containing two protease inhibitors

    HIV (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers led to an increase AUC(0-24) and CmOh rosuvastatin approximately 2 and 5 times, respectively. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections "Dosing and Administration", "Special instructions", table).

    Gemfibrozil and other lipid-lowering agents: fromThe joint use of rosuvastatin and gemfibrozil leads to an increase in 2 times CmOh in blood plasma and AUC rosuvastatin (see section "Special instructions"). Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrate is expected, possibly pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (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 as monotherapy (cf. section "Special instructions"). With simultaneous reception of the drug Rosuvastatin with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), patients are recommended an initial dose of 5 mg; taking in a dose of 40 mg is contraindicated in a joint appointment with fibrates (see the sections "Contraindications", "Method of administration and dose", "Special instructions").

    Ezetimibe: simultaneous application of rosuvastatin in a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase AUC rosuvastatin in patients with hypercholesterolemia (see table).It is impossible to exclude an increase in the risk of side effects due to the pharmacodynamic interaction between the drug Rosuvastatin and ezetimibe.

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

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

    Fusidic acid: Studies on the interaction of rosuvastatin and fusidic acid have not been conducted. As with the reception of other statins, post-marketing reports were received on cases of rhabdomyolysis in the joint administration of rosuvastatin and fusidic acid. Care must be taken to monitor patients. If necessary, temporary discontinuation of the drug Rosuvastatin.

    Interaction with drugs, which requires dose adjustment for rosuvastatin

    Dose of the drug Rosuvastatin should be adjusted if necessary for its joint use with drugs that increase AUC rosuvastatin. It is necessary to familiarize with the instruction on the use of these preparations before their appointment together with the drug Rosuvastatin. If an increase is expected AUC in 2 times or more, the initial dose of the drug Rosuvastatin should be 5 mg once a day. Also, the maximum daily dose of the drug should be adjusted Rosuvastatin so that the expected AUC rosuvastatin did not exceed that for a dose of 40 mg taken without the simultaneous administration of medications interacting with rosuvastatin. For example, the maximum daily dose of the drug Rosuvastatin when used concomitantly with gemfibrozil is 20 mg (increase AUC in 1,9 times), with ritonavir / atazanavir - 10 mg (increase AUC in 3.1 times).

    Table. The effect of concomitant therapy on AUC of rosuvastatin (data are listed in descending order) - the results of published clinical studies

    Complementary therapy regimen

    Mode of taking rosuvastatin

    Change AUC rosuvastatin

    1

    2

    3

    Cyclosporine 75-200 mg twice a day. 6 months

    10 mg once a day, 10 days

    An increase of 7.1 times

    Atazanavir 300 mg / ritonavir 100 mg once a day, 8 days

    10 mg once

    Increase 3.1-fold

    Symeprevir 150 mg once a day, 7 days

    10 mg once

    An increase of 2.8 times

    Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days

    20 mg once a day, 7 days

    An increase of 2.1 times

    Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours

    20 mg once

    2 times increase

    Gemfibrozil 600 mg twice a day. 7 days

    80 mg once

    Increase 1.9 times

    Eltrombopag 75 mg once a day, 10 days

    10 mg once

    Increase 1.6 times

    Darunavir 600 mg / ritonavir 100 mg twice daily, 7 days

    10 mg once a day, 7 days

    Increase by 1.5 times

    Tipranavir 500 mg / ritonavir 200 mg twice daily, 11 days

    10 mg once

    Increase by 1.4 times

    Dronedarone 400 mg twice daily

    No data

    Increase by 1.4 times

    Itraconazole 200 mg once daily. 5 days

    10 mg or 80 mg once

    Increase by 1.4 times

    Ezetimibe 10 mg once a day, 14 days

    10 mg once a day, 14 days

    Increase by 1.2 times

    Fosamprenavir 700 mg / ritonavir 100 mg twice daily, 8 days

    10 mg once

    Without changes

    Aleglitazar 0.3 mg, 7 days

    40 mg, 7 days

    Without changes

    Silymarin 140 mg three times a day, 5 days

    10 mg once

    Without changes

    Fenofibrate 67 mg three times a day, 7 days

    10 mg, 7 days

    Without changes

    Rifampicin 450 mg once daily, 7 days

    20 mg once

    Without changes

    Ketoconazole 200 mg twice daily, 7 days

    80 pennies

    Without changes

    Fluconazole 200 mg once daily, 11 days

    80 mg once

    Without changes

    Erythromycin 500 mg four times a day, 7 days

    80 mg once

    Decrease by 28%

    Baikalin 50 mg three times a day, 14 days

    20 mg once

    Decrease by 47%

    Effect of rosuvastatin on other drugs

    Antagonists of vitamin K: initiation of drug therapy Rosuvastatin or an increase in its dose in patients receiving simultaneously vitamin K antagonists (for example, warfarin), can lead to an increase in the International Normalized Relationship (INR). Abolition of the drug Rosuvastatin or a decrease in the dose of the drug may lead to a decrease in INR. In such cases, monitoring of INR is recommended.

    Oral contraceptives / hormone replacement therapy: simultaneouslyno the 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.

    Other medicines: no clinically significant interaction between rosuvastatin and digoxin is expected.

    Special instructions:

    Influence on the kidneys

    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 Rosuvastatin in a dose of 40 mg, it is recommended to monitor the indicators of kidney function during treatment.

    Influence on the musculoskeletal system

    When rosuvastatin was used in all doses, especially at doses exceeding 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy, in rare cases rhabdomyolysis.

    Determination of the activity of creatine phosphokinase (CK)

    Determination of CKK activity should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK, which may lead to incorrect interpretation of the results. 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 the repeated test confirms the initial activity of CKK (more than 5 times higher than the upper limit of the norm).

    Before the start of therapy

    When the drug is prescribed Rosuvastatin, as well as with the appointment of other HMG-CoA reductase inhibitors, care should be taken in patients with existing risk factors for myopathy / rhabdomyolysis. It is necessary to consider the relationship between risk and the possible benefits of therapy and conduct clinical monitoring.

    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 increased by no more than 5 times in comparison with the upper limit of the norm).

    If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering the drug Rosuvastatin or other inhibitors of HMG-CoA reductase in smaller doses with careful monitoring of the patient. Routine monitoring of the activity of CKK in the absence of symptoms is inappropriate. Very rare cases of immuno-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of proximal muscles and an increase in the activity of CK in the blood plasma during treatment or when stopping the intake of 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 (more than 1 g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics.

    Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous use of the drug is not recommended Rosuvastatin and gemfibrozil.

    It is necessary to carefully weigh the ratio of risk and possible benefit in the joint use of the drug Rosuvastatin and fibrates or lipid-lowering doses of nicotinic acid. Contraindicated drug intake Rosuvastatin in a dose of 40 mg together with fibrates (see the sections "Interaction with other medicines", "Contraindications").

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

    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. Reception of the drug Rosuvastatin should stop or reduce the dose of the drug if the activity of "liver" transaminases in the blood plasma is 3 times higher than the upper limit of the norm.

    In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the treatment of underlying diseasesshould be carried out before the start of treatment with the drug Rosuvastatin.

    Ethnic groups

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

    HIV protease inhibitors

    It is not recommended joint use of the drug Rosuvastatin with HIV protease inhibitors (see "Interactions with Other Drugs").

    Lactose

    A drug Rosuvastatin contraindicated in patients with lactose deficiency, intolerance to galactose and glucose-galactose malabsorption.

    Interstitial lung disease

    With the use of some statins, especially for a long time, there have been reports of single cases of interstitial lung disease. Manifestations of the disease can 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.

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

    There has been no research into the effect of rosuvastatin on the ability to drive vehicles or use mechanisms. Care should be taken when driving vehicles or performing work that requires an increased concentration of attention and speed of psychomotor reactions (dizziness may occur during therapy).

    Form release / dosage:

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

    Packaging:

    30 or 60 tablets in a can of high-density polyethylene.

    For a dosage of 5 mg

    10, 14, 15 or 30 tablets in a contour acrylic package of an opaque composite film (polyvinyl chloride / polyvinylidene chloride (PVC / PVDC) or polyvinyl chloride / polychlorotrifluoroethylene / ethylene vinyl alcohol / polyvinyl chloride (PVC / PCTFE / EVS / PVC)) and aluminum foil.

    3 contourcell packs of 10 tablets, 2, 4 or 6 contiguous cell packs of 14 tablets, 2, 4 or 6 contiguous cell packs of 15 tablets,1 or 3 contourcell packs of 30 tablets or one pot together with instructions for use in a pack of cardboard.

    For dosages of 10 mg and 20 mg

    10, 14 or 15 tablets in a contoured cell pack of an opaque composite film (PVC / PVDC or PVC / PCTFE / EVS / PVC) and aluminum foil.

    3 contourcell packs of 10 tablets, 2, 4 or 6 contour packs of 14 tablets, 2, 4 or 6 contiguous cell packs of 15 tablets each, or one bank along with instructions for use in a pack of cardboard.

    For a dosage of 40 mg

    6, 7, 10 or 15 tablets in a contour acrylic package of an opaque composite film (PVC / PVDC or PVC / PCTFE / EVS / PVC) and aluminum foil.

    5 contour cell packs of 6 tablets, 4 contourcell packs of 7 tablets. 6 contour cell packs of 10 tablets, 4 or 6 contiguous cell packs of 15 tablets, or one bank along with instructions for use in a pack of cardboard.

    Storage conditions:

    Store in a 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 expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004158
    Date of registration:28.02.2017
    Expiration Date:28.02.2022
    The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia
    Manufacturer: & nbsp
    Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia
    Information update date: & nbsp29.03.2017
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