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

Excipients: cellulose microcrystalline - 49.19 mg, starch and pregelatinized - 24.00 mg, silicon dioxide colloid (aerosil) - 0.80 mg, magnesium stearate - 0.80 mg;

tablet shell: opadrai pink 3.20 mg (lactose monohydrate - 1.28 mg, hypromellose - 0.90 mg, titanium dioxide - 0.75 mg, triacetin - 0.25 mg, carmine red dye - 0.02 mg).

ABOUTthe bottom is a film coated tablet, 10 mg contains:

active substance: rosuvastatin calcium - 10,42 mg (in terms of rosuvastatin 10.00 mg);

Excipients: cellulose microcrystalline - 98.38 mg, pregelatinized starch - 48.00 mg, silicon dioxide colloid (aerosil) - 1.60 mg, magnesium stearate - 1.60 mg;

tablet shell: opadray pink 6.40 mg (lactose monohydrate - 2.56 mg, hypromellose - 1.80 mg, titanium dioxide - 1.50 mg, triacetin - 0.50 mg, carmine red dye - 0.04 mg)

One tablet, film-coated, 20 mg contains:

active substance: rosuvastatin calcium - 20.84 mg (in terms of rosuvastatin 20.00 mg);

Excipients: cellulose microcrystalline - 196.76 mg, pregelatinized starch - 96.00 mg, silicon dioxide colloid (aerosil) - 3.20 mg, magnesium stearate - 3.20 mg:

tablet shell: opadrai pink 12,80 mg (lactose monohydrate - 5,12 mg, hypromellose - 3,60 mg, titanium dioxide - 3.00 mg, triacetin - 1.00 mg, dye carmine red - 0.08 mg).

Description:

Round, biconvex tablets, covered with a film coat from light pink to pink. On the cross-section - an inner layer of white or almost white 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:

A hypolipidemic drug, a selective competitive inhibitor of the enzyme HMG-CoA reductase, which converts 3-hydroxy-3-methylglutaryl CoA into mevalonate, the precursor of cholesterol (cholesterol).The main target of rosuvastatin is the liver, where the synthesis of cholesterol and catabolism of low-density lipoproteins (LDL) is carried out. Rosuvastatin increases the number of LDL receptors on the surface of liver cells, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total number of LDL and VLDL.

Rosuvastatin reduces the elevated concentrations of cholesterol-LDL cholesterol, total cholesterol, triglycerides (TG), increases the concentration of high density cholesterol-lipoproteins (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoV), cholesterol-VLDL , TG-VLDL and increases the concentration of apolipoprotein A-I (ApoA-I). As a result of the action of rosuvastatin, a decrease in the index of atherogenicity is observed, which characterizes the improvement of the lipid profile in patients with hypercholesterolemia.

The index of atherogenicity = (ОХС - XC-LPBP) / XC-LPBP.

The therapeutic effect develops within one week after starting treatment with rosuvastatin. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular intake of the drug.

Effective in adult patients with hypercholesterolemia, with or without hypertriglyceridemia, including in patients with diabetes mellitus and familial hypercholesterolemia.

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

Pharmacokinetics:

Absorption and distribution

The maximum concentration of rosuvastatin in blood plasma (C_max) is achieved approximately 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. Approximately 90% of rosuvastatin affects plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). 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-desmethyl-rosuvastatin and lactone metabolites. N-desmethylrozvastatin is about 50% less active than the original 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_1/2) is approximately 19 hours. The half-life does not change with an increase in the 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.

Specials patient populations

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 C_max (maximum concentration in the blood plasma) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Caucasians; Indian patients showed an increase in the median AUC and C_max in 1,3 times. Pharmacokinetic analysis revealed no clinically significant differences in the pharmacokinetics of rosuvastatin among Caucasoids and representatives of the Negroid race.

Renal insufficiency

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 failure (creatinine clearance (CK) less than 30 ml / min), the concentration of rosuvastatin in plasmablood is 3 times higher, and 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 the half-life of 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 the half-life of at least 2 times. 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, including Rosuvastatin, bind to transport proteins OATP1B1 (the polypeptide of organic anion transport, involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLCO1B1 (OATP1B1) p.521SS and ABCG2 (BCRP) p.421AA increased exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genotypes SLCO1B1 p.521TT and ABCG2 s. 421SS.

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 a supplement to diet and other lipid-lowering therapy (eg, LDL-apheresis), or in cases where such therapy is not effective enough;

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

- to slow the progression of atherosclerosis as 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 adults without clinical signs of IHD, 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 CHD.

Contraindications:

DFor the preparation 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 serum transaminase activity (more than 3 times the upper limit of the norm);

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

- Myopathy and predisposition to the development of myotoxic complications;

- simultaneous administration of cyclosporine;

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

For the drug 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 the serum activity of transaminases and any increase in serum transaminase activity (more than 3 times the upper limit of the norm) in patients with risk factors for myopathy / rhabdomyolysis, namely:

- renal failure of moderate severity (SC 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;

- use in patients of the Mongoloid race.

Carefully:

For the drug in a daily dose of 5 mg, 10 mg 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 when using other inhibitors of HMG-CoA reductase (statins) or fibrates; excessive use of alcohol; age over 65; state,at which there was an increase in the plasma concentration of rosuvastatin; race (Mongoloid race); simultaneous appointment with fibrates (see section "Pharmacokinetics"); liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or water-electrolyte disorders or uncontrolled convulsive seizures.

DFor the drug in daily dose of 40 mg:

Renal insufficiency of low severity (QC more 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 of the drug 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:

Rosuvastatin is contraindicated in pregnancy and during breastfeeding. 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 the case of diagnosing pregnancy during therapy, taking the drug should be stopped immediately.

Data on the allocation of rosuvastatin to breast milk are not available, therefore, during the period of breastfeeding, the drug should be discontinued (see "Contraindications").

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 the time of meal.

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 for target lipid concentrations.

The recommended initial dose for patients starting to take the drug, or for patients,translated from the administration of other inhibitors of HMG-CoA reductase, should be 5 or 10 mg of the drug Rosuvastatin 1 time per day. When choosing the initial dose should be guided by individual cholesterol and take into account the possible risk of cardiovascular complications, as well as the potential risk of side effects. If necessary, dosesa can be increased to greater after 4 weeks (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 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 familial hypercholesterolemia) who did not achieve the desired result of therapy when taking a dose of 20 mg and which will be ahoditsya under the supervision of a specialist (see. section "Special instructions"). It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg.

Do not administer a dose of 40 mg to patients who have not previously consulted a doctor.

After 2-4 weeks of therapy and / or with an increase in the dose of the drug Rosuvastatin it is necessary to monitor the lipid metabolism (if necessary, dose adjustment is required). The use of the drug in a higher dose than 40 mg is not justified due to the increased side effects and in most cases is not recommended.

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 (CC less than 30 ml / min), the drug Rosuvastatin it is contraindicated. Contraindicated use of the drug in a dose of 40 mg to patients with moderate impaired renal function (QC 30-60 ml / min) (see section "Special instructions" "Pharmacodynamics"). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

Rosuvastatin is contraindicated in patients with liver disease in the active phase (see section "Contraindications").

Special Populations. 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 appointing doses of 10 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 SLCO1B1 (OATP1B1) p.521NC and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCO1B1 p.521TT and ABCG2 p.421S. For patients carrying genotypes p.521CC 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 and other types of drug interactions").

Patients who are predisposed to myopathy

Contraindicated the appointment of the drug 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 (see the section "Contraindications").

Sopadjuvant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). When the drug is used together Rosuvastatin with medicines (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir), which increase the plasma concentration of rosuvastatin by interacting with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see "Specific guidance" and "Interaction with other drugs and other types of drug interactions "). 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 dose reduction (seesection "Interaction with other drugs and other types of drug interactions").

Side effects:

Side effects observed when taking the drug Rosuvastatin. usually expressed slightly and pass independently. As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly dose-dependent.

The incidence of adverse events is presented in accordance with the classification of the World Health Organization: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000): very rarely (<1/10000), frequency, unspecified (can not be calculated from available data).

The immune system:

Rarely: hypersensitivity reactions, including angioedema.

Endocrine system:

Often: diabetes mellitus type 2.

From the central nervous system:

Often: headache, dizziness.

From the side of the digestive tract:

Often: constipation, nausea, abdominal pain;

Rarely: pancreatitis.

From the skin:

Infrequent: itchy skin, rash, hives.

From the side of the musculoskeletal system:

Often: myalgia;

Rarely: Myopathy (including myositis), rhabdomyolysis.

Other:

Often: asthenic syndrome.

From the side of the urinary system:

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 10-20 mg of the drug and about 3% of patients receiving 40 mg of the drug. 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 side of the support-Promotional apparatus:

When using the drug Rosuvastatin in all doses, and especially when taking doses of the drug in excess of 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 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 side of the liver:

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

Laboratory indicators:

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

Postmarketing application

It has been reported that the following side effects in the post-marketing application of the drug Rosuvastatin:

FROMabout the side of the hematopoiesis system:

Unspecified frequency: thrombocytopenia.

From the side of the digestive tract:

Very rarely: jaundice, hepatitis;

Rarely: increased activity of "liver" transaminases;

Unspecified frequency: diarrhea.

From the side supportingly-Promotional apparatus:

Very rarely: arthralgia;

Unspecified frequency: immuno-mediated necrotizing myopathy.

Co the central nervous system:

Very rare: loss or loss of memory;

Unspecified frequency is peripheral neuropathy.

From the respiratory system:

Not specified frequency: cough, shortness of breath.

FROMabout the side of the urinary system:

Very rarely: hematuria.

From the skin and subcutaneous fat:

Unspecified frequency: Stevens-Johnson syndrome.

From the reproductive system and breast:

Unspecified frequency: gynecomastia.

Other:

Unspecified frequency: peripheral edema.

Some statins reported the following side effects: depression, sleep disturbance, including insomnia and "nightmarish" dreams, sexual dysfunction, hyperglycemia, increased concentration of glycosylated hemoglobin.

Single cases of interstitial lung disease have been reported, especially with prolonged use of drugs (see section "Special instructions").

Overdose:

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

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

Treatment: Specific treatment with an overdose of rosuvastatin or there is no specific antidote. 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. 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 was an average of 7 times higher than that seen in healthy volunteers (see Table 1). Does not affect the plasma concentration of cyclosporine. Rosuvastatin contraindicated in patients receiving ciclosporin (see section "Contraindications").

Inhibitors of human immunodeficiency virus protease (HIV): despite the fact that the exact mechanism of interaction is unknown, joint intake of HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin (see Table 1). 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 twofold and fivefold increase in AUC_(0-24)and C_max rosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections "Dosing and Administration", "Specific guidance", Table 1).

Gemfibrozil and other lipid-lowering drugs: joint application rosuvastatin and gemfibrozil leads to an increase in 2 times the maximum concentration of rosuvastatin in the blood plasma and AUC of rosuvastatin (see section "Special instructions"). Based on data on specific interactions,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 when used in monotherapy (see " Special instructions"). If the drug is simultaneously given with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / eut), an initial dose of 5 mg is recommended for patients, and a dose of 40 mg is contraindicated in a joint appointment with feirots (see "Contraindications", "Method application and dose "," Special instructions "),

Ezetimibe: simultaneous application of the drug 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 1). 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 magnesium and aluminum 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 C_max rosuvastatin by 30%. Such interaction can arise as a result of increased intestinal motility caused by the intake of erythromycin.

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. Therefore, no interaction of rosuvastatin with other drugs is expected at the metabolic level involving cytochrome P450. There was no clinically significant interaction of rosuvastatin with fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4).

Fusidic acid: studies on the interaction of rosuvastatin and fusidic acid were not conducted: as with the use of other statins, post-marketing reports on cases of rhabdomyolysis with simultaneous application of rosuvastatin and fusidic acid were obtained: patients should be monitored and, if necessary, temporary interruption of rosuvastatin administration.

Interaction with drugs, which requires dose adjustment for rosuvastatin (see table 1)

Dose of the drug Rosuvastatin should be adjusted if necessary for its joint application with drugs that increase exposure to rosuvastatin. It is necessary to familiarize with the instruction on the use of these preparations before their appointment simultaneously with the drug Rosuvastatin. If the exposure is expected to be 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 exposure to rosuvastatin does 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 with simultaneous application with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir - 10 mg (an increase in exposure by 3.1 times).

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

Complementary therapy regimen	Mode of taking rosuvastatin	Change AUC rosuvastatin
Cyclosporine 75-200 mg 2 times a day, 6 months	10 mg 1 time per day, 10 days	An increase of 7.1 times
Atazanavir 300 mg / ritonavir 100 mg 1 time per day, 8 days	10 mg once	Increase 3.1-fold
Simeprevir 152 mg 1 time per day, 7 days	10 mg once	Magnification 2.8 times
Lopinavir 400 mg / ritonavir 100 mg 2 times a day, 17 days	20 mg 1 time per 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 2 times a day, 7 days	80 mg once	Increase 1.9 times
Eltrombopag 75 mg 1 time per day, 10 days	10 mg once	Increase 1.6 times
Darunavir 600 mg / ritonavir 100 mg 2 times a day, 7 days	10 mg 1 time per day, 7 days	Increase by 1.5 times
Tipranavir 500 mg / ritonavir 200 mg 2 times a day, 11 days	10 mg once	Increase by 1.4 times
Dronedarone 400 mg 2 times a day.	No data	Increase by 1.4 times
Itraconazole 200 mg 1 time per day, 5 days	10 mg or 80 mg once	Increase by 1.4 times
Ezetimibe 10 mg 1 time per day, 14 days	10 mg 1 time per day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg 2 times a day, 8 days	10 mg once	Carrying changes
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 times in su, 5 days	10 mg once	Without changes
Fenofibrate 67 mg 3 times a day, 7 days	10 mg, 7 days	Without changes
Rifampin 450 mg 1 time per day, 7 days	20 mg once	Without changes
Ketoconazole 200 mg 2 times a day, 7 days	80 mg once	Without changes
Fluconazole 200 mg 1 time per day, 11 days	80 mg once	Without changes
Erythromycin 500 mg 4 times a day, 7 days	80 mg once	Decrease by 28%
Baikalin 50 mg 3 times a day, 14 days	20 mg once	Decrease by 47%

Effect of rosuvastatin on other drugs

Antagonists of vitamin K: the initiation of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both vitamin K antagonists (for example, warfarin), can lead to an increase in the International Normalized Relationship (INR).The cancellation of 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: 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 simultaneous use of the drug Rosuvastatin and hormone replacement therapy are absent, therefore, it is impossible to exclude a similar effect when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

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

Special instructions:

Renal Effects

In patients receiving high doses of the drug 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 at a dose of 40 mg, it is recommended to monitor the performance of kidneys during treatment.

FROMabout the side of the musculoskeletal system

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

Determination of the activity of creatine phosphokinase

Determination of CKK activity should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK, which may lead to incorrect interpretation of the results. In the event that the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be carried out. 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 the drug is prescribed Rosuvastatin as with the administration of other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis (see "With caution"), the risk-to-benefit ratio of therapy 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 increased by no more than 5 times compared with the upper limit of the norm). If the 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 increased activity of CKK in blood serum during treatment or with stopping of taking statins, including rosuvastatin, have been noted. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive drugs.

There were no signs of an increase in the effect on skeletal musculature when taking the drug 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. The risk-to-benefit ratio should be carefully weighed when the drug is administered together 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 drugs and other forms of drug interaction", "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 lipid metabolism (if necessary, dose adjustment is required).

Liver

It is recommended to carry out the determination of liver function indices before the start of therapy and 3 months after the start of therapy. Reception of the drug Rosuvastatin should stop or reduce the dose of the drug if the activity of "hepatic" 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, therapy for major illnesses should be performed prior to initiating treatment with the drug Rosuvastatin.

Special populations. Ethnic groups

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

ANDHIV protease inhibitors

It is not recommended to use the drug jointly with HIV protease inhibitors (see "Interaction with other drugs and other interactions").

Lactosis

The drug should not be used in patients with lactase deficiency, lactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

With the use of some statins, especially for a long time, there have been reports of single cases of interstitial lung disease. Manifestations of the disease can be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever). If 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, drug therapy Rosuvastatin was associated with an increased risk of developing type 2 diabetes.

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

There were no studies to study the effect of the drug Rosuvastatin on the ability to drive a vehicle and use mechanisms. Care should be taken when driving a motor vehicle or work that requires a high concentration of attention and speed of psychomotor reactions (dizziness, weakness may occur during therapy).

Form release / dosage:

Tablets, film-coated, 5 mg, 10 mg and 20 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 3 or 6 contour squares, together with the instruction for use, they are placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 FROM.

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-003104

Date of registration:21.07.2015

Expiration Date:21.07.2020

The owner of the registration certificate:ALSI Pharma, ZAO ALSI Pharma, ZAO Russia

Manufacturer: & nbsp

ALSI Pharma, ZAO Russia

Representation: & nbspALSI Pharma CJSC ALSI Pharma CJSC Russia

Information update date: & nbsp24.12.2016

Illustrated instructions

Instructions

Rosuvastatin (Rosuvastatin)