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

Microcrystalline cellulose	95.08 mg	89.87 mg	134.81 mg
Lactose	40.00 mg	40.00 mg	60.00 mg
Crospovidone	7.50 mg	7.50 mg	11.25 mg
Silica colloidal dioxide	0.33 mg	0.33 mg	0.50 mg
Magnesium stearate	1.88 mg	1.88 mg	2.82 mg

Sheath:

Butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1: 2: 1]

	1.10 mg	1.10 mg	1.65 mg
Macrogol - 6000	0.90 mg	0.90 mg	1.35 mg
Titanium dioxide	0.50 mg	0.50 mg	0.75 mg
Lactose Monohydrate	2.00 mg	2.00 mg	3.00 mg

1 tablet, film-coated, contains:

Core:

Active substance: 20mg 30mg 40mg

Calcium rosuvastatin 20.83 mg 31.25 mg 41.66 mg

(corresponding to rosuvastatin 20.83 mg 31.25 mg 41.66 mg)

Excipients:

Microcrystalline cellulose 179.75 mg 269.62 mg 359.50 mg

Lactose 80.00 mg 120.00 mg 160.00 mg

Crospovidone 15.00 mg 22.50 mg 30.00 mg

Silicon dioxide colloid 0.66 mg 0.99 mg 1.32 mg

Magnesium stearate 3.76 mg 5.64 mg 7.52 mg

Sheath:

Butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1: 2: 1]

	2.20 mg	3.30 mg	4.40 mg
Macrogol - 6000	1.80 mg	2.70 mg	3.60 mg
Titanium dioxide	1.00 mg	1.50 mg	2.00 mg
Lactose Monohydrate	4.00 mg	6.00 mg	8.00 mg

Description:

Tablets 5 mg:

round, biconvex tablets, coated with a white film shell, with a bevel, on one side the "5" marking, applied by embossing. * Two layers are visible on the cross-section, the core is white.

Tablets 10 mg:

round, biconvex tablets, coated with a white film shell, with a chamfer, on one side the "10" marking, applied by embossing. * Two layers are visible on the cross-section, the core is white.

Tablets 15 mg:

round, biconvex tablets, coated with a white film coating, with a chamfer, on one side the "15" marking, applied by embossing. * Two layers are visible on the cross-section, the core is white.

Tablets of 20 mg:

round, biconvex tablets, covered with a film shell of white color, with a bevel. * Two layers are visible on the cross-section, the core is white.

Tablets 30 mg:

capsular biconvex tablets, covered with a film coating of white color, with a risk on both sides.

* Two layers are visible on the cross-section, the core is white.

Tablets 40 mg:

capsular, biconvex tablets, covered with a film coating of white color. * Two layers are visible on the cross-section, the core is white.

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:

The drug Roxer ® is a lipid-lowering drug. The active substance of the drug-rosuvastatin, is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A into mevalonic acid, the precursor of cholesterol. The main target of rosuvastatin is the liver, where the synthesis of cholesterol (CS) and catabolism of low density lipoprotein (LDL) occurs. Increases the number of hepatic receptors for LDL on the surface of 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 elevated plasma concentrations of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C). It also reduces the concentration of apolipoprotein B (ApoB), XC-non-HDL, cholesterol-VLDL, TG-VLDL and increases the concentration of apolipoprotein A-I in blood plasma. Rosuvastatin 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 develops within one week after the initiation of therapy, after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by week 4 of therapy and is maintained with further regular intake of the drug.

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without accompanying hypertriglyceridemia, regardless of race, sex or age, including patients with diabetes mellitus or familial hypercholesterolemia.

In 80% of patients with Pall and lib type FH (with an average initial LDL-C concentration of approximately 4.8 mmol / L), the concentration of LDL-C is lower than mmol / L in the 10-mg dose of rosuvastatin.In patients with homozygous familial hypercholesterolemia rosuvastatin was used in doses of 20-40 mg, the average decrease was 22%.

The additive effect is noted in combination with fenofibrate for TG and nicotinic acid in lipid-lowering doses for the concentration of HDL-C.

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%. It is metabolized primarily by the liver, which is the main organ that synthesizes cholesterol and metabolizes LDL-C. The volume distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a nonspecific substrate of cytochrome P450. The main isoenzyme involved in the metabolism of rosuvastatin is isofermeng CYP2C9.

Isozymes CYP2C19, CYP3A4, CYP2D6 are less involved in metabolism. The main metabolites identified are N-desmethylrozuvastatin 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 plasma HMG-CoA reductase is provided by rosuvastatin, the rest - 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. The half-life period (T1 / 2) from the blood plasma is approximately 19 hours (does not change with increasing dose of the drug). The average geometric plasma clearance is 50 l / h (coefficient of variation is 21.7%). As in the case of other HMG-CoA reductase inhibitors, a membrane cholesterol transporter is involved in the "hepatic" capture of rosuvastatin, which 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.

Special 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 (the area under the concentration-time curve) and the maximum concentration (C_m_Oh) in the blood plasma of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with patients of the Caucasoid race; Indians 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 patients of European and Negroid races.

Renal insufficiency

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

Liver failure

In patients with hepatic insufficiency 7 and lower on the Child-Pugh scale, no increase in the systemic exposure of rosuvastatin has been detected. In two patients with hepatic insufficiency 8-9 on the Child-Pugh scale, an increase in the systemic exposure was observed, at least 2-fold. Experience with rosuvastatin in patients with hepatic insufficiency above 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.521N and ABCG2 (BCRP) c.421AA increase in exposure was noted (AUC) rosuvastatin 1.6 and 2.4 times, respectively, compared with carriers of genotypes SLCO1B1 c.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 diet and other non-drug treatments (eg, physical

exercise, weight loss) are insufficient.

- Family homozygous hypercholesterolemia - as an adjunct 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 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 plasma concentrations of total cholesterol and LDL-C.

- 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 plasma concentration of C-reactive protein (> 2 mg / L) with at least one of the additional risk factors, such as: hypertension, low plasma concentration of HDL-C, smoking, family history of early onset of CHD).

Contraindications:

At a daily dose of up to 30 mg

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

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

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

- myopathy;

- simultaneous administration of cyclosporine;

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

- pregnancy, the period of breastfeeding;

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

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

- age to 18 years.

At a daily dose of 30 mg and more

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

- renal insufficiency of moderate and severe degree (CC less than 60 ml / min);

- myopathy;

- simultaneous application of cyclosporine;

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

- pregnancy, the period of breastfeeding;

- use in women of childbearing age not using adequate methods of contraception;

- hypothyroidism;

- muscle diseases in the anamnesis (including in the family);

- myotoxicity with other inhibitors of HMG-CoA reductase or fibrates in history;

- excessive use of alcohol;

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

- simultaneous application of fibrates;

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

- patients of the Mongoloid race;

- age to 18 years.

Carefully:

At a daily dose of up to 30 mg

The presence of a risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism, hereditary muscle diseases in the anamnesis (including family history) and a previous history of muscle toxicity with the use of 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; racial affiliation (the Mongoloid race is Japanese and Chinese); simultaneous application with fibrates; liver disease inanamnesis; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled seizures, concurrent use with ezetimibe.

At a daily dose of 30 mg and more

Renal insufficiency of mild 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 electrolyte disorders or uncontrolled seizures, concurrent use with ezetimibe.

Pregnancy and lactation:

The drug Roxer® is contraindicated in pregnancy and lactation.

Women of reproductive age should apply adequate methods

contraception.

Since cholesterol and substances synthesized from cholesterol are important for the development of the fetus, the potential risk of inhibition of HMG-CoA reductase inhibitors for the fetus outweigh the benefits of the use of the drug during pregnancy.

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

Data on the allocation of rosuvastatin to breast milk are not available (it is known that other inhibitors of HMG-CoA reductase capable of excreted in breast milk), therefore, during breast-feeding, the drug should be discontinued.

Dosing and Administration:Inside, the tablet is not chewed and not crushed, swallowed whole, washed down with water, you can take at any time of the day, regardless of the time you eat. Before starting therapy with Roxer®, 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 national recommendations for target plasma 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 or 10 mg of the drug Roxer® once a day. With simultaneous use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), the patients are recommended an initial dose of 5 mg / day. When choosing the initial dose should be guided by individual concentration of cholesterol in the blood plasma and take into account the possible risk of developing cardiovascular complications, it is necessary also take into account the potential risk of side effects. If necessary, the dose can be increased after 4 weeks. In connection with the possible development of side effects with a dose of 40 mg / day, compared with lower doses of the drug, increasing the dose to a maximum of 40 mg / day should be considered only in patients with severe hypercholesterolemia and a high risk of cardiovascular events especially in patients from familial hypercholesterolemia), who did not achieve the desired result of therapy with a dose of 20 mg / day, and which will be monitored by a physician. It is recommended especially careful monitoring of patients receiving the drug at a dose of 40 mg / day.

Do not use a dose of 40 mg / day in 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 Roxer®, it is necessary to monitor the lipid metabolism (if necessary, 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 Roxer ® is contraindicated. The use of the drug Roxer® at a dose of more than 30 mg / day in patients with moderate and severe renal insufficiency (QC less than 60 ml / min) is contraindicated. Patients with moderate renal insufficiency have a recommended initial dose of the drug Roxer® of 5 mg / day.

Patients with hepatic insufficiency

The drug Roxer® is contraindicated in patients with liver disease in the active phase.

Use in elderly patients

No dose adjustment is required.

Ethnic groups

In patients of the Mongoloid race an increase in the systemic exposure of rosuvastatin was noted. For patients of the Mongoloid race, the recommended initial dose of the drug is Roxer® is 5 mg / day, the use of the drug Roxer® a dose of 40 mg is contraindicated.

Genetic polymorphism

In carriers of genotypes SLC01B1 (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (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 Roxer® is 20 mg once a day.

Patients who are predisposed to myotoxic complications

The use of the drug Roxer® in a dose of 40 mg to patients predisposed to the development of myotoxic complications is contraindicated. If it is necessary to apply doses K) and 20 mg / day, the recommended initial dose for this group of patients is 5 mg / day.

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). With the simultaneous use of the drug Roxer with medicines (such as ciclosporin, some human immunodeficiency virus (HIV) protease inhibitors, including a combination of ritonavir with atazapavir, lopivavir and / or tipranavir) that increase the concentration of rosuvastatin in blood plasma due to interaction with transport proteins may increase the risk of myopathy (including rhabdomyolysis). Please read the instructions for use of the above preparations prior to their appointment concomitantly with the preparation of Roxer®.In such cases, the possibility of using alternative therapy or temporary discontinuation of the drug Roxer® should be assessed. If you need to use the above drugs, you should evaluate the benefit-risk ratio of concomitant therapy with the drug Roxer® and consider the possibility of reducing its dose.

Side effects:Side effects observed with the use of the drug "Roxer", usually expressed slightly and pass independently. As with other inhibitors of HMG-CoA reductase, the incidence Absorption and distribution

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is an The side effects are mainly dose-dependent.

Classification of the frequency of development of side effects of the World Health Organization (WHO):

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

the frequency of the unknown can not be estimated from the available data.

Violations from the blood and lymphatic system:

frequency unknown: thrombocytopenia.

Immune system disorders: rarely: reactions are increased Sensitivity, including angioedema.

Disorders from the endocrine system:

often: type 2 diabetes mellitus.

Impaired nervous system: often: headache, dizziness;

very rare: loss or loss of memory;

frequency unknown: peripheral neuropathy.

Disturbances from the respiratory system, chest and mediastinal organs:

frequency unknown: cough, dyspnea.

Disorders from the digestive system:

often: constipation, nausea, abdominal pain;

rarely: pancreatitis;

very rarely: jaundice, hepatitis;

frequency unknown: diarrhea.

When rosuvastatin is used a dose-dependent increase is observed activity of "hepatic" transaminases in blood plasma for a small number patients. In most cases, it slightly, asymptomatically and temporarily.

Disturbances from the skin and subcutaneous fabrics:

infrequently: itchy skin, skin rash, hives;

frequency is unknown: Stevens-Johnson.

Disorders from the side of the skeletal- muscular and connective tissue:

often: myalgia;

rarely: myopathy (including myositis), rhabdomyolysis (with acute renal disease insufficiency or without it);

very rarely: arthralgia;

frequency is unknown: immuno-mediated necrotizing myopathy.

Dose-dependent increase in activity Creatine phosphokinase (CK) in plasma blood is observed in a small number patients who took rosuvastatin. AT most cases it is minor, asymptomatic and temporary. In case of an increase activity of CK in the blood plasma more than 5 times higher than the upper limit of the norm therapy should be suspended.

Disorders from the kidneys and urinary tract:

Have Patients receiving rosuvastatin therapy may be diagnosed with proteinuria. A change in the amount of protein in the urine (from absence or trace amounts to ++ or more) is 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 mean the occurrence of acute or progressive disease of the existing kidney disease.

Very rarely: hematuria.

Violations of the genitals and breast:

frequency unknown: gynecomastia.

General disorders and disorders at the site of administration:

often: asthenic syndrome;

frequency unknown: peripheral edema.

Laboratory indicators:

When rosuvastatin was used, the following changes in laboratory indicators: hyperglycemia, increased bilirubin concentration in blood plasma, activity of gamma-glutamyl-titerpeptidase, alkaline phosphatase in blood plasma, change serum concentration of thyroid hormones.

When using certain HMG-CoA reductase inhibitors (statins)

reported on the following side effects: depression, sleep disorders, including insomnia and "nightmarish" dreams, sexual dysfunction, increase in concentration

glycosylated hemoglobin.

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

Overdose:

The clinical picture of an overdose is not described. With the simultaneous administration of several daily doses of the drug, the pharmacokinetic parameters of rosuvastatin do not change. Treatment of overdose is symptomatic, control of liver function and activity of CKF is necessary; there is no specific antidote, hemodialysis is ineffective.

Interaction:

Effect of the use of other drugs on rosuvastatin

Inhibitors of transport proteins Rosuvastatin is a substrate for some transport proteins, in particular, OATP1B1 and BCRP. Simultaneous 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 1, sections "Dosing and Administration", "Special instructions").

Cyclosporin

With simultaneous application of rosuvastatin and cyclosporine, AUC rosuvastatin is an average of 7 times higher than that seen in healthy volunteers (see Table 1).Simultaneous application with rosuvastatin does not affect the concentration of cyclosporine in the blood plasma. The use of rosuvastatin is contraindicated in patients taking ciclosporin (see section "Contraindications").

HIV protease inhibitors

Simultaneous use of HIV protease inhibitors can significantly increase the exposure of rosuvastatin (see Table 1). Simultaneous use of 20 mg rosuvastatin and a combination of two HIV protease inhibitors (400 mg lopinavir / 100 mgritonavir) is accompanied by an increase in equilibrium AUC_(0-24₎ and FROMmrosuvastatin in 2 and 5 times, respectively. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors is not recommended (see section "Method of administration and dose", Table 1).

Gemfibrozil and other lipid-lowering agents

The simultaneous use of rosuvastatin and gemfibrozil leads to an increase in C_max and AUC rosuvastatin in blood plasma in 2 times (see section "Special instructions"). Based on the data on the specific interaction, no pharmacokinetically significant interaction with fenofibrate, possible pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (doses greater or equivalent 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 section "Special instructions"). Simultaneous application of fibrates and rosuvastatin in a daily dose of 30 mg is contraindicated. In such patients, therapy should begin at a dose of 5 mg / day (see the sections "Contraindications", "Method of administration and dose", "Special instructions").

Ezetimibe

The simultaneous use of rosuvastatin 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 the pharmacodynamic interaction between rosuvastatin and ezegimib, which is manifested by an increased risk of unwanted reactions.

Antacids

The simultaneous use of rosuvastatin and 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(o-t) rosuvastatin by 20% and its C_m_Oh by 30%. Such interaction can arise as a result of increased intestinal motility caused by the use 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 this isoenzyme system. Therefore, there is no interaction

rosuvastatin with other drugs (LS) at the level of metabolism involving isoenzymes of the cytochrome P450 system.

Clinically significant interactions between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4) not noted.

Fusidic acid

Research studies interaction between rosuvastatin and fusidic acid was not performed. As with other statins, post-marketing reports of cases of rhabdomyolysis with simultaneous application rosuvastatin and fusidic acid.

Patients should be closely monitored. If necessary, a temporary discontinuation of rosuvastatin is possible.

Interaction with drugs, which requires correction of the dose of rosuvastatin (see Table 1)

The dose of the drug Roxer® should be adjusted if it is necessary to simultaneously use it with LC, increasing exposure rosuvastatin. If an increase in exposure is expected to be 2 times or more, the initial dose of Roxer® should be 5 mg 1 time per day.

Also should be adjusted

the maximum daily dose of the drug Roxer®, so that the expected exposure of rosuvastatin does not exceed that for a dose of 40 mg taken without simultaneous administration of LC, interacting with rosuvastatin. For example, the maximum daily dose of the drug Roxer® with simultaneous use 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) - results of published clinical trials

Mode	Mode	Change
Concomitant therapy	Rosuvastatin administration	AUC rosuvastatin
Cyclosporine 75-200 mg 2 times 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
Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days	20 mg once a day, 7 days	An increase of 2.1 times
Gemfibrozil 600 mg 2 times a day, 7 days	80 mg once	Increase 1.9 times
Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours	20 mg once	2 times increase
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 a day, 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
Fosamplen- vir 700 mg / ritonavir 100 mg 2 times in day, 8 days	10 mg once	Without changes
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 times a day, 5 days	10 mg once	Without changes
Fenofibrate 67 mg 3 times a day, 7 days	10 mg, 7 days	Without changes
Rifampicin 450 mg once a 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 once a 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

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or an increase in its dose in patients taking concomitant vitamin K antagonists (for example, warfarin), can lead to an increase in the International Normalized Ratio (MHO). Removing rosuvastatin or reducing its dose may lead to a decrease MHO. In such cases, monitoring is recommended MHO.

Contraceptives for oral administration / hormone replacement therapy (HRT)

The simultaneous use of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when selecting a dose of hormonal contraceptives. Pharmacokinetic data on concurrent use

rosuvastatin and HRT are absent, therefore, it is impossible to exclude a similar effect when applying this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other medicines

Clinically significant interaction between rosuvastatin and digoxin is not expected.

Special instructions:

Impaired renal function

In patients receiving high doses of rosuvastatin (in particular 40 mg / day) tubular proteinuria was observed, which was detected with the help of test strips and in most cases was periodic or short-term. Such proteinuria does not indicate an acute or progressive comorbid kidney disease. The frequency of serious renal dysfunction, noted in the postmarketing study rosuvastatin, higher when taking a dose of 40 mg / day.In patients taking the drug Roxer ® at a dose of 30 or 40 mg / day, it is recommended to monitor the indicators of kidney function during treatment (at least every 3 months).

Influence on the musculoskeletal system

When using rosuvastatin in all doses, but in particular at doses exceeding 20 mg / day, the following effects on the locomotor apparatus were reported: myalgia, myopathy, in rare cases rhabdomyolysis. Very rare cases of rhabdomyolysis with simultaneous application of HMG-CoA reductase inhibitors and ezetimibe have been noted. This combination should be used with caution, since pharmacodynamic interaction can not be ruled out. As in the case of other HMG-CoA reductase inhibitors, the frequency of rhabdomyolysis during post-marketing use of the drug Roxer® is higher with a dose of 40 mg / day.

Determination of CKK activity

The activity of CK can not be determined after intensive physical exertion and in the presence of other possible causes of an increase in its activity; this can lead to incorrect interpretation of the results. If the initial activity of CK is significantly exceeded (5 times higher than the upper limit of the norm), after 5-7 days, a second analysis should be carried out.Do not start therapy if the results of repeated analysis confirm the initial high activity of CK (more than 5 times the upper limit of the norm).

Before starting therapy

Depending on the daily dose, the Roxer® drug should be given with caution to patients with existing risk factors for myopathy / rhabdomyolysis or drug use contraindicated (cm. sections "Contraindications" and "C" caution ").

Such factors include:

- impaired renal function;

- hypothyroidism;

- muscle diseases in the anamnesis (including in the family);

- myotoxic phenomena when taking other inhibitors of HMG-CoA reductase or fibrates in anamnesis;

- excessive use of alcohol;

- age over 65;

- conditions in which the concentration of rosuvastatin in the blood plasma may increase;

- simultaneous application of fibrates.

These patients need to assess the risk and possible benefits of therapy. Clinical monitoring is also recommended. If the initial activity of CK is more than 5 times higher than the upper limit of the norm, therapy with Roxer® can not be started.

During the period of drug therapy

The patient should be informed of the need to report immediately to the doctor in the event of an unexpected occurrence 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 no more than 5 times higher than the upper limit norms). If symptoms disappear and CPK activity returns to normal, consideration should be given to resuming the use of Roxer® or other HMG-CoA reductase inhibitors in smaller doses with careful medical supervision. Control of the activity of CKK in the absence of symptoms is inexpedient. Very rare cases of immuno-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of proximal muscles and increased activity of CKK in blood serum during therapy or when the use of inhibitors of HMG-CoA reductase, including rosuvastatin, are stopped.It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive means.

Signs of increased effects on skeletal muscle with rosuvastatin and concomitant therapy were not noted. However, there have been reports of an increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrolic acid derivatives (eg gemfibrozil), cyclosporine, nicotinic acid in lipid-lowering doses (> 1 g / day), antifungal agents azole, HIV protease inhibitors and macrolide antibiotics.

When used simultaneously with certain HMG-CoA reductase inhibitors, gemfibrozil increases the risk of myopathy. Thus, simultaneous use of the drug Roxer® and gemfibrozil is not recommended. Advantages of further changes in plasma lipid concentration the combined use of the drug Roxer® with fibrates or nicotinic acid in lipid-lowering doses should be carefully weighed against the possible risks.The drug Roxer® at a dose of 30 mg / day is contraindicated for combination therapy with fibrates. Due to the increased risk of rhabdomyolysis, Roxer® should not be used in patients with acute conditions that can lead to myopathy or conditions predisposing to the development of renal failure (eg, sepsis, arterial hypotension, extensive surgical interventions, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled convulsions).

Liver

Depending on the daily dose, the drug Roxer® should be used with caution in patients with excessive alcohol use and / or having a history of liver disease or its use is contraindicated (see "Contraindications" and "C" caution ").

It is recommended to carry out the determination of functional liver samples before the start of therapy and 3 months after the beginning of therapy. Use of the drug Roxer® should stop or reduce the dose of the drug, if the activity of "liver" transaminases in serum is 3 times higher the upper limit of the norm.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome before treatment with Roxer® should the main diseases.

Ethnic Features

During pharmacokinetic studies among representatives of the Mongoloid race compared with representatives European race plasma concentrations of rosuvastatin.

The drug Roxera® contains lactose, in with which it should not be applied patients with intolerance to lactose, deficiency of lactase, glucose- galactose malabsorption.

Interstitial lung disease

With the use of certain inhibitors HMG-CoA reductase, especially during long time, it was reported single cases of interstitial lung disease. Manifestations

diseases can be shortness of breath, unproductive cough and impairment general health (weakness, weight loss and fever). When suspected of interstitial lung disease should be discontinued therapy with HMG-CoA- reductase.

Diabetes mellitus type 2

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

Effect on the ability to drive transp. cf. and fur:Studies to study the effect of the drug Roxer® on the ability to drive vehicles and work with mechanisms have not been conducted. Nevertheless, taking into account the possibility of developing dizziness and other side effects, care must be taken when driving vehicles and other mechanisms that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg.

Packaging:

Tablets 5 mg, 10 mg, 15 mg and 20 mg: 10 or 14 tablets per blister of the combined material OPA / A1 / PVC-aluminum foil.

1, 2, 3, 6, 9 blisters (a blister for 10 tablets) or 1, 2, 4, 6 blisters (blister for 14 tablets), together with instructions for use, are placed in a cardboard pack. Tablets of 30 mg and 40 mg: 10 or 7 tablets per blister of the combined material OPA / A1 / PVC-aluminum foil.

1, 2, 3, 6, 9 blisters (10 blisters blister) or 2, 4, 8, 12 blisters (7 tablets blister) together with instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

3 years. Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001450

Date of registration:24.01.2012/25.04.2014

Date of cancellation:2017-01-24

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Information update date: & nbsp02.06.2016

Illustrated instructions

Instructions

Roxer® (Roxera®)