Rosulip - instructions for use, doses, side effects, contraindications

Active ingredient: each tablet contains 5 mg, 10 mg, 20 mg or 40 mg rosuvastatin (in the form, respectively, 5.34 mg, 10.68 mg, 21.36 mg and 42.72 mg zinc rosuvaetatin).

Auxiliaries: Ludipress 65,16 / 130,32 / 260,64 / 521,28 mg (lactose monohydrate (93%), povidone (3.5%), crospovidone (3.5%), crospovidone 3.75 / 7.5 / 15/30 mg, magnesium stearate 0.75 / 1.5 / 3/6 mg; Shell: opedraj II white 85P 18422 1,9 / 3,8 / 7,5 / 15 mg (polyvinyl alcohol (40%), titanium dioxide (25%), macrogol 3350 (20.2%), talc (14.8 %)).

Description:

Tablets 5 mg: Round biconvex tablets covered with a film coating of white or almost white color, with engraved E on one side of the tablet and number 591 on the other side of the tablet, without or almost no odor ..

Tablets 10 mg: Round biconvex tablets coated with a white or almost white film shell, engraved E on one side of the tablet and number 592 on the other side of the tablet, without or almost no odor.

Tablets of 20 mg: Round biconvex tablets covered with a film coating of white or almost white color, with engraved E and number 593 on one side of the tablet, without or almost no odor.

Tablets 40 mg: Oval biconvex tablets covered with a film coating of white or almost white color, with engraved E and number 594 on one side of the tablet, without or almost no odor.

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:

Absorption and distribution

The maximum concentration of rosuvastatin in the blood plasma is reached 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 binds to blood plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the isoenzyme СUR2С9. Isozymes СУР2С19, СУР3А4 and СУР2D6 are involved in metabolism to a lesser extent. The main revealed metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is about 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting 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 not absorbed rosuvastatin). The rest is excreted by the kidneys. The plasma half-life (T / 2) is approximately 19 hours. The half-life period does not change with increasing dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As with other inhibitors of HMG-CoA reductase, 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. Special populations of patients. Age and Sex Sex and age have no 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 plasma concentration) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Europeans; the Indian patients showed an increase in the median AUC and Cmax by a factor of 1.3. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race. Renal failure In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethyl does not change significantly. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration of N-desmethyl 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 In patients with different stages of hepatic insufficiency, an increase in rosuvastatin exposure in patients with grade 7 or lower on the Child-Pugh scale was not detected. In two patients with scores of 8 and 9 on the Child-Pugh scale, the exposure was increased by at least 2-fold. The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available. Genetic polymorphism HMG-CoA reductase inhibitors, including Rosulip®, bind to transport proteins OATP1B1 (a polypeptide for transport of organic anions involved in the capture of statins by hepatocytes) and VSGR (efflux transporter). The increase in the exposure (AUC) to rosuvastatin in 1.6 and 2.4 times, respectively, compared to carriers of genotypes SLCO1B1 C.521ET and ABCG2 with .42NCC, was noted in carriers of the genotypes SLCO1B1 (OATP1B1) with.521SS and ABCG2 (VSRP) C.421AA .

Pharmacokinetics:

Mechanism of action

Rosewatetin is a selective and competitive inhibitor of HMG-CoA reductase, a enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl coenzyme A into mevalonate, which is a precursor of cholesterol (Xc).Rozuvaetatin receptors increases the amount of low density lipoprotein (LDL) on the surface of liver cells, whereby the amplified - uptake and catabolism of LDL, and inhibits the synthesis of very low density lipoproteins (VLDL) in the liver. As a result, the total number of particles of VLDL and LDL is reduced.

Pharmacodynamic effects

It reduces the increased concentration of cholesterol low density lipoprotein (LDL-C), triglycerides and total cholesterol, and increases the concentration of cholesterol in high density lipoprotein (HDL-Xc). Furthermore, rozuvaetatin reduces the concentration of apolipoprotein B (apoB), cholesterol neLPVP (Xc-neLPVP), cholesterol, very low density lipoproteins (LDL-VLDL), triglycerides, very low density lipoproteins (TG-VLDL) and increases the amount of apolipoprotein A-1 (ApoA -1).

Also rosuvastatin reduces the ratio of Xc-LDL / Xc-HDL, total cholesterol / Xc-HDL, Xc-non-HDL / Xc-HDL and ApoB / ApoA-1.

The therapeutic effect of the drug manifests itself within one week after the start of treatment. Within 2 weeks of therapy, the effectiveness reaches a level that is 90% of the maximum possible.The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular admission.

The safety and efficacy of rosuvastatin in the infant population have not been proven. For this category of patients, the experience of using the drug is limited to a small number of patients (age 8 and older) with homozygous hereditary hypercholesterolemia.

Indications:Primary hypercholesterolemia (type IIa according to Fredriksen) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-medicamentous methods of treatment (for example, physical exercises, weight loss) are insufficient. Homozygous hereditary hypercholesterolemia as a supplement to the diet and other methods of treatment aimed at reducing the concentration of lipids in the blood (eg, apheresis of LDL), and

Also in cases when these methods are not effective enough.

Hypertriglyceridemia (type IV by Fredrickson) as a supplement to the diet.

To slow the progression of atherosclerosis as a supplement to the diet in patients, including those who are shown therapy to reduce the concentration of total cholesterol and LDL-C.

Prevention of major cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adults without clinical signs of coronary heart disease (CHD), but with an increased risk of its development (age over 50 for men and

over 60 years for women, increased concentration of C-reactive protein (>2 mg / L) with at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early onset of coronary artery disease).

Contraindications:

For tablets of 10 mg and 20 mg

-increased sensitivity to rosuvastatin and other components of the drug;

- liver disease in the active phase, including persistent increase in serum activity of transaminases and any increase in serum transaminase activity (more than 3 times higher than the upper limit of the norm (VGN);

-heavy renal dysfunction (KKene less than 30 ml / min);

-miopathy;

- simultaneous administration of cyclosporine;

- pregnancy, lactation, and the lack of adequate methods of contraception in women with a safe reproductive function;

predisposition to the development of myotoxic complications;

-baby age to 18 years (due to lack of sufficient clinical data, efficacy and safety are not established, see section "Special instructions");

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

For tablets 40 mg

- Hypersensitivity to rosuvastatin and other components of the drug;

- liver diseases in the active phase, including persistent increase in serum activity of transaminases and any increase in serum transaminase activity (more than 3 times as compared with IGN); experience of using the drug in patients with a score above 9 on the Child-Pugh scale is absent;

- simultaneous administration of cyclosporine;

- the presence of risk factors for myopathy / rhabdomyolysis: renal failure, 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 Asian race;

- pregnancy, lactation period, as well as the lack of adequate methods of contraception for women with a safe reproductive function;

-baby age to 18 years (due to lack of sufficient clinical data, efficacy and safety are not established, see section "Special instructions");

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

Carefully:

With caution use the drug in the form of 10 and 20 mg tablets in the presence of risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism, personal or family history of hereditary, muscular diseases and a previous history of muscle toxicity when using other inhibitors of HMG-CoA reductase or fibrates; at excessive use of alcohol; in patients older than 65 years; conditions, in which there was an increase in the plasma concentration of rosuvastatin; in patients of the Asian race; simultaneously with fibrates; with liver diseases in the anamnesis; sepsis; arterial hypotension; extensive surgical interventions, injuries; with severe metabolic, endocrine or electrolyte disturbances or uncontrolled convulsive seizures.

With caution, use the drug in the form of 40 mg tablets in patients with mild renal insufficiency (KC more than 60 ml / min), over the age of 65 years, with a history of liver disease, sepsis, hypotension, extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled convulsive seizures.

Pregnancy and lactation:

Rosulip is contraindicated in pregnancy and lactation (breastfeeding). When diagnosing pregnancy during therapy, taking the drug should be stopped immediately.

Women of reproductive age should apply adequate methods of contraception. Since Xc and the products of its biosynthesis are important for fetal development, the potential risk of inhibiting HMG-CoA reductase exceeds the benefit of using the drug. Data on the allocation of rosuvastatin, with breast milk are not available, so if you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, do not chew and do not grind the tablet, swallow whole, squeezed water.The drug can be administered at any time of the day, regardless of food intake. Before starting therapy with Rosulip®, 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 in

depending on the purpose of therapy and the therapeutic response to treatment, taking into account

current recommendations on 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 or 10 mg of Rosulip® once a day. When choosing the initial dose should be guided by individual cholesterol concentration and take into account the possible risk of cardiovascular complications, as well as to assess the potential risk of side effects

effects. If necessary, the dose may be increased to greater after 4 weeks (see.

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 titrating the dose above the recommended initial dose for 4 pedul therapy.

can be performed only in patients with severe hypercholesterolemia and with high

risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), in which the desired result was not achieved therapy when receiving doses of 20 mg, in which will be under the supervision of a specialist (see. section "Special instructions"). It is especially recommended

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 bulldog therapy and / or with an increase in dose needed Rozulip® control lipid metabolism (if necessary dose required correction).

Elderly patients

For treatment of patients older than 70 years, the recommended initial dose of 5 mg.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not

it takes. In patients with severe renal failure (creatinine clearance less than 30 mL / min.) Using the product Rozulip® contraindicated.Contraindicated use of the drug in a dose of 40 mg to patients with moderate impaired renal function (QC less than 30-60 ml / min.) (See section "Special instructions" and "Pharmacodynamics"). Patients with moderate impairment of renal function are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

Rosulip® is contraindicated in patients with active liver disease (see "Contraindications" section).

Special populations. Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to

different ethnic groups, an increase in the systemic exposure of rosuvastatin among Japanese and Chinese (see section "Special instructions").

This fact should be taken into account when prescribing Rosulip® to these patient groups.

When prescribing 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 the genotypes SLCO1B1 (OAP1B1) with .52NCC and ABCG2 (VSRP) c.421AA, it was noted

an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCO1B1

c.521ТТ and АВСG2 с.421СС.For patients carrying genotypes c.521SS or p.421AA, the recommended maximum dose of Rosulip® is 20 mg once a day (see the sections "Pharmacokinetics", "Special instructions" and "Interaction with other medicinal

means 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 "Contraindications").

Concomitant therapy

Rosuvaetatin binds to various transport proteins (in particular, to OATP1B1 and BCSR). When the drug Rosulip® is used together with medicines (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir, and / or tipranavir) that increase the concentration of rosuvastatin in plasma at the expense of

interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase (see below).sections "Special instructions" and "Interaction with other medicinal products and other types of drug interactions"). In such cases, you should read the instructions for using these drugs before they are prescribed with Rosulip®, assess the possibility of prescribing alternative therapy or temporarily stopping the use of Rosulip®. If

the use of the above drugs is necessary, the ratio of benefit and risk of concomitant therapy with Rosulip® should be assessed and the possibility of reducing its dose should be considered (see "Interactions with Other Drugs and Other Drug Interactions").

Side effects:

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

The frequency of undesirable effects is as follows:

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: type 2 diabetes mellitus

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: itching, rash, urticaria

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 receiving Rosulip®, 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

acute or progressing of existing kidney disease.

From the side of the musculoskeletal system

When using rosuvastatin preparations in all dosages and, especially when taking doses

of the preparation exceeding 20 mg, the following effects on the musculoskeletal system have been reported: myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with acute renal

insufficiency or without it.

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

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.

Laboratory indicators

When applying rosuvastatin, the following changes in laboratory parameters were also observed: increased glucose concentration, bilirubin, gamma-glutamyltranspeptidase activity, alkaline phosphatase, thyroid dysfunction.

Postmarketing application

The following side effects have been reported in the post-marketing application of rosuvastatin:

On the part 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 of the musculoskeletal system

Very rarely: arthralgia

Unspecified frequency: immunocompromised necrotizing myopathy

From the central nervous system

Very rare: loss or loss of memory

Unspecified frequency: peripheral neuropathy

From the respiratory system

Unspecified frequency: cough, dyspnea

From the side of the urinary system

Very rare: 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 disturbances. including insomnia and nightmarish dreams, sexual dysfunction, hyperglycemia, an increase in the concentration of glycosylation hemoglobin.

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

Changes in tendons, sometimes complicated by their rupture

Overdose:

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

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

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 BCCP. 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 and sections on "Dosage and administration" and "Special instructions").

Cyclosporine: with simultaneous application of rosuvastatin and cyclosporin AUC, rosuvastatin was an average of 7 times higher than that seen in healthy volunteers (see table). Does not affect the plasma concentration of cyclosporine. Rosulip® is contraindicated in patients taking ciclosporin (see the section "Contraindications"),

Inhibitors of the human immunodeficiency virus (HIV) protease: in spite of the fact that the exact

the mechanism of interaction is unknown, joint intake of HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin (see Table). A pharmacokinetic study on simultaneous use of 20 mg rosuvastatin with a combined preparation containing two HIV protease inhibitors (400 mg lopivavir / 100 mg ritonavir) in healthy volunteers resulted in approximately a twofold and fivefold increase in AUC (0-24) and C max rosuvastatin, respectively. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors is not recommended (see the sections on "Method of administration and dose", "Special instructions", table).

Gemfibrozil and other lipid-lowering agents: the combined use of rosuvastatin and gemfibrozil leads toan increase in 2 times the maximum concentration of rosuvastatin in the 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 increased the risk of myopathy with concomitant use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section "Special instructions"). With simultaneous administration of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), the initial dose of 5 mg is recommended for patients, the dose of 40 mg is contraindicated in a joint appointment with fibrates (see "Contraindications", " Method of administration and dose "," Special instructions ").

Ezetimibe: simultaneous use of the drug Rosulip® at a dose of 10 mg and ezetimibe at a dose of 10 mg

was accompanied by an increase in AUC of rosuvastatin in patients with hypercholesterolemia (see Fig.

table).It is impossible to exclude an increased risk of side effects due to the pharmacodynamic interaction between Rosulip® and ezetimibe.

Antacids: simultaneous use 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 in AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. Such interaction can arise as a result of increased intestinal motility caused by the administration of erythromycin. Isozymes of cytochrome P450: results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes.

Besides, rosuvastatin is a weak substrate for these isoenzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level with the participation of cytochrome P450 isoenzymes is not expected.There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes СУР2С9 and СУР3А4) and ketoconazole (inhibitor of isoenzymes СUR2А6 and СУР3А4).

Interaction with drugs, which requires dose adjustment for rosuvastatin

(see the table)

The dosage of Rosulia® should be adjusted when it is necessary to use it together with

medicines, increasing the exposure to rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of Rosulia® should be 5 mg once daily. Also, the maximum daily dose of Rosulia® should be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of medications that interact with rosuvastatin. For example, the maximum daily dose of Rosulia® with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

Table. The effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order) - results published clinical trials

Mode	Mode	Change
concomitant	admission	A11C
of therapy	rosuvastatin	rosuvastatin

Cyclosporin	10 mg 1 time per	The increase in
75-200 mg 2	days, 10 days	7.1 times
times per day, 6
months.

Atazanavir 300	10 mg	The increase in
mg / ritoavir	once	3.1 times
100 mg 1 time per
day, 8 days

Lopinavir 400	20 mg 1 time per	The increase in
mg / ritoavir	day, 7 days	2.1 times
100 mg 2 times in
day, 17 days


Gemfibrozil	80 mg	The increase in
600 mg 2 times in	once	1.9 times
day, 7 days
Eltrombopag	10 mg	The increase in
75 mg 1 time per	once	1.6 times
days, 10 days
Darunavir 600 mg / ritonavir 100 mg 2 times per 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
Dropedarone 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 once a day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg 2 times per day, 8 days	10 mg once	Without changes
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	Vez 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
Rifampin 450 mg once a day, 7 days	20 mg once	Without changes
Ketoconazole 200 mg 2 times per 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 per 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

Vitamin K antagonists: initiation of therapy rosuvastatin or an increase in the dose of the drug patients receiving concomitantly antagonists of vitamin K (for example, warfarin). can lead to an increase in the International Normalized Relationship (INR). Cancel rosuvastatin or a decrease in the dose of the drug can lead to a decrease in INR. Such cases, it is recommended to control INR.

Oral contraceptives / hormone replacement therapy: simultaneous application of rosuvastatin and oral contraceptives increases AUc Ethinyl estradiol and AUC norgestrel by 26% and 34% respectively. This increase plasma concentrations should be taken into accountwhen choosing a dose of oral contraceptives.

Pharmacokinetic data on simultaneous use of the drug Rosulip® and hormone replacement therapy Therefore, we can not exclude similar effect and when applying this combination. However, such a combination is widely was used during the clinical research and was well tolerated patients.

Other medicines: not expected clinically relevant interactions rosuvastatin with digoxin.

Special instructions:

Renal Effects

In patients who received high doses of the drug Rosulip® (mostly 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.

From the side of the musculoskeletal system

When using the drug Rosulip® in all dosages and, especially when taking doses of the drug, 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

Determination of the activity of CKK should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK. which can lead to incorrect interpretation of the results. If the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the baseline CK activity (more than 5 times higher than the upper limit of the norm).

Before the start of therapy

With the appointment of Rosulip®, as well as with the appointment of other inhibitors of HMG-CoA-

reductase, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis (see "With caution"), it is necessary to consider the relationship between the risk and possible benefits of therapy and conduct clinical follow-up.

During therapy

Inform the patient of the need for immediate communication to thethe appearance 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 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 to

the upper limit of the norm). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering Rosulip® or other HMG-CoA reductase inhibitors 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 increased effect on skeletal musculature when taking Rosulip® 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, the simultaneous administration of Rosulip® and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully weighed in conjunction with the use of Rosulip® and fibrates or lipid-lowering doses of nicotinic acid. Contraindicated taking Rosulip® in a dose of 40 mg together with fibrates (see the sections "Interaction with other drugs and other forms of drug interaction", "Contraindications").

After 2-4 weeks after the start of treatment and / or when the dose of Rosulip® is increased, it is necessarycontrol of lipid metabolism (if necessary, dose adjustment is required).

Liver

Similar to other HMG-CoA reductase inhibitors, the Rosulip® tablet, coated

shell, should be used with caution in the treatment of alcohol abusers and patients with underlying liver pathology.

It is recommended that the determination of liver function parameters be performed prior to initiation of therapy and

3 months after the start of therapy. Taking the drug Rosulip® 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 of the underlying diseases should be performed before starting treatment with Rosulip®.

Special populations. Ethnic groups

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

HIV protease inhibitors

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

Lactose

The drug should not be used in patients with lactase deficiency, intolerance

galactose and glucose-galactose malabsorption.

Interstitial lung disease

With the use of some statins, especially for a long time, it was reported

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 iptestichesky lung disease should stop therapy with statins.

Diabetes mellitus type 2

In patients at risk (with a glucose concentration of 5.6 to 6.9 mmol / l, c_

body mass index> 30 kg / m, with elevated triglycerides, hypertension) therapy

the drug Rosulip® was associated with an increased risk of developing type 2 diabetes.

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

There have been no studies to study the effect of Rosulip® on the ability to drive a vehicle and use mechanisms. Care should be taken when driving vehicles or work associated with increased concentration of attention and psychomotor reaction (dizziness may occur during therapy).

Form release / dosage:

Tablets film-coated 5 mg, 10 mg, 20 mg and 40 mg.

Packaging:

For 7 tablets in a blister of the combined film "coil" (polyamide / aluminum foil / PVC) // aluminum foil. 2. 4.8 or 12 blisters together with instructions for use in a cardboard box.

Storage conditions:Store at a temperature not exceeding 30 ° C. Keep the drug out of the reach of children!

Shelf life:3 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000799

Date of registration:03.10.2011/12.05.2015

Expiration Date:03.10.2016

The owner of the registration certificate:EGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Manufacturer: & nbsp

EGIS PHARMACEUTICALS, Plc Hungary

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp08.07.2016

Illustrated instructions

Instructions

Rosulip® (Rosulip®)