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

Excipients: lactose monohydrate (milk sugar) - 70.329 mg; cellulose microcrystalline - 12,307 mg; croscarmellose sodium - 4,577 mg; Povidone-K25 - 2,637 mg; silicon dioxide colloidal - 0.970 mg; magnesium stearate - 0.970 mg.

Shell composition: hypromellose - 1,650 mg; Macrogol 4000 to 0.450 mg; titanium dioxide - 0.900 mg.

Dosage of 10 mg

Active substance: rosuvastatin calcium - 10,420 mg, in terms of rosuvastatin - 10.0 mg.

Excipients: lactose monohydrate (sugar milk) - 140.658 mg; cellulose microcrystalline - 24.614 mg; croscarmellose sodium - 9,154 mg; povidone-K25 - 5,274 mg; silicon dioxide colloidal - 1,940 mg; magnesium stearate - 1,940 mg.

Shell composition: hypromellose - 3,300 mg; Macrogol 4000 to 0.900 mg; titanium dioxide - 1,800 mg.

Dosage of 20 mg

Active substance: rosuvastatin calcium - 20,830 mg, in terms of rosuvastatin - 20.0 mg.

Excipients: lactose monohydrate (sugar milk) - 132.329 mg; cellulose microcrystalline - 23,157 mg; croscarmellose sodium - 8.842 mg; povidone-K25 - 4.962 mg; silicon dioxide colloidal - 1,940 mg; magnesium stearate - 1,940 mg.

Shell composition: hypromellose - 3,300 mg; Macrogol 4000 to 0.900 mg; titanium dioxide - 1,800 mg.

Dosage 40.0 mg

Active substance: rosuvastatin calcium - 41,660 mg, in terms of rosuvastatin - 40.0 mg.

Excipients: lactose monohydrate (sugar milk) - 264.658 mg; microcrystalline cellulose - 46,314 mg; croscarmellose sodium - 17.684 mg; povidone-K25 9.924 mg; silicon dioxide colloidal - 3,880 mg; magnesium stearate - 3.880 mg.

Shell composition: hypromellose - 6,600 mg; macrogol - 4000 - 1,800 mg; titanium dioxide - 3,600 mg.

Description:Tabletki, covered with a film membrane of white or almost white color.

Dosage of 5, 20, 40 mg - round, biconcave form;

Dosage of 10 mg - round, biconcave form, with a risk on one side.

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:

Mechanism of action

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

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

Pharmacodynamics

Rosuvastatin decreases the increased concentration of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG) and increases the concentration of cholesterol - high density lipoprotein cholesterol (HDL-C) and also reduces the concentration of apolipoprotein B (apoB) neLPVP-cholesterol, HS- VLDL, VLDL-TG and increases levels of apolipoprotein AI (ApoA-I), decreases the ratio of LDL-C / HDL-C, total cholesterol / HDL-cholesterol and LDL-neLPVP / HDL-C ratio and apoB / ApoA-1. the possibility of a decrease in the appearance appears within one week after initiation of therapy with the drug Rosuvastatin, after 2 weeks of treatment reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week and is maintained with regular intake of the drug.

Clinical efficacy

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

In 80% of patients with hypercholesterolemia IIa and IIb type (according to Fredrickson classification (the average initial concentration of LDL-C is about 4.8 mmol / L), when taking the drug at a dose of 10 mg, the concentration of LDL-C is less than 3 mmol / l.

In patients with heterozygous familial hypercholesterolemia receiving rosuvastatin in a dose of 20-80 mg, there is a positive dynamics of the lipid profile. After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is reduced by 53%.

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

The additive effect is noted in combination with fenofibrate for the concentration of triglycerides and with nicotinic acid in lipid-lowering doses (more than 1 g / day) 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 %.

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 with albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastine 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-dis-methyl metabolite and lactone metabolites. Nis 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. Plasma half-life (T_1/2) is approximately 19 hours. T_1/2, 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 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 FROM_m_Oh (maximum concentration in blood plasma) of rosuvastatin in Asian patients (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Europeans; Indian patients showed an increase in the median AUC and FROM_m_Oh in 1,3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race.

Renal insufficiency

In patients with mild to moderate renal failure plasma concentrations of rosuvastatin or N-dis-methyl metabolite is not significantly changes. In patients with severe renal failure (creatinine clearance (CC) less than 30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and concentration Nis 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 varying degrees of hepatic insufficiency did not show an increase in T_1/2 rosuvastatin in patients with a score of 7 or lower on the Child-Pugh scale. In two patients with scores of 8 and 9 on the Child-Pugh scale, an increase in T_1/2, at least in 2 times. The experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is not available.

Genetic polymorphism

Inhibitors of HMG-CoA reductase, including rosuvastatin, bind to transport proteins OATP1B1 (a polypeptide transporting organic anions involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLCOIBI (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genes SLCOIBI p.52ITT and ABCG2 p.421S.

Indications:

- Primary hypercholesterolemia according to Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) As an adjunct to diet when diet and other non-pharmacological treatments (eg exercise, weight loss) are not sufficient.

- Family homozygous hypercholesterolemia as a supplement to a diet and other lipid-lowering therapy (eg, LDL-apheresis), or in cases when such therapy is not effective enough.

- Hypertriglyceridemia (type IV 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 coronary heart disease (CHD), but with an increased risk of its development (age over 50 for men and over 60 for women, increased concentration C-reactive protein (≥ 2 mg / L) in the presence of at least one of additional risk factors such as hypertension, low concentration of HDL-C, smoking, family history of early onset of CHD).

Contraindications:

For use in a daily dose of 5 mg, 10 mg and 20 mg:

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

- 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);

- patients with hepatic insufficiency;

- severe impairment of kidney function (QC less than 30 ml / min.);

- myopathy;

- simultaneous administration of cyclosporine;

- children and adolescents under 18;

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

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

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

For use in a daily dose of 40 mg:

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

- simultaneous administration of cyclosporine;

- 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);

- patients with hepatic insufficiency;

- patients with risk factors for myopathy / rhabdomyolysis

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

- hypothyroidism;

- personal or family anamnesis of muscular diseases;

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

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

- 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;

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

Carefully:

For use in a daily dose of 5 mg, 10 mg and 20 mg:

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 or fibrates; excessive use of alcohol; age over 65; conditions in which there was an increase in the plasma concentration of rosuvastatin; race (Mongoloid race); simultaneous appointment with fibrates;liver disease in history; sepsis; arterial hypotension; extensive surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders, or uncontrolled convulsive seizures.

For use in a daily dose of 40 mg:

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 convulsive seizures.

Application in pediatric practice

The effectiveness and safety of the drug in children under 18 years of age is not established.

The experience of using the drug in pediatric practice is limited to a small number of children (8 years and older) with family homozygous hypercholesterolemia. Currently, it is not recommended to apply Rosuvastatin the children under 18 years.

Pregnancy and lactation:

Rosuvastatin is contraindicated in pregnancy and during breastfeeding. Women of reproductive age should apply adequate methods of contraception against the background of Rosuvastatin treatment.

Since cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of using the drug in pregnant women.

When diagnosing pregnancy during therapy, taking the drug Rosuvastatin must be terminated immediately.

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

Dosing and Administration:

Inside, do not chew and do not break, swallow whole, washing down with 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 the current recommendations for 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 the drug Rosuvastatin 1 time per 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 assess the potential risk of side effects. If necessary, the dose may be increased to greater after 4 weeks.

In connection with the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug, increasing the dose to 40 mg, after additional doses above the recommended initial dose for 4 weeks of therapy, can only be carried out in patients with severe the degree of hypercholesterolemia and the 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 monitored by the sp cialist. 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).

Elderly patients

The initial recommended dose in patients over the age of 70 is 5 mg, otherwise no dosage adjustment is needed depending on age.

Patients with renal insufficiency

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

Contraindicated the use of all dosages of the drug Rosuvastatin in patients with severe renal failure (QC less than 30 ml / min.) (See section "Contraindications").

Contraindicated use of the drug at a dosage of 40 mg in patients with moderate impaired renal function (CC less than 60 ml / min.). Patients with moderate renal dysfunction (CC less than 60 mL / min.) Are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

A drug Rosuvastatin contraindicated in patients with liver disease in the active phase.

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 andthe Chinese. 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").

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.

Genetic polymorphism

In carriers of genotypes SLCOIBI (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCOIBI p.52ITT and ABCG2 p.421S. For patients carrying genotypes p.521SS or p.421AA, the recommended maximum dose of the drug Rosuvastatin is 20 mg once a day.

Concomitant therapy

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

Side effects:

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

The incidence of adverse events is as follows, according to the classification of the World Health Organization:

Often (> 1/100, <1/10); Infrequently (> 1/1000, <1/100); Rarely (> 1/10000); Very rarely (<1/10000), including individual messages; The frequency is not set to be calculated from the available data).

The immune system

Rarely: hypersensitivity reactions, including angioedema.

From the 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 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, proteinuriadecreases or disappears during therapy and does not mean the emergence of acute or progressive disease of the existing kidney.

From the side of the musculoskeletal system

In applying rosuvastatin all doses, and particularly when receiving doses greater than 20 mg have been reported for the following effects on the musculoskeletal system: myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with acute renal failure or without it.

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

From the side of the 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

Increasing the concentration of glucose, bilirubin, gamma-glutamyl 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:

Frequency not established: thrombocytopenia.

From the side of the digestive tract

Very rarely: jaundice, hepatitis.

Rarely: increased activity of "liver" transaminases.

Frequency not established: diarrhea.

From the side of the musculoskeletal system

Very rarely: arthralgia.

The frequency is not established: immuno-mediated necrotizing myopathy.

From the central nervous system

Very rare: loss or loss of memory.

Frequency not established: peripheral neuropathy.

From the respiratory system

The frequency is not established: cough, shortness of breath.

From the side of the urinary system

Very rarely: hematuria.

From the skin and subcutaneous fat

The frequency is not established: Stevens-Johnson syndrome.

From the side of the reproductive system

Very rarely: gynecomastia.

Other

Frequency not established: peripheral edema.

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

Single cases of interstitial lung disease have been reported, especially with prolonged use of drugs.

Overdose:

Symptoms: with the simultaneous administration of several daily doses, the pharmacokinetic parameters of rosuvastatin do not change.

Treatment: 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:

Inhibitors of transport proteins

Rosuvastatin binds to some transport proteins, in particular, to OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of transport proteins may be accompanied by an increase in the concentration of rosuvastatin in the blood plasma and an increased risk of myopathy.

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

Indirect anticoagulants: 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 prothrombin time (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.

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

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid (more than 1 g / day) increased the risk of myopathy with simultaneous use with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used in monotherapy.If the drug is simultaneously taken 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 with simultaneous appointment with fibrates (see section "Contraindications").

Ezetimibe: simultaneous application of rosuvastatin in a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase AUC rosuvastatin in patients with hypercholesterolemia (see Table 3). It is impossible to exclude an increase in the risk of side effects due to the pharmacodynamic interaction between the drug Rosuvastatin and ezetimibe.

HIV protease inhibitors (AIDS virus): despite the fact that the exact mechanism of interaction is unknown, joint intake of HIV protease inhibitors can lead to a significant increase in the exposure of rosuvastatin (see Table 3). The simultaneous administration of rosuvastatin and HIV protease inhibitors in the treatment of patients with HIV is not recommended.

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

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

Oral contraceptives / hormone replacement therapy: simultaneous the use of rosuvastatin and oral contraceptives increases the AUC of ethinylestradiol and AUC norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when choosing a dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of 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.

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, 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 isozymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 CYP3A4).

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

Dose of the drug Rosuvastatin should be adjusted if necessary, its simultaneous use with drugs that increase exposure to rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of the drug Rosuvastatin should be 5 mg 1 time per 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 that interact 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. The effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order)

Mode concomitant therapy	Mode of taking rosuvastatin	Change in AUC of 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 /	10 mg once	increase by 3.1 times
Symeprevir 152 mg once a day, 7 days	10 mg once	An increase of 2.8 times
Ritonavir 100 mg once a day, 8 days
Lopinavir 400 mg /	20 mg once a day, 7 days	An increase of 2.1 times
Ritonavir 100 mg twice daily, 17 days
Clopidogrel 300 mg (loading dose),
Then, 75 mg after 24 hours	20 m g once	2 times increase
Gemfibrozil 600 mg 2 times / day, 7 days	80 mg once	Increase 1.9 times
Eltrombopag 75 mg 1 time / day, 10 days	10 mg once	Increase 1.6 times
Darunavir 600 mg /	10 mg 1 time / day, 7 days	Increase by 1.5 times
Ritonavir 100 mg 2 times / day, 7 days
Tipranavir 500 mg	10 mg once	Increase by 1.4 times
Ritonavir 200 mg 2 times / day, 11 days
Dronedarone 400 mg twice daily	no data	Increase by 1.4 times
Itraconazole 200 mg 1 time / day, 5 days	10 mg or 80 mg once	Increase by 1.4 times
Ezetimibe 10mg 1 time / day, 14 days	10 mg once a day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg /	10 mg once	Without changes
Ritonavir 100 mg twice daily 8 days
Aleglitazar 0.3 mg 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 times / day, 5 days	10 mg once	Without changes
Fenofibrate 67 mg 3 times / day, 7 days	10 mg, 7 days	Without changes
Rifampicin 450 mg 1 time / day, 7 days	20 m g once	Without changes
Ketoconazole 200 mg 2 times / day, 7 days	80 mg once	Without changes
Fluconazole 200 mg 1 time / day, 11 days	80 mg once	Without changes
Erythromycin 500 mg 4 times / day, 7 days	80 mg once	Decrease by 28%
Baikalin 50 mg 3 times / day, 14 days	20 mg once	Decrease by 47%

Special instructions:

From the urinary system

In patients receiving high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate an acute kidney disease or progression of kidney disease.In patients taking the drug 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 rosuvastatin was used in all dosages 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. If the initial activity of CK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if a second test confirms the baseline CK activity (more than 5 times higher than the upper limit of the norm).

Before the start of therapy

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

During therapy

The patient should be informed of the need to report immediately to the doctor about cases of sudden onset of muscle pain, muscle weakness, or spasms, especially in combination with malaise and fever. In such patients, the activity of CK should be determined. Therapy should be discontinued if the activity of CK is significantly increased (more than 5 times compared with the upper limit of the norm) or if the symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CK is 5 times less than the upper limit of the norm ). If the symptoms disappear, and the activity of CPA returns to normal, consideration should be given to re-application of 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 the serum during treatment or with stopping of taking statins are noted. rosuvastatin.It may be necessary to conduct additional studies of the muscular system and nervous system, serological studies, as well as therapy with immunosuppressive drugs.

There were no signs of an increase in the effect on skeletal musculature upon admission rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid in lipid-lowering doses (more than 1 g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics.

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

It is necessary to carefully weigh the ratio of risk and possible benefit in the joint use of the drug Rosuvastatin and fibrates or lipid-lowering doses of nicotinic acid (more than 1 g / day).

Contraindicated drug intake Rosuvastatin in a dose of 40 mg together with fibrates.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).

Effects on liver function

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 among Chinese and Japanese patients an increase in the systemic concentration of rosuvastatin was noted in comparison with the figures obtained among Europeans.

HIV protease inhibitors

It is not recommended joint use of the drug with HIV protease inhibitors.

Lactose

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

Interstitial lung disease

When certain statins were used, especially for a long time, single cases of interstitial lung disease were reported. Manifestations of the disease may be shortness of breath, unproductive cough and deterioration, general well-being (weakness, weight loss and fever). If suspicion of interstitial lung disease should be stopped by statin therapy.

Diabetes mellitus type 2

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

Inhibitors of HMG-CoA reductase, incl. Rosuvastatin can increase the concentration of glucose in the blood.

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

There have been no studies on the effect of rosuvastatin 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:

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

Packaging:

By 7, 10, 14, 30 tablets into the contour cell package from the film polyvinylchloride and aluminum foil printed lacquered.

For 10, 14, 20, 28, 30, 40, 50 or 100 tablets in cans of polyethylene terephthalate for medicines, sealed with caps screwed on with the control of the first opening or a "push-turn" system of polypropylene or polyethylene, or polypropylene polymer cans for drugs sealed with lids pulled with the control of the first opening of polyethylene.

One jar or 1, 2, 3, 4, 5 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003648

Date of registration:20.05.2016

Expiration Date:20.05.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp13.07.2016

Illustrated instructions

Instructions

Rosuvastatin (Rosuvastatin)