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

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A into mevalonate, which is a precursor to 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 surface of cells, increasing the uptake and catabolism of LDL.

It also inhibits the synthesis of very low density lipoprotein cholesterol (VLDL) in liver cells, thereby reducing the total content of LDL and VLDL. Rosuvastatin reduces the high cholesterol - LDL, total cholesterol and triglycerides (TG), increases the high-density lipoprotein cholesterol (HDL-C), and also reduces the content of apolipoprotein B (ApoV), CS-non-HDL (total cholesterol deduction of HDL cholesterol, cholesterol-VLDL, T-VLDL and increases the level of apolipoprotein AI (ApoA-1). Rosuvastatin reduces the ratio of LDL-C-HDL cholesterol, total cholesterol / cholesterol-HDL cholesterol, cholesterol-HDL cholesterol and LDL cholesterol and ApoA / ApoA-1.

The therapeutic effect can be achieved within one week after the start of treatment, after 2 weeks 90% of the maximum possible effect is achieved. Usually the maximum possible therapeutic effect is achieved after 4 weeks and is maintained with further administration of the drug.

Clinical efficacy

Rosuvastatin is effective in the treatment of adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia, regardless of race, sex or age, as well as in the treatment of a particular category of patients, patients with diabetes mellitus or a hereditary form of familial hypercholesterolemia.

Rosuvastatin is effective for the treatment of patients with type IIa and IIb hypercholesterolemia

Frederickson (mean baseline level of LDL-C is about 4.8 mmol / L). In 80% of patients receiving 10 mg of rosuvastatin, the target values of the xc-LPP level established by the European Society for the Study of Atherosclerosis (less than 3 mmol / L) were achieved.

In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses from 20 to 80 mg according to the scheme of forced titration of doses, all taken doses had a significant effect on the changes in the parameters characterizing the lipid content and on the achievement of the goal of therapy. As a result of titration of doses up to 40 mg per day (12 weeks of therapy), the content of LDL-C has decreased by 53%. In 33% of patients, LDL cholesterol (below 3 mmol / L) was achieved, consistent with the guidelines of the European Society for the Study of Atherosclerosis.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average decrease in the content of LDL-C was 22%. In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dL, rosuvastatin in a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in blood plasma decreased significantly.

Additive effect is noted in combination with fenofibrate for TG and nicotinic acid (more than 1 g per day) for the content of cholesterol-HDL.

Studies on the effect of rosuvastatin on reducing the number of complications caused by lipid disorders, such as ischemic disease, have not yet been completed.

In patients with a low risk of coronary heart disease (defined as the Framingham risk less than 10% over a period of more than 10 years), with an average LDL-C content of 4.0 mmol / L (154.5 mg / dl) rosuvastatin in a dose of 40 mg / day significantly slowed the increase in the maximum value characterizing the thickening of the carotid artery wall in 12 segments, compared with placebo at a rate of -0.0145 mm / year (95% confidence interval (CI): -0.0196 up to -0.0093, with p <0.0001). A dose of 40 mg should be given only to patients with severe hypercholesterolemia and a high risk of developing cardiovascular disease.

Pharmacokinetics:

Absorption: the maximum concentration of rosuvastatin in the blood plasma is reached 5 hours after ingestion of the appropriate dose.Absolute bioavailability is approximately 20%.

Distribution: rosuvastatin is metabolized primarily by the liver, which is the main site for the synthesis of cholesterol and the clearance of the metabolism of LDL-C.

The volume distribution of rosuvastatin is approximately 134 liters. 90% of rosuvastatin binds to plasma proteins, mainly albumin.

Metabolism: is subject to limited metabolism (about 10%). Rosuvastatin is a rather non-core substrate for metabolism by enzymes of the cytochrome P450 system. CYP2C9 is the main isoenzyme involved in metabolism, while isoenzymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main metabolite - N-desmethyl, which is 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: approximately 90% of the administered dose of rosuvastatin is excreted unchanged from the body through the intestine (including absorbed and unabsorbed rosuvastatin), and the remainder is excreted unchanged by the kidneys. The half-life period (T1 / 2) is 19 hours, 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 in the case of other inhibitors of HMG-CoA reductase, a membrane cholesterol transporter through membranes is involved in the process of "hepatic" capture of rosuvastatin. protein with organic anions. This carrier plays an important role in the excretion of rosuvastatin by the liver.

Linearity: The systemic exposure of rosuvastatin increases in proportion to the dose. Changes in pharmacokinetic parameters when taking the drug several times a day are not noted.

Age and gender: sex and age have no clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Ethnic groups: Comparative studies of pharmacokinetics showed a twofold increase in the mean AUC (the area under the concentration-time curve) and TShsah (the time to reach the maximum concentration of the drug in the blood plasma) in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to those in the Caucasoid race.The Indians noted an excess of about 1.3 times the average value AUC and C_m_Oh. At the same time, the analysis of pharmacokinetics indices for the whole study population did not reveal clinically significant differences in the pharmacokinetics of the drug among representatives of Caucasoid, Negroid races, Latin Americans.

Renal insufficiency: In patients with mild to moderate renal impairment, the plasma concentration of rosuvastatin or NThe metabolite does not change significantly. In patients with severe renal failure (creatinine clearance (CC) less than 30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration NThe metabolite is 9 times higher than 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 varying degrees of hepatic insufficiency with a score of 7 or lower on the Child-Pugh scale, no increase in T1 / 2 of rosuvastatin was detected. However, in 2 patients with a score of 8 and 9 on the Child-Pugh scale, an elongation approximately 2-fold higher than that for patients with lower Child-Pugh scores was observed.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 Mertenil®, bind to transport proteins OATP1B1 (a polypeptide transporting organic anions involved in the capture of statins by hepatocytes) and BCRJP (efflux conveyor). In carriers of genotypes SLC01B1 (OATP1B1) p.521N and ABCG2 (BCRP) C.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genotypes SLC01B1 from.521TT and ABCG2 p.421S4.

Indications:

- Hypercholesterolemia and combined (mixed) dyslipidemic states to reduce the elevated concentrations of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides in serum as a supplement to diet therapy, when diet and other non-drug methods (eg exercise, weight loss) turn out to be insufficient.

- Family homozygous hypercholesterolemia as a supplement to diet therapy and other methods of lipid-lowering therapy (eg, LDL-apheresis) or in cases when such therapy is 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 who are shown therapy to reduce the concentration of total cholesterol and LDL-C.

- Primary prevention of cardiovascular complications (cardiovascular death, stroke, heart attack, unstable angina and arterial revascularization) in adults without clinical signs of coronary heart disease (CHD) but with an increased risk of its development (age over 50 years for men and older 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 5,10 and 20 mg

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

- liver diseases in the active phase, including persistent increase in the activity of "liver" transaminases, as well as any increase in the activity of transaminases in the serum more than 3 times compared with the upper limit of the norm;

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

- myopathy;

- simultaneous administration of cyclosporine;

- in patients predisposed to the development of myotoxic complications;

- pregnancy and the period of breastfeeding;

- in women of childbearing age who do not use reliable means of contraception;

- age under 18 years (effectiveness and safety not established);

- patients with hepatic insufficiency with a score above 9 on the Child-Pugh scale;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

For tablets 40 mg

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

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

- myopathy;

- simultaneous administration of cyclosporine;

- in patients predisposed to the development of myotoxic complications;

- pregnancy and the period of breastfeeding;

- 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 concentration of rosuvastatin in the blood plasma;

- patients of the Mongoloid race;

- simultaneous reception of fibrates;

- age under 18 years (effectiveness and safety not established);

- patients with hepatic insufficiency with a score above 9 on the Child-Pugh scale;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully:

For tablets 5,10 and 20 mg

The presence of a risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism; personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other inhibitors of HMG-CoA reductase or fibrates; excessive use of alcohol; conditions in which there was an increase in the plasma concentration of rosuvastatin;

age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or electrolyte disorders; uncontrolled epilepsy; race (Mongoloid race); simultaneous reception of fibrates.

For tablets 40 mg

The presence of risk of myopathy / rhabdomyolysis - renal failure of low severity (CK> 60 ml / min); age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or electrolyte disorders, uncontrolled epilepsy.

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, the drug Mertenil® is not recommended for use in children under 18 years of age.

Pregnancy and lactation:

The drug Mortenil® is contraindicated for use during pregnancy and during breastfeeding.

Women of childbearing age should use reliable and adequate contraception.

Since cholesterol and cholesterol biosynthesis products are of great importance for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of its use in pregnancy.

In case of pregnancy, the drug should be stopped immediately. Data on the allocation of rosuvastatin with breast milk are absent. If it is necessary to prescribe the drug, breastfeeding should be discontinued.

Dosing and Administration:

Before starting treatment, the patient should follow a standard diet with low cholesterol foods, which should continue throughout the treatment period. Doses of the drug should be selected individually in accordance with the purpose of the treatment and the therapeutic response of the patient to the therapy, taking into account modern generally accepted recommendations on target levels of lipids. Inside, at any time of the day, regardless of food intake, do not chew and do not grind, swallow whole, squeezed water.

The recommended initial dose of the drug is 5 mg or 10 mg once a day for both patients not previously taking statins, and for patients transferred to receive this drug after treatment with other inhibitors of HMG-CoA reductase. Choosing the initial dose of the drug, you should take into account the level of cholesterol in each individual patient,as well as the possible risk of developing cardiovascular complications and the potential risk of side effects. If necessary, after 4 weeks, you can do a dose adjustment.

Due to the increased risk of side effects, a dose increase of up to 40 mg should be given only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia) who did not receive a dose of 20 mg the level of cholesterol, and which will be under medical supervision. When appointing a dose of 40 mg, a thorough observation of the doctor is recommended. Do not administer a dose of 40 mg to patients who have not previously consulted a doctor!

Side effects:

Elderly patients

The recommended initial dose for patients over 70 years is 5 mg.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not required. The recommended initial dose of the drug is 5 mg for patients with renal insufficiency of moderate severity (CC less than 60 ml / min).The administration of the drug Mertenil® in any doses is contraindicated in patients with severe renal failure (see the section "Contraindications"), Patients with moderate renal insufficiency of the medication at a dose of 40 mg is contraindicated.

Patients with hepatic insufficiency

An increase in the systemic concentration of rosuvastatin in patients with a Child-Pugh score of 7 or lower was not detected. However, an increase in systemic drug concentration was observed in patients with Child-Pugh score 8 and 9. These patients should be monitored for liver function against therapy. Data on the taking of the drug by patients with a Child-Pugh score above 9 are not available. Patients with liver diseases in the active phase, the drug Mertenil® is contraindicated.

Ethnic groups

In patients of the Mongoloid race, an increase in the systemic concentration of rosuvastatin was noted, and at recommended doses of the drug in 10-20 mg, the patients in this group had an initial dose of 5 mg of the drug Mertenil®. The use of the drug in a dose of 40 mg to such patients is contraindicated (see section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLC01B1 (OATP1B1) p.521N and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCO1B1 P.521TT and ABCG2 p.421S. For patients carrying genotypes с.521СС or с.421АА the recommended maximum dose of the drug Мертенил® is 20 mg once a day (see the section "Pharmacokinetics").

Patients who are predisposed to myopathy

At the recommended doses of the drug in 10-20 mg, patients with a predisposition to myopathy the initial dose is 5 mg.

The use of the drug in a dose of 40 mg in such patients is contraindicated.

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B and BCRP). In the joint use of the drug Mertenil® with medicinal drugs (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir), which increase the plasma concentration of rosuvastatin by interacting with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see "Specific guidance" and "Interaction with other drugs "), In such cases, the possibility of prescribing alternative therapy or temporarily stopping the drug Mertenil® should be evaluated.If the use of the above drugs is necessary, the ratio of benefit and risk of concomitant therapy with Mertenil® should be evaluated and the possibility of reducing its dose should be considered (see "Interactions with Other Drugs").

Unwanted drug reactions (HLP), observed with rosuvastatin, are usually mild and temporary. In controlled clinical trials, fewer than 4% of patients who received rosuvastatin, were excluded from the study due to the development HLP.

Based on clinical trials and extensive post-marketing experience, Table 1 below shows the NLR profile at rosuvastatin. HLP are classified by the frequency of their occurrence and by the classes of systems of organs. Frequency HLP is represented as follows: often (≥1 / 100 to <1/10); infrequently (≥1 / 1000 to <1/100); rarely (≥1 / 10000 to <1/1000); very rarely (<1/10000); frequency is unknown (can not be estimated from available data).

Table 1. Undesirable drug reactions

Class of organ system	Often		Infrequently		Rarely		Rarely		Frequency unknown
Violations of the blood and lymphatic system					Thrombocytopenia
Immune system disorders					Reactions hypersensitivity on the one hand, including angioneuroti- edema
Disorders from the endocrine system	Diabetes mellitus type 2¹
Disorders of the psyche									Depression
Disturbances from the nervous system		Headache Dizziness						Polyneuropathy Memory loss		Sleep disorders (including insomnia and "nightmarish " dreaming)
Disturbances from the respiratory system, chest and mediastinal organs										Cough Shortness of breath
Disorders from the gastrointestinal tract		Constipation Nausea Pain in stomach				Pancreatitis				Diarrhea
Disturbances from the liver and bile ducts						Increased activity of "liver" transaminases		Jaundice Hepatitis
Disturbances from the skin and subcutaneous tissues				Skin itching Rash Hives						Syndrome Stevens- Johnson
Disturbances from musculoskeletal and connective tissue		Myalgia				Myopathy (including myositis) Rhabdomyolysis		Arthralgia		Immunoopos redox necrotizing providing myopathy
Disorders from the kidneys and urinary tract								Hematuria
Violations of the genitals and mammary gland								Gynecomatia
Are common disorders and disorders at the site of administration		Asthenic syndrome								Peripheral edema
¹The frequency will depend on the presence or absence of risk factors (fasting glucose concentration> 5.6 mmol / L, BMI> 30 kg / m², elevated triglyceride concentration, history of arterial hypertension).

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

The incidence of rhabdomyolysis, marked side effects from the kidneys and liver increases in patients taking rosuvastatin 40 mg.

Disorders from the kidneys and urinary tract: when taking rosuvastatin, proteinuria, mainly of tubular origin, was observed. Changes in the protein content in the urine (from lack or presence of trace amounts to the level of ++ and higher) were detected in less than 1% of patients taking 10 and 20 mg rosuvastatin and approximately 3% of patients taking the drug at a dose of 40 mg. The minimum change in the amount of protein in the urine, expressed as a change from zero level or the presence of traces to the level +, was observed when taking the drug at a dose of 20 mg.In most cases, proteinuria decreased and passed independently during the treatment. When analyzing the data of clinical studies, there is no causal relationship between proteinuria and acute or progressive kidney disease. Hematuria was observed in a number of patients treated with rosuvastatin, but clinical studies have shown that the incidence of such cases is very low.

Disturbances from the musculoskeletal and connective tissue: the effect on skeletal muscles that causes myalgia, myopathy (including myositis) and, in rare cases, rhabdomyolysis with or without development of acute renal failure, was observed in patients taking any dose of rosuvastatin, in particular a dose above 20 mg. An increase in the activity of creatine phosphokinase (CK), depending on the dose taken, was found in patients taking rosuvastatin, but in most cases these manifestations were insignificant, asymptomatic and temporary. If the activity of CK is 5 times higher than the upper limit of the norm, then treatment should be discontinued (see section "Special instructions").

Disorders from the liver and bile ducts: as with the administration of other inhibitors of HMG-CoA reductase, an increase in the activity of "hepatic" transaminases, depending on the dose taken, was found in a small number of patients who took rosuvastatin. In most cases, this increase was moderately expressed, asymptomatic and transient. Some statins reported the following HLP:

- sexual dysfunction;

- In extremely rare cases, interstitial lung disease, especially

with prolonged use of drugs;

- tendon diseases, in some cases complicated by rupture.

Impact on laboratory and instrumental research results:

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

Overdose:

Specific treatment for overdose does not exist.

In case of an overdose, it is recommended to carry out symptomatic treatment and supportive measures. It is necessary to monitor the liver function and the degree of activity of CK.Hemodialysis in this case is probably ineffective.

Interaction:

Effect of the use of other drugs on rosuvastatin

Inhibitors of transport proteins: rosuvastatin binds to some transport proteins, in particular, to OATP1B1 and BCRP. The concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in the blood plasma and an increased risk of myopathy (see Table 2 and the sections "Dosing and Administration" and "Special instructions").

Cyclosporin: while taking rosuvastatin and cyclosporine AUC rosuvastatin increased by 7 times compared with the values obtained in healthy volunteers (see the section "Contraindications"), Joint application leads to an increase in the concentration of rosuvastatin in blood plasma by 11 times. With simultaneous administration of drugs, changes in the concentration of cyclosporine in the blood plasma were not detected.

Gemfibrozil and other drugs that reduce lipid levels: simultaneous administration of rosuvastatin and gemfibrozil leads to an increase in 2 times C_m_Oh and AUC rosuvastatin (see section "Special instructions").

Based on the data of the study of specific interactions, no corresponding pharmacokinetic interaction with fenofibrates is expected, but pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and a nicotinic acid in lipid-lowering doses (1 g or more per day) with simultaneous administration with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can cause myopathy and when taken in monotherapy. Simultaneous administration of 40 mg rosuvastatin and fibrates is contraindicated (see sections "Special instructions" and "Contraindications"). With simultaneous administration with gemfibrozil and other lipid-lowering agents, the initial dose of the drug Mertenil® should not exceed 5 mg.

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

Inhibitors of proteases: although the exact mechanism of interaction is unknown, simultaneous administration of rosuvastatin with protease inhibitors may lead to an elongation of the half-life of rosuvastatin. In a pharmacokinetic study with simultaneous administration of 20 mg rosuvastatin and a combined preparation containing two protease inhibitors (400 mg lopinavir / 100 mg ritonavir), healthy volunteers showed a 2-fold increase AUC(o-24) and 5 times the C_m_Oh rosuvastatin, respectively. Therefore, simultaneously appoint rosuvastatin and protease inhibitors in the treatment of patients with HIV are not recommended.

Antacids: simultaneous administration of rosuvastatin and antacids in a suspension containing aluminum or magnesium hydroxide, can lead to a decrease in the concentration of rosuvastatin in blood plasma by approximately 50%. This action is less pronounced if antacids are administered 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: simultaneous administration of rosuvastatin and erythromycin may lead to a decrease AUC(o-t) rosuvastatin by 20% and C_m_Oh rosuvastatin - by 30%. This relationship can be caused by increased intestinal motility caused by the intake of erythromycin.

Isozymes of cytochrome P450: results of studies in vitro and in vivo showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a rather weak substrate for these enzymes. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4), or ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4). Combined use of itraconazole (inhibitor of isoenzyme CYP3A4) and rosuvastatin increases AUC rosuvastatin by 28% (it is clinically insignificant). Therefore, any interaction of drugs associated with cytochrome P450 metabolism is not expected.

Interaction with drugs, which requires dose adjustment for rosuvastatin (see Table 2)

The dose of the drug Mertenil® should be adjusted when it is necessary to use it together with drugs that increase the exposure to rosuvastatin. If an increase in exposure is expected to be 2 times or more, the initial dose of Mertenil® should be 5 mg once daily. Also, the maximum daily dose of Mortenil® 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 the drug Mertenil® with simultaneous application with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times) /

Table 2. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are listed in descending order) - the results of published clinical studies.

Complementary therapy regimen	Mode of taking rosuvastatin	Change AUC rosuvastatin
Cyclosporine 75-200 mg 2 times a day, 6 months.	10 mg 1 time per day, 10 days	An increase of 7.1 times
Atazanavir 300 mg / ritonavir 100 mg 1 time per day, 8 days	10 mg once	Increase 3.1-fold
Lopinavir 400 mg / ritonavir 100 mg 2 times per day, 17 days	20 mg 1 time per 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
Eltrombopag 75 mg 1 time per day, 10 days	10 mg once	Increase 1.6 times
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
Dronedarone 400 mg 2 times a day.	No data	Increase by 1.4 times
Itraconazole 200 mg 1 time per day, 5 days	10 mg or 80 mg once	Increase by 1.4 times
Ezetimibe 10 mg 1 time per day, 14 days	10 mg 1 time per day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir 100 mg 2 times per 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
Rifampin 450 mg 1 time per 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

Antagonists of vitamin K: as in the case of other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both vitamin K antagonists (for example, warfarin or other coumarin anticoagulants) can lead to an increase in the international normalized ratio (MHO). Cancellation or reduction of the dose of rosuvastatin may cause a decrease MHO. In such cases, monitoring MHO.

Oral contraceptives / hormone replacement therapy:

simultaneous administration of rosuvastatin and oral contraceptives may increase AUC Ethinyl estradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma concentrations should be considered when choosing a dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy are not available, therefore, it is impossible to exclude a similar effect when using this combination. However, this combination of drugs was widely used by women during clinical trials and was well tolerated.

Other medicines: no clinically significant interaction is expected with simultaneous administration of rosuvastatin and digoxin.

Special instructions:

Renal Effects

Proteinuria, mainly of tubular origin, was noted in patients receiving high doses of the drug Mertenil®, in particular 40 mg, but in most cases it was periodic or short-term. It is shown that such proteinuria does not mean the emergence of acute or progressive disease of the existing kidney disease. The frequency of serious impairment of kidney function is increased by taking 40 mg rosuvastatin. It is recommended that kidney function be monitored during therapy with Mertenil®.

From the side of the musculoskeletal system

With the use of the drug Mertenil® in all dosages, and especially when taking the drug at a dose exceeding 20 mg, myalgia, myopathy and, in rare cases, rhabdomyolysis, were detected. Very rarely there was rhabdomyolysis with simultaneous administration of ezetimibe and inhibitors of HMG-CoA reductase. In this case, the pharmacological interaction of the drugs can not be ruled out, therefore, together with Mertenil® and ezetimibe should be used with caution (see section "Interaction with other drugs"). The incidence of rhabdomyolysis with administration of 40 mg of rosuvastatin increases.

Determination of creatine phosphokinase

Determination of the activity of CKD should not be performed after intensive physical exertion causing an increase in CK, as this may make interpretation of the results difficult. If the activity of CK is increased before the start of therapy more than 5 times higher than the upper limit of the norm, a second measurement should be made after 5-7 days. If re-measurement confirms the baseline CK score (5-fold higher than the upper limit of the norm), therapy with Mertenil® should not be started.

Before the start of therapy

The drug Mertenil®, like other inhibitors of HMG-CoA reductase, should be used with extreme caution in patients with existing risk factors for myopathy / rhabdomyolysis. Such factors include:

- kidney failure;

- hypothyroidism (for a dose of 40 mg see the section "Contraindications");

- own or family history of muscle diseases (for a dose of 40 mg see the section "Contraindications");

- presence in the anamnesis of myotoxicity on the background of taking other inhibitors of HMG-CoA reductase or fibrates (for a dose of 40 mg see the section "Contraindications");

- alcohol abuse (for a dose of 40 mg see the section "Contraindications");

- age over 65;

- conditions, accompanied by an increase in the concentration of the drug in the blood plasma (see section "Interaction with other drugs") (for a dose of 40 mg, see the section "Contraindications");

- simultaneous reception of fibrates (for a dose of 40 mg see the section "Contraindications"),

In such patients, the risk-to-benefit ratio of therapy should be assessed and clinical observation performed throughout the course of therapy.

During therapy

It is recommended that patients be informed of the need to report promptly to the doctor about cases of unexpected muscle pain, muscle weakness, or spasms, especially when combined with a malaise or fever!

In such patients, it is necessary to monitor the activity of CK. Treatment should be discontinued if the CKK activity is more than 5 times higher than the norm or if the muscle symptoms are severe and cause daily discomfort throughout the day (even if the activity of CK is 5 times lower than the upper limit of the norm). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administering Mertenil® orthe appointment of an alternative inhibitor of HMG-CoA reductase in smaller doses with careful monitoring of the patient. Regular monitoring of the activity of CK in patients with no symptoms of rhabdomyolysis 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 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.

However, an increase in the number of cases of myositis and myopathy was detected in patients, Taking other inhibitors of HMG-CoA reductase together with derivatives of fibroic acid, including gemfibrozil, ciclosporin, nicotinic acid in lipid-lowering doses, antifungal drugs, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors.Therefore, simultaneous administration of rosuvastatin and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully evaluated when rosuvastatin is combined with fibrates or nicotinic acid in lipid-lowering doses (> 1 g). Contraindicated simultaneous administration of rosuvastatin in a dose of 40 mg and fibrates (see the sections "Interaction with other drugs" and "Side effect"). The drug Mertenil® should not be prescribed to patients with acute, severe illnesses suggesting myopathy or with the possible development of secondary renal failure (for example: sepsis, hypertension, surgery, trauma, metabolic syndrome, seizures, endocrine disorders, electrolyte disorders (see section "Carefully").

Liver

Like other HMG-CoA reductase inhibitors, Mertenil® should be used with extreme caution in patients who abuse alcohol or who have a history of liver disease.

It is recommended to perform the determination of liver function indicators before and after 3 months after the start of treatment.If the activity of "hepatic" transaminases in the blood serum is 3 times higher than the upper limit of the norm, stop taking the drug or reduce the dose taken (see section "Method of administration and dose"). The frequency of serious violations of the liver (associated mainly with an increase in the activity of "liver" transaminases), increases with the intake of 40 mg of the drug.

Secondary hypercholesterolemia

In patients with secondary hypercholesterolemia due to hypothyroidism, nephrotic syndrome, therapy of the underlying disease should be performed prior to the initiation of treatment with the drug Mertenil®.

Special populations. Ethnic groups

In the course of pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin among patients of the Mongoloid race was found in comparison with the data obtained among patients - representatives of the Caucasoid race (see the section "Dosing and Administration" and "Pharmacokinetics"),

Inhibitors of proteases

Simultaneous administration of rosuvastatin with protease inhibitors is not recommended (see section

"Interaction with other drugs").

Lactose

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

Interstitial lung disease

With the use of some statins, especially for a long time, there have been reports of single cases of interstitial lung disease. Manifestations of the disease can be shortness of breath, unproductive cough and deterioration in overall health (weakness, weight loss and fever). If suspicion of interstitial lung disease should be stopped by statin therapy.

Diabetes mellitus type 2

There is evidence that statins, like a class, cause an increase in blood glucose and in some patients at high risk of diabetes in the future can provoke a level of hyperglycemia, which shows the standard treatment of diabetes mellitus. However, this risk is outweighed by a reduced risk of developing vascular complications, so there is no reason to stop treatment with statins. In patients at risk for hyperglycemia (fasting glucose from 5.6 to 6.9 mmol / L, BMI> 30 kg / m², elevated triglyceride concentration, hypertension), clinical and biochemical indicators should be monitored in accordance with national guidelines.

Effect on the ability to drive transp. cf. and fur:Studies to study the effect of the drug Mertenil® on the ability to drive a vehicle and use of technical means were not conducted. Care should be taken when driving a motor vehicle or work that requires a high concentration of attention and speed of psychomotor reactions (dizziness may occur during therapy).

Form release / dosage:

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

Packaging:

For 10 tablets, film-coated with a dosage of 5 mg, 10 mg, 20 mg and 40 mg in a contiguous cell pack of foil PA / Al / PVC and aluminum foil printed lacquer.

For 3, 6 or 9 contour packs for tablets with a dosage of 5 mg, 10 mg, 20 mg and 40 mg together with the instructions for use are placed in a pack of cardboard with the control of the first opening.

Storage conditions:

In the original packaging at a temperature of no higher than 30 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000278/10

Date of registration:25.01.2010 / 02.02.2018

Expiration Date:Unlimited

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER-RUS, CJSC Russia

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp03.05.2018

Illustrated instructions

Instructions

Mertenil® (Mertenil®)