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Composition:


active ingredient: rosuvastatin;


1 tablet contains rosuvastatin calcium 5.2 mg, 10.4 mg, 20.8 mg or 41.6 MG, which is equivalent to rosuvastatin 5 mg, 10 mg, 20 mg or 40 mg;


excipients: calcium citrate, microcrystalline cellulose, hydroxypropylcellulose, mannitol (e 421), lactose anhydrous, crospovidone, magnesium stearate;


film coating (5 mg tablets): polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, tartrazine (E 102), yellow sunset FCF (E 110), indigocarmine (E 132);


film coating (tablets of 10 mg, 20 mg, 40 mg): polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, tartrazine (E 102), special red AC (E 129), yellow sunset FCF (E 110), indigocarmine (E 132).


Dosage form. Film-coated tablets.


Basic physical and chemical properties:


5 mg tablets: round tablets with a biconvex surface, film-coated, yellow in color;


10 mg tablets: round tablets with a biconvex surface, film-coated, pink in color;


20 mg tablets: oval-shaped tablets with a biconvex surface, with a risk on one side, Film-coated, pink in color;


tablets of 40 mg: tablets of oblong shape with a biconvex surface, with a risk on one side, Film-coated, pink color.


Pharmacotherapeutic group. Lipid-lowering agents. HMG-CoA reductase inhibitors.


ATX code C10A A07.


Pharmacological properties.


Pharmacodynamics.


Mechanism of action


Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, an enzyme that determines the reaction rate and converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a cholesterol precursor. The main site of action of rosuvastatin is the liver, a target organ for lowering cholesterol levels.


Rosuvastatin increases the number of LDL receptors on the surface of liver cells, increasing LDL uptake and catabolism, and inhibits VLDL synthesis in the liver, thus reducing the total number of VLDL and LDL particles.

Clinical characteristics.


Indications.


Treatment of hypercholesterolemia


Adults, adolescents, and children over 10 years of age with primary hypercholesterolemia (Type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (Type IIb) as a supplement to the diet, when diet compliance and the use of other non-medicinal products (for example, exercise, weight loss) is insufficient.


For Homozygous Familial Hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (for example, LDL apheresis) or when such treatment is inappropriate.


Prevention of cardiovascular disorders


Prevention of significant cardiovascular disorders in patients who are estimated to be at high risk of the first case of cardiovascular disorders (see Section "pharmacodynamics"), as an adjunct to the correction of other risk factors. 


Contraindications.


Evoyd® is contraindicated:


- patients with hypersensitivity to rosuvastatin or any of the excipients of the drug;


- patients with active liver disease, including persistent increases in serum transaminases of unknown etiology and any increases in serum transaminases that are three times higher than the upper limit of normal (ULN);


- patients with severe renal impairment (creatinine clearance ;


- patients with myopathy;


- patients receiving cyclosporine at the same time;


- during pregnancy and lactation, as well as women of reproductive age who do not use appropriate contraceptives.


A dose of 40 mg is contraindicated in patients with a tendency to myopathy/rhabdomyolysis.


These risk factors include:


- moderate renal impairment (creatinine clearance


- hypothyroidism;


- the presence of a personal or family history of hereditary muscle diseases;


- a history of myotoxicity with the use of other HMG-CoA reductase inhibitors or fibrates;


- alcohol abuse;


- situations that may lead to an increase in the concentration of the drug in the blood plasma;


- belonging to the Mongoloid race;


- concomitant use of fibrates (see the sections "application features", "interactions with other drugs and other types of interactions" and "pharmacokinetics").


Interactions with other drugs and other types of interactions.


Effect of concomitant medications on rosuvastatin


Transport protein inhibitors


Rosuvastatin is a substrate of some transport proteins, including the hepatic uptake transporter OATP1B1 and the eflux transporter BCRP. Concomitant use of Evoyd® with drugs that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "dosage and administration", "application features", "interaction with other drugs and other types of interactions", Table 2).


Cyclosporine


During the period of concomitant use of Evoid® and cyclosporine, the AUC values of rosuvastatin were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Evoyd® is contraindicated in patients receiving cyclosporine at the same time (see the section "contraindications").


Concomitant administration did not affect the concentration of cyclosporine in blood plasma.


Protease inhibitors


Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors can significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant use of 10 mg of rosuvastatin and a combination drug containing two protease inhibitors (300 mg of atazanavir/100 mg of ritonavir) in healthy volunteers was accompanied by an increase in the AUC and Cmax of rosuvastatin by approximately 3 and 7 times, respectively. Concomitant use of Evoyd® and some combinations of protease inhibitors is possible after careful analysis of the need for dose adjustment of Evoyd®, taking into account the expected increase in rosuvastatin exposure (see sections "dosage and administration", "application features", "interaction with other drugs and other types of interactions", Table 2).


Gemfibrozil and other lipid lowering agents


Concomitant use of Evoyd® and gemfibrozil resulted in a 2-fold increase in the AUC and Cmax of rosuvastatin (see the section "application features").


Based on the data of Special Studies, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (≥1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when co-administered with HMG-CoA reductase inhibitors, probably due to the fact that they can cause myopathy when used alone. A dose of 40 mg is contraindicated with concomitant use of fibrates (see the sections "contraindications" and "application features"). Such patients should also start therapy with a dose of 5 mg.


Ezetimibe


Concomitant use of Evoid® at a dose of 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia resulted in a 1.2-fold increase in the AUC of rosuvastatin (Table 2). Pharmacodynamic interactions between Evoyd® and ezetimibe cannot be excluded, which may lead to adverse events (see the section "application features").


Antacids


Concomitant use of Evoyd® with antacid suspensions containing aluminum or magnesium hydroxide reduced the concentration of brosuvastatin in blood plasma by approximately 50%. This effect was less pronounced when using antacids 2 hours after Evoyd®. The clinical significance of this interaction has not been studied.


Erythromycin


Concomitant use of Evoid® and erythromycin reduced the AUC of rosuvastatin by 20 %, and Cmax – by 30 %. This interaction may be caused by increased intestinal motility due to the action of erythromycin.

Application features.


Effects on the kidneys


Proteinuria, which was detected as a result of analysis on test strips and which was mainly of tubular origin, was observed in patients treated with high doses of rosuvastatin, in particular 40 mg, and in most cases was temporary or intermittent. Proteinuria was not a harbinger of acute or progressive kidney disease (see Section "adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with a dose of 40 mg. In patients taking the drug at a dose of 40 mg, renal function should be regularly checked during follow-up.


Effects on skeletal muscles


Skeletal muscle disorders, such as myalgia, myopathy, and occasionally rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, especially more than 20 mg. Isolated cases of rhabdomyolysis have been reported with ezetimibe in combination with HMG-CoA reductase inhibitors. The possibility of pharmacodynamic interactions cannot be excluded (see the section "interactions with other drugs and other types of interactions"), and therefore this combination should be used with caution. 


As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis associated with rosuvastatin was higher in the post-marketing period at a dose of 40 mg. Rare cases of immuno-mediated necrotizing myopathy, clinically manifested by persistent proximal muscle weakness and elevated serum creatine kinase levels, have been reported during treatment or after discontinuation of statin treatment, including rosuvastatin. In this case, additional neuromuscular and serological studies, treatment with immunosuppressive drugs may be necessary.


Creatine kinase levels


Creatine kinase (CC) levels should not be measured after significant physical activity or in the presence of other probable causes of increased CC that may complicate the interpretation of the results. If baseline CC levels are significantly elevated (>5 times higher than ULN), a second analysis should be performed within 5-7 days to confirm the results. If the results of repeated analysis confirm that the initial value of CC is more than 5 times higher than VNM, the use of the drug should not be started.


Before starting treatment


Evoyd®, like other HMG-CoA reductase inhibitors, should be used with caution in patients with a tendency to myopathy/rhabdomyolysis. These risk factors include:


- impaired renal function;


- hypothyroidism;


- the presence of a personal or family history of hereditary muscle diseases;


- a history of myotoxicity with the use of other HMG-CoA reductase inhibitors or fibrates;


- alcohol abuse;


- age > 70 years;


- situations that may lead to an increase in plasma levels of the drug (see the sections "dosage and administration", "interactions with other drugs and other types of interactions" and "pharmacokinetics");


- concomitant use of fibrates.


In such patients, the treatment-related risk should be evaluated in comparison with the expected benefit; clinical monitoring is also recommended. If baseline CC levels are significantly elevated (>5 times higher than ULN), treatment should not be initiated.


During the treatment period


Patients should be asked to report muscle pain, weakness, or seizures of unknown etiology immediately, especially if they are accompanied by malaise or fever. In such patients, CC levels should be measured. The drug should be discontinued if the CC level is significantly elevated (>5 times higher than the ULN) or if muscle symptoms are severe and cause daily discomfort (even if the CC level is ≤ 5 ULN). If symptoms disappear and the CC level returns to normal, therapy with Evoyd® or an alternative HMG-CoA reductase inhibitor can be resumed at the lowest dose and under close supervision. There is no need to regularly check CC levels in asymptomatic patients. Very rarely, cases of immuno-mediated necrotizing myopathy (IONM) have been reported during or after statin therapy, including rosuvastatin. Clinical manifestations of IONM include weakness of the proximal muscles and increased serum creatine kinase levels, which persists even after discontinuation of statins.


In clinical studies, there was no evidence of an increased effect on skeletal muscle in a small number of patients taking rosuvastatin and concomitant medications. However, an increase in the incidence of myositis and myopathy was observed in patients taking other HMG-CoA reductase inhibitors together with fibroic acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungal drugs, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when co-administered with certain HMG-CoA reductase inhibitors. Therefore, it is not recommended to use Evoyd® in combination with gemfibrozil. The benefits of further changes in lipid levels when using Evoyd® in combination with fibrates or niacin should be carefully weighed against the potential risks associated with the use of such combinations. A dose of 40 mg is contraindicated with concomitant use of fibrates (see the sections "interactions with other drugs and other types of interactions" and "adverse reactions").


Evoyd® should not be used in patients with acute, serious conditions that indicate myopathy or the possibility of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, significant surgery, trauma, severe metabolic, endocrine and electrolyte disorders, or uncontrolled seizures).


Effects on the liver


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


It is recommended to check the biochemical parameters of liver function before starting treatment and 3 months later. The use of Evoyd® should be discontinued or the dose reduced if the level of transaminases in the serum is more than three times higher than the upper limit of normal. The frequency of reports of serious liver events (mainly increased levels of liver transaminases) in the post-marketing period was higher with a dose of 40 mg.


In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should first be treated before starting therapy with Evoyd®.


In the post-marketing period, fatal or non-fatal cases of hepatic insufficiency have occasionally been reported in patients taking statins, including rosuvastatin. If serious liver damage with clinical symptoms and/or hyperbilirubinemia or jaundice develops during treatment with Evoyd®, the drug should be discontinued immediately. If no other causes are found, do not resume treatment with Evoyd®.


Race


Pharmacokinetic studies show an increase in exposure in patients of the Mongoloid race by about half compared to Europeans. For such patients, it is necessary to adjust the dosage of Evoyd® (see the sections "dosage and administration", "contraindications" and "pharmacokinetics"). For patients of the Mongoloid race, the initial dose of Evoidu® is 5 mg. Elevated plasma concentrations of rosuvastatin were observed in Asian patients (see Section "application features" and "pharmacokinetics"). Increased systemic exposure should be taken into account in the treatment of Mongoloid patients in whom hypercholesterolemia is not adequately controlled at doses up to 20 mg.


Protease inhibitors


Increased systemic exposure to rosuvastatin was observed in individuals who used rosuvastatin in combination with various protease inhibitors in combination with ritonavir. Consideration should be given to both the benefits of reducing lipid levels with Evoyd® in patients with HIV receiving protease inhibitors, and the possibility of increasing the concentration of rosuvastatin in blood plasma at the beginning of therapy and when increasing the dose of Evoyd® in patients receiving protease inhibitors. Concomitant use of the drug with protease inhibitors is not recommended if the dose of Evoidu® has not been adjusted (see below). (see "dosage and Administration" and "interactions with other drugs and other types of interactions").


Lactose intolerance


Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not use this medication.


Interstitial lung disease


Exceptional cases of interstitial lung disease have been reported during the use of certain statins, especially with long-term treatment (see Section "adverse reactions"). Symptoms of this condition include shortness of breath, an unproductive cough, and general deterioration (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statins should be discontinued.


Diabetes mellitus

Some evidence suggests that statins increase blood glucose levels and, in some patients at high risk of developing diabetes in the future, may cause hyperglycemia at a level where proper diabetes treatment is necessary. This threat, however, outweighs the reduction in the risk of vascular disorders when using statins, and therefore it should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose level 5.6 – 6.0 mmol/L, BMI >30 kg/m2, elevated triglyceride levels, arterial hypertension) should be monitored both clinically and biochemically in accordance with national guidelines.


As with other HMG-CoA reductase inhibitors, rosuvastatin increased HbA1c and serum glucose levels. In some cases, these indicators may exceed the limit value for the diagnosis of diabetes mellitus, especially in patients at high risk of developing diabetes.


Rosuvastatin as monotherapy does not cause a decrease in the baseline concentration of cortisol in blood plasma and does not affect the reserve of the adrenal glands. Caution should be exercised when using Evoid® and other medications that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine at the same time.


Children


Estimates of linear height (height), body weight, BMI (body mass index), and secondary characteristics of puberty according to Tanner in children aged 10 to 17 years who took rosuvastatin are limited to a period of 1 year. After 52 weeks of the study treatment, no effect on height, body weight, BMI, or puberty was found (See section "pharmacodynamics"). Experience in clinical trials of the drug in children and adolescents is limited, and the long-term effect of rosuvastatin (>1 year) on puberty is unknown.


In a clinical study in children and adolescents who took rosuvastatin for 52 weeks, an increase in CC >10 times higher than VNM and muscle symptoms after exercise or increased physical activity were observed more often compared to those in adults (see Section "adverse reactions").


Use during pregnancy or lactation.


Evoyd® is contraindicated during pregnancy and lactation.


Women of reproductive age should use appropriate contraceptives.


Since cholesterol and other products of cholesterol biosynthesis play a significant role in fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefit of using the drug during pregnancy. Data from animal studies on toxic effects on reproductive function are limited. If the patient becomes pregnant while using this medication, treatment should be stopped immediately.


Since another drug in this class enters human breast milk and given that HMG-CoA reductase inhibitors can cause serious adverse reactions in infants, women who need treatment with Evoyd® should be advised to refrain from breastfeeding. There are no data on the penetration of the drug into human breast milk (see the section "contraindications").


Ability to influence the reaction rate when driving vehicles or other mechanisms.


Studies of the effect of Evoyd® on the ability to drive a car and work with other mechanisms have not been conducted. However, given the pharmacodynamic properties of the drug, it is unlikely that Evoyd® will affect this ability. When driving vehicles or working with other mechanisms, the possibility of dizziness during treatment should be taken into account.


Dosage and administration.


Before starting treatment, the patient should be prescribed a standard hypocholesterolemic diet, which he should follow throughout treatment. The dose should be selected individually, depending on the purpose of therapy and the patient's response to treatment, according to the recommendations of current generally accepted guidelines.


Evoyd® can be taken at any time of the day, regardless of food intake.


Treatment of hypercholesterolemia


The recommended starting dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those who have been transferred to a drug with another HMG-CoA reductase inhibitor. When choosing the initial dose, you should take into account the cholesterol levels in each individual patient and the risk of cardiovascular disorders in the future, as well as the likelihood of adverse reactions. If necessary, you can increase the dose to the next level after 4 weeks (see the section "pharmacodynamics"). Due to the fact that against the background of using the drug at a dose of 40 mg, adverse reactions occur more often than at lower doses (see the section "adverse reactions"), it is necessary to finally titrate the dose to 40 mg only in patients with severe hypercholesterolemia and a high risk of cardiovascular disorders (in particular, patients with familial hypercholesterolemia). At the beginning of taking the drug at a dose of 40 mg, specialist supervision is recommended.


Prevention of disorders of the cardiovascular system


In a study to reduce the risk of cardiovascular disorders, the drug was used at a dose of 20 mg per day (see the section "pharmacodynamics").


Elderly patients


The recommended starting dose for patients > 70 years of age is 5 mg (see the section "special instructions for use"). No other age-related dose adjustment is required.


Patients with renal insufficiency


Patients with mild to moderate renal impairment do not need to adjust the dose.


Recommended starting dose for patients with moderate renal impairment (creatinine clearance in patients with severe renal impairment is contraindicated in all doses (see sections "contraindications" and "pharmacokinetics").


Patients with impaired liver function


No increase in systemic exposure to rosuvastatin was observed in patients with impaired liver function rated at 7 or less on the Child–Pugh scale. However, in individuals with disorders of 8 and 9 points on the Child–Pugh scale, systemic exposure increased (see the section "pharmacokinetics"). In such patients, it is advisable to assess renal function (see the section "application features"). There is no experience of using the drug in patients who scored more than 9 points on the Child–Pugh scale. Evoyd® is contraindicated in patients with active liver diseases (see the section "contraindications").


Race


In patients of the Mongoloid race, increased systemic exposure of the drug was observed (see the sections "contraindications", "application features" and "pharmacokinetics"). The recommended starting dose for patients of Asian origin is 5 mg; a dose of 40 mg is contraindicated in such patients.


Genetic polymorphism


Certain types of genetic polymorphism can lead to increased exposure to rosuvastatin (see Section "pharmacokinetics"). Patients with known presence of these types of polymorphism are recommended to use a lower daily dose of Evoyd®.


Patients with a tendency to develop myopathy


The recommended starting dose for patients with risk factors for myopathy is 5 mg (see the section "special instructions for use").


A dose of 40 mg is contraindicated in some of these patients (see the section "contraindications").


Simultaneous use


Rosuvastatin is a substrate of various transport proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases with the simultaneous use of Evoidu® with certain drugs that may increase the concentration of rosuvastatin in plasma due to interaction with these transport proteins (for example, cyclosporine and certain protease inhibitors, including combinations of ritonavir with atazanavir, lopinavir and/or tipranavir; see the sections "application features" and "interactions with other drugs and other types of interactions"). If possible, the use of alternative medications should be considered and, if necessary, therapy with Evoyd®should be temporarily interrupted. If concomitant use of these drugs with Evoid® cannot be avoided, the benefits and risks associated with concomitant use should be carefully weighed and the dose of Evoid® adjusted accordingly (see the section "interactions with other drugs and other types of interactions").


Children.


The use of the drug in children should be carried out only by a specialist.


It is used in children and adolescents aged 10 to 17 years (boys at the stage of development II and above Tanner and girls who started menstruating at least a year ago).


The usual starting daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg per day. The drug is usually taken orally in doses from 5 mg to 20 mg once a day. Increase the dose should be in accordance with the individual response of the child to treatment and tolerability of the drug, following the recommendations for the treatment of children (see the section "features of use"). Before starting rosuvastatin therapy, children and adolescents should be prescribed a standard hypocholesterolemic diet, which patients should follow throughout treatment. The safety and efficacy of the drug at doses greater than 20 mg in this population have not been studied.


Tablets of 40 mg are not used in children.


Children under 10 years of age


Experience in treating children under 10 years of age is limited to using the drug in a small number of patients (aged 8 to 10 years) with homozygous familial hypercholesterolemia. Thus, Evoyd® is not recommended for use in children under 10 years of age.


Overdose.


There is no specific treatment for overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be taken if necessary. Liver function and CC levels should be monitored. The effectiveness of hemodialysis is unlikely.

Tags: Rosuvastatin