Evoid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EVOID® (AVOID)

Composition:

Active substance: rosuvastatin;

One tablet contains rosuvastatin calcium 5.2 mg, 10.4 mg, 20.8 mg, or 41.6 mg, equivalent to rosuvastatin 5 mg, 10 mg, 20 mg, or 40 mg;

Excipients: calcium citrate, microcrystalline cellulose, hydroxypropylcellulose, mannite (E 421), lactose, crospovidone, magnesium stearate;

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

Film coating (10 mg, 20 mg, 40 mg tablets): polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, tartrazine (E 102), ponceau 4R (E 129), sunset yellow FCF (E 110), indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: yellow, round, biconvex, film-coated tablets;

10 mg tablets: pink, round, biconvex, film-coated tablets;

20 mg tablets: pink, oval, biconvex, film-coated tablets with a score line on one side;

40 mg tablets: pink, elongated, biconvex, film-coated tablets with a score line on one side.

Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors.

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the rate-limiting step that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for reducing cholesterol levels.

Rosuvastatin increases the number of LDL receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL cholesterol, total cholesterol, and triglycerides, and increases HDL cholesterol levels. It also reduces levels of apolipoprotein B, non-HDL-C, LDL-C, triglyceride-rich VLDL, and increases apolipoprotein A-I levels (Table 1). Evoyd® also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean percentage change from baseline)

Dose	N	LDL-C	Total Cholesterol	HDL-C	Triglycerides	Non-HDL-C	apoB	apoA-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

The therapeutic effect is achieved within 1 week after initiation of the drug, with 90% of the maximum effect reached within 2 weeks. The maximum effect is usually achieved within 4 weeks and persists thereafter.

Clinical efficacy and safety

Rosuvastatin is effective in the treatment of adults with hypercholesterolemia—with or without hypertriglyceridemia—regardless of race, sex, or age, as well as in patients from special groups such as those with diabetes or familial hypercholesterolemia.

Based on pooled study data, rosuvastatin effectively reduces cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C level approximately 4.8 mmol/L) to target values established by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80% of patients receiving rosuvastatin 10 mg achieve EAS-recommended target LDL-C levels (<3 mmol/L).

Favorable effects of rosuvastatin on lipid parameters and achievement of target levels in patients with heterozygous familial hypercholesterolemia are observed at doses of 20–80 mg. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C is reduced by 53%. Target EAS LDL-C levels (<3 mmol/L) were achieved in 33% of patients.

In the general population of patients with homozygous familial hypercholesterolemia, rosuvastatin at doses of 20–40 mg reduces LDL-C levels by an average of 22%.

An additive effect of rosuvastatin on triglyceride reduction is observed when used in combination with fenofibrate, and on HDL-C elevation when used in combination with niacin (see section "Special precautions").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score <10% over 10 years), a mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness [CIMT]) were randomized into two groups and received either 40 mg of rosuvastatin or placebo once daily for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95% confidence interval: -0.0196, -0.0093; p<0.0001]. The change from baseline was -0.0014 mm/year (-0.12%/year (statistically non-significant)) in the rosuvastatin group compared to progression of +0.0131 mm/year (1.12%/year (p<0.0001)) in the placebo group. A direct correlation between CIMT reduction and reduced risk of cardiovascular events has not been demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who are not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should be prescribed only to patients with severe hypercholesterolemia and high cardiovascular risk (see section "Dosage and administration").

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular diseases was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to receive either placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean of 2 years.

LDL-C concentrations decreased by 45% (p<0.001) in the rosuvastatin group compared to the placebo group.

In a post-hoc analysis of a high-risk subgroup with baseline Framingham risk score >20% (1558 participants), a significant reduction in the incidence of the composite endpoint including cardiovascular death, stroke, and myocardial infarction was observed in the rosuvastatin group compared to placebo (p=0.028). The absolute risk reduction was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc analysis of another high-risk subgroup (9302 participants overall) with baseline SCORE ≥5% (extrapolated to include participants over 65 years), a significant reduction in the composite endpoint including cardiovascular death, stroke, and myocardial infarction was observed in the rosuvastatin group compared to placebo (p=0.0003). The absolute risk reduction expressed as event rate was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p=0.076).

In the JUPITER trial, 6.6% of participants in the rosuvastatin group and 6.2% in the placebo group discontinued the study drug due to adverse events. The most common adverse events leading to discontinuation were myalgia (0.3% in the rosuvastatin group, 0.2% in placebo), abdominal pain (0.03% in the rosuvastatin group, 0.02% in placebo), and rash (0.02% in the rosuvastatin group, 0.03% in placebo). The most common adverse events observed in the rosuvastatin group with a frequency greater than or equal to that in the placebo group were urinary tract infections (8.7% in rosuvastatin, 8.6% in placebo), nasopharyngitis (7.6% in rosuvastatin, 7.2% in placebo), back pain (7.6% in rosuvastatin, 6.9% in placebo), and myalgia (7.6% in rosuvastatin, 6.6% in placebo).

Children

In a double-blind, randomized, multicenter, placebo-controlled 12-week study (n=176, 97 male and 79 female participants) followed by a 40-week open-label dose titration period (n=173, 96 male and 77 female participants), patients aged 10–17 years (Tanner stages II–IV, girls with at least 1 year since menarche) with heterozygous familial hypercholesterolemia received rosuvastatin 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At study initiation, approximately 30% of patients were aged 10–13 years, and approximately 17%, 18%, 40%, and 25% were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0% in the rosuvastatin 5, 10, and 20 mg groups, respectively, compared to 0.7% in the placebo group.

At the end of the 40-week open-label dose titration period aimed at achieving target levels (maximum dose 20 mg once daily), target LDL-C levels <2.8 mmol/L were achieved in 70 of 173 patients (40.5%).

After 52 weeks of investigational treatment, no effect on growth, weight, BMI, or sexual maturation was observed (see section "Special precautions"). Clinical trial experience in children and adolescents is limited, and the long-term effects of rosuvastatin (>1 year) on sexual maturation are unknown. This study (n=176) is not suitable for comparing rare adverse events.

Rosuvastatin was also studied in a two-year open-label trial with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage <II–V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n=64) were titrated up to a maximum of 10 mg once daily, and patients aged 10 to 17 years (n=134) up to a maximum of 20 mg once daily.

After 24 months of rosuvastatin treatment, the least-squares mean reduction in LDL-C from baseline was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least-squares mean reduction in LDL-C from baseline was -43% (baseline: 234 mg/dL, month 24: 124 mg/dL), -45% (baseline: 234 mg/dL, month 24: 124 mg/dL), and -35% (baseline: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to <10, 10 to <14, and 14 to <18 years, respectively.

Treatment with rosuvastatin at doses of 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, apoB, and apoB/apoA-1. Each of these changes demonstrated improved lipid responses and was maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special precautions").

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, rosuvastatin 20 mg once daily was compared to placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase with diet, during which patients were treated with rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis continued these treatments throughout the study.

A statistically significant (p=0.005) reduction in LDL-C levels (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of rosuvastatin 20 mg treatment compared to placebo. Statistically significant reductions were also observed in total cholesterol (20.1%, p=0.003), non-HDL-C (22.9%, p=0.003), and apoB (17.1%, p=0.024). Reductions in TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of rosuvastatin 20 mg compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg followed by 6 weeks of placebo was maintained over 12 weeks of continuous therapy. One patient showed further reductions in LDL-C (8.0%), total cholesterol (6.7%), and non-HDL-C (7.4%) after 6 weeks of treatment with dose titration to 40 mg.

During continued open-label treatment with rosuvastatin 20 mg in 9 of these patients up to 90 weeks, LDL-C reduction was maintained between -12.1% and -21.3%.

In an open-label dose escalation study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0%), total cholesterol (19.2%), and non-HDL-C (21.0%) from baseline after 6 weeks of rosuvastatin 20 mg treatment corresponded to that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived the obligation to submit results of rosuvastatin studies in all subgroups of children with homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and for prevention of cardiovascular disorders (see section "Dosage and administration" for information on pediatric use).

Pharmacokinetics

Absorption

The maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is significantly taken up by the liver, the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 2C19, 3A4, and 2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin; the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The mean geometric value of plasma clearance is approximately 50 L/h (coefficient of variation: 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C, which plays an important role in hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with repeated daily administration.

Special patient groups

Age and sex

There is no clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia are similar to those in adult volunteers (see section "Children").

Race

Pharmacokinetic studies have shown that median AUC and Cmax values in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) are approximately twice as high as in Caucasians; in Indians, median AUC and Cmax values are approximately 1.3 times higher. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Negroid patients.

Renal impairment

In a study involving patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in individuals with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and N-desmethyl metabolite levels were 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.

Hepatic impairment

In a study involving patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in patients scoring 7 or less on the Child-Pugh scale. However, in two patients scoring 8 and 9 on the Child-Pugh scale, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients scoring more than 9 on the Child-Pugh scale is lacking.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. With specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA, rosuvastatin exposure (AUC) is increased compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Routine genotyping is not required in clinical practice, but patients with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 years (total of 214 patients) showed that drug exposure in children was lower or similar to that in adult patients. Rosuvastatin exposure was predictable according to dose and duration of administration over more than 2 years of observation.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

For adults, adolescents, and children aged 6 years and older with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb), as an adjunct to diet, when dietary measures and other non-pharmacological interventions (e.g., physical exercise, weight reduction) are insufficient.

For adults, adolescents, and children aged 6 years and older with homozygous familial hypercholesterolemia, as an adjunct to diet and other lipid-lowering treatments (e.g., LDL apheresis), or when such treatment is inappropriate.

Prevention of cardiovascular disorders

Prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see section "Pharmacodynamics"), as an adjunct to correction of other risk factors.

Contraindications.

Evoide® is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of the medicinal product;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology, and any increases in serum transaminases that are three times or more above the upper limit of normal (ULN);
• in patients with severe renal impairment (creatinine clearance <30 mL/min);
• in patients with myopathy;
• in patients concurrently receiving the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• in patients concurrently receiving cyclosporine;
• during pregnancy or breastfeeding, and in women of childbearing potential who are not using appropriate contraceptive measures.

The 40 mg dose is contraindicated in patients with a predisposition to myopathy/rhabdomyolysis.

Factors contributing to this risk include:

• moderate renal impairment (creatinine clearance <60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• conditions that may lead to increased plasma concentration of the medicinal product;
• Mongoloid race;
• concomitant use of fibrates.

(See sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics").

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant medicinal products on rosuvastatin

Inhibitors of transporter proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of Evoide® with medicinal products that inhibit these transporter proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other forms of interaction", Table 2).

Cyclosporine

During concomitant use of Evoide® and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Evoide® is contraindicated in patients who are concurrently receiving cyclosporine (see section "Contraindications").

Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of Evoide® with certain protease inhibitor combinations may be possible after careful assessment of the need for dose adjustment of Evoide®, considering the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other forms of interaction", Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant use of Evoide® and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special precautions").

Based on data from specific 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 used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used individually. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions"). Such patients should also start therapy with a 5 mg dose.

Ezetimibe

Concomitant use of Evoide® 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between Evoide® and ezetimibe, potentially leading to adverse effects, cannot be excluded (see section "Special precautions").

Antacid medicinal products

Concomitant use of Evoide® with suspensions of antacids containing aluminium hydroxide or magnesium hydroxide reduced rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after Evoide®. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of Evoide® and erythromycin reduced rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to enhanced intestinal motility caused by erythromycin.

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Additionally, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2)

When use of Evoide® with other medicinal products capable of increasing rosuvastatin exposure is necessary, the dose of Evoide® should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) is expected, Evoide® therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of Evoide® should be adjusted so that the expected rosuvastatin exposure does not exceed the exposure observed with a 40 mg/day dose without interacting medicinal products; for example, when used with gemfibrozil, the Evoide® dose would be 20 mg (exposure increased 1.9-fold), when used with ritonavir/atazanavir combination – 10 mg (exposure increased 3.1-fold).

If the medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the Evoide® dose above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

(AUC; in descending order of magnitude) based on published data from clinical studies

Dosing regimen of the interacting medicinal product	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + voxilaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4-fold
Ciclosporin from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Obitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2-fold
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increase in rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting medicinal product	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Eltrombopag 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-fold
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5-fold
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4-fold
Dronedarone 400 mg twice daily	Unknown	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Decrease in rosuvastatin AUC
Dosing regimen of the interacting medicinal product	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baykaline 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

* Data presented as fold change represent the ratio between rosuvastatin used in combination and rosuvastatin used alone. Data presented as % change represent the % difference relative to rosuvastatin administered alone.

Increases are indicated by ↑, decreases by ↓.

** Several interaction studies were conducted at different rosuvastatin doses; the table presents the most significant ratio.

Medicinal products/combinations that had no clinically significant effect on rosuvastatin AUC ratio when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg three times daily for 7 days; fluconazole 200 mg once daily for 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; ketoconazole 200 mg twice daily for 7 days; rifampicin 450 mg once daily for 7 days; silymarin 140 mg three times daily for 5 days.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of EVOID® or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation of EVOID® or dose reduction may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of EVOID® and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, respectively. This increase should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients receiving EVOID® and HRT simultaneously; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products

Digoxin

According to specific interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) has not yet been established. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

In patients for whom systemic use of fusidic acid is considered necessary, treatment with EVOID® should be discontinued for the entire duration of fusidic acid therapy. See also section "Special precautions for use".

Paediatric population

Interaction studies have been conducted only in adults. The extent of interaction in children is unknown.

Special precautions for use.

Renal effects

Proteinuria detected by urine dipstick testing, predominantly of tubular origin, has been observed in patients treated with high doses of rosuvastatin, particularly 40 mg, and in most cases was transient or intermittent. Proteinuria was not a predictor 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 the 40 mg dose. In patients receiving the 40 mg dose, renal function should be monitored regularly during follow-up.

Skeletal muscle effects

Adverse events affecting skeletal muscle, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rare cases of rhabdomyolysis have been reported with ezetimibe used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), and therefore such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the frequency of post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher at the 40 mg dose.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured following significant physical exertion or in the presence of other likely causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (>5 times the upper limit of normal [ULN]), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK levels exceed 5 times the ULN, treatment with rosuvastatin should not be initiated.

Before starting treatment

Evoide®, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age >70 years;
• conditions that may lead to increased plasma levels of the drug (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

In such patients, the treatment-related risk should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are markedly elevated (>5 times ULN), treatment should not be initiated.

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The medicinal product should be discontinued if CK levels are markedly elevated (>5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤5 ULN). After symptoms resolve and CK levels return to normal, therapy with Evoide® or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close monitoring. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin. Clinical features of IMNM include proximal muscle weakness and persistently elevated serum creatine kinase levels, even after discontinuation of statins.

Clinical trials have not provided evidence of increased skeletal muscle effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the concomitant use of Evoide® with gemfibrozil is not recommended. The benefit of further lipid-lowering with Evoide® in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Evoide® should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving fusidic acid in combination with statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is required, e.g., for the treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered only on a case-by-case basis and under close medical supervision.

Evoide® should not be used in patients with acute, serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Hepatic effects

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

It is recommended to assess liver function biochemistry before starting treatment and again after 3 months. Treatment with Evoide® should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating therapy with Evoide®.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in patients of Mongoloid race compared to Caucasians (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics").

Protease inhibitors

Increased systemic exposure of rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with Evoide® in HIV patients receiving protease inhibitors and the potential for increased plasma concentration of rosuvastatin at the initiation of therapy and with dose escalation of Evoide® in patients receiving protease inhibitors should be considered. Concomitant use of the product with protease inhibitors is not recommended unless the dose of Evoide® is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Lactose intolerance

This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Patients with known sugar intolerances should consult their physician before taking this medicinal product.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported during treatment with some statins, particularly with long-term use (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

There is evidence that statins increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, the reduction in vascular risk with statin therapy outweighs this risk, and therefore it should not be a reason for discontinuing statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER study, the overall incidence of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

Myasthenia gravis / ocular myasthenia

In isolated cases, statins have been reported to induce de novo or exacerbate existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, Evoide® should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics according to Tanner in children aged 6 to 17 years treated with rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics").

In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CK elevations >10 times ULN and muscle symptoms following physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

This medicinal product contains the excipients tartrazine (E 102) and sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Evoide® is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis play a crucial role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any benefit from using the medicinal product during pregnancy. Animal reproductive toxicity data are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be stopped immediately.

Rosuvastatin crosses into rat milk. There are no data on the excretion of the medicinal product into human breast milk (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of Evoide® on the ability to drive vehicles or operate machinery have not been conducted. However, given the pharmacodynamic properties of the medicinal product, it is unlikely that Evoide® will affect such ability. When driving vehicles or operating machinery, the possibility of dizziness during treatment should be considered.

Method of Administration and Dosage.

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which must be maintained throughout the treatment period. The dosage should be individually adjusted according to therapeutic goals and the patient's response to treatment, in accordance with current accepted guidelines.

The medicinal product Evoid® can be taken at any time of day, regardless of food intake.

Treatment of Hypercholesterolemia

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those switching from another HMG-CoA reductase inhibitor. The choice of initial dose should take into account individual patient cholesterol levels, future cardiovascular risk, and the likelihood of developing adverse reactions. If necessary, the dose may be increased to the next level after 4 weeks (see section "Pharmacodynamics"). Since adverse reactions occur more frequently with the 40 mg dose than with lower doses (see section "Adverse Reactions"), dose titration up to the maximum dose of 40 mg should be reserved only for patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia), in whom treatment goals have not been achieved with a 20 mg dose and who will be under regular monitoring (see section "Special Warnings and Precautions for Use"). Specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Disorders

In a study on reducing the risk of cardiovascular events, the medicinal product was administered at a dose of 20 mg once daily (see section "Pharmacodynamics").

Elderly Patients

The recommended initial dose for patients aged >70 years is 5 mg (see section "Special Warnings and Precautions for Use"). No other dose adjustment based on age is required.

Patients with Renal Impairment

No dose adjustment is required for patients with mild or moderate renal impairment.

The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of Evoid® in patients with severe renal impairment is contraindicated at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic impairment scoring 7 or less on the Child–Pugh scale. However, systemic exposure increased in individuals scoring 8 or 9 on the Child–Pugh scale (see section "Pharmacokinetics"). Renal function assessment is advisable in such patients (see section "Special Warnings and Precautions for Use"). Experience with the medicinal product in patients scoring more than 9 on the Child–Pugh scale is lacking. Evoid® is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the drug has been observed in patients of Mongoloid race (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). The recommended initial dose for patients of Mongoloid race is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphism types should be prescribed a lower daily dose of Evoid®.

Patients Predisposed to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg (see section "Special Warnings and Precautions for Use").

The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Concomitant Use

Rosuvastatin is a substrate of several transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Evoid® is co-administered with certain medicinal products that may increase rosuvastatin plasma concentrations due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir, and/or tipranavir; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Alternative treatments should be considered whenever possible, and temporary interruption of Evoid® therapy may be necessary. If concomitant use of these medicinal products with Evoid® cannot be avoided, the benefit and risk of concomitant therapy should be carefully weighed, and the Evoid® dose should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

Administration of the medicinal product to children should be performed only by a specialist.

Children and Adolescents Aged 6 to 17 Years (Tanner Stage ˂II-V).

Heterozygous Familial Hypercholesterolemia

The usual initial daily dose for children and adolescents with heterozygous familial hypercholesterolemia is 5 mg once daily.

• The usual dose for children aged 6 to 9 years with heterozygous familial hypercholesterolemia is 5 mg to 10 mg orally once daily. The safety and efficacy of doses exceeding 10 mg in this population have not been studied.
• The usual dose for children aged 10 to 17 years with heterozygous familial hypercholesterolemia is 5 mg to 20 mg orally once daily. The safety and efficacy of doses exceeding 20 mg in this population have not been studied.

The dose should be increased according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which must be maintained throughout treatment.

Homoyzgous Familial Hypercholesterolemia

The recommended maximum dose for children aged 6 to 17 years with homozygous familial hypercholesterolemia is 20 mg once daily.

The recommended initial dose is 5 mg to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation to the maximum dose of 20 mg once daily should be based on the individual child's response to treatment and drug tolerability, in accordance with pediatric treatment recommendations (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which must be maintained throughout treatment.

Experience with doses exceeding 20 mg in this population is limited.

40 mg tablets should not be used in children.

Children Under 6 Years of Age

The safety and efficacy of the medicinal product in children under 6 years of age have not been established. Therefore, Evoid® is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote for overdose. In case of overdose, symptomatic treatment should be administered and supportive measures taken as necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions.

Adverse events observed during rosuvastatin use are generally mild and transient.

Table 3 presents the adverse reaction profile of rosuvastatin based on clinical trials and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ classes.

According to frequency, adverse reactions are categorized as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Table 3

Adverse reactions based on clinical trial data and post-marketing experience

System organ class	Common	Uncommon	Rare	Very rare	Frequency not known
Blood and lymphatic system disorders			Thrombocytopenia
Immune system disorders			Hypersensitivity reactions, including angioneurotic edema
Endocrine disorders	Diabetes mellitus1
Psychiatric disorders					Depression
Nervous system disorders	Headache, dizziness			Polyneuropathy, memory loss	Peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis
Eye disorders					Ocular myasthenia
Respiratory, thoracic and mediastinal disorders					Cough, dyspnea
Gastrointestinal disorders	Constipation, nausea, abdominal pain		Pancreatitis		Diarrhea
Hepatobiliary disorders			Elevated levels of liver transaminases	Jaundice, hepatitis
Skin and subcutaneous tissue disorders		Pruritus, rash, urticaria			Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders	Myalgia		Myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture	Arthralgia	Tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy
Renal and urinary disorders				Hematuria
Reproductive system and breast disorders				Gynecomastia
General disorders and administration site conditions	Asthenia				Edema

1 Frequency depends on the presence of risk factors (fasting glucose level ≥5.6 mmol/L, BMI >30 kg/m², elevated triglyceride levels, history of arterial hypertension).

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions tends to be dose-dependent.

Renal effects

Proteinuria, detected by urine dipstick testing and predominantly of tubular origin, has been observed in patients treated with rosuvastatin. Changes in urinary protein content from zero or trace to "++" or higher were observed in <1% of patients intermittently during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients at the 40 mg dose. A slight increase in the frequency of change in protein content from zero or trace to "+" was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. Based on clinical studies and post-marketing surveillance data, there is currently no evidence of a causal relationship between proteinuria and acute or progressive kidney disease.

Cases of hematuria have been reported during rosuvastatin treatment; however, the frequency was low according to clinical trial data.

Skeletal muscle effects

Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been reported with all rosuvastatin doses, particularly at doses >20 mg.

In patients taking rosuvastatin, dose-dependent increases in CK levels have been observed; in most cases, this phenomenon was mild, asymptomatic, and transient. If CK levels are elevated (>5 times the ULN), treatment should be discontinued (see section "Dosage and Administration").

Hepatic effects

As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin have experienced dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient.

With the use of some statins, the following adverse effects have been reported:

• sexual dysfunction;
• isolated cases of interstitial lung disease, particularly with long-term use (see section "Dosage and Administration").

The frequency of reports of rhabdomyolysis and serious renal and hepatic adverse events (mainly increased hepatic transaminase activity) is higher with the 40 mg dose.

Children

Elevated creatine kinase levels >10 times above ULN and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week clinical study in children and adolescents compared to adults (see section "Dosage and Administration"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach and sight of children.

Packaging.

Film-coated tablets, 5 mg, 10 mg, 20 mg, or 40 mg, pack sizes of 30 (10×3) or 60 (10×6) in blisters (manufactured from bulk packaging by the manufacturer Biofarma Sp. z o.o., Poland).

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and site of operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.