Suvardio

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUCARDIO (SUVARDIO)

Composition:

Active substance: rosuvastatin;

1 tablet contains 5 mg, 10 mg, or 20 mg of rosuvastatin (as rosuvastatin calcium);

Excipients: anhydrous lactose, colloidal anhydrous silicon dioxide, silicified microcrystalline cellulose, corn starch, talc, sodium stearyl fumarate;

Coating: hypromellose, mannitol (E 421), macrogol 6000, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: round brown film-coated tablets;

10 mg tablets: round brown film-coated tablets, with "RSV 10" embossed on one side;

20 mg tablets: round brown film-coated tablets, with "RSV 20" embossed on one side.

Pharmacotherapeutic group.

Lipid-lowering 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 that catalyzes the rate-limiting step in the conversion of 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 receptor particles 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

Suvardio reduces elevated levels of LDL-cholesterol, total cholesterol, and triglycerides, and increases HDL-cholesterol levels. It also reduces levels of apolipoprotein B, non-HDL-cholesterol, VLDL-cholesterol, triglyceride-rich VLDL, and increases apolipoprotein A-I levels (Table 1). Suvardio also reduces the ratios of LDL-cholesterol/HDL-cholesterol, total cholesterol/HDL-cholesterol, non-HDL-cholesterol/HDL-cholesterol, and apolipoprotein B/apolipoprotein A-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 treatment, 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

Suvardio is effective in the treatment of adults with hypercholesterolemia—with or without hypertriglyceridemia—regardless of race, gender, or age, as well as in patients from special populations such as those with diabetes mellitus or familial hypercholesterolemia.

Based on pooled Phase III trial data, Suvardio effectively reduced 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). Approximately 80% of patients receiving the 10 mg dose achieved EAS-recommended LDL-C target levels (<3 mmol/L).

In a large study of 435 patients with heterozygous familial hypercholesterolemia, Suvardio was administered at doses ranging from 20 to 80 mg using an intensified dose-titration regimen. The beneficial effect of the drug on lipid parameters and achievement of target levels was observed at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C decreased by 53%. Target EAS LDL-C levels (<3 mmol/L) were achieved in 33% of patients.

In an open-label dose-titration study, the response to Suvardio at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased by an average of 22%.

In clinical studies involving a limited number of patients, an additive effect of Suvardio on triglyceride reduction was observed when used in combination with fenofibrate, and an increase in HDL-C levels was observed 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 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 reduction in CIMT and reduced risk of cardiovascular events has not been demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who do not represent the target population for Suvardio 40 mg. The 40 mg dose should only be prescribed 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 events 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), with a mean follow-up 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 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 all-cause 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 of age), 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 all-cause mortality rate in this high-risk subgroup remained unchanged (p=0.076).

In the JUPITER study, 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 rosuvastatin, 0.02% in placebo), and rash (0.02% in rosuvastatin, 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 at doses of 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At baseline, 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 mg, 10 mg, 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), the target LDL-C level of <2.8 mmol/L was 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"). This study (n=176) is not suitable for comparison of rare adverse events.

Rosuvastatin was also evaluated in a 2-year open-label study with targeted 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 to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n=134) to a maximum dose of 20 mg once daily.

After 24 months of 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 response 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 with 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 dietary adherence during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period 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 (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg 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 treatment with rosuvastatin 20 mg compared to placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo treatment 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, the reduction in LDL-C remained between -12.1% and -21.3%.

In an open dose-titration study of 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 treatment with rosuvastatin 20 mg 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 pediatric subgroups 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. Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution. Rosuvastatin is significantly taken up by the liver, which is 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 CYP2C19, CYP3A4, and CYP2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and 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 geometric mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via 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 populations

Age and gender. No clinically significant effect of age or gender on rosuvastatin pharmacokinetics has been observed in adults. Pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were 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 African patients.

Renal impairment. In a study of patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in patients with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin were three times higher and N-desmethyl metabolite levels nine 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 of patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in patients with Child-Pugh scores of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients with Child-Pugh scores >9 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.

Children. Two pharmacokinetic studies of rosuvastatin in children with heterozygous familial hypercholesterolemia aged 10–17 years and 6–17 years (total 214 patients) showed that drug exposure in children is similar to or lower than in adult patients. Rosuvastatin exposure over dose and time was predictable over a two-year period.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia.

For adults, adolescents, and children aged 6 years and older with primary hypercholesterolemia (type IIa) (excluding heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb), as an adjunct to diet when dietary or 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 interventions (e.g., low-density lipoprotein apheresis), or when such therapy is not feasible.

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.

SUWARDIO is contraindicated:

• in patients with hypersensitivity to rosuvastatin or 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 serum transaminase elevations exceeding three times 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 and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

The 40 mg dose is contraindicated in patients with 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 concentrations of the medicinal product;
• Mongoloid race;
• concomitant use of fibrates.

(See sections "Special precautions for use", "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 drugs 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 administration of rosuvastatin with medicinal products that inhibit these transporter proteins may increase rosuvastatin plasma concentrations and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", Table 1).

Cyclosporine

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients 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 1). 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 rosuvastatin with certain protease inhibitor combinations may be possible after careful consideration of rosuvastatin dose adjustment, given the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", Table 1).

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific studies, a pharmacokinetic interaction of clinical significance with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions for use"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

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

Antacid medicinal products

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

Erythromycin

Concomitant administration of rosuvastatin 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. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions with medicinal products 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 1)

When co-administration of rosuvastatin with other medicinal products that may increase rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg dose in the absence of interacting medicinal products; for example, when used with gemfibrozil, the rosuvastatin dose should be limited to 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, to 10 mg (3.1-fold increase in exposure).

If the medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required; however, caution should be exercised when increasing the SUWARDIO dose above 20 mg.

Table 1

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increased rosuvastatin AUC by 2 times or more
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	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
Cyclosporine from 75 mg twice daily up 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
Paritaprevir 150 mg/ombitasvir 25 mg/ ritonavir 100 mg once daily and 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
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Elotrombopag 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 **
Decreased rosuvastatin AUC
Dosing regimen of the interacting drug	Rosuvastatin dosing regimen	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Scutellaria baicalensis 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

* Data presented as fold change represent the ratio between administration of rosuvastatin in combination versus rosuvastatin administered alone. Data presented as % change represent the percentage difference relative to values when rosuvastatin is administered alone.

Increases are indicated by the symbol ↑, decreases by ↓.

** Several drug interaction studies were conducted at different doses of rosuvastatin; the most significant ratios are presented in Table 2.

Drugs/combinations that showed 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 medications

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin 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 rosuvastatin or reduction of its dose 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 rosuvastatin and oral contraceptives resulted in increases of 26% and 34% in AUC of ethinylestradiol and norgestimate, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients receiving rosuvastatin and HRT concurrently, so a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on 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 used concomitantly 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 fusidic acid treatment is considered necessary, rosuvastatin therapy should be discontinued for the entire duration of fusidic acid treatment. See also section "Special precautions for use".

Tickagrelor

Ticagrelor may cause renal impairment and may affect renal excretion of rosuvastatin, thereby increasing the risk of rosuvastatin accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine kinase (CK) levels, and rhabdomyolysis. During concomitant use of ticagrelor, monitoring of renal function and CK levels is recommended, as well as careful monitoring of rosuvastatin.

Children

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 higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in nature. Proteinuria was not a predictor of acute or progressive renal disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. Renal function should be regularly monitored in patients receiving rosuvastatin at a dose of 40 mg.

Effects on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly at doses exceeding 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe 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 strenuous physical exercise or in the presence of other potential 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 should not be initiated.

Before starting treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution to 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. Treatment should not be initiated if baseline CK levels are markedly elevated (>5 × ULN).

During treatment

Patients should be advised to promptly report any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are markedly elevated (>5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 × ULN). Therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision once symptoms have resolved and CK levels have returned to normal. 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 and 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, nicotinic acid, 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 rosuvastatin with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin 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").

Rosuvastatin 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 is considered necessary, statin therapy should be discontinued for the 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 on a case-by-case basis and under close medical supervision.

Rosuvastatin should not be administered to patients with acute, serious conditions indicating myopathy or risk of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with rosuvastatin use, which may be life-threatening or even fatal. Patients should be informed of the potential signs and symptoms of severe skin reactions and monitored closely during rosuvastatin treatment. If signs or symptoms suggestive of such reactions occur, rosuvastatin should be discontinued immediately and alternative therapy considered.

If a serious reaction such as Stevens-Johnson syndrome or DRESS syndrome develops during rosuvastatin treatment, re-initiation of therapy with this medicinal product should be avoided.

Hepatic effects

As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume alcohol excessively and/or have a history of liver disease.

It is recommended to assess hepatic biochemical parameters before starting treatment and again after 3 months. Treatment with rosuvastatin 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) is 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 rosuvastatin.

Race

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

Protease inhibitors

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

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

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

Children

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years taking 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 levels >10 times ULN and muscle symptoms following physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Lactose intolerance.

The product contains lactose. This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains sodium. Caution is advised when administering to patients on a sodium-restricted diet.

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

Use during pregnancy or breastfeeding.

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use reliable contraception.

Since cholesterol and other products of cholesterol biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition during pregnancy outweighs any benefit from therapy. Animal studies indicate limited delayed toxic effects. If pregnancy occurs during treatment, therapy should be discontinued immediately.

Since another medicinal product of this class passes into human breast milk and considering that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring treatment with rosuvastatin should be advised not to breastfeed. Data on the passage of rosuvastatin into human breast milk are lacking (see section "Contraindications").

Ability to drive and use machines.

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. When driving or operating machinery, the possibility of dizziness during treatment should be considered.

Dosage and Administration

Before initiating therapy, patients should be placed on a standard low-cholesterol diet, which should be continued throughout treatment. Dosages should be individualized according to therapeutic goals and patient response, in accordance with current established guidelines.

Rosuvastatin can be taken at any time of day, regardless of food intake.

The tablet should not be chewed or crushed. It should be swallowed whole with water.

Treatment of hypercholesterolemia.

The recommended initial dose is 5 or 10 mg orally once daily for patients who have not previously received statin therapy, or for those who have previously received other HMG-CoA reductase inhibitors. The choice of initial dose should take into account individual factors such as cholesterol levels, future cardiovascular risk, and the likelihood of adverse reactions. Dose adjustments, if necessary, should be made after 4 weeks. Increasing the dose to 40 mg is recommended only for the treatment of patients with severe hypercholesterolemia and high cardiovascular risk (particularly in patients with familial hypercholesterolemia), when treatment with 20 mg daily does not achieve the desired effect, provided regular medical monitoring is maintained, due to increased risk of adverse reactions.

Prevention of cardiovascular events.

In clinical trials evaluating the effect of the drug on reducing cardiovascular risk, the dose used was 20 mg once daily.

Elderly patients.

When treating patients aged 70 years and older, the recommended initial dose is 5 mg. No further age-related dose adjustment is required.

Patients with renal impairment.

Dose adjustment is not required when treating patients with mild or moderate renal impairment.

For patients with moderate renal impairment (creatinine clearance < 60 mL/min), the recommended initial dose is 5 mg. Rosuvastatin is contraindicated in patients with severe renal impairment at any dose.

Patients with hepatic impairment.

In patients with hepatic impairment classified as 7 or less on the Child-Pugh scale, no increase in systemic exposure to rosuvastatin was observed. However, in patients with scores of 8 or 9 on the Child-Pugh scale, systemic exposure increased. Renal function assessment is advisable in these patients. Experience with the drug in patients scoring more than 9 on the Child-Pugh scale is lacking. Rosuvastatin is contraindicated in patients with active liver disease.

Race.

Increased systemic exposure to the drug has been observed in patients of Mongoloid race. The recommended initial dose in such patients is 5 mg.

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 rosuvastatin.

Patients predisposed to myopathy.

The recommended initial dose for patients predisposed to myopathy is 5 mg.

Concomitant use.

Rosuvastatin is a substrate for various transport proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when the drug is co-administered with certain medicinal products that can increase rosuvastatin plasma concentrations via interaction with these transport proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir). Alternative treatments should be considered whenever possible, and rosuvastatin therapy may be temporarily discontinued if necessary. In situations where concomitant use of these drugs with rosuvastatin cannot be avoided, the benefits and risks of combination therapy should be carefully weighed, and the rosuvastatin dose should be selected with caution.

Pediatric use.

The use of this medicinal product in 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 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 to 20 mg orally once daily. The safety and efficacy of doses exceeding 20 mg in this population have not been studied.

Dose increases should be based on the individual child's response to treatment and drug tolerability, in accordance with pediatric treatment recommendations (see section "Special precautions for use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should 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 to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation up 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 precautions for use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

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

Tablets of 40 mg are not 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 studied. Therefore, Suvardio is not recommended for use in children under 6 years of age.

Overdose.

In case of overdose, symptomatic treatment should be provided and supportive therapy initiated as needed. Monitoring of liver function and creatine kinase levels is required. Hemodialysis is likely ineffective.

Adverse reactions.

Adverse events observed during rosuvastatin use are usually mild and transient. 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 (≥ 1/10000 to < 1/1000), very rare (< 1/10 000), and frequency not known (cannot be estimated from the available data).

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, amnesia	Peripheral neuropathy, sleep disorders (including insomnia and nightmares) Myasthenia gravis
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, drug reaction with eosinophilia and systemic symptoms (DRESS 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
Eye disorders					Ocular myasthenia

1 The frequency depends on the presence of risk factors (fasting glucose ≥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 dipstick testing, predominantly of tubular origin, has been observed in patients treated with Suvardio. Changes in urinary protein content from zero or trace to ++ or higher were observed in <1% of patients intermittently during treatment with doses of 10 and 20 mg, and in approximately 3% of patients at the 40 mg dose. A slight increase in the frequency of changes from zero or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously while continuing therapy. According to data from clinical studies and post-marketing surveillance, to date there is no established causal relationship between proteinuria and acute or progressive kidney disease.

Cases of hematuria have been reported during treatment with Suvardio; according to clinical studies, its frequency was low.

Musculoskeletal effects

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

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this phenomenon was mild, asymptomatic, and transient. If CK levels are elevated (>5 times the upper limit of normal), treatment should be discontinued (see section "Special precautions").

Hepatic effects

As with other HMG-CoA reductase inhibitors, a dose-dependent increase in transaminase levels has been observed in a small number of patients receiving rosuvastatin; in most cases, this was mild, asymptomatic, and transient.

With the use of certain statins, the following adverse events have been reported:

Sexual dysfunction.

Isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions").

The frequency of reports of rhabdomyolysis and serious renal and hepatic adverse events (predominantly increased hepatic transaminase activity) is higher when the medicinal product is used at a dose of 40 mg.

Children

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

Reporting suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing period of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from moisture at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

7 tablets in a blister; 4 blisters (7 × 4) in a cardboard box.

10 tablets in a blister; 3 (10 × 3), 6 (10 × 6), or 10 (10 × 10) blisters in a cardboard box.

15 tablets in a blister; 2 (15 × 2) or 4 (15 × 4) blisters in a cardboard box.

14 tablets in a blister; 2 blisters (14 × 2) in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

or

Lek Pharmaceuticals d.d.

or

Lek S.A.

Manufacturer's address and place of business.

Verovškova 57, 1526 Ljubljana, Slovenia

or

Trimlini 2d, 9220 Lenart, Slovenia

or

Podlipje 16, Strzykow, 95-010, Poland.