Klivas 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Clivas 10 (clivas 10) and Clivas 20 (clivas 20)

Composition:

Active substance: rosuvastatin;

One tablet contains 10.4 mg of rosuvastatin calcium (equivalent to 10 mg of rosuvastatin) or 20.8 mg of rosuvastatin calcium (equivalent to 20 mg of rosuvastatin);

Excipients: mannite (E 421), sodium croscarmellose, magnesium hydroxide, calcium carbonate, anhydrous sodium carbonate, silicon dioxide (colloidal hydrophobic), colloidal hydrated silicon dioxide, magnesium stearate;

Film-coating suspension: iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172), polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets, film-coated, pink in color, with a score line.

Pharmacotherapeutic group. Lipid-modifying agents. Lipid-modifying agents, plain. HMG-CoA reductase inhibitors. Rosuvastatin.

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics

Mechanism of action

Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes 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 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 (LDL-C), total cholesterol, and triglycerides (TG), while increasing levels of high-density lipoprotein cholesterol (HDL-C). It reduces apolipoprotein B (apoB), non-HDL-C, LDL-C, TG in VLDL, and increases apolipoprotein A-I (apoA-I) (Table 1). It 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 becomes apparent within 1 week after initiation of rosuvastatin therapy; after 2 weeks of treatment, the effect reaches 90% of the maximum possible. The maximum effect is generally achieved by 4 weeks and persists thereafter.

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex, or age, as well as in patients in special populations such as those with diabetes mellitus or familial hypercholesterolemia.

Combined phase III trial data show that rosuvastatin effectively reduced cholesterol levels to target values established by the European Atherosclerosis Society (EAS; 1998) in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L); approximately 80% of patients receiving the drug at a dose of 10 mg achieved EAS target LDL-C levels (<3 mmol/L).

In a large study of 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses of 20 to 80 mg using an intensive dose-titration regimen. The drug showed favorable effects on lipid parameters and achievement of target levels 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.

An open-label dose-titration study evaluated the response to rosuvastatin at doses of 20–40 mg 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 trials involving a limited number of patients, an additive effect of rosuvastatin on triglyceride reduction was observed when used in combination with fenofibrate, and an additive effect on HDL-C elevation 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 10-year Framingham risk score <10%), mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness [CIMT]) were randomized to receive either 40 mg of rosuvastatin once daily or placebo for 2 years. Compared with 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 cardiovascular event risk has not been demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who do not represent 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).

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 retrospective 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 overall mortality rate remained unchanged in this high-risk group (p=0.193). In a retrospective analysis of another high-risk subgroup (9302 participants overall) with baseline SCORE risk ≥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 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 the placebo group), abdominal pain (0.03% in the rosuvastatin group, 0.02% in the placebo group), and rash (0.02% in the rosuvastatin group, 0.03% in the placebo group). 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 the rosuvastatin group, 8.6% in the placebo group), nasopharyngitis (7.6% in the rosuvastatin group, 7.2% in the placebo group), back pain (7.6% in the rosuvastatin group, 6.9% in the placebo group), and myalgia (7.6% in the rosuvastatin group, 6.6% in the placebo group).

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 entry, 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 (maximum dose 20 mg once daily) to achieve target levels, 70 of 173 patients (40.5%) achieved the target LDL-C level of <2.8 mmol/L.

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 comparing rare adverse events.

Rosuvastatin was also studied in a 2-year open-label, dose-titration trial in 198 children aged 6 to 17 years (88 male and 110 female participants, Tanner stage <II–V) with heterozygous familial hypercholesterolemia. 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 those aged 10 to 17 years (n=134) to a maximum dose of 20 mg once daily.

After 24 months of rosuvastatin treatment, the mean reduction in LDL-C from baseline, estimated by least squares method, was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the mean reduction in LDL-C from baseline, estimated by least squares method, 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 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 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 diet and rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment with rosuvastatin 20 mg preceded or followed by a 6-week placebo period, 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 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 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 reductions were maintained between -12.1% and -21.3%.

In an open-label dose-titration 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 hypercholesterolem inflamm, primary combined (mixed) dyslipidemia, and for prevention of cardiovascular disorders (see section "Dosage and administration" for information on use in children).

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, the primary site of cholesterol synthesis and LDL-C clearance. Its volume of distribution 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 metabolites identified are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin; lactone metabolites are 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 drug). The remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The half-life does not change with increasing dose. The geometric mean value of plasma drug 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 OATP1B1, which plays an important role in the 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 sex

There is no clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. Exposure to rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than in adult patients with dyslipidemia (see section "Children").

Race

Pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese, and Korean), median AUC and Cmax values are approximately twice as high as in Caucasians; in Indians, median AUC and Cmax values are increased by approximately 1.3-fold. Pharmacokinetic analysis of ethnic groups did not reveal clinically significant differences in pharmacokinetics among Caucasians and Africans.

Renal impairment

In a study of patients with varying degrees of renal impairment, plasma concentrations of rosuvastatin and N-desmethyl metabolite were not significantly altered in patients with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin were three times higher and N-desmethyl concentrations 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 evidence of increased rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, elimination half-life was prolonged by approximately two-fold compared to patients with lower Child-Pugh scores. Experience with rosuvastatin in patients with Child-Pugh scores above 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 recommended in clinical practice, but patients with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Children

Pharmacokinetic studies of rosuvastatin (in tablet form) in two studies in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total 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.

• Hypersensitivity to rosuvastatin or any excipient;
• 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);
• severe renal impairment (creatinine clearance < 30 mL/min);
• myopathy;
• concomitant use of the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• concomitant use of cyclosporine;
• pregnancy and breastfeeding;
• women of childbearing potential who are not using appropriate contraceptive measures.

The 40 mg dose is contraindicated in patients with factors predisposing to myopathy/rhabdomyolysis. These factors 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 levels of the drug;
• patients of 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 medicinal products on rosuvastatin.

Inhibitors of transport proteins.

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

Cyclosporine.

When rosuvastatin and cyclosporine were administered concomitantly, the AUC of rosuvastatin was on average 7 times higher than in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients already receiving cyclosporine (see section "Contraindications").

Concomitant use did not affect plasma concentrations of cyclosporine.

Gemfibrozil and other lipid-lowering medicinal products.

Concomitant use of rosuvastatin and gemfibrozil resulted in a doubling of Cmax and AUC of rosuvastatin (see section "Special precautions for use"). Based on data from specific studies, a pharmacokinetically relevant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they can cause myopathy even when used alone. The 40 mg dose of rosuvastatin is contraindicated when used concomitantly with fibrates (see sections "Contraindications" and "Special precautions for use"). In such cases, treatment with rosuvastatin should also be initiated at a dose of 5 mg.

Ezetimibe.

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

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 approximately 3- and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin with certain combinations of protease inhibitors may be possible after careful consideration of rosuvastatin dose adjustment based on 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 2).

Antacids.

Concomitant use of rosuvastatin and antacids containing aluminum or magnesium hydroxide reduces rosuvastatin 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 use of rosuvastatin and erythromycin reduced rosuvastatin AUС(0-t) by 20% and Cmax by 30%. This interaction may be due to increased intestinal peristalsis 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, drug interactions related to cytochrome 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).

Ticagrelor.

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to impaired renal function, increased CK levels, and rhabdomyolysis.

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

When rosuvastatin must be used concomitantly with other medicinal products that may increase rosuvastatin exposure, the rosuvastatin dose should be adjusted. If a doubling 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 exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting medicinal products; for example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required, but caution should be exercised when increasing the rosuvastatin 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

Increased rosuvastatin AUC by 2-fold 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, 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine 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
Paritaprevir 150 mg/ombitasvir 25 mg/ ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	Data not available	↑ 2.5-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
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1-fold
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2-fold
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-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	Data not available	↑ 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 %
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47 %

* Data presented as fold change represent the ratio between co-administration and administration of rosuvastatin alone. Data expressed as % change represent the % difference relative to values when rosuvastatin is administered alone.

Increases are indicated by ↑, decreases by ↓.

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

The following drugs/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin when co-administered with rosuvastatin:

aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg, 7 days, three times daily; fluconazole 200 mg, 11 days, once daily; fosamprenavir 700 mg/ritonavir 100 mg, 8 days, twice daily; ketoconazole 200 mg, 7 days, twice daily; rifampicin 450 mg, 7 days, once daily; silimarina 140 mg, 5 days, three times daily.

Effect of rosuvastatin on concomitant medications.

Vitamin K antagonists.

As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or dose escalation in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Following discontinuation or dose reduction of rosuvastatin, the INR may decrease. INR should therefore be monitored appropriately in such cases.

Oral contraceptives/hormone replacement therapy (HRT).

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of medicinal products in patients receiving rosuvastatin and HRT simultaneously; therefore, a potential interaction cannot be ruled out. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products.

Digoxin.

Based on data from 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 or 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 is considered necessary, rosuvastatin therapy should be discontinued for the duration of fusidic acid treatment. See also section "Special precautions".

Children.

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

Special precautions for use.

Renal effects.

Cases of proteinuria (detected by dipstick testing), predominantly of tubular origin and mostly transient or intermittent, have been reported in patients treated with rosuvastatin at high doses, particularly 40 mg. Proteinuria does not indicate acute or progressive renal disease (see section "Adverse reactions"). The frequency of serious renal adverse events reported in post-marketing studies is higher with the 40 mg dose. Renal function should be monitored regularly 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 treated with any dose of rosuvastatin, particularly at doses > 20 mg. Cases of rhabdomyolysis have been reported rarely when ezetimibe is used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be ruled out; 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 possible alternative 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]), an additional test should be performed within 5–7 days to confirm the results. If the repeat test confirms CK levels > 5 times ULN, treatment with the medicinal product should not be initiated.

Before initiating treatment.

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with risk factors for myopathy/rhabdomyolysis. These risk factors include:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity associated with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may increase rosuvastatin plasma levels (see sections "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

In such patients, the risks and potential benefits of treatment should be carefully weighed; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 times ULN).

During treatment.

Patients should be advised to promptly report any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. Treatment should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and impair daily activities (even if CK levels ≤ 5 × ULN).

If symptoms resolve and CK levels return to normal, rosuvastatin or an alternative HMG-CoA reductase inhibitor may be cautiously reintroduced at the lowest dose and under close supervision.

Routine monitoring of CK levels in patients without the above-mentioned symptoms is not required.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin.

Clinical manifestations of IMNM include proximal muscle weakness and elevated serum creatine phosphokinase levels, which persist even after discontinuation of statin therapy.

There have been reports that statins may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms of these conditions worsen, treatment with the medicinal product Clivas should be discontinued. Recurrences have been reported upon initial or repeated use of the same or another statin.

During clinical trials, no increased effect on skeletal muscle was observed in a small number of patients receiving rosuvastatin and concomitant medications.

However, an increased incidence of myositis and myopathy has been observed in patients receiving 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 co-administered with certain HMG-CoA reductase inhibitors. Therefore, rosuvastatin is not recommended to be used in combination with gemfibrozil. The potential benefit of further lipid-lowering effects with concomitant use of rosuvastatin and fibrates or niacin should be weighed against the potential risks of such combination therapy. Concomitant use of rosuvastatin 40 mg and fibrates is contraindicated (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 life-saving, 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 and statins in combination (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 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid treatment is required, e.g., for 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 predisposing to myopathy or increasing the risk of renal failure secondary to rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances; uncontrolled seizures).

Severe skin adverse reactions.

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

If a serious reaction such as SJS or DRESS develops in a patient during treatment with Clivas, re-administration of this medicinal product to that patient is absolutely contraindicated.

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.

Liver function tests are recommended before starting treatment and again after 3 months of therapy. If serum transaminase levels exceed three times the upper limit of normal, rosuvastatin should be discontinued or the dose reduced. Serious hepatic dysfunction (mainly elevated liver transaminases) has been reported more frequently in the post-marketing period with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated before starting rosuvastatin.

Race.

Pharmacokinetic studies have shown approximately twofold higher systemic exposure in Mongoloid racial groups compared to Caucasians (see sections "Pharmacokinetics", "Posology and method of administration", and "Contraindications").

Protease inhibitors.

Increased systemic exposure to rosuvastatin has been observed in individuals receiving 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 should be considered. Concomitant use of the medicinal product with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Posology and method of 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 deterioration in general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus.

Evidence suggests that statins as a class may increase blood glucose levels and, in some patients at high risk of developing diabetes, may lead to hyperglycemia requiring treatment for diabetes. However, the reduction in vascular risk with statin therapy outweighs this risk, and therefore should not be a reason for discontinuing statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI > 30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER trial, 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.

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 receiving rosuvastatin is limited to a 2-year period. After 2 years of 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-related symptoms following physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any possible benefit from using the medicinal product during pregnancy. If a patient becomes pregnant while taking the medicinal product, treatment should be discontinued immediately.

Rosuvastatin is excreted into rat milk. There are no data on excretion into human breast milk (see section "Contraindications").

Ability to affect the speed of reactions while driving or operating machinery.

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, due to its pharmacodynamic properties, it is unlikely that rosuvastatin affects this ability. Dizziness during rosuvastatin treatment should be taken into account when driving or operating machinery.

Method of Administration and Dosage

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout the treatment period. The dosage should be individually adjusted according to the therapeutic goal and treatment efficacy, taking into account current generally accepted guidelines.

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

The tablet should not be chewed, but may be divided to facilitate swallowing. Swallow with water.

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.

When selecting the initial dose, the individual patient's cholesterol levels, potential cardiovascular risk, and the potential risk of adverse reactions should be considered. If necessary, the dose may be increased after 4 weeks (see section "Pharmacodynamics").

Since adverse reactions occur more frequently with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose titration up to the maximum of 40 mg should only be performed in patients with severe hypercholesterolemia and high cardiovascular risk (particularly patients with familial hypercholesterolemia) who have not achieved the desired response with a 20 mg dose, and who must be under regular monitoring (see section "Special Warnings and Precautions for Use"). Specialist monitoring is recommended when initiating treatment with the 40 mg dose.

Prevention of cardiovascular events.

In clinical trials, the dose of the medicinal product associated with reduced risk of cardiovascular complications was 20 mg daily (see section "Pharmacodynamics").

Use in elderly patients.

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

Patients with renal impairment.

No dosage adjustment is necessary in patients with mild to 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 Clivas is contraindicated in patients with severe renal impairment at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with hepatic impairment.

No increase in systemic exposure to rosuvastatin was observed in patients with Child-Pugh score of 7 or less. However, increased systemic exposure has been reported in patients with Child-Pugh score of 8 or 9. Renal function should be assessed in such patients (see section "Special Warnings and Precautions for Use"). Experience with the use of the medicinal product in patients with Child-Pugh score above 9 is lacking. Clivas is contraindicated in patients with active liver disease (see section "Contraindications").

Race.

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

Patients predisposed to myopathy.

The recommended initial dose for patients predisposed to 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").

Genetic polymorphism.

Certain types of genetic polymorphism may lead to increased exposure to rosuvastatin. Patients known to have such polymorphism types are recommended to receive a lower daily dose of the medicinal product.

Concomitant use.

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin 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 medicinal products should be considered, if possible, and temporary interruption of Clivas therapy should be considered if necessary. If concomitant use of these medicinal products with Clivas cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the dose of the medicinal product 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 only be performed by a specialist.

Children 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 above 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 above 20 mg in this population have not been studied.

The dose should be increased according to the individual child's response to treatment and tolerability of the medicinal product, in accordance with 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 should be maintained throughout treatment.

Homogeneous 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 to the maximum of 20 mg once daily should be based on the individual child's response to treatment and tolerability of the medicinal product, in accordance with 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 should be maintained throughout treatment.

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

The 40 mg tablets are not to 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 studied. Therefore, Clivas 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 and supportive measures should be implemented as necessary. Monitoring of liver function and CK levels is required. Hemodialysis is unlikely to be effective.

Adverse Reactions

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

In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

The adverse reaction profile of rosuvastatin, based on clinical trials and extensive post-marketing experience, is presented below. Adverse reactions are classified by frequency and by system organ class (SOC).

Adverse reactions are listed below by frequency of occurrence: common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Rare – thrombocytopenia.

Immune system disorders:
Rare – hypersensitivity reactions, including angioedema.

Endocrine disorders:
Common – diabetes mellitus¹.

Nervous system disorders:
Common – headache, dizziness; very rare – polyneuropathy, memory loss; frequency not known – peripheral neuropathy, sleep disorders, including insomnia and nightmares, myasthenia gravis.

Psychiatric disorders:
Frequency not known – depression.

Respiratory, thoracic and mediastinal disorders:
Frequency not known – cough, dyspnea.

Gastrointestinal disorders:
Common – constipation, nausea, abdominal pain; rare – pancreatitis; frequency not known – diarrhea.

Hepatobiliary disorders:
Rare – increased levels of liver transaminases; very rare – jaundice, hepatitis.

Skin and subcutaneous tissue disorders:
Uncommon – pruritus, rash, urticaria; frequency not known – Stevens-Johnson syndrome, DRESS syndrome (clinically characterized by eosinophilia and systemic symptoms).

Eye disorders:
Frequency not known – ocular form of myasthenia.

Musculoskeletal and connective tissue disorders:
Common – myalgia; rare – myopathy (including myositis) and rhabdomyolysis, lupus-like syndrome, muscle rupture; very rare – arthralgia; frequency not known – tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy.

Renal and urinary disorders:
Very rare – hematuria.

Reproductive system and breast disorders:
Very rare – gynecomastia.

General disorders:
Common – asthenia; frequency not known – edema.

¹ 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 is dose-dependent.

Renal effects

Proteinuria, predominantly of tubular origin (as determined by "dipstick test"), has been observed in patients treated with rosuvastatin.

Changes in urinary protein levels from absent or trace to ++ or higher were recorded at certain time points in < 1% of patients receiving rosuvastatin 10 mg or 20 mg, and in approximately 3% of patients receiving 40 mg.

A slight increase in the frequency of proteinuria from absent or trace to + was observed with the 20 mg dose. In most cases, the severity of proteinuria decreased or resolved spontaneously while continuing rosuvastatin treatment.

Based on available clinical trial and post-marketing data, there is currently no evidence of a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed in patients treated with rosuvastatin; however, its 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 observed with all rosuvastatin doses, particularly with doses > 20 mg.

Patients receiving rosuvastatin have shown dose-dependent increases in creatine kinase (CK) levels; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times the upper limit of normal (ULN)), 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.

Adverse events reported with some statins include:

Sexual dysfunction; isolated cases of interstitial lung disease, particularly with long-term therapy (see section "Special precautions").

The incidence of rhabdomyolysis and serious renal and hepatic adverse events (mainly elevated liver transaminases) was higher with the 40 mg dose.

Pediatric population

Elevations in 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 pediatric clinical trial compared to adults (see section "Special precautions"). However, the safety profile of rosuvastatin in children was similar to that in adults.

Shelf life

2 years.

Storage conditions

Store in the original packaging, out of reach of children, at temperatures not exceeding 25 °C.

Packaging

10 tablets per blister pack, 1, 3, or 9 blister packs per cardboard box.

Prescription status

Prescription only.

Manufacturer

LLC "Pharma Start"

Manufacturer's address and location of operations

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine