Rovamed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROVAMED® (ROVAMED)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains rosuvastatin calcium 5.21 mg equivalent to rosuvastatin 5 mg, or rosuvastatin calcium 10.419 mg equivalent to rosuvastatin 10 mg, or rosuvastatin calcium 20.838 mg equivalent to rosuvastatin 20 mg, or rosuvastatin calcium 41.676 mg equivalent to rosuvastatin 40 mg;

Excipients: microcrystalline cellulose, type 101; colloidal anhydrous silicon dioxide; crospovidone, type A; microcrystalline cellulose, type 102; lactose monohydrate; magnesium stearate;

Film coating: Opadry II Yellow 33K12488 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; yellow iron oxide) (5 mg tablets);

Opadry II Pink 33K94423 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; red iron oxide) (10 mg tablets);

Opadry II Pink 33K94423 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; red iron oxide) (20 mg tablets);

Opadry II Pink 33K94424 (HPMC 2910/hypromellose 6 cP; titanium dioxide (E 171); lactose monohydrate; triacetin; red iron oxide) (40 mg tablets).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets – yellow, round, biconvex film-coated tablets with the inscription "ROS" above "5" on one side and no inscription on the other side;

10 mg tablets – pink, round, biconvex film-coated tablets with the inscription "ROS" above "10" on one side and no inscription on the other side;

20 mg tablets – pink, round, biconvex film-coated tablets with the inscription "ROS" above "20" on one side and no inscription on the other side;

40 mg tablets – pink, oval, biconvex film-coated tablets with the inscription "ROS" on one side and "40" on the other side.

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

ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the enzyme 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 cholesterol reduction.

Rosuvastatin increases the number of low-density lipoprotein (LDL) receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic effects. Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (apoB), non-HDL-C, VLDL-C, very-low-density lipoprotein triglycerides (VLDL-TG), and increases apolipoprotein A-I (apoA-I) levels (see Table 1). Rosuvastatin 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 percent 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. Rosuvastatin 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 or familial hypercholesterolemia.

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

In a large study involving 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 to 80 mg using an intensified 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.

In an open-label dose-titration study, the response to rosuvastatin 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 trials involving a limited number of patients, an additive effect of rosuvastatin on triglyceride reduction was observed when used in combination with fenofibrate, and on HDL-C elevation when used in combination with niacin (see section "Special precautions").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a 10-year Framingham risk score <10%) and a mean LDL-C level of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness, CIMT) were randomized into two groups and received either 40 mg of rosuvastatin 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 (CI) -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. No direct correlation between reduction in CIMT and reduction in cardiovascular event risk was demonstrated. The METEOR study included patients with low risk of ischemic heart disease, who are not representative of the target population for the 40 mg dose of the drug. 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 diseases was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to receive either placebo (n=8,901) or rosuvastatin 20 mg once daily (n=8,901), with a mean follow-up of 2 years.

LDL-C concentration 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 a baseline Framingham risk score >20% (1,558 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 1,000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc analysis of another high-risk subgroup (9,302 participants) with a baseline SCORE risk ≥5% (extrapolated to include participants aged ≥65 years), a significant reduction in the composite endpoint including cardiovascular death, stroke, and myocardial infarction was observed in the rosuvastatin group compared to placebo (p=0.0003). The absolute risk reduction expressed as event rate was 5.1 events per 1,000 patient-years. The overall 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 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 daily 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, body weight, body mass index (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 evaluated in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage <II–V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n=64) were titrated 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 rosuvastatin treatment, the least squares mean reduction from baseline in LDL-C was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least squares mean reduction from baseline in LDL-C 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, apolipoprotein B (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 evaluated versus 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 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 rosuvastatin 20 mg treatment compared to placebo. Statistically significant reductions were also observed in total cholesterol (20.1%, p=0.003), non-HDL-C (22.9%, p=0.003), and apoB (17.1%, p=0.024). Reductions in TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of rosuvastatin 20 mg treatment compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg treatment followed by 6 weeks of placebo was maintained over 12 weeks of continuous therapy. One patient showed further reductions in LDL-C (8.0%), total cholesterol (6.7%), and non-HDL-C (7.4%) after 6 weeks of treatment with dose titration to 40 mg.

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

In an open 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 hypercholesterolemia, primary combined (mixed) dyslipidemia, and for prevention of cardiovascular disorders (see section "Dosage and administration" for information on use in children).

Pharmacokinetics.

Absorption. The 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. 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-mediated metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, 3A4, and 2D6. 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 drug), with the remainder excreted in urine. Approximately 5% of rosuvastatin 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/hour (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 was observed in adults. Rosuvastatin pharmacokinetics in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

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

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

Hepatic impairment. In a study involving patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in individuals 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 greater than 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 are recommended to receive a lower daily dose of Rosuvastatin.

Children. Two pharmacokinetic studies of rosuvastatin (as tablets) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 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 activity, 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.

Rovamed**®** is contraindicated

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of the medicinal product;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any increase in serum transaminases 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 types of interactions");
• 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 predisposed 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;

− situations that may lead to increased plasma concentration of the drug;

− Mongoloid race;

− concomitant use of fibrates.

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

Interaction with other medicinal products and other types of interactions.

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 Rovamed**®** with medicinal products that inhibit these transporter proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

Cyclosporine. During concomitant use of Rovamed**®** and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). The medicinal product is contraindicated in patients who are concurrently receiving cyclosporine (see section "Contraindications"). Concomitant use did not affect plasma concentrations of cyclosporine.

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 resulted in increases in AUC and Cmax of rosuvastatin by approximately 3 and 7 times, respectively. Concomitant use of Rovamed**®** with certain combinations of protease inhibitors may be possible after careful consideration of dose adjustment of Rovamed**®**, taking into account the expected increase in rosuvastatin exposure (see sections "Interactions with other medicinal products and other types of interactions", "Special precautions", "Dosage and administration", Table 2).

Gemfibrozil and other lipid-lowering agents. Concomitant use of Rovamed**®** and gemfibrozil resulted in a doubling of AUC and Cmax of rosuvastatin (see section "Special precautions"). Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (≥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 coadministered with fibrates (see sections "Contraindications" and "Special precautions"). Such patients should also initiate therapy with a 5 mg dose.

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

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

Erythromycin. Concomitant administration of Rovamed**®** 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, drug interactions due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2). When coadministration of Rovamed**®** with other medicinal products capable of increasing rosuvastatin exposure is necessary, the dose of Rovamed**®** should be adjusted. If an approximately 2-fold or greater increase in AUC is expected, Rovamed**®** therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of Rovamed**®** should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg daily dose in the absence of interacting medicinal products; for example, when used with gemfibrozil, the Rovamed**®** dose should be 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir combination – 10 mg (3.1-fold increase in exposure), and with cyclosporine – 5 mg (7.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required; however, 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	Change 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 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
Ortho-symeprevir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3-fold
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg, single dose, 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	Change in rosuvastatin AUC*
Elvitegravir 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**
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baykaline 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

\Data presented as fold change represent the ratio between rosuvastatin used in combination versus rosuvastatin used alone. Data presented as % change represent the % difference relative to values when rosuvastatin is used alone.

Increases are indicated by ↑, no change by –, and decreases by ↓.

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

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

Effect of rosuvastatin on concomitant medicinal products

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

Oral contraceptives/hormone replacement therapy (HRT). Concomitant use of Rovamet**®** with oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma concentrations should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients receiving Rovamet**®** and HRT; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products.

Digoxin. Based on specific interaction studies, no clinically significant interaction with digoxin is expected.

Fusidic acid. Drug interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is co-administered with statins. The mechanism of this interaction (pharmacodynamic 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 treatment is considered necessary, rosuvastatin therapy should be discontinued for the duration of fusidic acid treatment. See also section "Special precautions".

Paediatric population. Interaction studies have been performed 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 in most cases was transient or intermittent. 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. In patients receiving the 40 mg dose, renal function should be monitored regularly during treatment.

Musculoskeletal effects. 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 ezetimibe used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section "Interaction with other medicinal products and other forms of interaction"), 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 with the 40 mg dose.

Creatine kinase (CK) levels. CK levels should not be measured following strenuous physical exercise or in the presence of other possible causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (>5 times ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK exceeds 5 times ULN, treatment should not be initiated.

Before starting therapy. Rovamend**®**, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis.

Risk factors include:

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

In such patients, the risks associated with treatment should be weighed against the expected benefits, and clinical monitoring is recommended. If baseline CK levels are markedly elevated (>5 times ULN), treatment should not be initiated.

During treatment. Patients should be advised to report immediately any unexplained muscle pain, weakness, or tenderness, especially if accompanied by malaise or fever. CK levels should be measured in such patients. Treatment should be discontinued if CK levels are markedly elevated (>5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK ≤ 5 times ULN). After symptoms resolve and CK levels return to normal, therapy with Rovamend**®** or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose under close supervision. Routine CK monitoring 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 CK levels, even after discontinuation of statin therapy.

Clinical studies have not shown increased musculoskeletal effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reduct enzyme inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, co-administration of Rovamend**®** with gemfibrozil is not recommended. The benefit of further lipid-lowering with Rovamend**®** 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").

Rovamend**®** should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered 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 Rovamend**®** and fusidic acid should be considered on a case-by-case basis and under close medical supervision.

Rovamend**®** should not be administered to patients with acute, serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

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, Rovamend**®** should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.

Hepatic effects. As with other HMG-CoA reductase inhibitors, Rovamend**®** should be used with caution in patients who abuse alcohol and/or have a history of liver disease. It is recommended to assess liver biochemical parameters before starting treatment and again after 3 months. Treatment with Rovamend**®** should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

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

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

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 Rovamend**®** in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the initiation of therapy and with dose escalation of Rovamend**®** in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the dose of Rovamend**®** is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

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

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 (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus. Some evidence suggests that statins increase blood glucose levels and may induce hyperglycemia sufficient to require treatment in some patients at high risk of developing diabetes. However, the reduction in vascular risk with statin therapy outweighs this risk, which should not be a reason to discontinue statin treatment. Patients at risk (fasting glucose 5.6–6.9 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 was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels of 5.6–5.9 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 treated with rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CK 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").

Use during pregnancy or breastfeeding.

Rovamend**®** is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should 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 benefit from drug use during pregnancy. Animal reproductive toxicity data are limited. If a patient becomes pregnant while taking this drug, treatment should be discontinued immediately.

Rosuvastatin is excreted into the milk of rats. There are no data on excretion in human breast milk (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. However, given the pharmacodynamic properties of the drug, it is unlikely that rosuvastatin would affect such ability. Nevertheless, dizziness during treatment should be considered when driving or operating machinery.

Dosage and Administration

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which must be continued throughout the course of therapy. The dose should be individually titrated based on therapeutic goals and the patient's response to treatment, in accordance with current accepted guidelines.

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

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

Prevention of cardiovascular events. In clinical trials evaluating cardiovascular risk reduction, the drug was administered at a dose of 20 mg once daily (see section "Pharmacodynamics").

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

Patients with renal impairment. No dose adjustment is necessary for patients with mild or moderate renal dysfunction. 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. Rovamed® is contraindicated in patients with severe renal impairment at any dose (see sections "Pharmacokinetics" and "Contraindications").

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

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

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

Patients predisposed to myopathy. The recommended initial dose for patients at risk of developing myopathy is 5 mg (see section "Special Warnings and Precautions for Use").

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

Concomitant use. Rosuvastatin is a substrate of 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 combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir; see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). Alternative medicinal products should be considered where possible, and temporary discontinuation of Rovamed® therapy may be necessary. If concomitant use of these medicinal products with Rovamed® cannot be avoided, the benefit-risk balance should be carefully evaluated and the dose of Rovamed® appropriately adjusted (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children.

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

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

Homozygous familial hypercholesterolemia

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

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

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

40 mg tablets are not to be used in children.

Children under 6 years of age

The safety and efficacy of the drug in children under 6 years of age have not been studied. Therefore, the drug is not recommended for use in children under 6 years of age.

Overdose.

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

Adverse Reactions

Adverse reactions observed during the use of rosuvastatin are generally mild and transient. In controlled clinical trials, fewer than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

The following is the adverse reaction profile of rosuvastatin based on clinical trials and extensive post-marketing experience. Adverse reactions are classified by frequency and system organ classes (SOC). Frequencies are defined as follows: 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.

Psychiatric disorders:
Frequency not known – depression.

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

Eye disorders:
Frequency not known – ocular myasthenia.

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.

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

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 plasma glucose ≥5.6 mmol/L, BMI >30 kg/m², elevated triglycerides, 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 rosuvastatin. Changes in urinary protein content from negative or trace to ++ or higher were observed in <1% of patients at certain time points during treatment with 10 mg and 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of change from negative or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued therapy. To date, clinical trial and post-marketing data have not established a causal relationship between proteinuria and acute or progressive kidney disease.

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

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 rosuvastatin, particularly at doses >20 mg.

Dose-dependent increases in creatine kinase (CK) levels have been observed in patients receiving rosuvastatin; in most cases, this 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"). Tendon disorders, sometimes complicated by ruptures, have also been reported.

Hepatic effects. As with other HMG-CoA reductase inhibitors, a small number of patients receiving rosuvastatin have experienced dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient. Increases in HbA1c levels have also been observed during rosuvastatin treatment.

Adverse reactions such as sexual dysfunction have been reported with some statins. Isolated cases of interstitial lung disease, particularly with long-term use, have also been reported (see section "Special precautions").

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

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

Reporting suspected adverse reactions. Reporting suspected adverse reactions after a medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the Ukrainian pharmacovigilance system.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister, 3, 6, or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Medochemie Ltd (Central Factory)/Medochemie LTD (Central Factory).
2. Medochemie Limited/Medochemie Limited.

Manufacturer's address and location of operations.

1. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.
2. Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.