Rosister

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

Composition:

active substance: rosuvastatin;

1 tablet contains 10 mg or 20 mg of rosuvastatin;

excipients: lactose monohydrate; microcrystalline cellulose; crospovidone; calcium phosphate; magnesium stearate;

coating: Opadry II Pink film coating: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); triacetin; iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets of pink color.

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 reducing cholesterol levels.

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 (TG), and increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (ApoB), non-HDL cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), triglyceride-rich VLDL, and increases levels of apolipoprotein A-I (ApoA-I). Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I.

Therapeutic effect is achieved within 1 week of starting treatment, with 90% of the maximum effect reached within 2 weeks. Maximum effect is typically achieved by 4 weeks and maintained thereafter.

Clinical Efficacy and Safety

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

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

In a large study of patients with heterozygous familial hypercholesterolemia receiving rosuvastatin 20–80 mg under an intensive dose-titration regimen, the drug demonstrated 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 LDL-C levels (<3 mmol/L) were achieved in 33% of patients.

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

In clinical studies involving a limited number of patients, an additive effect of rosuvastatin on triglyceride reduction was observed when used in combination with fenofibrate, and an increase in HDL-C levels was observed when used in combination with niacin (see section "Special Warnings and Precautions for Use").

In a multicenter, double-blind, placebo-controlled clinical trial, patients aged 45–70 years with low risk of ischemic heart disease (defined as a Framingham risk score <10% over 10 years), mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (defined by increased carotid intima-media thickness—CIMT) received either 40 mg rosuvastatin or placebo once daily for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites. A direct correlation between reduction in CIMT and reduction in cardiovascular event risk was not demonstrated. The study included patients at low risk of ischemic heart disease, who are not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should be reserved only for patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see section "Dosage and Administration").

In a study evaluating rosuvastatin for primary prevention of atherosclerotic cardiovascular disease, the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular events was assessed in men (≥50 years) and women (≥60 years).

Participants were randomly assigned to receive either placebo or rosuvastatin 20 mg once daily and were followed for a mean of 2 years.

LDL-C concentrations decreased by 45% in the rosuvastatin group compared to the placebo group.

In a retrospective analysis of a high-risk subgroup with a baseline Framingham risk score >20%, a significant reduction in the incidence of the composite endpoint (including cardiovascular death, stroke, and myocardial infarction) was observed in the rosuvastatin group compared to placebo. The absolute risk reduction was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group. In a retrospective analysis of a high-risk subgroup with a baseline SCORE risk ≥5% (extrapolated to include participants over 65 years), a significant reduction in the incidence of the composite endpoint (including cardiovascular death, stroke, and myocardial infarction) was observed in the rosuvastatin group compared to placebo. 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.

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 reactions. The most common adverse reactions leading to discontinuation were myalgia, abdominal pain, and rash. The most common adverse reactions observed in the rosuvastatin group with a frequency greater than or equal to that in the placebo group were urinary tract infections, nasopharyngitis, back pain, and myalgia.

Children

In a double-blind, randomized, multicenter, placebo-controlled 12-week study followed by a 40-week open-label dose-titration period, 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 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 (maximum dose 20 mg once daily) to achieve target levels, 40.5% of patients achieved the target LDL-C level of <2.8 mmol/L.

After 52 weeks of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special Warnings and Precautions for Use"). This study (n=176) is not suitable for comparing rare adverse reactions.

Rosuvastatin was also evaluated in a 2-year open-label study with target dose titration in 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 6–9 years were titrated to a maximum dose of 10 mg once daily, and those aged 10–17 years to a maximum of 20 mg once daily.

Treatment with rosuvastatin 5 mg, 10 mg, and 20 mg 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-I. Each of these changes indicated 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 Warnings and Precautions for Use").

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 6–17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active dietary lead-in phase during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis continued these treatments throughout the study.

A statistically significant reduction in LDL-C was observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. Statistically significant reductions in total cholesterol, non-HDL-C, and ApoB were also observed. Reductions in TG, LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I were observed after 6 weeks of treatment with rosuvastatin 20 mg compared to placebo. The reduction in LDL-C after 6 weeks of rosuvastatin 20 mg treatment followed by 6 weeks of placebo was maintained throughout the 12-week continuous therapy period. One patient showed further reductions in LDL-C, total cholesterol, and non-HDL-C after 6 weeks of treatment with dose titration to 40 mg.

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

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

Pharmacokinetics

Absorption. Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

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

Metabolism. Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 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% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The geometric mean value of plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP1B1, which plays an important role in hepatic elimination of rosuvastatin.

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

Special Patient Populations

Age and Gender. No clinically significant effect of age or gender on rosuvastatin pharmacokinetics has been observed in adults. Rosuvastatin exposure 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 median AUC and Cmax values in Mongoloid race patients (Japanese, Chinese, Filipino, Vietnamese, and Korean) are approximately twice as high as in Caucasians; in Indian patients, median AUC and Cmax values are increased by approximately 1.3-fold. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Negroid race patients.

Renal Impairment. In a study of patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in patients with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and N-desmethyl metabolite levels 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 of patients with varying degrees of hepatic dysfunction, no evidence of increased rosuvastatin exposure was observed in patients classified as Child-Pugh score 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 score >9 is lacking.

Genetic Polymorphism. The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transporter 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 if a patient is known to have such a polymorphism, a lower daily dose of rosuvastatin is recommended.

Children.

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 years 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 treatment 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 events

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.

Rosuvastatin® 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 elevations of serum transaminases that are 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 receiving concomitant combination therapy with sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
• in patients receiving concomitant cyclosporine;
• during pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

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

Factors contributing to this risk include:

• moderate renal impairment (creatinine clearance < 60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• conditions that may lead to increased plasma concentration of the medicinal product;
• Mongoloid race;
• concomitant use of fibrates (see sections "Pharmacokinetics", "Interaction with other medicinal products and other types of interactions", and "Special precautions for use").

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

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

Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers was associated with approximately 3- and 7-fold increases in rosuvastatin AUC and Cmax, respectively. Concomitant use of rosuvastatin and 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 types of interactions", Table 2).

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

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions for use"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe. Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 1). A pharmacodynamic interaction between rosuvastatin and ezetimibe, potentially leading to adverse effects, cannot be excluded (see section "Special precautions for use").

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

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

Tickagrelor. 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 decreased renal function, elevated creatine phosphokinase levels, and rhabdomyolysis.

Cytochrome P450 enzymes. Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. Additionally, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions resulting from 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 concomitant use of rosuvastatin with other medicinal products capable of increasing rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in drug exposure (AUC) is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with a 40 mg daily dose without interacting drugs; for example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (1.9-fold increase in exposure), and when used with the 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; however, caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 1

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increased AUC of rosuvastatin by 2 times or more
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxelaprevir (400 mg-100 mg-100 mg) + voxelaprevir (100 mg) once daily for 15 days	10 mg, single dose	↑ 7.4 times
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1 times
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2 times
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8 times
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1 times
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7 times
Obitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily/dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6 times
Teriflunomide	Data not available	↑ 2.5 times
Glecaprevir 200 mg/elbasvir 50 mg once daily, 11 days	10 mg, single dose	↑ 2.3 times
Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days	5 mg once daily, 7 days	↑ 2.2 times
Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days	20 mg once daily, 7 days	↑ 2.1 times
Capmatinib 400 mg twice daily	10 mg, single dose	↑ 2.1 times
Clopidogrel 300 mg, then 75 mg after 24 hours	20 mg, single dose	↑ 2 times
Fostamatinib 100 mg twice daily	20 mg, single dose	↑ 2.0 times
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9 times
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9 times
Increased AUC of rosuvastatin less than 2 times
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Elvitegravir 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6 times
Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days	10 mg once daily, 7 days	↑ 1.5 times
Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days	10 mg, single dose	↑ 1.4 times
Dronedarone 400 mg twice daily	Unknown	↑ 1.4 times
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4 times **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2 times **
Decreased AUC of rosuvastatin
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	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 change by "x" times represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the percentage difference relative to values observed with rosuvastatin administered alone.

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

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

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

Effect of rosuvastatin on concomitant medicinal products

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

Oral contraceptives/hormone replacement therapy (HRT). Co-administration of rosuvastatin with oral contraceptives increased AUC of ethinylestradiol and norgestimate by 26% and 34%, 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 concurrently receiving rosuvastatin 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 dedicated interaction studies, no clinically significant interaction with digoxin is expected.

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

Paediatric population

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

Special precautions for use.

Renal effects

Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in most cases. Proteinuria was not a predictor of acute or progressive renal disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. Renal function should be monitored regularly in patients taking the medicinal product at a dose of 40 mg.

Skeletal muscle effects

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking rosuvastatin at any dose, particularly above 20 mg. Very rare cases of rhabdomyolysis have been reported with ezetimibe 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 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]), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK values exceed 5 times the ULN, treatment should not be initiated.

Before starting treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular 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 medicinal product (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration");
• concomitant use of fibrates.

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

During treatment

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

There have been reports that statins, including rosuvastatin, may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, rosuvastatin should be discontinued. Recurrences have been reported upon first or subsequent exposure to the same or another statin.

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

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered life-saving, statin therapy should be discontinued for the duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving fusidic acid 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 seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid is required, e.g., for treatment of severe infections, the necessity of concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision.

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

Severe skin adverse reactions

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

If a patient develops a serious reaction such as SJS or DRESS associated with rosuvastatin use, re-initiation of rosuvastatin therapy in that patient is contraindicated.

Hepatic effects

Like 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 should be performed before starting treatment and again after 3 months. Rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher 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 therapy.

Race

Pharmacokinetic studies indicate increased exposure in Mongoloid racial groups compared to Caucasians (see sections "Posology and method of administration", "Contraindications", and "Pharmacokinetics").

Protease inhibitors

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

Lactose intolerance

This medicinal product should not be used 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 with some statins, particularly with long-term use (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes

Evidence suggests that statins as a class increase blood glucose levels and may induce hyperglycaemia requiring treatment in some patients at high risk of developing type 2 diabetes. However, the reduction in vascular risk with statin use outweighs this risk, and therefore should not be a reason to discontinue 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 study, the overall incidence of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.

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

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

Ability to drive and use machines

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

Dosage and Administration

Prior to initiating therapy, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment. The dosage should be individually adjusted based on therapeutic goals and the patient's response to treatment, following recommendations of current widely accepted guidelines.

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

Treatment of Hypercholesterolemia

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

Prevention of Cardiovascular Events

In clinical trials aimed at reducing cardiovascular event risk, the medicinal product was administered at a dose of 20 mg 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 adjustments based on age are required.

Patients with Renal Impairment

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

The recommended initial dose for patients with moderate renal impairment (creatinine clearance <60 mL/min) is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment.

The use of Rosister® is contraindicated in any dosage in patients with severe renal impairment (see sections "Pharmacokinetics" and "Contraindications").

Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic impairment scoring 7 or less on the Child-Pugh scale. However, systemic exposure increased in patients scoring 8 or 9 on the Child-Pugh scale (see section "Pharmacokinetics"). Renal function assessment is advisable in such patients (see section "Special Warnings and Precautions for Use"). There is no experience with the use of the medicinal product in patients scoring more than 9 points on the Child-Pugh scale.

Rosister® is contraindicated in patients with active liver disease (see section "Contraindications").

Race

Increased systemic exposure to the medicinal product 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 Mongoloid race is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic Polymorphism

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

Patients Predisposed to Myopathy

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

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

Concomitant Therapy

Rosuvastatin is a substrate for 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 plasma concentrations of rosuvastatin 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 "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). Alternative medicinal products should be considered whenever possible, and temporary discontinuation of rosuvastatin therapy may be necessary. If concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit-risk balance should be carefully evaluated and the dose of Rosister® adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

The medicinal product should be administered to children 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 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"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment.

Homozogous 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"). Prior to initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment.

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

Tablets of 40 mg 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, Rosister® 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 implemented as necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions

Adverse events observed during rosuvastatin administration are generally mild and transient. In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.

List of adverse reactions in tabular form

The table below presents the adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are classified by frequency and system organ classes (SOC).

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

Table 2

Adverse reactions based on clinical studies and post-marketing experience

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

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

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

Renal effects

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

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

Skeletal muscle effects

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

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; 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 "Dosage and Administration").

Hepatic effects

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

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

Sexual dysfunction.

Isolated cases of interstitial lung disease, particularly with long-term use (see section "Dosage and Administration").

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

Children

Elevated 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 clinical study involving children and adolescents compared to adults (see section "Dosage and Administration"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse reactions according to the national reporting system.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of its business activities.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua