Sutan

Ukraine
Brand name Sutan
Form tablets, film-coated
Active substance / Dosage
rosuvastatin · 10 mg
Prescription type prescription only
ATC code
C10AA07
Registration number UA/20764/01/01
Manufacturer NOBEL ILAC SANAYI VE TICARET A.S.

Table of Contents

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUTAN (SUTAN)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains rosuvastatin calcium equivalent to rosuvastatin 10 mg, 20 mg or 40 mg;

Excipients: lactose monohydrate, calcium carbonate, microcrystalline cellulose, crospovidone, hydroxypropylcellulose, magnesium stearate, Opadry KB Low viscosity Orange 310A130010 coating, Opadry KB Low viscosity White 310A180023 coating, Opadry KB Low Viscosity Red 310A150019 coating, Kollicoat Protect coating, talc;

Composition of Opadry KB Low viscosity Orange 310A130010 coating: polyethylene glycol-polyvinyl alcohol copolymer, copovidone, titanium dioxide (E 171), kaolin, sodium lauryl sulfate, sunset yellow FCF (E 110);

Composition of Opadry KB Low viscosity White 310A180023 coating: polyethylene glycol-polyvinyl alcohol copolymer, copovidone, titanium dioxide (E 171), kaolin, sodium lauryl sulfate;

Composition of Opadry KB Low Viscosity Red 310A150019 coating: polyethylene glycol-polyvinyl alcohol copolymer, copovidone, titanium dioxide (E 171), kaolin, sodium lauryl sulfate, carmine (E 120);

Composition of Kollicoat Protect coating: polyethylene glycol-polyvinyl alcohol copolymer, polyvinyl alcohol, silicon dioxide.

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Lipid-lowering agents. HMG-CoA reductase inhibitors.

ATC code: C10AA07.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

Rosuvastatin increases the number of 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 LDL-cholesterol, total cholesterol, and triglycerides, and increases levels of high-density lipoprotein (HDL) cholesterol. It also reduces levels of apolipoprotein B (apoB), non-HDL cholesterol (non-HDL-C), VLDL-cholesterol, VLDL-triglycerides (VLDL-TG), and increases apolipoprotein A-I (apoA-I) (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 percentage change from baseline)

Dose

N

LDL-C

Total Cholesterol

HDL-C

Triglycerides

non-HDL-C

apoB

apoA-I

Placebo

13
  • 7
  • 5

3
  • 3
  • 7
  • 3

0

5

17
  • 45
  • 33

13
  • 35
  • 44
  • 38

4

10

17
  • 52
  • 36

14
  • 10
  • 48
  • 42

4

20

17
  • 55
  • 40

8
  • 23
  • 51
  • 46

5

40

18
  • 63
  • 46

10
  • 28
  • 60
  • 54

0

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

Clinical efficacy and safety

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

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

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

In an open-label dose-escalation 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 on average by 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 precautions for use").

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

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

Study participants were randomly assigned to receive either placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901), with a mean follow-up of 2 years.

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

In a retrospective analysis of a high-risk subgroup with baseline Framingham risk score >20% (1558 participants), a significant reduction in the incidence of the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (p = 0.028), 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 (p = 0.193). In a retrospective analysis of a high-risk subgroup (9302 participants overall) with baseline SCORE [Systematic Coronary Risk Evaluation] ≥5% (extrapolated to include data from participants over 65 years of age), a significant reduction in the composite endpoint including cardiovascular death, stroke, and myocardial infarction (p = 0.0003) 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 (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 at doses of 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At study initiation, approximately 30% of patients were aged 10–13 years, and approximately 17%, 18%, 40%, and 25% were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0% in the rosuvastatin 5 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), target LDL-C levels <2.8 mmol/L were achieved in 70 of 173 patients (40.5%).

After 52 weeks of investigational treatment, no effect on growth, body weight, BMI [body mass index], or sexual maturation was observed (see section "Special precautions for use"). This study (n = 176) is not suitable for comparison of rare adverse events.

Rosuvastatin was also studied in a 2-year open-label dose-titration study 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 mean reduction from baseline LDL-C, estimated by least squares method, was –43% (baseline: 236 mg/dL, month 24: 133 mg/dL). In each age group, the mean reduction from baseline LDL-C, estimated by least squares method, was –43% (baseline: 234 mg/dL, month 24: 124 mg/dL), –45% (baseline: 234 mg/dL, month 24: 124 mg/dL), and –35% (baseline: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to <10, 10 to <14, and 14 to <18 years, respectively.

Treatment with rosuvastatin at doses of 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C, total cholesterol/HDL-C, triglycerides/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 for use").

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, the effect of rosuvastatin 20 mg once daily versus placebo was evaluated in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase with dietary adherence, during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients receiving 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) occurred 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 triglycerides, 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-escalation study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0%), total cholesterol (19.2%), and non-HDL-C (21.0%) from baseline after 6 weeks of rosuvastatin 20 mg treatment corresponded to that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

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

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

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-mediated metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 2C19, 3A4, and 2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, 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 (combined absorbed and unabsorbed active substance), with the remainder excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours and does not increase with dose. The geometric mean plasma clearance of the drug is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C, which plays an important role in hepatic elimination of rosuvastatin.

Linearity

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

Special patient groups

Age and sex. No clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin has been observed in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

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

Renal impairment. In a study of patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or N-desmethyl metabolite were observed in individuals with mild or moderate impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin were 3 times higher and levels of the N-desmethyl metabolite 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 of patients with varying degrees of hepatic impairment, no signs of increased rosuvastatin exposure were observed in patients with Child-Pugh scores of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. There is no experience with rosuvastatin use in patients with Child-Pugh scores greater than 9.

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 such polymorphisms are recommended to use a lower daily dose of the drug.

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

Clinical characteristics

Indications

Treatment of hypercholesterolemia

The medicinal product is indicated for use in 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.

The medicinal product is indicated for use in 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 not feasible.

Prevention of cardiovascular events

The medicinal product is indicated for the prevention of major cardiovascular events in patients who are 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 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 exceed 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 lactation, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

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

Risk factors include:

  • moderate renal impairment (creatinine clearance <60 mL/min);
  • hypothyroidism;
  • personal or family history of hereditary muscle disorders;
  • history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
  • alcohol abuse;
  • situations that may lead to increased plasma concentration of the medicinal product;
  • belonging to the 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 use of rosuvastatin 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 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 cyclosporine concurrently (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 approximately 3- and 7-fold increases in AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations may be considered after careful evaluation of rosuvastatin dose adjustment, taking into account the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

Gemfibrozil and other lipid-lowering agents

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

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 (≥1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used individually. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Contraindications" and "Special precautions"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

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

Antacid medicinal products

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

Erythromycin

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

Ticagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to 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. 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 adjustment of rosuvastatin dose (see also Table 2)

When it is necessary to use rosuvastatin with other medicinal products capable of increasing rosuvastatin exposure, the dose of the medicinal product should be adjusted. If an increase in drug exposure (AUC) of at least 2-fold 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 the exposure observed with a 40 mg/day dose without concomitant use of interacting medicinal products; for example: when used with gemfibrozil, the rosuvastatin dose would be 20 mg (1.9-fold increase in exposure); when used with ritonavir/atazanavir combination, the dose would be 10 mg (3.1-fold increase in exposure).

If the medicinal product increases rosuvastatin AUC by less than 2-fold, no dose reduction is required initially; 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

At least 2-fold increase in rosuvastatin AUC

Dosing regimen of the interacting drug

Rosuvastatin dosing regimen

Changes in rosuvastatin AUC*

Sofosbuvir/velpatasvir/voxilaprevir (400 mg / 100 mg / 100 mg) + voxilaprevir (100 mg) once daily for 15 days

10 mg, single dose

↑ 7.4-fold

Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months

10 mg once daily, 10 days

↑ 7.1-fold

Darolutamide 600 mg twice daily, 5 days

5 mg, single dose

↑ 5.2-fold

Regorafenib 160 mg once daily, 14 days

5 mg, single dose

↑ 3.8-fold

Atazanavir 300 mg / ritonavir 100 mg once daily, 8 days

10 mg, single dose

↑ 3.1-fold

Velpatasvir 100 mg once daily

10 mg, single dose

↑ 2.7-fold

Paritaprevir 150 mg / ombitasvir 25 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days

5 mg, single dose

↑ 2.6-fold

Teriflunomide

No data available

↑ 2.5-fold

Glecaprevir 200 mg / elbasvir 50 mg once daily, 11 days

10 mg, single dose

↑ 2.3-fold

Glecaprevir 400 mg / pibrentasvir 120 mg once daily, 7 days

5 mg once daily, 7 days

↑ 2.2-fold

Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days

20 mg once daily, 7 days

↑ 2.1-fold

Capmatinib 400 mg twice daily

10 mg, single dose

↑ 2.1-fold

Clopidogrel 300 mg, then 75 mg after 24 hours

20 mg, single dose

↑ 2-fold

Fostamatinib 100 mg twice daily

20 mg, single dose

↑ 2-fold

Febuxostat 120 mg once daily

10 mg, single dose

↑ 1.9-fold

Gemfibrozil 600 mg twice daily, 7 days

80 mg, single dose

↑ 1.9-fold

Less than 2-fold increase in rosuvastatin AUC

Dosing regimen of the interacting drug

Rosuvastatin dosing regimen

Changes in rosuvastatin AUC*

Elotrombopag 75 mg once daily, 5 days

10 mg, single dose

↑ 1.6-fold

Darunavir 600 mg / ritonavir 100 mg twice daily, 7 days

10 mg once daily, 7 days

↑ 1.5-fold

Tipranavir 500 mg / ritonavir 200 mg twice daily, 11 days

10 mg, single dose

↑ 1.4-fold

Dronedarone 400 mg twice daily

No data available

↑ 1.4-fold

Itraconazole 200 mg once daily, 5 days

10 mg, single dose

↑ 1.4-fold **

Ezetimibe 10 mg once daily, 14 days

10 mg once daily, 14 days

↑ 1.2-fold **

Decrease in rosuvastatin AUC

Dosing regimen of the interacting drug

Rosuvastatin dosing regimen

Changes in rosuvastatin AUC*

Erythromycin 500 mg four times daily, 7 days

80 mg, single dose

↓ 20%

Baicalin 50 mg three times daily, 14 days

20 mg, single dose

↓ 47%

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

Increase is indicated by ↑, decrease by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; 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 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 or dose increase of rosuvastatin in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation or dose reduction of rosuvastatin may lead to a decrease in INR. In such cases, appropriate monitoring of INR is recommended.

Oral contraceptives / hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives increased the 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 receiving rosuvastatin and HRT concurrently; 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

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

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

Children

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

Special precautions for use

Renal effects

Proteinuria detected by 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 serious renal events in post-marketing studies was higher with the 40 mg dose. Renal function should be regularly monitored in patients taking the 40 mg dose of this medicinal product.

Effects on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking rosuvastatin, particularly at doses exceeding 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"), and therefore such combination should be used with caution. As with other HMG-CoA reductase inhibitors, the frequency of rhabdomyolysis associated with rosuvastatin in the post-marketing period was higher at the 40 mg dose.

Creatine kinase levels

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

Before starting treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution 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 "Posology and method of administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
  • concomitant use of fibrates.

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

During treatment

Patients should be advised to promptly report 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). If symptoms resolve and CK levels return to normal, therapy may be restarted at the lowest dose with close monitoring, either with the same or an alternative HMG-CoA reductase inhibitor. 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 that persist even after discontinuation of statins.

Statins may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with Sutent should be discontinued. Recurrences have been reported after initial or repeated use of the same or another statin.

In clinical trials, there was no evidence of increased skeletal muscle effects in a small number of patients taking rosuvastatin and concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, the concomitant use of rosuvastatin with gemfibrozil is not recommended. The benefit of further lipid-lowering with rosuvastatin in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated when fibrates are used concomitantly (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin treatment should be discontinued for the entire duration of fusidic acid therapy. 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 therapy is required, e.g., for treatment of severe infections, the need for concomitant use of rosuvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision.

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

Severe skin adverse reactions

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

If a serious reaction such as SJS or DRESS syndrome develops in relation to rosuvastatin use, re-initiation of rosuvastatin therapy in such patients is contraindicated.

Hepatic effects

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

Liver function tests should be performed before starting treatment and again after 3 months. Treatment with rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The number 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 rosuvastatin therapy.

Race

Pharmacokinetic studies indicate approximately twofold higher exposure in Mongoloid race patients 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 combined with ritonavir. Both the benefit of lipid-lowering with the medicinal product in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with dose escalation should be carefully considered. Concomitant use of the medicinal product with certain protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Lactose intolerance

This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, 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

Evidence suggests that statins, as a class, increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus. However, the reduction in cardiovascular risk with statins outweighs this risk, and therefore it should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) require clinical and biochemical monitoring according to current guidelines.

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

Paediatric population

Assessment of linear growth (height), body weight, BMI (body mass index), and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. After 2 years of 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 the ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

This medicinal product contains lactose monohydrate. Patients with known sugar intolerances should consult their physician before taking this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

This medicinal product contains the colouring agent sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive methods.

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 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 has been shown to be excreted into the milk of rats. There are no data on its excretion into human breast milk (see section "Contraindications").

Effects on ability to drive and use machines

No studies on the effects of rosuvastatin on the ability to drive or operate machinery have been conducted. However, given the pharmacodynamic properties of the medicinal product, it is unlikely to affect such ability. Dizziness may occur during treatment, and this should be taken into account when driving or operating machinery.

Dosage and Administration

Prior to initiating therapy, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment. The dose should be individualized depending on the therapeutic goal and the patient's response to treatment, in accordance with current generally accepted guidelines.

Rosuvastatin can be administered 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 been treated with 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 adverse reactions. If necessary, the dose may be increased to the next level after 4 weeks (see section "Pharmacodynamics"). Because adverse reactions occur more frequently with the 40 mg dose than with lower doses (see section "Adverse Reactions"), dose titration up to the maximum dose of 40 mg should be reserved only for patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved treatment goals with a 20 mg dose and who will be under close monitoring (see section "Special Warnings and Precautions for Use"). Close specialist supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

In a clinical trial 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

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 Sutent in patients with severe renal impairment is contraindicated at any dose (see sections "Contraindications" and "Pharmacokinetics").

Patients with Hepatic Impairment

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic impairment scoring 7 or less on the Child-Pugh scale. However, systemic exposure increased in individuals scoring 8 or 9 on the Child-Pugh scale (see section "Pharmacokinetics"). Renal function should be assessed in such patients (see section "Special Warnings and Precautions for Use"). There is no experience with the use of the drug in patients with hepatic impairment scoring more than 9 on the Child-Pugh scale. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Race

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

Genetic Polymorphism

Certain types of genetic polymorphism may lead to increased exposure to rosuvastatin (see section "Pharmacokinetics"). Patients with such polymorphisms are recommended to receive a lower daily dose of the drug.

Patients Predisposed to Myopathy

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

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

Concomitant Use

Rosuvastatin is a substrate of several transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases with concomitant use of rosuvastatin and certain medicinal products that may increase its plasma concentration due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir, and/or tipranavir; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Consideration should be given to using alternative medicinal products and, if necessary, temporarily discontinuing rosuvastatin therapy. If concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit and risk of concomitant use should be carefully weighed, and the rosuvastatin dose should be adjusted accordingly (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

The use of the drug in children should be prescribed only by a specialist.

Children and adolescents aged 6 to 17 years (Tanner stage <II–V).

Heterozygous Familial Hypercholesterolemia

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

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

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 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 to 10 mg once daily, depending on age, body weight, and prior statin use. The dose may be increased up to the maximum of 20 mg once daily 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 maintained throughout treatment.

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

Tablets of 40 mg should not 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, the patient should be treated symptomatically and supportive measures should be taken as needed. Liver function and creatine kinase (CK) levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse Reactions

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

List of adverse reactions

The table below presents the adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are listed by organ systems.

The frequency of adverse reactions is categorized as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Table 3

Adverse reactions based on clinical studies and post-marketing experience

Body systems

Common

Uncommon

Rare

Very rare

Frequency unknown

Blood and lymphatic system disorders

Thrombocytopenia

Immune system disorders

Hypersensitivity reactions, including angioedema

Endocrine disorders

Diabetes mellitus1

Psychiatric disorders

Depression

Nervous system disorders

Headache, dizziness

Peripheral neuropathy, 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 liver transaminase levels

Jaundice, hepatitis

Skin and subcutaneous tissue disorders

Pruritus, rash, urticaria

Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Musculoskeletal and connective tissue disorders

Myalgia

Myopathy (including myositis), rhabdomyolysis,

lupus-like syndrome, muscle rupture

Arthralgia

Tendon disorders, sometimes complicated by ruptures,

immune-mediated necrotizing myopathy

Renal and urinary disorders

Hematuria

Reproductive system and breast disorders

Gynecomastia

General disorders and administration site conditions

Asthenia

Edema

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 mg and 20 mg doses, and in approximately 3% of patients at the 40 mg dose. A slight increase in the frequency of changes from zero or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued therapy. Based on clinical studies 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; according to clinical trial data, its frequency was low.

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; this phenomenon was mostly mild, asymptomatic, and transient. If CK levels are elevated (>5 times the upper limit of normal), treatment should be discontinued (see section "Special precautions for use").

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

With the use of some statins, adverse effects such as sexual dysfunction have been reported; isolated cases of interstitial lung disease, particularly with long-term use, have also been observed (see section "Special precautions for use").

The number of cases of rhabdomyolysis and serious renal and hepatic adverse events (mainly increased hepatic transaminase activity) is higher when the drug is used at the 40 mg dose.

Children. In a 52-week clinical study, 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 children and adolescents compared to adults (see section "Special precautions for use"). 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 medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

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

Keep out of reach of children.

Packaging. 14 tablets per blister pack, 1 or 2 blisters per cardboard box. 15 tablets per blister pack, 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Nobel Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and location of operations. Sancaklar Quarter, Eskisehir Yolu Akcakoca Highway No: 299, 81100 Duzce, Turkey.