Rosustar tablets 20 mg No. 30

Instructions for Rosustar tablets 20 mg No. 30

Composition

active ingredient: rosuvastatin;

1 film-coated tablet contains rosuvastatin (as rosuvastatin calcium) 10 mg, 20 mg or 40 mg;

Excipients: lactose monohydrate; microcrystalline cellulose (type 102); calcium hydrogen phosphate; crospovidone; magnesium stearate;

Opadry® II Pink 85F240091 film coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, iron oxide red (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties:

10 mg - round, biconvex, pink film-coated tablets, engraved with “RS 10” on one side and plain on the other;

20 mg - round biconvex tablets, film-coated, pink, engraved with “RS 20” on one side and plain on the other;

40 mg - round, biconvex, pink film-coated tablets, engraved with "RS 40" on one side and plain on the other.

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors. ATC code C10A A07.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, a target organ for lowering 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 the hepatic synthesis of very low-density lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic action

Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol, and triglycerides and increases high-density lipoprotein (HDL) cholesterol. It also reduces apolipoprotein B (apoB), non-HDL-cholesterol (C), VLDL-C, triglycerides (TG) and increases apolipoprotein A (apoA-I) (Table 1). Rosuvastatin also reduces the LDL-C/HDL-C, total-C/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I ratios.

Table 1 Dose response in patients with primary hypercholesterolemia types IIa and IIb (adjusted mean percent change from baseline)

The therapeutic effect is achieved within 1 week after the start of rosuvastatin use, 90% of the maximum effect is achieved after 2 weeks. The maximum effect is usually achieved after 4 weeks and continues thereafter.

Clinical efficacy.

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

In pooled phase III studies, rosuvastatin effectively reduced cholesterol levels in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C of approximately 4.8 mmol/L) to the target values established by the recognized guidelines of the European Association for the Study of Atherosclerosis (EAS; 1998); approximately 80% of patients taking rosuvastatin 10 mg achieved the EAS target LDL-C (<3 mmol/L).

In a large study, 435 patients with heterozygous familial hypercholesterolemia received rosuvastatin in doses ranging from 20 to 80 mg in an up-titration regimen. Favorable effects 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%. In 33% of patients, normal LDL-C levels were achieved by EAS (< 3 mmol/L).

In an open-label, up-titration study, the response to rosuvastatin 20-40 mg was studied in 42 patients with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels were reduced by an average of 22%.

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of coronary heart disease (defined as Framingham risk < 10% over 10 years), mean LDL-C 4.0 mmol/L (154.5 mg/dL), but subclinical atherosclerosis (defined as increased carotid intima-media thickness – CIMST) were randomized to receive either 40 mg rosuvastatin or placebo once daily for 2 years. Compared with placebo, rosuvastatin significantly slowed the progression of maximum CIMST 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 insignificant) in the rosuvastatin group compared to a progression of +0.0131 mm/year (1.12%/year, p<0.0001) in the placebo group. No direct correlation between the reduction in TCIMSA and the reduction in the risk of cardiovascular events was demonstrated. The METEOR study enrolled patients with low risk of coronary heart disease who were not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should only be used in patients with severe hypercholesterolemia and high risk of cardiovascular events (see section “Method of administration and dosage”).

In the Rosuvastatin Intervention Trial to Support the Use of Statins in Primary Prevention (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular disease was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years).

Study participants were randomly assigned to placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and were followed for an average of 2 years.

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

A retrospective analysis of the high-risk subgroup of patients with a baseline Framingham score >20% (1558 participants) showed a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction (p = 0.028) in the rosuvastatin group compared with 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). A retrospective analysis of the high-risk subgroup (9302 participants in total) with a baseline SCORE score ≥ 5% (extrapolated to include participants over 65 years of age) showed a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction (p = 0.0003) in the rosuvastatin group compared with placebo. The absolute risk reduction, expressed as the 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 rosuvastatin-treated patients and 6.2% of placebo-treated patients discontinued rosuvastatin due to adverse events. The most common adverse events leading to discontinuation were myalgia (0.3% rosuvastatin, 0.2% placebo), abdominal pain (0.03% rosuvastatin, 0.02% placebo), and rash (0.02% rosuvastatin, 0.03% placebo). The most common adverse events observed in the rosuvastatin group at a frequency greater than or equal to that observed 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).

Special patient groups.

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 rosuvastatin titration period (n = 173, 96 male and 77 female participants), patients aged 10-17 years (Tanner stage II-IV, girls who had started menstruating at least 1 year ago) 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 the beginning of the study, approximately 30% of patients were aged 10-13 years and approximately 17%, 18%, 40% and 25% of them were in Tanner stages II, III, IV and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0%, respectively, in the rosuvastatin 5, 10, and 20 mg groups compared with 0.7% in the placebo group.

At the end of the 40-week open-label dose titration period to target (maximum dose was 20 mg once daily), 70 of 173 patients (40.5%) achieved a target LDL-C level of less than 2.8 mmol/L.

Rosuvastatin was also studied in a 2-year, open-label, target-titration study in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female, Tanner stage

After 24 months of treatment with rosuvastatin, the least squares mean reduction from baseline in LDL-C was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least squares mean reduction from baseline in LDL-C was -43% (baseline: 234 mg/dL, month 24: 124 mg/dL), -45% (baseline: 234 mg/dL, month 24: 124 mg/dL), and -35% (baseline: 241 mg/dL, month 24: 153 mg/dL) in the age groups 6 to <10, 10 to <14, and 14 to <18 years, respectively.

Rosuvastatin 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total-C, non-HDL-C, LDL-C/HDL-C, total-C/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, apoB, apoB/apoA-1. Each of these changes demonstrated improvements in lipid responses and were maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI or puberty was observed (see section 4.4).

A randomized, double-blind, placebo-controlled, multicenter, crossover study evaluated rosuvastatin 20 mg once daily versus placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included an active 4-week dietary lead-in phase during which patients were treated with rosuvastatin 10 mg, a crossover phase consisting of a 6-week period of rosuvastatin 20 mg with or without a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received rosuvastatin 20 mg. Patients receiving ezetimibe or apheresis continued to receive this treatment throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. There were also statistically significant reductions in total-C (20.1%, p = 0.003), non-HDL-C (22.9%, p = 0.003), and apoB (17.1%, p = 0.024). Reductions in TG, LDL-C/HDL-C, total-C/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo was maintained through 12 weeks of continuous therapy. One patient had further reductions in LDL-C (8.0%), total-C (6.7%), and non-HDL-C (7.4%) after 6 weeks of treatment with dose titration to 40 mg.

During continuation of open-label treatment with rosuvastatin 20 mg, 9 of these patients maintained LDL-C reductions ranging from -12.1% to -21.3% for up to 90 weeks.

In an open-label, up-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction from baseline in LDL-C (21.0%), total-C (19.2%), and non-HDL-C (21.0%) 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 the results of studies with rosuvastatin in all subsets of the paediatric population in homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia and for the prevention of cardiovascular events (see section 4.2 for information on paediatric use).

Pharmacokinetics.

Absorption.

After oral administration, the maximum concentration (Cmax) of rosuvastatin in plasma is reached after approximately 5 hours. Absolute bioavailability is approximately 20%.

Distribution.

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

Metabolism.

Rosuvastatin undergoes minor metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with 2C19, 3A4 and 2D6 playing a somewhat smaller role. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.

Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (absorbed and unabsorbed active substance together), the rest is excreted in the urine. Approximately 5% is excreted in the urine in unchanged form. The half-life from blood plasma is approximately 19 hours and does not increase with increasing dose. The geometric mean plasma clearance is approximately 50 l/h (coefficient of variation - 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs with the participation of the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity.

Systemic exposure (AUC) of rosuvastatin increases in proportion to the dose. With multiple daily administration, pharmacokinetic parameters do not change.

Special patient groups.

Patients of different ages and genders.

There was no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

Patients of different races.

Pharmacokinetic studies have shown that in Asian patients (Japanese, Chinese, Filipino, Vietnamese and Koreans) the median AUC and Cmax values are approximately twice as high as in Caucasians; in Indians the median AUC and Cmax values are increased by approximately 1.3 times. Population pharmacokinetic analysis has not revealed any clinically significant differences between Caucasian and Negroid patients.

Patients with renal impairment.

In a study in patients with varying degrees of renal impairment, no changes in plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in subjects with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), plasma concentrations of rosuvastatin were 3-fold higher and those of the N-desmethyl metabolite were 9-fold higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.

Patients with liver dysfunction.

In a study of patients with varying degrees of hepatic impairment, there was no evidence of increased exposure to rosuvastatin in patients with Child-Pugh scores of 7 or less. However, in 2 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 in patients with Child-Pugh scores greater than 9.

Patients with genetic polymorphism.

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, occurs with the participation of transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms of SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. With certain forms of the SLCO1B1 p.521CC and ABCG2 p.421AA polymorphisms, rosuvastatin exposure is increased compared with the SLCO1B1 p.521TT or ABCG2 p.421CC genotypes. Specific genotyping is not provided in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of rosuvastatin.

Children.

The pharmacokinetic parameters in children with heterozygous familial hypercholesterolemia aged 10 to 17 years have not been fully determined. A small pharmacokinetic study of rosuvastatin (tablet form) in 18 pediatric patients showed that its exposure in children is similar to that in adults. The results also indicate that no significant dose-proportional deviations are expected.

Indication

Treatment of hypercholesterolemia.

Use in adults, adolescents and children aged 6 years and over with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet when diet and other non-pharmacological measures (e.g. exercise, weight loss) are insufficient.

Use in adults, adolescents and children aged 6 years and over with homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering agents (e.g. LDL apheresis) or in cases where such treatment is inappropriate.

Prevention of cardiovascular disorders.

Use to prevent major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see Pharmacodynamics), as an adjunct to correction of other risk factors.

Contraindication

Hypersensitivity to rosuvastatin or any of the excipients of the drug.

Active liver disease, including persistent elevations of plasma transaminases of unknown etiology and any elevation of plasma transaminases greater than three times the upper limit of normal (ULN).

Severe renal impairment (creatinine clearance < 30 ml/min).

Myopathy.

Concomitant use of cyclosporine.

Concomitant use of the combination of sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”).

Pregnancy.

Use in women of reproductive age who are not using adequate contraception.

Rosuvastatin 40 mg is contraindicated in patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:

moderate renal impairment (creatinine clearance < 60 ml/min);

hypothyroidism;

presence of a personal or family history of hereditary muscle diseases;

history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;

alcohol abuse;

situations that may lead to an increase in the concentration of rosuvastatin in the blood plasma;

belonging to the Asian race;

simultaneous use of fibrates (see sections "Special instructions for use", "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 medications on rosuvastatin.

Inhibitors of transport proteins.

Rosuvastatin is a substrate for several transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2, 4.4, and 4.5).

Cyclosporine.

When co-administered with cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Concomitant use of these agents is contraindicated (see section "Contraindications"). Co-administration with rosuvastatin did not affect the plasma concentration 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, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in rosuvastatin AUC and Cmax by approximately 3- and 7-fold, respectively. Concomitant use of rosuvastatin and some combinations of protease inhibitors is possible after careful consideration of rosuvastatin dose adjustment based on the expected increase in rosuvastatin exposure (see sections “Method of administration and dosage”, “Special instructions for use”, “Interaction with other medicinal products and other forms of interaction”, Table 2).

Gemfibrozil and other lipid-lowering agents.

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

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but 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, probably because they can cause myopathy when used alone. Concomitant use of rosuvastatin 40 mg and fibrates is contraindicated (see sections 4.3 and 4.4). In such patients, rosuvastatin should be started at a dose of 5 mg.

Ezetimibe.

Concomitant administration of rosuvastatin 10 mg and ezetimibe 10 mg to patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse reactions, cannot be excluded (see section 4.4).

Antacids.

Concomitant use with antacid suspensions containing aluminum or magnesium hydroxide reduced the plasma concentration 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.

Co-administration with erythromycin decreased rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility due to erythromycin.

Ticagrelor.

Concomitant use with ticagrelor may cause renal failure and may affect the renal excretion of rosuvastatin, increasing the risk of its accumulation. In some cases, the combined use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when these agents are used concomitantly.

Cytochrome P450 enzymes.

In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for 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).

If it is necessary to use rosuvastatin with other drugs that can increase the exposure of rosuvastatin, the dose of rosuvastatin should be adjusted. If it is expected that the exposure (AUC) of rosuvastatin will increase by approximately 2 or more times, its use should be started at a dose of 5 mg 1 time per day. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure of rosuvastatin does not exceed the exposure observed when taking a dose of 40 mg / day without the use of drugs that interact with it; for example, when used with gemfibrozil, the dose of rosuvastatin will be 20 mg (an increase in exposure of 1.9 times), when used with the combination of ritonavir / atazanavir - 10 mg (an increase of 3.1 times).

If another drug increases the AUC of rosuvastatin by less than 2 times, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of this drug to more than 20 mg.

Table 2 Effect of concomitant medications on rosuvastatin exposure

(AUC; in descending order of magnitude) from published clinical trial data

* Data presented as x-fold change represents the ratio between rosuvastatin in combination and alone. Data presented as % change represents the % difference relative to rosuvastatin alone.

Increase is indicated by ↑, no change by ↔, decrease by ↓.

** Several interaction studies have been conducted at different doses of rosuvastatin, the most significant relationship is shown in the table.

Effect of rosuvastatin on concomitant medications.

Vitamin K antagonists.

As with other HMG-CoA reductase inhibitors, when starting or increasing the dose of rosuvastatin in patients receiving concomitant vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants), an increase in the international normalized ratio (INR) may occur. Discontinuation of rosuvastatin or dose reduction may lead to a decrease in INR. In such cases, appropriate monitoring of INR is advisable.

Oral contraceptives/hormone replacement therapy (HRT).

Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. This increase should be taken into account when selecting the dose of oral contraceptives. There are no pharmacokinetic data in patients taking rosuvastatin and HRT at the same time, so a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Digoxin.

According to special interaction studies, a clinically significant interaction of rosuvastatin with digoxin is not expected.

Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, is increased when fusidic acid is used concomitantly with statins. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is not yet known. Rhabdomyolysis (including fatalities) has been reported in patients receiving this combination.

If treatment with fusidic acid is necessary, rosuvastatin should be discontinued for the entire duration of fusidic acid treatment (see section "Special warnings and precautions for use").

Special patient groups.

Children.

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

Application features

Effect on the kidneys.

Proteinuria, predominantly of tubular origin, detected by dipstick analysis, has been observed in patients taking higher doses of rosuvastatin, including 40 mg, and in most cases was transient or intermittent. Proteinuria was not a harbinger of acute or progressive renal disease (see section 4.8). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. When using the drug at a dose of 40 mg, renal function should be monitored regularly.

Effect on skeletal muscles.

Skeletal muscle disorders, such as myalgia, myopathy and, rarely, rhabdomyolysis, have been reported in patients taking rosuvastatin at all doses, particularly above 20 mg. Isolated cases of rhabdomyolysis have been reported when ezetimibe was administered in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded (see section 4.5), and therefore this combination should be used with caution.

As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis associated with rosuvastatin in the post-marketing period was higher at the 40 mg dose.

Effect on creatine kinase levels.

Creatine kinase (CK) levels should not be measured after significant exercise or in the presence of possible alternative causes of CK elevation that may complicate interpretation of results. If baseline CK levels are significantly elevated (> 5 times ULN), a repeat test should be performed within 5-7 days to confirm the results. If the repeat test results confirm that baseline CK is greater than 5 times ULN, the drug should not be initiated.

Before starting rosuvastatin.

The drug, like other HMG-CoA reductase inhibitors, should be used with caution in patients with a predisposition to myopathy/rhabdomyolysis. Risk factors for this include:

kidney dysfunction;

hypothyroidism;

presence of a personal or family history of hereditary muscle diseases;

history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;

alcohol abuse;

age > 70 years;

situations that may lead to increased plasma levels of the drug (see sections “Method of administration and dosage”, “Interaction with other medicinal products and other types of interactions” and “Pharmacokinetics”);

concomitant use of fibrates.

In such patients, the risk of treatment should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are significantly elevated (> 5 times the ULN), the drug should not be initiated.

During the period of use of rosuvastatin.

Patients should be asked to report immediately any unexplained muscle pain, weakness or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are significantly