Roxera film-coated tablets 40 mg blister No. 30

Instructions for Roxera film-coated tablets 40 mg blister No. 30

Composition

active ingredient: 1 film-coated tablet contains 5 mg or 10 mg, or 15 mg, or 20 mg, or 30 mg, or 40 mg of rosuvastatin (as rosuvastatin calcium);

excipients: microcrystalline cellulose, lactose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

film coating: methacrylate copolymer, macrogol 6000, titanium dioxide (E 171), lactose monohydrate.

Dosage form

Film-coated tablets.

Main physicochemical properties:

5 mg: white, round, slightly biconvex, film-coated tablets with beveled edges and engraved with “5” on one side;

10 mg: white, round, slightly biconvex, film-coated tablets with beveled edges and engraved with “10” on one side;

15 mg: white, round, slightly biconvex, film-coated tablets with beveled edges and engraved with “15” on one side;

20 mg: white, round, film-coated tablets with a beveled edge;

30 mg: white, biconvex, film-coated, capsule-shaped tablets with a score on both sides;

40 mg: white, biconvex, film-coated, capsule-shaped tablets.

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors.

ATX 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 LDL receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of VLDL, thus reducing the total number of VLDL and LDL particles.

Pharmacodynamic action

Roxera® reduces elevated LDL-cholesterol, total cholesterol, and triglycerides and increases HDL-cholesterol levels. It also reduces apoB, non-HDL-C, VLDL-C, TG-VLDL-C, and increases apoA-I levels (Table 1). Roxera® 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 percentage change from baseline)

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

Clinical efficacy and safety

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

According to the pooled data of phase III studies, Roxera® effectively reduced cholesterol levels in the majority of patients with hypercholesterolemia type IIa and IIb (mean initial LDL-C level approximately 4.8 mmol/l) to the target values established by the recognized guidelines of the European Atherosclerosis Society (EAS; 1998); approximately 80% of patients taking the drug at a dose of 10 mg were able to achieve the normative target levels of LDL-C according to EAS (<3 mmol/l).

In a large study, 435 patients with heterozygous familial hypercholesterolemia received Roxera® in doses from 20 to 80 mg according to the scheme of increased dose titration. The beneficial effect of the drug on lipid parameters and achievement of target levels was noted 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, normative LDL-C levels were achieved according to EAS (<3 mmol/l).

In an open-label, up-titration study, the response to Roxera® at doses of 20–40 mg was studied in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the general population, LDL-C levels decreased 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), a mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but subclinical atherosclerosis (defined as increased carotid intima-media thickness (CIMT)) 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 CIMT at 12 carotid 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. A direct correlation between the reduction in TCIMSA and the reduction in the risk of cardiovascular disorders was not demonstrated. The METEOR study included patients with low risk of coronary heart disease, who are not representatives of the target population for the use of the drug Roxera® at a dose of 40 mg. The 40 mg dose should be prescribed only to patients with severe hypercholesterolemia and a high risk of cardiovascular disorders (see section “Method of administration and dosage”).

In the Rosuvastatin Intervention Trial to Support the Use of Statins as 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 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.

In a post-hoc analysis of the high-risk subgroup of patients with a baseline Framingham score >20% (1558 participants), there was a significant reduction in the incidence of the composite endpoint of cardiovascular death, stroke, and myocardial infarction (p=0.028) in the rosuvastatin group compared with placebo. The absolute risk reduction for events was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc 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), there was 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 an event rate, was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p=0.076).

In the JUPITER trial, 6.6% of rosuvastatin-treated patients and 6.2% of placebo-treated patients discontinued study drug due to adverse events. The most common adverse events leading to discontinuation were myalgia (0.3% rosuvastatin-treated patients, 0.2% placebo-treated patients), abdominal pain (0.03% rosuvastatin-treated patients, 0.02% placebo-treated patients), and rash (0.02% rosuvastatin-treated patients, 0.03% placebo-treated patients). 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).

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 dose-titration period (n=173, 96 male and 77 female participants), patients aged 10–17 years (Tanner stages 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.

After 52 weeks of study treatment, no effect on growth, weight, BMI or puberty was observed (see section 4.4). This study (n=176) is not suitable for comparison of rare adverse events.

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

Peak plasma concentrations of rosuvastatin are reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is extensively metabolized in the liver, which is the primary site of cholesterol synthesis and LDL-cholesterol 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 limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin undergoes only minimal P450-mediated metabolism and that this metabolism is not clinically relevant. CYP2C9 was the major isoenzyme involved in metabolism, with 2C19, 3A4 and 2D6 being involved to a lesser extent. The major metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone form being considered clinically inactive. Rosuvastatin has more than 90% inhibitory activity against HMG-CoA reductase circulating in the general circulation.

Approximately 90% of a rosuvastatin dose is excreted unchanged in the feces (consisting of absorbed and unabsorbed active substance), and the remainder is excreted in the urine. Approximately 5% is excreted unchanged in the urine. The plasma half-life is approximately 20 hours. The half-life does not increase with high doses. The geometric mean plasma clearance is approximately 50 liters/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important for the elimination of rosuvastatin from the liver.

Linearity

Systemic exposure to rosuvastatin increases in proportion to the dose. There is no change in pharmacokinetic parameters after multiple daily administration.

Patient groups

Age and gender

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").

Race

Pharmacokinetic studies demonstrate an approximately 2-fold increase in AUC and Cmax of rosuvastatin in patients of Asian origin (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with patients of the Caucasian race; in Indians, an approximately 1.3-fold increase in mean AUC and Cmax values is observed. Pharmacokinetic analysis of the patient group did not reveal any clinically significant differences in pharmacokinetics between representatives of the Caucasian and Negroid races.

Kidney failure

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

Liver failure

In a study involving 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, at least a 2-fold increase in systemic exposure was observed in two patients with Child-Pugh scores of 8 and 9.

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.521СС and ABCG2 p.421АА polymorphisms, rosuvastatin exposure (AUC) is increased compared to the SLCO1B1 p.521ТТ or ABCG2 p.421СС genotypes. Special genotyping is not provided in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of Roxera®.

Children

Two studies of the pharmacokinetics of rosuvastatin (tablets) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (total of 214 patients) showed that the drug exposure in children was lower or similar to that in adult patients. The exposure of rosuvastatin was predictable according to the dose and duration of administration over 2 years of observation.

Indication

Treatment of hypercholesterolemia

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 inadequate.

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

Prevention of cardiovascular disorders

Prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event, as an adjunct to correction of other risk factors.

Contraindication

Doses of 5 mg, 10 mg, 15 mg and 20 mg are contraindicated:

patients with hypersensitivity to rosuvastatin or to any inactive ingredient;

patients with active liver disease, including those of unknown etiology, persistent elevation of serum transaminases and elevation of any serum transaminase more than 3 times the upper limit of normal;

patients with severe renal impairment (creatinine clearance < 30 ml/min);

patients with myopathy;

patients who are concomitantly taking cyclosporine;

patients taking sofosbuvir/velpatasvir/voxilaprevir concomitantly (see “Interaction with other medicinal products and other types of interactions”);

during pregnancy or breastfeeding, as well as women of reproductive age who do not use appropriate contraception;

children under 6 years old.

Doses of 30 mg and 40 mg are contraindicated:

patients with hypersensitivity to rosuvastatin or to any inactive ingredient;

patients with active liver disease, including unexplained, persistent elevations in serum transaminases and any elevation in serum transaminases greater than 3 times the upper limit of normal;

patients who are concomitantly taking cyclosporine;

during pregnancy or breastfeeding and women of reproductive age who do not use appropriate contraception;

children;

Patients with myopathy or pre-existing risk factors for myopathy/rhabdomyolysis; such factors include: moderate renal impairment (creatinine clearance < 60 ml/min); hypothyroidism; personal or family history of congenital muscle disorders; history of muscle toxicity with another HMG-CoA reductase inhibitor or fibrate; alcohol dependence; situations where plasma levels may be increased (e.g. severe hepatic impairment); Asian descent; concomitant use of fibrates; age over 70 years.

Interaction with other medicinal products and other types of interactions

Rosuvastatin is a substrate for certain transport proteins, including OATP1B1, which provides hepatic transport, and the efflux transporter BCRP. Simultaneous administration of Roxera® with drugs that are inhibitors of these transport proteins may lead to an increase in the concentration of rosuvastatin in the blood plasma and an increase in the risk of myopathy.

When it is necessary to use Roxera® together with other drugs that increase the exposure of rosuvastatin, the dose of Roxera® should be adjusted. It should be started with a dose of 5 mg once a day if an increase in exposure (AUC) of approximately 2 times or more is expected. The maximum daily dose of Roxera® should be adjusted so that the expected exposure of rosuvastatin does not exceed the concentration observed when taking a daily dose of 40 mg of Roxera® in the absence of drug interactions. For example, a dose of 5 mg of Roxera® with simultaneous use with cyclosporine (7.1-fold increase in exposure), a dose of 10 mg of Roxera® with simultaneous use with a combination of ritonavir/atazavir (3.1-fold increase), and a dose of 20 mg of Roxera® with simultaneous use with gemfibrozil (1.9-fold increase).

Antacids

Co-administration of rosuvastatin with an antacid suspension containing aluminum and magnesium hydroxide resulted in a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect was reduced when the antacid was taken 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Fenofibrates, fibric acid derivatives

Although no pharmacokinetic interaction has been observed between rosuvastatin and fenofibrate, a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate and other fibric acids, including nicotinic acid, may increase the risk of myopathy when administered concomitantly with HMG-CoA reductase inhibitors.

Cyclosporine

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

Concomitant use did not affect the plasma concentrations of cyclosporine.

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of treatment with Roxera® or gradual dose increase in patients concomitantly receiving vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants) may lead to an increase in the International Normalized Ratio (INR). After discontinuation of Roxera® or dose reduction, INR may decrease. In such cases, it is advisable to monitor INR appropriately. In patients receiving vitamin K antagonists, it is recommended to monitor INR both at the beginning of treatment with Roxera® and after discontinuation or with subsequent dose changes.

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 AUC and Cmax of rosuvastatin by approximately 3 and 7 times, respectively. The simultaneous use of Roxera® and some combinations of protease inhibitors is possible after careful consideration of the dose adjustment of Roxera®, 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 drugs

Based on data from specific interaction studies, no significant pharmacokinetic interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and niacin (nicotinic acid) in lipid-lowering doses (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they can lead to myopathy when used alone. The dose of Roxera® 40 mg is contraindicated with concomitant use of fibrates.

Treatment with Roxera® in such cases should also be started with a dose of 5 mg.

Ezetimibe

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

Erythromycin

Simultaneous use of Roxera® and erythromycin reduced the AUC(0-t) of rosuvastatin by 20% and Cmax by 30%. This interaction may be caused by increased intestinal peristalsis due to the action of erythromycin.

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).

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 ↓.

Drugs/combinations that did not have a clinically significant effect on the AUC ratio of rosuvastatin when used simultaneously: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days 3 times a day; fluconazole 200 mg for 11 days 1 time a day; fosamprenavir 700 mg / ritonavir 100 mg for 8 days 2 times a day; ketoconazole 200 mg for 7 days 2 times a day; rifampin 450 mg for 7 days 1 time a day; silymarin 140 mg for 5 days 3 times a day.

Oral contraceptives/hormone replacement therapy (HRT)

The simultaneous use of Roxera® and oral contraceptives led to an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. The increase in plasma levels should be taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of the drugs in patients taking Roxera® and HRT simultaneously, so the possibility of interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicines

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

In clinical studies, Roxera® was used concomitantly with antihypertensive, antidiabetic agents, and hormone replacement therapy. These studies did not show any evidence of clinically significant adverse interactions.

Fusidic acid

The risk of myopathy, including rhabdomyolysis, may be increased by concomitant systemic use of fusidic acid with statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is not yet known. There have been reports of rhabdomyolysis (including fatal outcomes) in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin should be discontinued for the duration of fusidic acid treatment.

Lopinavir/ritonavir

In a pharmacological study, concomitant use of Roxera® and a combination drug containing two protease inhibitors (lopinavir 400 mg/ritonavir 100 mg) in healthy volunteers was associated with an approximately two-fold and five-fold increase in steady-state AUC(0-24) and Cmax for rosuvastatin, respectively. Interactions between Roxera® and other protease inhibitors have not been studied.

Ticagrelor

Ticagrelor may cause renal failure and affect the renal excretion of rosuvastatin, increasing the risk of rosuvastatin accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has resulted in decreased renal function, increased CPK levels, and rhabdomyolysis. Monitoring of renal function and CPK is recommended when ticagrelor and rosuvastatin are used concomitantly.

Children

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

Application features

Effects on the kidneys

In patients taking Roxera® in high doses, especially 40 mg, cases of proteinuria (determined by the "strip test"), mainly tubular in origin and in most cases temporary or short-lived, have been reported. Proteinuria did not indicate acute or progressive renal disease. Adverse renal events in the post-marketing period were more common with the 40 mg dose. In patients taking the drug in a dose of 30 or 40 mg, renal function should be checked regularly.

Effects on skeletal muscles

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients taking all doses of Roxera®, and especially at doses above 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded, and therefore such a combination should be used with caution.

As with other HMG-CoA reductase inhibitors, cases of rhabdomyolysis associated with the use of Roxera® in the post-marketing period occurred more often at a dose of 40 mg. There are reports of rare cases of immune-mediated necrotizing myopathy, clinically manifested by persistent proximal muscle weakness and increased levels of