Rosumac

INSTRUCTIONS for medical use of the medicinal product Rosumak (Rosumak®)

Composition:

Active substance: rosuvastatin;

One film-coated tablet contains 5 mg, 10 mg, 20 mg, or 40 mg of rosuvastatin as rosuvastatin calcium;

Excipients: tablet core: microcrystalline cellulose; colloidal anhydrous silicon dioxide; crospovidone; lactose monohydrate; magnesium stearate;

coating: hypromellose; titanium dioxide (E 171); lactose monohydrate; glycerol triacetate; yellow iron oxide (E 172) (for 5 mg tablets); red iron oxide (E 172) (for 10 mg, 20 mg, and 40 mg tablets).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: yellow, round, biconvex, film-coated tablets with an imprint «ROS» above «5» on one side;

10 mg tablets: pink, round, biconvex, film-coated tablets with an imprint «ROS» above «10» on one side;

20 mg tablets: pink, round, biconvex, film-coated tablets with an imprint «ROS» above «20» on one side;

40 mg tablets: pink, oblong, biconvex, film-coated tablets with an imprint «ROS» on one side and «40» on the other side.

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 enzyme that limits the rate of reaction and converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a cholesterol precursor. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol reduction.

Rosuvastatin increases the number of low-density lipoprotein (LDL) receptors on the surface of liver cells, enhancing LDL uptake and catabolism, 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 (TG), and increases high-density lipoprotein cholesterol (HDL-C). It also reduces levels of apolipoprotein B (apoB), non-HDL cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), very low-density lipoprotein triglycerides (VLDL-TG), and increases apolipoprotein A (apoA-I) (see Table 1). Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I.

Table 1

Dose-response in patients with primary hypercholesterolemia type IIa and IIb

(adjusted mean 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 the medicinal product, with 90% of the maximum effect reached within 2 weeks. Maximum effect is usually achieved within 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 patients from special populations, such as those with diabetes mellitus or familial hypercholesterolemia.

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

In a large study involving 435 patients with heterozygous familial hypercholesterolemia, rosuvastatin was administered at doses ranging from 20 mg 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%. The EAS target LDL-C level (<3 mmol/L) was achieved in 33% of patients.

In an open-label dose-titration study, the response to rosuvastatin at doses of 20–40 mg was evaluated in 42 patients (including 8 children) with homozygous familial hypercholesterolemia. In the overall population, LDL-C levels decreased by an average of 22%.

In clinical 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 was observed when used in combination with niacin (see section "Special precautions").

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with a low risk of ischemic heart disease (defined as a Framingham risk score <10% over 10 years), 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 with 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 non-significant)) 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 reduction in cardiovascular event risk has not been demonstrated. The METEOR study included patients with a low risk of ischemic heart disease, who are not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and a high risk of cardiovascular disorders (see section "Dosage and administration").

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular diseases was evaluated in 17,802 men (≥50 years) and women (≥60 years). Study participants were randomly assigned to receive either placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901), with a mean follow-up of 2 years. LDL-C concentration decreased by 45% (p < 0.001) in the rosuvastatin group compared to the placebo group.

In a 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 another high-risk subgroup (9302 participants total) with baseline SCORE risk ≥5% (extrapolated to include data from participants aged 65 years and older), a significant reduction in the incidence of events 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 investigational medicinal product due to adverse reactions. The most common adverse reactions 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 reactions 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 daily 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 (maximum dose: 20 mg once daily) to achieve target levels, 70 out of 173 patients (40.5%) achieved the target LDL-C level of less than 2.8 mmol/L.

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

Rosuvastatin was also evaluated in a 2-year open-label study with target dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female participants, Tanner stage <II–V). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) were titrated to a maximum dose of 20 mg once daily.

After 24 months of rosuvastatin treatment, the least-squares mean reduction in LDL-C from baseline was -43% (baseline: 236 mg/dL, month 24: 133 mg/dL). For each age group, the least-squares mean reduction in LDL-C from baseline 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 the following secondary lipid and lipoprotein variables: HDL-C, total cholesterol, non-HDL-C, LDL-C/HDL-C ratio, total cholesterol/HDL-C ratio, triglycerides/HDL-C ratio, non-HDL-C/HDL-C ratio, apolipoprotein B (apoB), and apoB/apoA-1 ratio. Each of these changes demonstrated improved lipid responses and was maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special precautions").

In a randomized, double-blind, placebo-controlled, multicenter crossover study, rosuvastatin 20 mg once daily was compared with placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase on diet, during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients on ezetimibe or apheresis continued these treatments throughout the study.

A statistically significant (p = 0.005) reduction in LDL-C (22.3%; 85.4 mg/dL or 2.2 mmol/L) was observed after 6 weeks of rosuvastatin 20 mg treatment compared to placebo. Statistically significant reductions in total cholesterol (20.1%, p = 0.003), non-HDL-C (22.9%, p = 0.003), and apoB (17.1%, p = 0.024) were also observed. Reductions in triglycerides, LDL-C/HDL-C ratio, total cholesterol/HDL-C ratio, non-HDL-C/HDL-C ratio, and apoB/apoA-I ratio 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 treatment 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-label dose-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction in LDL-C (21.0%), total cholesterol (19.2%), and non-HDL-C (21.0%) from baseline after 6 weeks of rosuvastatin 20 mg treatment corresponded to that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

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

Pharmacokinetics

Absorption

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

Distribution

Rosuvastatin is significantly 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, predominantly to albumin.

Metabolism

Rosuvastatin undergoes minimal metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-mediated metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from CYP2C19, CYP3A4, and CYP2D6. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitor activity.

Elimination

Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed 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 value of plasma clearance is approximately 50 L/h (coefficient of variation: 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter 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. Exposure to rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than that in adult patients with dyslipidemia (see section "Children").

Race

Pharmacokinetic studies have shown that median values of the area under the concentration-time curve (AUC) and Cmax in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese, and Korean) are approximately twice as high as in Caucasians; in Indian patients, median AUC and Cmax values are approximately 1.3 times higher. Population pharmacokinetic analysis did not reveal clinically significant differences between Caucasian and Negroid patients.

Renal impairment

In a study in 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 N-desmethyl metabolite levels were 9 times higher than in healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing 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 a Child-Pugh score of 7 or less. However, in two patients with Child-Pugh scores of 8 and 9, systemic exposure was at least twice as high as in patients with lower scores. Experience with rosuvastatin in patients with a Child-Pugh score greater than 9 is lacking.

Genetic polymorphism

The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP encoded by the SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genes. Certain variants of these genes, such as SLCO1B1 c.521CC and ABCG2 c.421AA, are associated with approximately 1.6- and 2.4-fold higher rosuvastatin exposure (AUC), respectively, compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. For patients with these genotypes (SLCO1B1 c.521CC or ABCG2 c.421AA), a lower daily dose of rosuvastatin is recommended.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 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 intake over more than 2 years of observation.

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

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

For adults, adolescents, and children aged 6 years and older with homozygous familial hypercholesterolemia, as an adjunct to diet and other lipid-lowering treatments (e.g., LDL apheresis), or when such treatment is inappropriate.

Prevention of cardiovascular disorders

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

Contraindications.

Rosuvastatin is contraindicated:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients of the medicinal product;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any increase in serum transaminases exceeding 3 times the upper limit of normal (ULN);
• in patients with severe renal impairment (creatinine clearance <30 mL/min);
• in patients with myopathy;
• in patients receiving concomitant combination therapy with sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction");
• in patients receiving concomitant cyclosporine;
• during pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures.

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

Factors contributing to this risk include:

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

Interaction with other medicinal products and other forms of interactions.

Effect of concomitant drugs on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin is a substrate for certain 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 "Interaction with other medicinal products and other forms of interactions", "Special precautions for use", and "Dosage and administration", 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 (see section "Contraindications").

Concomitant use did not affect cyclosporine plasma concentrations.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin with certain protease inhibitor combinations may be considered after careful evaluation and dose adjustment of rosuvastatin, based on expected increases in rosuvastatin exposure (see sections "Interaction with other medicinal products and other forms of interactions", "Special precautions for use", and "Dosage and administration", Table 2).

Gemfibrozil and other lipid-lowering agents

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

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

Ezetimibe

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

Antacid medicinal products

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

Erythromycin

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

Ticagrelor

Ticagrelor has been shown to increase rosuvastatin concentrations, potentially increasing the risk of myopathy. The benefit of preventing serious cardiovascular events should be weighed against the risks associated with increased rosuvastatin plasma concentrations.

Cytochrome P450 enzymes

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 mediated by P450 metabolism are not expected. No clinically significant interactions have been observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring dose adjustment of rosuvastatin (see also Table 2)

When co-administration of rosuvastatin with other medicinal products that may increase rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in AUC is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure does not exceed that observed with a 40 mg daily dose in the absence of interacting drugs; for example, when used with gemfibrozil, the rosuvastatin dose would be 20 mg (1.9-fold increase in exposure), and when used with ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required; however, caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increased rosuvastatin AUC by 2-fold or more
Dosing regimen of 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 up 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
Roxadustat 200 mg every other day	10 mg, single dose	↑ 2.9-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Momelotinib 200 mg once daily, 6 days	10 mg, single dose	↑ 2.7-fold
Ticagrelor 90 mg twice daily, 2 days	10 mg, single dose	↑ 2.6-fold
OBV/PTV/r (ombitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily) and dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	Data not 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	↑ 2.0-fold
Febuxostat 120 mg once daily	10 mg, single dose	↑ 1.9-fold
Tafamidis 61 mg twice daily on days 1 and 2, then once daily from day 3 to day 9	10 mg, single dose	↑ 2.0-fold
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increased rosuvastatin AUC less than 2-fold
Dosing regimen of 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	Unknown	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Decreased rosuvastatin AUC
Dosing regimen of 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 % difference relative to values when rosuvastatin is administered alone.

Increases are indicated by ↑, decreases by ↓.

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

Medicinal products/combinations that did not have a clinically significant effect on the rosuvastatin AUC ratio when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg for 7 days, three times daily; fluconazole 200 mg for 11 days, once daily; fosamprenavir 700 mg/ritonavir 100 mg for 8 days, twice daily; ketoconazole 200 mg for 7 days, twice daily; rifampicin 450 mg for 7 days, once daily; silymarin 140 mg for 5 days, three times daily.

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

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

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant administration of rosuvastatin and oral contraceptives resulted in a 26% and 34% increase in AUC of ethinylestradiol and norgestimate, 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, the combination has been widely used in women in clinical studies 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, may be increased when systemic fusidic acid is used concomitantly with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) has not yet been fully elucidated. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving this combination.

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

Paediatric population

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

Special precautions for use.

Effect on kidneys

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

Effect on skeletal muscle

Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking rosuvastatin at any dose, particularly at doses exceeding 20 mg. Rhabdomyolysis has very rarely 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 post-marketing reports of rhabdomyolysis associated with rosuvastatin use was higher at the 40 mg dose.

Creatine kinase levels

Creatine kinase (CK) levels should not be measured following significant physical exertion or in the presence of other possible alternative causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (>5 times the upper limit of normal [ULN]), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK levels exceed 5 times the ULN, initiation of the medicinal product is not recommended.

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

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

During treatment

Patients should be advised to report immediately any unexplained muscle pain, weakness, or cramps, 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 ≤ 5 × ULN). After symptoms resolve and CK levels return to normal, therapy with rosuvastatin or another HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including with rosuvastatin. Clinical manifestations of IMNM include proximal muscle weakness and persistently elevated serum CK levels, even after discontinuation of statin therapy.

In isolated cases, statins, including rosuvastatin, have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, rosuvastatin should be discontinued. Recurrences have been reported upon re-challenge with the same or another statin.

Clinical trials have not shown increased skeletal muscle effects in a small number of patients taking rosuvastatin with concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, 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 of stopping fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be restarted 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid is required, e.g., for treatment of severe infections, the need for concomitant administration 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 indicative of myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with rosuvastatin (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely. If signs or symptoms suggestive of such reactions occur, the drug should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome or DRESS syndrome, treatment with the drug must be discontinued immediately and not restarted.

Effect on liver

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

Biochemical markers of liver function should be assessed before starting treatment and again after 3 months. Rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed three times the ULN. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose.

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

Race

Pharmacokinetic studies indicate increased exposure in patients of Mongoloid race compared to Caucasians (see sections "Pharmacological properties", "Contraindications", and "Dosage and administration").

Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin 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 considered. Concomitant use of the medicinal product with certain protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Lactose intolerance

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

Interstitial lung disease

Rare cases of interstitial lung disease have been reported during treatment with some statins, particularly with long-term use (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and general deterioration (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

Evidence suggests that statins as a class may increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus. However, the reduction in vascular risk with statin use outweighs this risk, and therefore it should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

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

Children

Assessment of linear growth (height), body weight, BMI, and secondary sexual characteristics by Tanner staging in children aged 6 to 17 years treated with rosuvastatin is limited to a 2-year period. After 2 years of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). In a clinical study in children and adolescents treated with rosuvastatin for 52 weeks, CK levels >10 times ULN and muscle symptoms after physical exertion or increased physical activity were reported more frequently than in adults (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any benefit from using the drug during pregnancy. Animal reproductive toxicity data are limited. If a patient becomes pregnant while taking this medicinal product, treatment should be discontinued immediately.

Limited data from published reports suggest that rosuvastatin is present in human breast milk. Rosuvastatin is excreted in rat milk. Due to the mechanism of action of rosuvastatin, there is a potential risk of adverse reactions in the breastfed infant. Rosuvastatin is contraindicated during breastfeeding. No effect on fertility has been observed after rosuvastatin use.

Ability to drive and use machines

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

Method of administration and dosage.

Before initiating treatment, patients should be placed on a standard hypocholesterolemic diet, which must be maintained throughout the treatment period. The dosage should be individually adjusted depending on the therapeutic goal and the patient's response to treatment, in accordance with current generally accepted guidelines.

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

Hypercholesterolemia treatment

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

Cardiovascular disorder prevention

In the cardiovascular risk reduction study, the drug was administered at a dose of 20 mg per day (see section "Pharmacodynamics").

Elderly patients

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

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. Rosuvastatin is contraindicated in patients with severe renal impairment at any dose (see sections "Pharmacological properties" and "Contraindications").

Patients with hepatic impairment

No increase in systemic exposure of 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 "Pharmacological properties"). Renal function assessment is advisable in such patients (see section "Special precautions"). There is no experience with the use of the drug in patients scoring more than 9 points 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 "Pharmacological properties", "Contraindications", and "Special precautions"). The recommended initial dose for patients of Mongoloid race is 5 mg; the 40 mg dose is contraindicated in these patients.

Genetic polymorphism

Genotypes SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown to be associated with increased rosuvastatin exposure. For patients with known c.521CC or c.421AA genotypes, half the usual recommended dose is recommended, with a maximum rosuvastatin dose of 20 mg once daily (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics").

Patients predisposed to myopathy

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

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

Concomitant use

Rosuvastatin is a substrate of various transport proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that may increase rosuvastatin plasma concentrations due to interactions with these transport proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). Alternative medicinal products should be considered if possible, and rosuvastatin therapy may be temporarily interrupted if necessary. 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 drug should be administered to children only by a specialist.

Children and adolescents aged 6 to 17 years (Tanner stage ˂II-V).

Heterozygous familial hypercholesterolemia

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

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

The dose should be increased according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special precautions"). A standard hypocholesterolemic diet should be prescribed to children and adolescents before initiating rosuvastatin therapy and should be maintained throughout treatment.

Homoygous 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 ranges from 5 mg to 10 mg once daily, depending on age, body weight, and prior statin use. Dose escalation to the maximum of 20 mg once daily should be based on the individual child's response to treatment and drug tolerability, following pediatric treatment recommendations (see section "Special precautions"). A standard hypocholesterolemic diet should be prescribed to children and adolescents before initiating rosuvastatin therapy and maintained throughout treatment.

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

The 40 mg tablets are not 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, rosuvastatin is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote for overdose. In case of overdose, symptomatic treatment and supportive measures should be initiated as necessary. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be effective.

Adverse reactions.

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

Table 3 presents the adverse reaction profile of rosuvastatin based on data from clinical studies and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ classes (SOC).

Adverse reactions are categorized by frequency as follows: common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥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 data from clinical studies and post-marketing experience

System organ class	Common	Uncommon	Rare	Very rare	Frequency not known
Blood and lymphatic system disorders			Thrombocytopenia
Immune system disorders			Hypersensitivity reactions, including angioneurotic edema
Endocrine disorders	Diabetes mellitus1
Psychiatric disorders					Depression
Nervous system disorders	Headache, dizziness			Polyneuropathy, memory loss	Peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis
Respiratory, thoracic and mediastinal disorders					Cough, dyspnea
Eye disorders					Ocular myasthenia
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-induced eosinophilia with 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 ≥5.6 mmol/L, BMI >30 kg/m², elevated TG 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 urine 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 while continuing therapy. To date, based on clinical trials and post-marketing surveillance, no causal relationship has been established between proteinuria and acute or progressive kidney disease.

Hematuria has been reported during rosuvastatin treatment; however, its frequency was low according to clinical trial data.

Skeletal muscle effects

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

In patients taking rosuvastatin, dose-dependent increases in creatine kinase (CK) levels have been observed; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (>5 times the upper limit of normal), treatment should be discontinued (see section "Special precautions").

Hepatic effects

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

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

Sexual dysfunction.

Isolated cases of interstitial lung disease, particularly with long-term use (see section "Special precautions").

The frequency of reports 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

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

Reporting of adverse reactions after drug registration is highly important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and location of operations.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.