Rosuvastatin ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSUVASTATIN IS

Composition:

Active substance: rosuvastatin;

1 tablet contains rosuvastatin calcium 5.2 mg (equivalent to rosuvastatin 5 mg) or rosuvastatin calcium 10.4 mg (equivalent to rosuvastatin 10 mg), or rosuvastatin calcium 20.8 mg (equivalent to rosuvastatin 20 mg), or rosuvastatin calcium 41.6 mg (equivalent to rosuvastatin 40 mg);

Excipients: MicroceLac® 100 (monohydrate lactose, microcrystalline cellulose), calcium hydrogen phosphate dihydrate, crospovidone, sodium hydrogencarbonate, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E 171), triacetin, polysorbate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets.

Pharmacotherapeutic group.

Lipid-lowering agents. HMG-CoA reductase inhibitors. Rosuvastatin. ATC code C10AA07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Rosuvastatin increases the number of low-density lipoprotein (LDL) receptors on the surface of liver cells, enhancing the uptake and catabolism of LDL, and inhibits hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces levels of apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), VLDL cholesterol (VLDL-C), triglyceride-rich VLDL (TG-VLDL), and increases apolipoprotein A-I (ApoA-I) levels (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	Apo B	Apo A-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

The therapeutic effect is achieved within 1 week after initiation of treatment with the medicinal product, and 90 % of the maximum effect is reached within 2 weeks. Maximum therapeutic response 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, gender, or age, as well as in the treatment of patients in special populations, such as those with diabetes mellitus or patients with familial hypercholesterolemia.

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

In a large study involving 435 patients with heterozygous familial hypercholesterolemia treated with rosuvastatin at doses of 20 to 80 mg using an intensive dose-titration regimen, the medicinal product demonstrated favorable effects on lipid parameters and achievement of target levels across all doses. After dose titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C levels decreased by 53 %. The recommended 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 on average by 22 %.

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

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (defined as a 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 rosuvastatin 40 mg once daily or placebo for 2 years. Compared to placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid artery sites by -0.0145 mm/year [95 % confidence interval -0.0196, -0.0093; p < 0.0001]. The change from baseline was -0.0014 mm/year [-0.12 %/year (statistically 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 reduced risk of cardiovascular events has not been demonstrated. This study included patients with low risk of ischemic heart disease, who do not represent the target population for rosuvastatin 40 mg use. The 40 mg dose should be prescribed only to patients with severe hypercholesterolemia and high risk of cardiovascular disorders (see section "Dosage and administration").

In the JUPITER trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin), 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 two groups and received either rosuvastatin 20 mg once daily (n = 8901) or placebo (n = 8901) for a mean duration of 2 years. LDL-C concentrations decreased by 45 % (p < 0.001) in the rosuvastatin group compared to the placebo group.

Post-hoc analysis of data from a high-risk subgroup with a baseline Framingham risk score > 20 % (1558 participants) showed a significant reduction in the incidence of the composite endpoint including cardiovascular death, stroke, and myocardial infarction (p = 0.028) in the rosuvastatin group compared to the placebo group. The absolute risk reduction expressed as event rate was 8.8 cases per 1000 patient-years. The all-cause mortality rate remained unchanged in this high-risk subgroup (p = 0.193). Post-hoc analysis of data from another high-risk subgroup (9302 participants overall) with a baseline SCORE risk ≥ 5 % (extrapolated to include data from participants over 65 years of age) showed a significant reduction in the incidence of the composite endpoint including cardiovascular death, stroke, and myocardial infarction (p = 0.0003) in the rosuvastatin group compared to the placebo group. The absolute risk reduction expressed as event rate was 5.1 cases per 1000 patient-years. The all-cause mortality rate in this high-risk subgroup remained unchanged (p = 0.076).

In the JUPITER trial, 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–V, girls with at least 1 year since onset of menstruation) with heterozygous familial hypercholesterolemia received rosuvastatin 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, 10, and 20 mg groups, respectively, compared to 0.7 % in the placebo group. At the end of the 40-week open-label dose-titration period aimed at achieving target levels (maximum dose 20 mg once daily), the target LDL-C level of < 2.8 mmol/L was achieved in 70 of 173 patients (40.5 %). After 52 weeks of investigational treatment, no effect on growth, body weight, body mass index (BMI), or sexual maturation was observed (see section "Special instructions"). This study (n = 176) is not suitable for comparison of rare adverse reactions.

The efficacy and safety of rosuvastatin were 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, < II–V Tanner stages). The initial dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) had their dose titrated up to a maximum of 10 mg once daily, and patients aged 10 to 17 years (n = 134) up to a maximum 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—6 to < 10 years, 10 to < 14 years, and 14 to < 18 years—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), respectively. Treatment with rosuvastatin at doses of 5, 10, 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, total cholesterol/HDL-C, triglycerides/HDL-C, non-HDL-C/HDL-C, ApoB, and ApoB/ApoA-I. Changes in each of these parameters indicated improved lipid responses and were maintained over 2 years. After 24 months of treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Special instructions").

In a randomized, double-blind, placebo-controlled, multicenter, crossover study, the efficacy of rosuvastatin 20 mg once daily versus placebo was evaluated in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase with diet adherence, during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment period, and a 12-week maintenance phase during which all patients received rosuvastatin 20 mg. Patients receiving ezetimibe or apheresis continued these treatments throughout the study. A statistically significant (p = 0.005) reduction in LDL-C levels (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 were also observed in total cholesterol (20.1 %, p = 0.003), non-HDL-C (22.9 %, p = 0.003), and ApoB (17.1 %, p = 0.024). Reductions in triglycerides, LDL-C/HDL-C 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 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, the reduction in LDL-C was maintained between -12.1 % and -21.3 % up to 90 weeks in 9 of these patients.

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 studies on the use of rosuvastatin in all subgroups of children with homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia, and for the prevention of cardiovascular disorders.

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, primarily to albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (approximately 10 %). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a non-specific 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 % unchanged). The plasma elimination half-life is approximately 19 hours and does not increase with dose escalation. The geometric mean value of plasma clearance of rosuvastatin 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 the 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 gender

No clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults has been observed. Exposure to rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than exposure in adult patients with dyslipidemia (see subsection "Children" of this section).

Race

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

Renal impairment

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

Hepatic impairment

In a study involving 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 to rosuvastatin was at least twice as high as in patients with lower scores. Experience with rosuvastatin use 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. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphic forms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with increased exposure (AUC) of rosuvastatin compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. Specific genotyping is not required in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of rosuvastatin.

Children

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

Clinical characteristics.

Indications.

Treatment of hypercholesterolemia

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

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

Prevention of cardiovascular events

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

Contraindications.

Hypersensitivity to rosuvastatin or to any other component of the medicinal product.

Active liver disease, including persistent elevations of serum transaminases of unknown etiology and any serum transaminase elevations exceeding three times the upper limit of normal (ULN).

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

Myopathy.

Concomitant use of the combination sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of cyclosporine.

Pregnancy or breastfeeding.

The medicinal product is contraindicated 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. Risk factors include:

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

Interaction with other medicinal products and other forms of interaction.

Effect of concomitant medicinal products on rosuvastatin

Inhibitors of transporter proteins

Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transporter proteins may increase plasma concentrations of rosuvastatin and increase the risk of myopathy (see sections "Interaction with other medicinal products and other forms of interaction" (Table 2), "Special warnings and precautions for use", and "Dosage and administration").

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 concomitantly (see section "Contraindications"). Concomitant use of rosuvastatin did not affect plasma concentrations of cyclosporine.

Protease inhibitors

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

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 warnings and precautions for use").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (≥ 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special warnings and precautions for use"). Such patients should also start 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). Pharmacodynamic interaction between rosuvastatin and ezetimibe, potentially leading to adverse effects, cannot be excluded (see section "Special warnings and precautions for use").

Antacid medicinal products

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

Erythromycin

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

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a non-specific substrate of these isoenzymes. Therefore, interactions involving rosuvastatin and other medicinal products due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Ticagrelor

Ticagrelor may affect renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine kinase (CK) levels, and development of rhabdomyolysis.

Interactions requiring rosuvastatin dose adjustment (see Table 2)

When co-administration of rosuvastatin with other medicinal products capable of increasing rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in rosuvastatin exposure (AUC) is expected, rosuvastatin therapy should be initiated at a dose of 5 mg once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting medicinal products; for example, when co-administered with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure), and when co-administered with ritonavir/atazanavir, the dose should be 10 mg (3.1-fold increase in exposure). If a medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction of rosuvastatin is required, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.

Table 2

Effect of concomitant medicinal products on rosuvastatin exposure

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

Increase in rosuvastatin AUC by 2 times or more than 2 times
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + voxilaprevir (100 mg) once daily, 15 days	10 mg, single dose	↑ 7.4-fold
Cyclosporine from 75 mg twice daily to 200 mg twice daily, 6 months	10 mg once daily, 10 days	↑ 7.1-fold
Darolutamide 600 mg twice daily, 5 days	5 mg, single dose	↑ 5.2-fold
Regorafenib 160 mg once daily, 14 days	5 mg, single dose	↑ 3.8-fold
Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days	10 mg, single dose	↑ 3.1-fold
Velpatasvir 100 mg once daily	10 mg, single dose	↑ 2.7-fold
Paritaprevir 150 mg/ombitasvir 25 mg/ ritonavir 100 mg once daily/ dasabuvir 400 mg twice daily, 14 days	5 mg, single dose	↑ 2.6-fold
Teriflunomide	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 single loading dose, then 75 mg after 24 hours	20 mg, single dose	↑ 2.0-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
Gemfibrozil 600 mg twice daily, 7 days	80 mg, single dose	↑ 1.9-fold
Increase in rosuvastatin AUC less than 2-fold
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Elvitegravir 75 mg once daily, 5 days	10 mg, single dose	↑ 1.6-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	Data not available	↑ 1.4-fold
Itraconazole 200 mg once daily, 5 days	10 mg, single dose	↑ 1.4-fold **
Ezetimibe 10 mg once daily, 14 days	10 mg once daily, 14 days	↑ 1.2-fold **
Decrease in rosuvastatin AUC
Dosing regimen of the interacting drug	Dosing regimen of rosuvastatin	Changes in rosuvastatin AUC*
Erythromycin 500 mg four times daily, 7 days	80 mg, single dose	↓ 20%
Baicalin 50 mg three times daily, 14 days	20 mg, single dose	↓ 47%

* Data presented as change by "x" times represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the % difference relative to values observed with rosuvastatin administered alone.

Increases are indicated by the symbol "↑", decreases by "↓".

** Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is indicated in Table 2.

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

Effect of rosuvastatin on concomitant medicinal products

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation of therapy with rosuvastatin or increasing its dose in patients concurrently taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction of its dose may result in 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 norgestrel, respectively. Such increases in plasma concentrations should be considered when selecting the dose of oral contraceptives. Data on the pharmacokinetics of rosuvastatin and hormone replacement therapy agents when co-administered are lacking; therefore, a similar effect cannot be excluded when this combination is used. However, this combination has been widely used in women during clinical trials and was well tolerated.

Other medicinal products

Digoxin

Based on dedicated studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

No interaction studies between rosuvastatin and fusidic acid have been conducted. The risk of developing myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid preparations are co-administered with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) has not yet been established. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination of medicinal products. If systemic fusidic acid therapy is necessary, treatment with rosuvastatin should be discontinued for the entire duration of fusidic acid treatment. See also section "Special precautions".

Children

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

Special precautions for use.

Effect on kidneys

Proteinuria of predominantly tubular origin, detected by urine dipstick testing, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and in most cases was transient or intermittent. 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 of rosuvastatin 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 above 20 mg. Rhabdomyolysis has very rarely been reported with ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be ruled out (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 is higher with the 40 mg dose.

Creatine kinase levels

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

Before starting treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
• alcohol abuse;
• age > 70 years;
• conditions that may lead to increased plasma levels of rosuvastatin (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration");
• concomitant use of fibrates.

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

During treatment

Patients should be informed to promptly report to their physician 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 resolution of symptoms and normalization of CK levels, therapy with rosuvastatin or an alternative 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 elevated serum CK levels, which persist even after discontinuation of statins.

In several cases, statin therapy has been reported to induce de novo myasthenia gravis or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). Treatment with Rosuvastatin IS should be discontinued if symptoms worsen. Recurrences have been reported after re-administration of the same or another statin.

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

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid treatment is considered life-saving, 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 concomitant fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be informed to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid therapy is required, e.g., for treatment of severe infectious diseases, the necessity of concomitant use of rosuvastatin and fusidic acid should be evaluated on a case-by-case basis and conducted 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, and electrolyte disorders, or uncontrolled seizures).

Effect on liver

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

Biochemical liver function tests should be performed before starting treatment and 3 months thereafter. Rosuvastatin should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of reports of serious hepatic events (mainly elevated liver transaminases) in the post-marketing period is higher with the 40 mg dose.

In the post-marketing period of rosuvastatin use, rare cases of liver failure, including fatal cases, have been reported in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develops during rosuvastatin treatment, rosuvastatin should be discontinued immediately. Reinitiation of rosuvastatin therapy should not be considered if no other cause is identified.

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

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with rosuvastatin use, which may be life-threatening or fatal (see section "Adverse reactions"). Before initiating therapy with Rosuvastatin IS, patients should be informed about the signs and symptoms of severe skin reactions. Patients should be closely monitored during treatment for the appearance of such symptoms. If symptoms suggestive of severe skin adverse reactions occur, the medicinal product should be discontinued immediately and alternative treatment considered. Patients who have experienced such serious reactions as Stevens-Johnson syndrome or DRESS syndrome with Rosuvastatin IS should not be rechallenged with the drug.

Race

Pharmacokinetic studies indicate that rosuvastatin exposure is approximately doubled in Mongoloid race patients compared to Caucasian race patients (see sections "Pharmacological properties", "Contraindications", and "Posology and method of administration").

Protease inhibitors

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

Lactose intolerance

This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Lung interstitial 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 in health (increased fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes

Some evidence suggests that statins as a class increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes in the future. 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, body mass index (BMI) > 30 kg/m², elevated triglycerides, hypertension) should be monitored clinically and biochemically according to national guidelines.

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

Children

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

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential must use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis play a crucial role in fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of rosuvastatin use during pregnancy. Animal reproductive toxicity data are limited. If a patient becomes pregnant while taking Rosuvastatin IS, treatment should be discontinued immediately.

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

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of rosuvastatin on the ability to drive or operate machinery have not been conducted. However, given the pharmacodynamic properties of rosuvastatin, it is unlikely that the medicinal product affects this 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 cholesterol-lowering diet, which should be continued throughout the treatment period. The dosage should be individually adjusted based on the therapeutic goal and the patient's response to treatment, in accordance with current accepted guidelines.

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

Hypercholesterolemia Treatment

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously received 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 risk of cardiovascular events, and the likelihood of adverse reactions. If necessary, the dose may be increased to the next level after 4 weeks (see section "Pharmacological Properties"). Due to the higher incidence of adverse reactions with the 40 mg dose compared to lower doses (see section "Adverse Reactions"), dose titration to 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly patients with familial hypercholesterolemia) who have not achieved treatment goals with a 20 mg dose and who will be under regular monitoring (see section "Special Warnings and Precautions for Use"). Medical supervision is recommended when initiating treatment with the 40 mg dose.

Prevention of Cardiovascular Events

In a cardiovascular risk reduction study, rosuvastatin was administered at a dose of 20 mg daily (see section "Pharmacological Properties").

Elderly Patients

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

Patients with Renal Impairment

Dose adjustment is not required for 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 these patients. 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 to rosuvastatin was observed in patients with hepatic impairment scoring 7 or less on the Child-Pugh scale. However, systemic exposure increased in patients scoring 8 or 9 on the Child-Pugh scale (see section "Pharmacological Properties"). Renal function assessment is advisable in such patients (see section "Special Warnings and Precautions for Use"). Experience with rosuvastatin in patients scoring more than 9 on the Child-Pugh scale is lacking. Rosuvastatin is contraindicated in patients with active liver disease (see section "Contraindications").

Race

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

Genetic Polymorphism

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

Patients Predisposed to Myopathy

The recommended initial dose for patients with risk factors for myopathy is 5 mg (see section "Special Warnings and Precautions for Use"). The 40 mg dose is contraindicated in some of these patients (see section "Contraindications").

Concomitant Use

Rosuvastatin is a substrate of various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that may increase rosuvastatin plasma concentrations due to interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"). If possible, alternative medicinal products should be considered, and rosuvastatin therapy may be temporarily interrupted. If concomitant use of these medicinal products with rosuvastatin cannot be avoided, the benefit-risk ratio of concomitant use should be carefully evaluated, and the rosuvastatin dose should be appropriately adjusted (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

Administration of the medicinal product to children should be performed only by a specialist.

Children and Adolescents Aged 6 to 17 Years (˂II–V Tanner Stages)

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

Dosage should be increased according to the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which 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 is 5–10 mg once daily, depending on age, body weight, and prior statin use. The dose may be increased up to the maximum of 20 mg once daily, based on the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special Warnings and Precautions for Use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained throughout treatment.

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

Tablets of 40 mg are not used in children.

Children Under 6 Years of Age

The safety and efficacy of the medicinal product in children under 6 years of age have not been studied. Therefore, the medicinal product is not recommended for use in children under 6 years of age.

Overdose.

There is no specific antidote for overdose. Treatment should be symptomatic, and supportive measures should be taken if necessary. Monitoring of liver function and creatine kinase levels is required. Hemodialysis is unlikely to be effective.

Adverse Reactions

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

Below is the profile of adverse reactions associated with rosuvastatin use, based on clinical trial data and extensive post-marketing experience. Adverse reactions are classified by frequency and by system organ classes.

Frequency categories are defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Nervous system disorders:
Common – headache, dizziness;
Very rare – polyneuropathy, memory loss;
Not known – peripheral neuropathy, sleep disorders (including insomnia and nightmares), myasthenia gravis.

Eye disorders:
Not known – ocular form of myasthenia gravis.

Psychiatric disorders:
Not known – depression.

Gastrointestinal disorders:
Common – constipation, nausea, abdominal pain;
Rare – pancreatitis;
Not known – diarrhea.

Hepatobiliary disorders:
Rare – increased liver transaminase levels;
Very rare – jaundice, hepatitis.

Endocrine disorders:
Common – diabetes mellitus [frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of hypertension)].

Respiratory, thoracic and mediastinal disorders:
Not known – cough, dyspnea.

Blood and lymphatic system disorders:
Rare – thrombocytopenia.

Immune system disorders:
Rare – hypersensitivity reactions, including angioedema.

Skin and subcutaneous tissue disorders:
Uncommon – pruritus, rash, urticaria;
Not known – Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders:
Common – myalgia;
Rare – myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle rupture;
Very rare – arthralgia;
Not known – tendon disorders, sometimes complicated by rupture, immune-mediated necrotizing myopathy.

Renal and urinary disorders:
Very rare – hematuria.

Reproductive system and breast disorders:
Very rare – gynecomastia.

General disorders:
Common – asthenia;
Not known – edema.

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

Renal effects

Proteinuria of predominantly tubular origin, detected by urine dipstick testing, has been observed in patients taking rosuvastatin. Changes in urinary protein content from 0 or trace to "++" or higher were observed in < 1% of patients at certain time points with rosuvastatin doses of 10 and 20 mg, and in approximately 3% at the 40 mg dose. A slight increase in the frequency of changes from 0 or trace to "+" was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously with continued treatment. To date, data from clinical trials and post-marketing surveillance have not established a causal relationship between proteinuria and acute or progressive kidney disease.

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

Musculoskeletal effects

Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, including cases complicated by acute renal failure, have been observed with rosuvastatin at any dose, particularly at doses > 20 mg.

Patients taking rosuvastatin have shown dose-dependent increases in creatine kinase (CK) levels. In most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued (see section "Special warnings and precautions for use").

Hepatic effects

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

Adverse events such as sexual dysfunction have been reported with some statins. Isolated cases of interstitial lung disease, particularly with long-term use, have also been reported (see section "Special warnings and precautions for use").

The frequency of reports of rhabdomyolysis and serious renal and hepatic adverse events (mainly increased hepatic transaminase activity) is higher with rosuvastatin 40 mg.

Paediatric population

Elevated creatine kinase levels > 10 × ULN 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 warnings and precautions for use"). However, the safety profile of rosuvastatin in children was similar to that in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 3 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

"INTERSYM" Limited Liability Company with Additional Liability.

Manufacturer's address and location of operations.

40-A, 21st km of Starokyivska Road, Odesa, Ukraine, 65025.