Rosuvastatin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSUVASYN (ROSUVASIN)

Composition:

Active substance: rosuvastatin;

1 tablet contains rosuvastatin 5 mg or 10 mg or 20 mg or 40 mg (as rosuvastatin calcium);

Excipients: lactose monohydrate; microcrystalline cellulose; crospovidone; magnesium stearate; colloidal anhydrous silicon dioxide; film coating: hydroxypropylmethylcellulose; hydroxypropylcellulose; polyethylene glycol; titanium dioxide (E 171); iron oxide yellow (E 172) (for 5 mg); iron oxide red (E 172) (for 10, 20 and 40 mg).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets – yellow, round, biconvex, film-coated tablets with "5" engraved on one side;

10 mg tablets – pink, round, biconvex, film-coated tablets with "10" engraved on one side;

20 mg tablets – pink, round, biconvex, film-coated tablets with "20" engraved on one side;

40 mg tablets – pink, oval, biconvex, film-coated tablets with "40" engraved on one side.

Pharmacotherapeutic group.

Lipid-lowering agents. HMG-CoA reductase inhibitors.

ATC code C10A A07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol (CH). The primary site of action of rosuvastatin is the liver, which plays a key role in the regulation of cholesterol levels.

Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, enhancing the uptake and catabolism of LDL, thereby suppressing the synthesis of very-low-density lipoproteins (VLDL), and consequently reducing total LDL and VLDL levels.

Pharmacodynamic effects

Rosuvastatin reduces elevated levels of LDL-cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), while slightly increasing HDL-cholesterol (HDL-C) levels.

It reduces levels of apolipoprotein B (ApoB), non-HDL-C, VLDL-C, TG-VLDL, and slightly increases apolipoprotein A-I (ApoA-I) levels (Table 1). It also reduces the ratios of LDL-C/HDL-C, TC/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)

The therapeutic effect is observed within 1 week after initiation of rosuvastatin therapy; after 2 weeks of treatment, the effect reaches 90% of the maximum possible. The maximum effect is generally achieved by 4 weeks and maintained throughout treatment.

Clinical efficacy

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

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

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

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

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

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of ischemic heart disease (IHD) (defined as a Framingham risk score <10% over 10 years), mean LDL-C 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 rosuvastatin once daily or placebo 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 risk has not been demonstrated. Patients included in the METEOR study had low IHD risk and are not representative of the target population for 40 mg rosuvastatin. The 40 mg dose should only be prescribed to patients with severe hypercholesterolemia and high cardiovascular risk (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=8,901) or rosuvastatin 20 mg once daily (n=8,901) and were followed for a mean of 2 years.

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

In a post-hoc analysis of a high-risk subgroup with baseline Framingham risk score >20% (1,558 participants), a significant reduction in the incidence of the composite endpoint including cardiovascular death, stroke, and myocardial infarction was observed in the rosuvastatin group compared to placebo (p=0.028). The absolute risk reduction was 8.8 events per 1,000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc analysis of another high-risk subgroup (9,302 participants total) with baseline SCORE risk ≥5% (extrapolated to include participants over 65 years of age), a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction was observed in the rosuvastatin group compared to placebo (p=0.0003). The absolute risk reduction expressed as event rate was 5.1 events per 1,000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p=0.076).

In the JUPITER study, 6.6% of participants in the rosuvastatin group and 6.2% in the placebo group discontinued the study drug due to adverse events. The most common adverse events leading to discontinuation were: myalgia (0.3% in the rosuvastatin group, 0.2% in placebo), abdominal pain (0.03% in rosuvastatin, 0.02% in placebo), and rash (0.02% in rosuvastatin, 0.03% in placebo). The most common adverse events observed in the rosuvastatin group with a frequency greater than or equal to that in the placebo group were urinary tract infections (8.7% in rosuvastatin, 8.6% in placebo), nasopharyngitis (7.6% in rosuvastatin, 7.2% in placebo), back pain (7.6% in rosuvastatin, 6.9% in placebo), and myalgia (7.6% in rosuvastatin, 6.6% in placebo).

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 5, 10, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At study initiation, approximately 30% of patients were aged 10–13 years, and approximately 17%, 18%, 40%, and 25% were at Tanner stages II, III, IV, and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0% in the rosuvastatin 5, 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, weight, BMI, or sexual maturation was observed (see section "Special instructions"). Clinical trial experience in children and adolescents is limited, and the long-term effects of rosuvastatin (>1 year) on sexual maturation are unknown. This study (n=176) is not suitable for comparing rare adverse events.

Rosuvastatin was also evaluated in a 2-year open-label study with targeted dose titration in 198 children with heterozygous familial hypercholesterolemia aged 6–17 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 6–9 years (n=64) were titrated up to a maximum dose of 10 mg once daily, and those aged 10–17 years (n=134) up to a maximum of 20 mg once daily.

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

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, total cholesterol/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, ApoB, and ApoB/ApoA-I. 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 instructions").

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 6–17 years) with homozygous familial hypercholesterolemia. The study included a 4-week active run-in phase with diet, during which patients received rosuvastatin 10 mg, followed by a crossover phase consisting of a 6-week treatment period with rosuvastatin 20 mg preceded or followed by a 6-week placebo treatment, and a 12-week maintenance phase during which all patients received 20 mg rosuvastatin. Patients receiving ezetimibe or apheresis continued these treatments throughout the study.

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

During continued open-label treatment with rosuvastatin 20 mg in 9 patients, LDL-C reduction remained between –12.1% and –21.3% up to 90 weeks.

In an open dose-titration study in 7 evaluable children and adolescents (aged 8–17 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 previously mentioned study in children and adolescents with homozygous familial hypercholesterolemia.

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

Pharmacokinetics

Absorption and distribution

Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Bioavailability is approximately 20%. Rosuvastatin is significantly taken up by the liver, the primary site of cholesterol synthesis and LDL-C clearance. Its volume of distribution is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (approximately 10%). Rosuvastatin is not a significant substrate for cytochrome P450 enzyme metabolism. The main isoenzyme involved in rosuvastatin metabolism is CYP2C9. CYP2C19, CYP3A4, and CYP2D6 play minor roles. The main metabolites identified are N-desmethyl and lactone metabolites. N-desmethylrosuvastatin is approximately 50% less active than rosuvastatin, and lactone metabolites are pharmacologically 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 rosuvastatin). The remainder is excreted in urine. The plasma elimination half-life is approximately 19 hours. The half-life does not change with increasing dose. The geometric mean clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves 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 multiple daily doses.

Special patient populations

Age and gender

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

Ethnic groups

Comparative pharmacokinetic studies of rosuvastatin in patients of Mongoloid race living in Asia showed approximately a twofold increase in AUC and Cmax compared to patients of Caucasian race living in Europe and Asia; in Indians, median AUC and Cmax values were increased by approximately 1.3 times. No influence of genetic or environmental factors on the observed differences in pharmacokinetic parameters was identified. Pharmacokinetic analysis across different ethnic groups did not reveal clinically significant differences in pharmacokinetics among Caucasian and Negroid race patients.

Patients with renal impairment

In patients with mild or moderate renal impairment, plasma concentrations of rosuvastatin and N-desmethylrosuvastatin are not significantly altered. In patients with severe renal impairment (creatinine clearance <30 mL/min), plasma concentrations of rosuvastatin are 3 times higher and N-desmethylrosuvastatin 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.

Patients with hepatic impairment

No increase in the elimination half-life of rosuvastatin was observed in patients with Child-Pugh scores of 7 or lower. However, in two patients with Child-Pugh scores of 8 and 9, the half-life was prolonged at least twofold. Experience with rosuvastatin use in patients with Child-Pugh scores above 9 is lacking.

Genetic polymorphism

HMG-CoA reductase inhibitors, including rosuvastatin, bind to transport proteins OATP1B1 and BCRP. Patients with polymorphisms in the SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genes are at risk of increased rosuvastatin exposure. The individual polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with increased rosuvastatin exposure (AUC) by approximately 1.7 and 2.4 times, respectively, compared to the SLCO1B1 c.521TT or ABCG2 genotypes. Routine genotyping in clinical practice is not required, but patients with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.

Children

Two pharmacokinetic studies of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 years (total 214 patients) showed that drug exposure in children was lower or similar to that in adult patients. Rosuvastatin exposure corresponded to predicted values based on 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 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 drug;
• in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any increases in serum transaminases exceeding three times the upper limit of normal (ULN);
• in patients with severe renal impairment (creatinine clearance <30 mL/min);
• in patients with myopathy;
• in patients concurrently receiving the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
• in patients concurrently receiving cyclosporine;
• during pregnancy or 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 associated with such risk include:

• moderate renal impairment (creatinine clearance <60 mL/min);
• hypothyroidism;
• personal or family history of hereditary muscular 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 "Special precautions", "Interaction with other medicinal products and other types of interactions", and "Pharmacokinetics").

Interaction with other medicinal products and other types of interactions.

Effect of concomitant drugs on rosuvastatin

Inhibitors of transporter proteins

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

Cyclosporine

During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients who are concurrently 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 and 100 mg ritonavir) in healthy volunteers was associated with increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin with certain combinations of protease inhibitors may be possible after careful consideration of rosuvastatin dose adjustment based on the expected increase in rosuvastatin exposure (see sections "Dosage and administration", "Special precautions", "Interaction with other medicinal products and other types of interactions", Table 2).

Gemfibrozil and other lipid-lowering agents

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

Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (> or equal to 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 when used concomitantly with fibrates (see sections "Contraindications" and "Special precautions"). Such patients should also initiate therapy with a 5 mg dose.

Ezetimibe

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

Antacids

Concomitant use of rosuvastatin with suspensions of antacids containing aluminum 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 intestinal motility caused by erythromycin.

Ticagrelor

Ticagrelor may cause 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 impaired renal function, elevated creatine phosphokinase levels, and rhabdomyolysis.

Cytochrome P450 enzymes

Results from in vitro and in vivo studies indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions with 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).

Interactions requiring rosuvastatin dose adjustment (see also 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 drug 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 rosuvastatin exposure does not exceed that observed with a 40 mg/day dose in the absence of interacting drugs; for example, when used with gemfibrozil, the rosuvastatin dose should be 20 mg (1.9-fold increase in exposure), when used with the ritonavir/atazanavir combination, 10 mg (3.1-fold increase in exposure).

If a medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the dose of Rosuvasin 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

* Data presented as a change in fold represent the ratio between administration of rosuvastatin in combination versus alone. Data presented as % change represent the % difference relative to values when rosuvastatin is administered alone.

An increase is indicated by ↑, no change by ↔, and a decrease by ↓.

** Several interaction studies were conducted at different doses of rosuvastatin; the most significant ratio is presented in the table.

Medicinal products/combinations that showed no clinically significant effect on the AUC ratio of rosuvastatin when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg three times daily for 7 days; fluconazole 200 mg once daily for 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; ketoconazole 200 mg twice daily for 7 days; rifampicin 450 mg once daily for 7 days; silymarin 140 mg three times daily for 5 days.

Effect of rosuvastatin on concomitant medicinal products.

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, initiation 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 drugs in patients concurrently receiving rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicinal products

Digoxin

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

Fusidic acid

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

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 for use".

Paediatric population

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

Special precautions for use.

Renal effects

Proteinuria, detected by urine dipstick testing and predominantly of tubular origin, has been observed in patients treated with higher doses of Rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in most cases. Proteinuria was not a predictor of acute or progressive 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 taking the medicinal product at a dose of 40 mg.

Effects on skeletal muscle

Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with all doses of rosuvastatin, particularly at doses exceeding 20 mg. Cases of rhabdomyolysis have very rarely been reported when ezetimibe is used in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded; therefore, such combination should be used with caution.

As with other HMG-CoA reductase inhibitors, cases of rhabdomyolysis associated with rosuvastatin have occurred more frequently 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 possible alternative causes of elevated enzyme levels, which may interfere with interpretation of results. If initial CK levels are markedly elevated (> 5 × ULN) within 5–7 days, a confirmatory test should be performed. If the repeat test confirms an initial level > 5 × ULN, treatment should not be initiated.

Before treatment

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

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscular disorders;
• history of myotoxicity caused by 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 "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
• concomitant use of fibrates.

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

During treatment

Patients should be advised to report immediately any unexplained muscle pain, muscle weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be determined. Treatment should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause discomfort in daily life (even if CK levels ≤ 5 × ULN). If symptoms resolve and CK levels return to normal, Rosuvastatin or an alternative HMG-CoA reductase inhibitor may be reinitiated at the lowest dose and under close monitoring. Routine monitoring of CK levels in patients without the aforementioned symptoms is not required.

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 creatine kinase levels that persist even after discontinuation of statins.

There have been reports that statins, including rosuvastatin, may induce or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with Rosuvastatin should be discontinued. Recurrences have been reported upon initial or repeated use of the same or another statin.

In clinical studies, no increased effect on skeletal muscle was observed in a small number of patients taking rosuvastatin and concomitant medications. However, an increased frequency 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 coadministered with certain HMG-CoA reductase inhibitors; therefore, Rosuvastatin is not recommended for use in combination with gemfibrozil. The potential additional benefit on lipid levels when Rosuvastatin is used concomitantly with fibrates or niacin should be weighed against the potential risks of such combination therapy. Concomitant use of Rosuvastatin at a dose of 40 mg with fibrates is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Rosuvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin 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 a combination of fusidic acid and statins (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy may be resumed seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid therapy is required, e.g., for the treatment of severe infections, concomitant use of Rosuvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision.

Rosuvastatin should not be administered to patients with acute, serious conditions that predispose to myopathy or increase the risk of renal failure secondary to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Severe cutaneous adverse reactions

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

If a serious reaction such as SJS or DRESS develops in association with Rosuvastatin use, re-administration of Rosuvastatin to that patient is contraindicated.

Hepatic effects

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.

Liver function should be assessed before starting treatment and again after 3 months of therapy. Rosuvastatin should be discontinued if serum transaminase levels exceed three times the upper limit of normal (ULN). Serious hepatic disorders (predominantly elevated hepatic transaminases) have been reported more frequently with the 40 mg dose.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of the underlying condition should be initiated before starting Rosuvastatin.

Race

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

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 in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Interstitial lung disease

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

Diabetes mellitus

Evidence suggests that statins 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 should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.0 mmol/L, BMI >30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to national guidelines.

In the JUPITER study, 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 (body mass index), and secondary sexual characteristics according to Tanner in children aged 6 to 17 years taking rosuvastatin is limited to a 2-year period. After 2 years of study 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 following physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse reactions").

Lactose intolerance

The product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

Rosuvastatin is contraindicated during pregnancy and breastfeeding.

Women of childbearing potential should use appropriate contraceptive methods during treatment with Rosuvastatin.

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

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

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, it is unlikely that Rosuvastatin will affect this ability. Dizziness during treatment should be considered when driving or operating machinery.

Dosage and Administration

Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout treatment. The dose should be individualized based on therapeutic goals and treatment efficacy, following established guidelines.

Rosuvastatin can be taken at any time of day, with or without food.

The tablet should not be chewed or crushed; it should be swallowed whole with water.

Hypercholesterolemia treatment

The recommended initial dose is 5 or 10 mg orally once daily, both for patients who have not previously used statins and for those who have used other HMG-CoA reductase inhibitors. The choice of initial dose should take into account the patient's individual cholesterol levels, future cardiovascular risk, and the potential risk of adverse reactions (see below). If necessary, the dose may be increased after 4 weeks to the next level. Since adverse reactions occur more frequently with the 40 mg dose than with lower doses, dose titration up to the maximum of 40 mg should be reserved only for patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved the desired response with a 20 mg dose and who require regular monitoring. Specialist supervision is recommended when initiating the 40 mg dose.

Prevention of cardiovascular disorders

In clinical trials evaluating reduction of cardiovascular complications, the daily dose of the drug was 20 mg.

Use in elderly patients

The recommended initial dose for patients aged over 70 years is 5 mg. No other dose adjustments based on age are required.

Dosing in patients with renal impairment

No dose adjustment is necessary for patients with mild to 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.

Dosing in patients with hepatic impairment

No increase in systemic exposure to rosuvastatin has been observed in patients with Child-Pugh class 7. However, increased systemic exposure has been noted in patients classified as Child-Pugh class 8 and 9. Renal function should be assessed in such patients. There is no experience with the use of the drug in patients with Child-Pugh class above 9. Rosuvastatin is contraindicated in patients with active liver disease.

Race

Increased systemic exposure to the drug has been observed in patients of Mongolian race. The recommended initial dose for patients of Mongolian race is 5 mg. The 40 mg dose is contraindicated in these patients.

Genetic polymorphism

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

Dosing in patients predisposed to myopathy

The recommended initial dose for patients predisposed to myopathy is 5 mg. The 40 mg dose is contraindicated in some of these patients.

Concomitant use

Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when Rosuvastatin is taken concomitantly with certain medicinal products capable of increasing rosuvastatin plasma concentrations through interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir). Alternative treatment should be considered whenever possible, and temporary discontinuation of Rosuvastatin therapy may be necessary. In situations where concomitant administration of these medicinal products with Rosuvastatin cannot be avoided, the benefits and risks of combination therapy should be carefully weighed, and the dose of Rosuvastatin should be selected with caution.

Children

The use of the drug in children should be performed 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 in this population have not been studied.
• 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 in this population have not been studied.

Dose increases should be based on the individual child's response to treatment and drug tolerability, following recommendations for pediatric treatment (see section "Special precautions for use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be continued throughout treatment.

The 40 mg tablets are not intended for use in children.

Homozigous 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 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 recommendations for pediatric treatment (see section "Special precautions for use"). Before initiating rosuvastatin therapy, children and adolescents should be placed on a standard hypocholesterolemic diet, which should be continued 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. Treatment is symptomatic and supportive care is recommended. Monitoring of liver function and CK levels is required. Hemodialysis is unlikely to be effective.

Side effects

Side effects observed with the use of rosuvastatin are usually mild and transient. The side effects are listed below according to frequency of occurrence: common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:
Rare – thrombocytopenia.

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

Endocrine disorders:
Common – diabetes mellitus^1.

Psychiatric disorders:
Frequency not known – depression.

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

Eye disorders:
Frequency not known – ocular myasthenia.

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

Gastrointestinal disorders:
Common – constipation, nausea, abdominal pain; rare – pancreatitis; frequency not known – diarrhea.

Hepatobiliary disorders:
Rare – increased levels of liver transaminases; very rare – jaundice, hepatitis.

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

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

Reproductive system and breast disorders:
Very rare – gynecomastia.

Renal and urinary disorders:
Very rare – hematuria.

General disorders:
Common – asthenia; frequency not known – edema.

As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions depends on the dose.

^1Frequency depends on the presence of risk factors (fasting plasma glucose ≥ 5.6 mmol/L, body mass index > 30 kg/m^2, elevated triglyceride levels, history of hypertension).

Renal effects

Cases of proteinuria, mostly of tubular origin (detected by test strip), have been observed in patients taking rosuvastatin. Changes in urine protein content from "absent" or "trace" to "++" or higher were recorded in < 1% of patients receiving 10 mg or 20 mg doses, and in approximately 3% of patients receiving the 40 mg dose. A slight increase in the frequency of urine protein elevation from "absent" or "trace" to "+" was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously during continued treatment. Review of clinical trial and post-marketing data to date has not revealed a causal relationship between proteinuria and acute or progressive kidney disease.

Hematuria has been observed infrequently in patients taking rosuvastatin.

Musculoskeletal effects

Skeletal muscle-related changes such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been observed with all doses of rosuvastatin, particularly with doses > 20 mg. Rare cases of rhabdomyolysis, sometimes associated with renal failure, have been reported with rosuvastatin and other statins.

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

Hepatic effects

As with other HMG-CoA reductase inhibitors, a dose-dependent increase in transaminase levels has been observed in a small number of patients taking 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, serious kidney and liver disorders (mainly increased hepatic transaminase activity) is higher when the drug is used at a dose of 40 mg.

Pediatric population

Elevations in creatine kinase levels >10 times above 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 precautions"). However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, out of the reach of children, at a temperature not exceeding 30 °C.

Packaging.
10 tablets per blister, 3 or 6 blisters per cardboard box (5 mg and 10 mg tablets); 3 blisters per cardboard box (20 mg and 40 mg tablets).

Prescription status. Prescription only.

Manufacturer.

Apotex Inc.

Manufacturer's address and location of business activity.

150 Signet Drive, Toronto, Ontario, Canada, M9L 1T9
4100 Weston Road, Weston, Ontario, Canada, M9L 2Y6