Rosuvastatin IC film-coated tablets 20 mg blister No. 30

Instructions for Rosuvastatin IC film-coated tablets 20 mg blister No. 30

Composition

active ingredient: 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 (lactose monohydrate, microcrystalline cellulose), calcium hydrogen phosphate dihydrate, crospovidone, sodium bicarbonate, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E 171), triacetin, polysorbate.

Dosage form

Film-coated tablets.

Main physicochemical properties: round tablets with a biconvex surface, film-coated, white in color.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics.

Mechanism of action

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

Pharmacodynamic effects

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

Table 1

Dose response in patients with primary hypercholesterolemia types IIa and IIb

(adjusted mean percentage change from baseline)

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

Clinical efficacy and safety

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

In pooled phase III studies, rosuvastatin was effective in lowering LDL-C in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L) to the target values established by the recognized European Atherosclerosis Society (EAS; 1998); approximately 80% of patients receiving rosuvastatin 10 mg achieved the EAS target LDL-C (<3 mmol/L).

In a large study of 435 patients with heterozygous familial hypercholesterolemia who received rosuvastatin in doses from 20 to 80 mg in an up-titration regimen, the drug had a beneficial effect on lipid parameters and achieved target levels at all doses. After titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C levels decreased by 53%. In 33% of patients, the norm of LDL-C was achieved by EAS (< 3 mmol/L).

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

In a multicenter, double-blind, placebo-controlled clinical trial (METEOR), 984 patients aged 45–70 years with low risk of coronary heart disease (defined as Framingham risk < 10% over 10 years), a mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis [defined as increased carotid intima-media thickness (CIMT)] were randomized to receive either rosuvastatin 40 mg once daily or placebo for 2 years. Compared with placebo, rosuvastatin significantly slowed the progression of maximum CIMT at 12 carotid sites by -0.0145 mm/year [95% confidence interval -0.0196, -0.0093; p < 0.0001]. The change from baseline was -0.0014 mm/year [-0.12%/year (not statistically significant)] in the rosuvastatin group compared with a progression of +0.0131 mm/year [1.12%/year (p < 0.0001)] in the placebo group. A direct correlation between the reduction in TCIMSA and the reduction in the risk of cardiovascular events was not demonstrated. This study included patients with low risk of coronary heart disease, who are not representative of the target population for rosuvastatin 40 mg. The 40 mg dose should only be administered to patients with severe hypercholesterolemia and high risk of cardiovascular events (see section 4.2).

In the JUPITER (Judging Statins for Primary Prevention: Rosuvastatin Intervention Trial) study, the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular events was evaluated in 17,802 men (≥ 50 years) and women (≥ 60 years). Participants were randomly assigned to receive either rosuvastatin 20 mg (n = 8901) or placebo (n = 8901) once daily for a median of 2 years. LDL-C levels were reduced by 45% (p < 0.001) in the rosuvastatin group compared with the placebo group.

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

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

Children

The efficacy and safety of rosuvastatin were also studied in a 2-year, open-label, target-titration study in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 males and 110 females, < Tanner Stage II–V). The starting dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6 to 9 years (n = 64) were titrated to a maximum dose of 10 mg once daily, and patients aged 10 to 17 years (n = 134) were titrated to a maximum dose of 20 mg once daily. After 24 months of rosuvastatin treatment, the mean least squares reduction from baseline in LDL-C 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 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), respectively. Rosuvastatin 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, TG/HDL-C, non-HDL-C/HDL-C, ApoB, ApoB/ApoA-I. Changes in each of these parameters demonstrated improvements in lipid responses and were maintained for 2 years. After 24 months of treatment, no effects on growth, body weight, BMI or puberty were observed (see section 4.4).

A randomized, double-blind, placebo-controlled, multicenter, crossover study evaluated the efficacy of rosuvastatin 20 mg once daily versus placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included an active 4-week dietary lead-in phase during which patients received rosuvastatin 10 mg, a crossover phase consisting of a 6-week period of rosuvastatin 20 mg followed by or followed by 6 weeks of placebo, and a 12-week maintenance phase during which all patients received rosuvastatin 20 mg. Patients receiving ezetimibe or apheresis continued to receive this treatment throughout the study. A statistically significant (p = 0.005) reduction in LDL-C (22.3%; 85.4 mg/dL, or 2.2 mmol/L) was observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. Statistically significant reductions were observed in total-C (20.1%, p = 0.003), non-HDL-C (22.9%, p = 0.003), and ApoB (17.1%, p = 0.024). Reductions in TG, LDL-C/HDL-C ratio, total-C/HDL-C, non-LDL-C/HDL-C and ApoB/ApoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo was maintained for 12 weeks of continuous therapy. In one patient, further reductions in LDL-C (8.0%), total-C (6.7%) and non-HDL-C (7.4%) were observed after 6 weeks of treatment with dose titration to 40 mg. During continuation of open-label treatment with rosuvastatin 20 mg, 9 of these patients maintained LDL-C reductions ranging from -12.1% to -21.3% through 90 weeks.

In an open-label, up-titration study in 7 evaluable children and adolescents (aged 8 to 17 years) with homozygous familial hypercholesterolemia (see above), the percentage reduction from baseline in LDL-C (21.0%), total-C (19.2%), and non-HDL-C (21.0%) after 6 weeks of treatment with rosuvastatin 20 mg was consistent with that observed in the aforementioned study in children and adolescents with homozygous familial hypercholesterolemia.

The European Medicines Agency has waived its obligation to provide the 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 concentration of rosuvastatin in blood plasma (Cmax) is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Distribution

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

Metabolism

Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a non-specific substrate for metabolism mediated by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with a somewhat smaller role played by the isoenzymes CYP2C19, CYP3A4 and CYP2D6. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the circulating HMG-CoA reductase inhibitory activity.

Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (absorbed and unabsorbed active substance together), the rest is excreted in the urine (approximately 5% - unchanged). The half-life from blood plasma is approximately 19 hours and does not increase with increasing dose. The geometric mean 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 with the participation of the membrane transporter OATP-C, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases in proportion to the 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 was observed in adults. Rosuvastatin exposure in children and adolescents with heterozygous familial hypercholesterolemia was similar to or lower than that in adult patients with dyslipidemia (see Pediatrics in this section).

Race

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

Kidney failure

In a study involving patients with varying degrees of renal impairment, no changes in the plasma concentrations of rosuvastatin or the N-desmethyl metabolite were observed in patients with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the plasma concentrations of rosuvastatin were 3 times higher and the N-desmethyl metabolite 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.

Liver failure

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

Genetic polymorphism

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

Children

Two studies of the pharmacokinetics of rosuvastatin (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 was similar to or lower than that in adults. Rosuvastatin exposure was predictable according to dose and duration of administration over 2 years of observation.

Indication

Treatment of hypercholesterolemia

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

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

Prevention of cardiovascular disorders

For the prevention of major cardiovascular events in patients estimated to be at high risk of a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.

Contraindication

Hypersensitivity to rosuvastatin or any other component of the drug.

Active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevation of serum transaminases greater than 3 times the upper limit of normal (ULN).

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

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

Concomitant use of cyclosporine.

Pregnancy or breastfeeding.

The drug is contraindicated in women of reproductive age who are not using adequate contraception.

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

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

hypothyroidism;

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

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

alcohol abuse;

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

belonging to the Mongoloid race;

concomitant use of fibrates (see sections "Pharmacological properties", "Interaction with other medicinal products and other types of interactions" and "Special instructions for use").

Interaction with other medicinal products and other types of interactions

Effect of concomitant medications on rosuvastatin

Transport protein inhibitors

Rosuvastatin is a substrate for several transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections “Interaction with other medicinal products and other forms of interaction” (table 2), “Special warnings and precautions for use” and “Method and dosage”).

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 concomitant cyclosporine (see section "Contraindications"). Concomitant use of rosuvastatin did not affect the concentration of cyclosporine in the blood plasma.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in rosuvastatin AUC and Cmax by approximately 3- and 7-fold, respectively. Concomitant use of rosuvastatin and some combinations of protease inhibitors may be possible after careful consideration of the dose adjustment of rosuvastatin due to the expected increase in its exposure (see sections “Interaction with other medicinal products and other forms of interaction” (Table 2), “Special instructions for use” and “Method and dosage”).

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, but a 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, probably because they can cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). These patients should also be started on the 5 mg dose.

Ezetimibe

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

Antacid medications

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

Erythromycin

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

Cytochrome P450 enzymes

In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a non-specific substrate of these isoenzymes. Therefore, interactions of rosuvastatin with other drugs as a result of 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 may affect the renal excretion of rosuvastatin, increasing the risk of its accumulation. Although the exact mechanism is unknown, in some cases, the simultaneous use of ticagrelor and rosuvastatin led to a decrease in renal function, an increase in creatine kinase (CK) levels, and the development of rhabdomyolysis.

Interactions requiring dose adjustment of rosuvastatin (see table 2)

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

Table 2

Effect of concomitant medications on rosuvastatin exposure

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

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

Increase is indicated by the icon "↑", decrease - "↓".

The following drugs/combinations had no clinically significant effect on the AUC of rosuvastatin when co-administered: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg 3 times a day, 7 days; fluconazole 200 mg 1 time a day, 11 days; fosamprenavir 700 mg/ritonavir 100 mg 2 times a day, 8 days; ketoconazole 200 mg 2 times a day, 7 days; rifampin 450 mg 1 time a day, 7 days; silymarin 140 mg 3 times a day, 5 days.

Effect of rosuvastatin on concomitant medications

Vitamin K antagonists

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

Oral contraceptives/hormone replacement therapy (HRT)

Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. Such increases in plasma concentrations should be taken into account when selecting the dose of oral contraceptives. Data on the pharmacokinetics of rosuvastatin and hormone replacement therapy drugs during their concomitant use are not available, so a similar effect cannot be excluded when using such a combination. However, the combination has been widely used in women in clinical trials and was well tolerated.

Other medicines

Digoxin

According to special studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies of rosuvastatin with fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased by concomitant use of systemic fusidic acid with statins. The mechanism of such an interaction (pharmacodynamic or pharmacokinetic, or both) is not yet clear. There have been reports of rhabdomyolysis (including fatal cases) in patients receiving this combination of drugs. If the use of systemic fusidic acid is necessary, treatment with rosuvastatin should be discontinued for the entire period of treatment with fusidic acid. See also section "Special instructions".

Children

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

Application features

Effects on the kidneys

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

Effects on skeletal muscles

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

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

Creatine kinase level

Creatine kinase (CK) levels should not be measured after significant exercise or in the presence of possible alternative causes.