Preventor film-coated tablets 10 mg No. 30

Instructions for Preventor film-coated tablets 10 mg No. 30

Composition

active ingredient: rosuvastatin;

1 tablet contains rosuvastatin 10 mg in the form of rosuvastatin calcium 10, 40 mg or rosuvastatin 20 mg in the form of rosuvastatin calcium 20, 80 mg;

excipients: lactose monohydrate, microcrystalline cellulose, calcium hydrogen phosphate, crospovidone, povidone, magnesium stearate, Opadry II 85F pink.

Dosage form

Film-coated tablets.

Main physicochemical properties: round tablets with a biconvex surface, coated with a pink film coating.

Pharmacotherapeutic group

Hypolipidemic agents.

HMG-CoA reductase inhibitors. Rosuvastatin. ATC code C10A A07.

Pharmacological properties

Pharmacodynamics.

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

The drug reduces elevated levels of LDL-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-1 (apoA-I) [see Table 1].

The drug also reduces the LDL-C/HDL-C ratio, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I ratio.

Table 1

Dose response in patients with primary hypercholesterolemia types IIa and IIb

(adjusted average percentage change from baseline)

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

Clinical efficacy and safety

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

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

In a large study, 435 patients with heterozygous familial hypercholesterolemia received rosuvastatin in doses ranging from 20 mg to 80 mg in an up-titration regimen. The drug showed beneficial effects 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%. In 33% of patients, LDL-C was normalized 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 subclinical atherosclerosis (defined as increased carotid intima-media thickness [CIMT]) were randomized to receive either 40 mg rosuvastatin or placebo once daily for 2 years. Compared with placebo, rosuvastatin significantly slowed the progression of maximal CIMT at 12 carotid sites by -0.0145 mm/year [95% confidence interval -0.0196, -0.0093; p<0.0001]. The change from The mean change from baseline in the rosuvastatin group was -0.0014 mm/year (-0.12%/year (not statistically significant)) compared with a progression of +0.0131 mm/year (1.12%/year [p<0.0001]) in the placebo group. No direct correlation was demonstrated between the reduction in TCIMSA and the reduction in the risk of cardiovascular events. The METEOR study enrolled patients at low risk of coronary heart disease who were not in the target population for the 40 mg dose of Preventor. The 40 mg dose should only be used in patients with severe hypercholesterolemia and high risk of cardiovascular events (see section 4.2).

In the Rosuvastatin Intervention Trial to Support the Use of Statins as Primary Prevention (JUPITER), the effect of rosuvastatin on the incidence of major atherosclerotic cardiovascular disease was evaluated in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and were followed for an average of 2 years.

LDL-C concentration decreased by 45% (p<0.001) in the rosuvastatin group compared to 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 placebo. The absolute risk reduction for events was 8.8 events per 1000 patient-years. The overall mortality rate remained unchanged in this high-risk group (p=0.193). In a post-hoc analysis of the high-risk subgroup (9302 participants in total) with a baseline SCORE score ≥ 5% (extrapolated to include participants aged 65 years and older), there was a significant reduction in the composite endpoint of cardiovascular death, stroke, and myocardial infarction (p = 0.0003) in the rosuvastatin group compared with placebo. The absolute risk reduction, expressed as an event rate, was 5.1 events per 1000 patient-years. The overall mortality rate in this high-risk subgroup remained unchanged (p = 0.076).

In the JUPITER study, 6.6% of rosuvastatin-treated patients and 6.2% of placebo-treated patients discontinued study drug due to adverse reactions. The most common adverse reactions 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 reactions observed in the rosuvastatin group with a frequency greater than or equal to that observed in the placebo group were urinary tract infections (8.7% in the rosuvastatin group, 8.6% in the placebo group), nasopharyngitis (7.6% in the rosuvastatin group, 7.2% in the placebo group), back pain (7.6% in the rosuvastatin group, 6.9% in the placebo group), and myalgia (7.6% in the rosuvastatin group, 6.6% in the placebo group).

Children

In a double-blind, randomized, multicenter, placebo-controlled, 12-week study (n = 176, 97 male and 79 female participants) followed by a 40-week (n = 173, 96 male and 77 female participants) open-label rosuvastatin dose-titration period, patients aged 10–17 years (Tanner stages II–IV, girls who had started menstruating at least 1 year ago) with heterozygous familial hypercholesterolemia received rosuvastatin 5 mg/day, 10 mg/day, or 20 mg/day or placebo for 12 weeks, after which all participants received rosuvastatin daily for 40 weeks. At the beginning of the study, approximately 30% of patients were aged 10–13 years and approximately 17%, 18%, 40% and 25% of them were in Tanner stages II, III, IV and V, respectively.

LDL-C levels decreased by 38.3%, 44.6%, and 50.0%, respectively, in the rosuvastatin 5 mg, 10 mg, and 20 mg groups compared with 0.7% in the placebo group.

At the end of the 40-week open-label dose titration period to target (maximum dose was 20 mg once daily), 70 of 173 patients (40.5%) achieved a target LDL-C level of less than 2.8 mmol/L.

Rosuvastatin was also studied in a 2-year, open-label, target-titration study in 198 children with heterozygous familial hypercholesterolemia aged 6 to 17 years (88 male and 110 female, Tanner stage

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

Rosuvastatin 5 mg, 10 mg, and 20 mg also resulted in statistically significant mean changes from baseline in the following secondary lipid and lipoprotein variables: HDL-C, total-C, non-HDL-C, LDL-C/HDL-C, total-C/HDL-C, TG/HDL-C, non-HDL-C/HDL-C, apoB, apoB/apoA-1. Each of these changes demonstrated improvements in lipid responses and were maintained over 2 years.

After 24 months of treatment, no effect on growth, body weight, BMI or puberty was observed (see section 4.4).

A randomized, double-blind, placebo-controlled, multicenter, crossover study evaluated rosuvastatin 20 mg once daily versus placebo in 14 children and adolescents (aged 6 to 17 years) with homozygous familial hypercholesterolemia. The study included an active 4-week dietary lead-in phase during which patients were treated with rosuvastatin 10 mg, a crossover phase consisting of a 6-week period of rosuvastatin 20 mg with or without 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. There were also statistically significant reductions in total-C (20.1%, p = 0.003), non-HDL-C (22.9%, p = 0.003), and apoB (17.1%, p = 0.024). Reductions in TG, LDL-C/HDL-C, total-C/HDL-C, non-HDL-C/HDL-C, and apoB/apoA-I were also observed after 6 weeks of treatment with rosuvastatin 20 mg compared with placebo. The reduction in LDL-C after 6 weeks of treatment with rosuvastatin 20 mg followed by 6 weeks of placebo was maintained through 12 weeks of continuous therapy. One patient had further reductions in LDL-C (8.0%), total-C (6.7%), and non-HDL-C (7.4%) after 6 weeks of treatment with dose titration to 40 mg.

During continuation of open-label treatment with rosuvastatin 20 mg, 9 of these patients maintained LDL-C reductions ranging from -12.1% to -21.3% for up to 90 weeks.

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

The European Medicines Agency has waived the obligation to submit the results of studies with rosuvastatin in all subsets of the paediatric population in homozygous familial hypercholesterolemia, primary combined (mixed) dyslipidemia and for the prevention of cardiovascular events (see section 4.2 for information on paediatric use).

Pharmacokinetics.

Absorption

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. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism

Rosuvastatin undergoes minor metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved is CYP2C9, with 2C19, 3A4 and 2D6 playing a somewhat smaller role. 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), and the remainder is excreted in the urine. Approximately 5% is excreted in the urine unchanged. The plasma half-life is approximately 19 hours and does not increase with increasing dose. The geometric mean plasma clearance of the drug 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

There was no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers (see section "Children").

Race

Pharmacokinetic studies 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 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 dysfunction

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

Patients with liver failure

In patients with varying degrees of hepatic insufficiency with a Child-Pugh score of 7 and below, no increase in the half-life of rosuvastatin was observed. However, in patients with a score of 8 and 9 on the Child-Pugh scale, an approximately 2-fold increase in the half-life was observed compared with the same indicator in patients with lower Child-Pugh scores. There is no experience with the use of rosuvastatin in patients with a score above 9 on the Child-Pugh scale.

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

Children

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

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

Contraindication

Hypersensitivity to rosuvastatin or to any of the excipients 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.

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

Myopathy.

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

Concomitant use with cyclosporine.

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;

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

history of myotoxicity caused by the use of other HMG-CoA reductase inhibitors or fibrates;

alcohol abuse;

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

patients belonging to the Mongoloid race;

concomitant use of fibrates (see sections "Pharmacokinetics", "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 4.4 and 4.8, Dosage and Administration, Table 2).

Cyclosporine

During concomitant use, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 2). Preventor is contraindicated in patients concomitantly using cyclosporine (see section "Contraindications"). Concomitant use did not affect the concentration of cyclosporine in blood plasma.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase the AUC of rosuvastatin (see Table 2). For example, in a pharmacokinetic study, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in AUC and Cmax of rosuvastatin by approximately 3 and 7 times, respectively. The simultaneous use of the drug Preventor and some combinations of protease inhibitors is possible after careful consideration of dose adjustment of the drug, taking into account the expected increase in AUC of rosuvastatin (see sections “Interaction with other medicinal products and other types of interactions”, “Special instructions for use” and “Method of administration and dosage”, 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 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 (> or = 1 g/day) of niacin (nicotinic acid) 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 reactions, cannot be excluded (see section 4.4).

Antacids

Concomitant use of rosuvastatin with antacid suspensions containing aluminum or magnesium hydroxide reduced the plasma concentration 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 decreased rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility due to erythromycin.

Ticagrelor:

Ticagrelor may cause renal failure and also affects the renal excretion of rosuvastatin, increasing the risk of rosuvastatin accumulation. Although the exact mechanism is unknown, in some cases, concomitant use of ticagrelor and rosuvastatin has resulted in decreased renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.

Cytochrome P450 enzymes

In vitro and in vivo studies have shown that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions resulting from P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

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

If the drug increases the AUC of rosuvastatin by less than 2 times, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of the drug Preventor to more than 20 mg.

Table 2

Effect of concomitant medications on rosuvastatin exposure

(AUC; in descending order of magnitude)

* 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 by the ↓ icon.

** Several interaction studies have been conducted at different doses of the drug rosuvastatin, the most significant relationship is presented in Table 2.

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

Effect of rosuvastatin on concomitant medications

Vitamin K antagonists

As with other HMG-CoA reductase inhibitors, when initiating or increasing the dose of Preventor in patients receiving concomitant vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant), an increase in the International Normalized Ratio (INR) may occur. Discontinuation of Preventor or dose reduction may result in a decrease in the INR. Appropriate monitoring of INR is recommended in such cases.

Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, 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 taking rosuvastatin and HRT at the same time, so a similar effect cannot be excluded. However, the combination has been widely used in women in clinical studies and was well tolerated.

Digoxin

Based on interaction studies, no clinically significant interaction is expected.

Fusidic acid

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

In patients in whom systemic fusidic acid is considered necessary, the use of Preventor should be discontinued for the duration of the fusidic acid treatment. See also section "Special warnings and precautions for use".

Children

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

Application features

Effects on the kidneys

Proteinuria, detected by dipstick analysis and predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and in most cases has been transient or intermittent. Proteinuria was not a harbinger of acute or progressive renal disease (see section 4.8).

Renal adverse reactions were more common with the 40 mg dose. Patients taking the 40 mg dose should have their renal function monitored regularly.

Effects on skeletal muscles

Musculoskeletal disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been reported in patients taking rosuvastatin at all doses, particularly doses greater than 20 mg. Isolated cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded and this combination should be used with caution.

As with other HMG-CoA reductase inhibitors, reports of rhabdomyolysis associated with the use of rosuvastatin occurred more frequently with the 40 mg dose.

Determination of creatine phosphokinase (CPK) levels

CPK levels should not be measured after significant exercise or when there are possible alternative causes of CPK elevation that may complicate interpretation of results. If baseline CPK levels are significantly elevated (> 5 times the upper limit of normal), additional confirmatory testing should be performed within 5–7 days. If the repeat test result confirms the baseline level > 5 times the upper limit of normal, treatment should not be initiated.

Before starting treatment

Rosuvastatin, like other HMG-CoA reductase inhibitors, should be prescribed with caution to patients with risk factors for myopathy/rhabdomyolysis.

Such factors include:

kidney dysfunction;

hypothyroidism;

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

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

alcohol abuse;

age > 70 years;

situations that may lead to an increase in the level of rosuvastatin in the blood plasma (see sections "Pharmacokinetics", "Interaction with other medicinal products and other types of interactions" and "Method of administration and dosage");

simultaneous use of fibrates.

In such patients, the risk of treatment should be weighed against the expected benefit; clinical monitoring is also recommended. If baseline CPK levels are significantly elevated (> 5 times the upper limit of normal), treatment should not be initiated.

During treatment

Patients should be advised to immediately report to their physician any unexplained muscle pain, weakness, or cramps.