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 a 6-week placebo treatment, 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 above-mentioned 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 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. Its volume of distribution is approximately 134 L. Almost 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 metabolites of rosuvastatin identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, the lactone metabolites are 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 combined). The rest is excreted in the urine. Approximately 5% is excreted unchanged in the urine. The plasma half-life is approximately 19 hours. The half-life does not change 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. With multiple daily administration, pharmacokinetic parameters do not change.
Special patient populations
Age and gender
There is no clinically significant effect of age and gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children with heterozygous familial hypercholesterolemia were similar to those in adult volunteers.
Race
It is known that pharmacokinetic studies have shown that in patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) the median AUC and Cmax values are approximately twice as high as in Caucasians; in Indians the median AUC and Cmax values are increased by approximately 1.3 times. Pharmacokinetic analysis of ethnic groups did not reveal clinically significant differences in pharmacokinetics between representatives of the Caucasian and Negroid races.
Kidney dysfunction
In patients with mild or moderate renal impairment, the plasma concentrations of rosuvastatin and N-desmethyl do not change significantly. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the plasma concentrations of rosuvastatin are 3 times higher, and the N-desmethyl is 9 times higher, than in healthy volunteers. The plasma concentrations of rosuvastatin in patients on hemodialysis were approximately 50% higher than in healthy volunteers.
Liver dysfunction
It is known that in a study of patients with varying degrees of hepatic insufficiency with a Child-Pugh score of 7 and below, no signs of increased exposure to rosuvastatin were found. However, in two patients with a score of 8 and 9 on the Child-Pugh scale, an approximately 2-fold increase in half-life was noted compared with a similar 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. With certain forms of the SLCO1B1 p.521CC and ABCG2 p.421AA polymorphisms, rosuvastatin exposure (AUC) is increased compared with the SLCO1B1 p.521TT or ABCG2 p.421CC genotypes. Specific genotyping is not provided in clinical practice, but patients with such polymorphisms are recommended to use a lower daily dose of rosuvastatin.
Children
It is known that two studies of the pharmacokinetics of rosuvastatin (in tablet form) in children with heterozygous familial hypercholesterolemia aged 10 to 17 years or 6 to 17 years (a total of 214 patients) showed that the drug exposure in children was lower than or similar to that in adult patients. The exposure of rosuvastatin was predicted 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 in cases where 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 5.1), as an adjunct to correction of other risk factors.
Contraindication
- Hypersensitivity to rosuvastatin or any excipient;
- active liver disease, including persistent elevations of serum transaminases of unknown etiology and any elevation of serum transaminases greater than three times the upper limit of normal (ULN);
- severe renal impairment (creatinine clearance < 30 ml/min);
- myopathy;
- simultaneous administration of the combination of sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”);
- simultaneous administration of cyclosporine;
- pregnancy and breastfeeding;
- women of reproductive age who do not use adequate contraception.
- moderate renal impairment (creatinine clearance < 60 ml/min);
- hypothyroidism;
- presence of hereditary muscle diseases in the individual or family history;
- history of myotoxicity caused by other HMG-CoA reductase inhibitors or fibrates;
- alcohol abuse;
- situations that may lead to an increase in the level of the drug in the blood plasma;
- patients belonging to the Mongoloid race;
- concomitant use of fibrates.
(See sections “Special instructions for use”, “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 medications on rosuvastatin.
Inhibitors of transport proteins.
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 4.2, 4.4, and 4.5).
Cyclosporine.
When rosuvastatin and ciclosporin were co-administered, the AUC of rosuvastatin was on average 7 times higher than in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients already receiving ciclosporin (see section "Contraindications").
Concomitant use did not affect the plasma concentration of cyclosporine.
Gemfibrozil and other hypolipidemic drugs.
Concomitant use of rosuvastatin and gemfibrozil resulted in a two-fold increase in Cmax and AUC of rosuvastatin. Based on data from specific studies, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and niacin (nicotinic acid) in lipid-lowering doses (> or equal to 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they can also cause myopathy when used alone. The dose of rosuvastatin 40 mg is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special instructions"). Treatment with rosuvastatin in such cases should also be started with a dose of 5 mg.
Ezetimibe.
Concomitant administration of rosuvastatin 10 mg and ezetimibe 10 mg in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse effects, cannot be excluded (see section 4.4).
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. Co-administration of rosuvastatin and some combinations of protease inhibitors is possible after careful consideration of rosuvastatin dose adjustment based on the expected increase in rosuvastatin exposure (see sections “Method of administration and dosage”, “Special instructions for use”, “Interaction with other medicinal products and other forms of interaction”, table 2).
Antacids.
Concomitant use of rosuvastatin and antacids containing aluminum or magnesium hydroxide reduces rosuvastatin 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(0-t) 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 weak substrate of these isoenzymes. Therefore, drug-drug interactions associated with cytochrome P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Ticagrelor.
Ticagrelor may affect the 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 resulted in decreased renal function, increased CPK levels, and rhabdomyolysis.
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 of the drug (AUC) 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 the drug; for example, when used with gemfibrozil, the dose of rosuvastatin 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 rosuvastatin above 20 mg.
Table 2
Effect of concomitant medications on rosuvastatin exposure
(AUC; in descending order of magnitude) from published clinical trial data
| Increase in rosuvastatin AUC by 2-fold or more than 2-fold |
| Dosing regimen of the interacting drug | Rosuvastatin dosage regimen | Changes in rosuvastatin AUC* |
| Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + voxilaprevir (100 mg) once daily, 15 days | 10 mg, single dose | ↑ 7.4 times |
| Cyclosporine 75 mg twice daily to 200 mg twice daily, 6 months | 10 mg once daily, 10 days | ↑ 7.1 times |
| Darolutamide 600 mg, twice daily, 5 days | 5 mg, single dose | ↑ 5.2 times |
| Regorafenib 160 mg, once daily, 14 days | 5 mg, single dose | ↑ 3.8 times |
| Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days | 10 mg, single dose | ↑ 3.1 times |
| Velpatasvir 100 mg, once daily | 10 mg, single dose | ↑ 2.7 times |
Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg, once daily/dasabuvir 400 mg twice daily, 14 days | 5 mg, single dose | ↑ 2.6 times |
| Teriflunomide | Data missing | ↑ 2.5 times |
| Grazoprevir 200 mg/elbasvir 50 mg, once daily, 11 days | 10 mg, single dose | ↑ 2.3 times |
| Glecaprevir 400 mg/pibrentasvir 120 mg, once daily, 7 days | 5 mg, once daily, 7 days | ↑ 2.2 times |
| Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days | 20 mg once daily, 7 days | ↑ 2.1 times |
| Capmatinib 400 mg twice daily | 10 mg, single dose | ↑ 2.1 times |
| Clopidogrel 300 mg, then 75 mg 24 hours later | 20 mg, single dose | ↑ 2 times |
| Fostamatinib 100 mg twice daily | 20 mg, single dose | ↑ 2.0 times |
| Febuxostat 120 mg once daily | 10 mg, single dose | ↑ 1.9 times |
| Gemfibrozil 600 mg twice daily, 7 days | 80 mg, single dose | ↑ 1.9 times |
| Increase in rosuvastatin AUC less than 2-fold |
| Dosing regimen of the interacting drug | Rosuvastatin dosage regimen | Changes in rosuvastatin AUC* |
| Eltrombopac 75 mg once daily, 5 days | 10 mg, single dose | ↑ 1.6 times |
| Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days | 10 mg once daily, 7 days | ↑ 1.5 times |
| Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days | 10 mg, single dose | ↑ 1.4 times |
| Dronedarone 400 mg twice daily | Data missing | ↑ 1.4 times |
| Itraconazole 200 mg once daily, 5 days | 10 mg, single dose | ↑ 1.4 times ** |
| Ezetimibe 10 mg once daily, 14 days | 10 mg once daily, 14 days | ↑ 1.2 times ** |
| Decrease in rosuvastatin AUC |
| Dosing regimen of the interacting drug | Rosuvastatin dosage regimen | Changes in rosuvastatin AUC* |
| Erythromycin 500 mg 4 times a day, 7 days | 80 mg, single dose | ↓ 20% |
| Baicalin 50 mg three times a day, 14 days | 20 mg, single dose | ↓ 47% |
* 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 rosuvastatin, the most significant relationship is presented in Table 2.
The following medicinal products/combinations had no clinically significant effect on the AUC ratio of rosuvastatin when co-administered with the following medicinal products:
aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg, 7 days, 3 times a day; fluconazole 200 mg, 11 days, 1 time a day; fosamprenavir 700 mg/ritonavir 100 mg, 8 days, 2 times a day; ketoconazole 200 mg, 7 days, 2 times a day; rifampin 450 mg, 7 days, 1 time a day; silymarin 140 mg, 5 days, 3 times a day.
Effect of rosuvastatin on concomitant medications.
As with other HMG-CoA reductase inhibitors, initiation of treatment with rosuvastatin or gradual dose increase in patients receiving concomitant vitamin K antagonists (e.g. warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). After discontinuation of rosuvastatin or dose reduction, the INR may decrease. In such cases, it is advisable to monitor the INR appropriately.
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. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of the drugs in patients taking rosuvastatin and HRT simultaneously, so the possibility of interaction cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.
Other medicines.
Digoxin.
Based on data from specific 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 this interaction (pharmacodynamic or pharmacokinetic, or both) is not yet clear. Rhabdomyolysis (including some fatal cases) has been reported in patients receiving this combination.
In patients in whom systemic fusidic acid is considered necessary, rosuvastatin treatment should be discontinued for the duration of fusidic acid treatment. See also section 4.4.
Children.
It is known that interaction studies have only been conducted in adults. The extent of interaction in children is unknown.
Application features
Effect on the kidneys.
It is known that patients taking rosuvastatin at high doses, especially 40 mg, have experienced cases of proteinuria (determined by the "dipstick test"), mainly tubular in origin and in most cases transient or intermittent. Proteinuria did not indicate acute or progressive renal disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose. In patients taking the drug at a dose of 40 mg, renal function should be checked regularly.
Effect on skeletal muscles.
Skeletal muscle disorders, such as myalgia, myopathy and, rarely, rhabdomyolysis, have been reported in patients receiving rosuvastatin at all doses, particularly at doses >20 mg. Rhabdomyolysis has been reported in isolated cases when ezetimibe is used in combination with HMG-CoA reductase inhibitors. The possibility of a pharmacodynamic interaction cannot be excluded 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 was higher at the 40 mg dose.
Creatine kinase level.
Creatine kinase (CK) levels should not be measured after significant exercise or when there are possible alternative causes of CK elevation that may complicate interpretation of results. If the initial CK level is significantly elevated (> 5 times ULN), additional testing should be performed within 5-7 days to confirm the results. If the retest result confirms the initial level > 5 times the upper limit of normal, the drug should not be started.
Before starting treatment.
Rosuvastatin, like other HMG-CoA reductase inhibitors, should be administered with caution to patients with factors predisposing to the development of myopathy/rhabdomyolysis. Such factors include:
kidney dysfunction;
hypothyroidism;
presence of hereditary muscle diseases in an individual or family history;
history of myotoxicity caused by other HMG-CoA reductase inhibitors or fibrates;
alcohol abuse;
age > 70 years;
situations that may lead to increased levels of the drug in the blood plasma (see sections “Method of administration and dosage”, “Interaction with other medicinal products and other types of interactions” and “Pharmacokinetics”);
concomitant use of fibrates
