Tevastor, 5 mg, film-coated tablets, 30 pcs.
Inside,
at any time of the day, regardless of food intake. The tablet should be swallowed whole with water, without chewing or crushing.
If it is necessary to take the drug at a dose of 5 mg, the 10 mg tablet should be divided in half.
Before starting therapy with Tevastor®, the patient should begin following a standard lipid-lowering diet and continue to follow it during treatment. The dose of the drug should be individualized depending on the indication and therapeutic response, taking into account current recommendations for target lipid levels. The recommended starting dose of Tevastor® for patients starting to take the drug or for patients switched from taking other HMG-CoA reductase inhibitors is 5 or 10 mg 1 time / day. When choosing the initial dose, one should be guided by the patient’s cholesterol level and take into account the risk of developing cardiovascular complications, and it is also necessary to assess the potential risk of side effects. If necessary, after 4 weeks the dose can be increased.
Patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially patients with familial hypercholesterolemia)
Those who did not achieve the desired result when taking a dose of 20 mg during 4-week therapy should be under the supervision of a physician when increasing the dose of the drug to 40 mg due to a possible increase in the risk of side effects.
Particularly careful monitoring of patients receiving the drug at a dose of 40 mg is recommended. After 2–4 weeks of therapy and/or increasing the dose of Tevastor®, monitoring of lipid metabolism parameters is necessary.
In elderly patients (over 65 years old)
It is recommended to start treatment with a dose of 5 mg.
Patients with kidney failure
In patients with renal failure, no dose adjustment is required. The use of Tevastor® in any dose is contraindicated in severe renal failure (creatinine clearance less than 30 ml/min). The use of Tevastor® at a dosage of 40 mg is contraindicated in patients with moderate renal impairment (creatinine clearance less than 60 ml/min). For patients with moderate renal impairment, an initial dose of 5 mg is recommended.
Special populations. Ethnic groups.
When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in the systemic concentration of rosuvastatin was noted among the Japanese and Chinese (see “Special Instructions”). This fact should be taken into account when using the drug Tevastor® in these groups of patients. For Asian patients, the recommended starting dose is 5 mg. The use of Tevastor® at a dose of 40 mg is contraindicated in patients of the Asian race.
Genetic polymorphism.
Carriers of the SLCO1B1 (OATP1B1) c.52ICC and ABCG2 (BCRP) c.421AA genotypes showed an increase in exposure (AUC) to rosuvastatin compared to carriers of the SLCO1B1 c.521TT and ABCG2 c.421CC genotypes. For patients carrying genotypes c.521CC or c.421AA, the recommended maximum daily dose of Tevastor® is 20 mg once a day (see “Pharmacokinetics”, “Special instructions” and “Interaction”).
Predisposition to myopathy.
The use of Tevastor® at a dose of 40 mg is contraindicated in patients with factors that may indicate a predisposition to the development of myopathy (see “Special Instructions”). When using doses of 10 and 20 mg, an initial dose of 5 mg is recommended for patients in this group.
Concomitant therapy.
Rosuvastatin binds to various transport proteins (in particular OATP1B1 and BCRP). When using Tevastor® with cyclosporine and HIV protease inhibitors (including a combination of ritonavir with atazanavir, lopinavir), the risk of myopathy (including rhabdomyolysis) increases, so alternative therapy or temporary withdrawal of Tevastor® should be considered. If the simultaneous use of these drugs is unavoidable, the benefit-risk ratio of concomitant therapy with Tevastor® should be assessed and the possibility of reducing its dose should be considered.
Tevastor
With the simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers, while the plasma concentration of cyclosporine did not change. Simultaneous use leads to an 11-fold increase in the plasma concentration of rosuvastatin in the blood plasma.
Initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (eg, warfarin) may lead to an increase in prothrombin time (increase in MHO). Discontinuation of rosuvastatin or reduction of its dose may lead to a decrease in MHO (in such cases, monitoring of MHO is recommended).
Concomitant use of rosuvastatin and ezetimibe did not reveal changes in AUC or Cmax for either drug. However, their pharmacodynamic interaction and the occurrence of adverse effects cannot be excluded.
The simultaneous use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax in blood plasma and AUC of rosuvastatin. According to special studies, no relevant pharmacokinetic interaction with fenofibrate has been noted, but pharmacodynamic interaction is possible. Hemofibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors (probably due to the fact that HMG-CoA inhibitors can cause myopathy when used as monotherapy) .
Although the exact mechanism of interaction of rosuvastatin with protease inhibitors is unknown, their simultaneous use may cause a persistent increase in the effect of rosuvastatin. In pharmacokinetic studies in healthy volunteers, coadministration of 20 mg rosuvastatin and a combination of protease inhibitors (lopinavir 400 mg/ritonavir 100 mg) caused approximately 2- and 5-fold increases in AUC and Cmax, respectively. Therefore, the simultaneous use of rosuvastatin and protease inhibitors in the treatment of patients with HIV is not recommended.
The simultaneous use of rosuvastatin and antacid suspensions containing aluminum and magnesium hydroxide leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.
Concomitant use of rosuvastatin and erythromycin leads to a decrease in rosuvastatin AUC by 20% and rosuvastatin Cmax by 30%, probably as a result of increased intestinal motility caused by erythromycin.
Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUC of norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives while using rosuvastatin.
Based on studies of the interaction of rosuvastatin with digoxin, no clinically significant interaction has been identified.
The results of in vivo and in vitro studies showed that rosuvastatin is neither an inhibitor nor an inducer of isoenzymes of the cytochrome P450 system. In addition, rosuvastatin is a weak substrate for these isoenzymes. There was no clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) and ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Co-administration of rosuvastatin and itraconazole (CYP3A4 inhibitor) increases the AUC of rosuvastatin by 28% (clinically insignificant). Thus, interactions involving the cytochrome P450 system are not expected.
Rosuvastatin-Teva
The effect of the use of other drugs on rosuvastatin
Transport protein inhibitors:
rosuvastatin binds to some transport proteins, in particular OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in plasma concentrations of rosuvastatin and an increased risk of developing myopathy (see Table 1 and sections “Dosage and Administration” and “Special Instructions”).
Cyclosporine
: with simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 1). Does not affect plasma concentrations of cyclosporine. Rosuvastatin is contraindicated in patients taking cyclosporine (see section "Contraindications").
Human immunodeficiency virus (HIV) protease inhibitors:
Although the exact mechanism of interaction is unknown, coadministration of HIV protease inhibitors may result in a significant increase in exposure to rosuvastatin (see Table 1). A pharmacokinetic study of co-administration of 20 mg rosuvastatin with a combination drug containing two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers resulted in an approximately two-fold and five-fold increase in AUC(0-24) and Cmax of rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Method of administration and dosage”, “Special instructions”, table 1).
Gemfibrozil and other lipid-lowering drugs
: the combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in the maximum concentration of rosuvastatin in the blood plasma and the AUC of rosuvastatin (see section "Special instructions"). Based on specific interaction data, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible.
Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section "Special Instructions" ). When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), an initial dose of the drug of 5 mg is recommended for patients; taking a dose of 40 mg is contraindicated when co-administered with fibrates (see sections “Contraindications”, “Method” application and dose", "Special instructions").
Ezetimibe
: Concomitant use of rosuvastatin at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). An increased risk of side effects due to the pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded.
Antacids
: simultaneous use of rosuvastatin and antacid suspensions containing magnesium and aluminum hydroxide leads to a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.
Erythromycin
: simultaneous use of rosuvastatin and erythromycin leads to a decrease in AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by erythromycin.
Cytochrome P450 isoenzymes:
in vivo and in vitro
studies showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level involving cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction of rosuvastatin with fluconazole (an inhibitor of the CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of the CYP2A6 and CYP3A4 isoenzymes).
Fusidic acid:
No studies have been conducted to study the interaction of rosuvastatin and fusidic acid. As with other statins, during post-marketing use of rosuvastatin, there have been reports of cases of rhabdomyolysis with co-administration of rosuvastatin and fusidic acid. Careful monitoring of patients is necessary. If necessary, it is possible to temporarily stop taking Rosuvastatin-Teva.
Interactions with drugs that require dose adjustment of rosuvastatin
(see table 1)
The dose of rosuvastatin should be adjusted if it is necessary to use it together with drugs that increase the AUC of rosuvastatin. If an increase in AUC by 2 times or more is expected, the initial dose of rosuvastatin should be 5 mg once daily. The maximum daily dose of rosuvastatin should also be adjusted so that the expected AUC of rosuvastatin does not exceed that of a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of rosuvastatin when used simultaneously with gemfibrozil is 20 mg (increase in exposure by 1.9 times), with ritonavir/atazanavir - 10 mg (increase in AUC by 3.1 times).
Table 1. Effect of concomitant therapy on rosuvastatin exposure (AUC, data in descending order) - results of published clinical studies
| Concomitant therapy regimen | Rosuvastatin dosage regimen | Change in rosuvastatin AUC |
| Cyclosporine 75-200 mg 2 times a day, 6 months. | 10 mg once a day, 10 days | 7.1x magnification |
| Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days | 10 mg once | 3.1x magnification |
| Simeprevir 150 mg once a day, 7 days | 10 mg once | 2.8x magnification |
| Lopinavir 400 mg/ritonavir 100 mg twice a day, 17 days | 20 mg once a day, 7 days | 2.1x magnification |
| Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours | 20 mg once | 2x magnification |
| Gemfibrozil 600 mg 2 times a day, 7 days | 80 mg once | 1.9x magnification |
| Eltrombopag 75 mg once daily, 10 days | 10 mg once | 1.6x magnification |
| Darunavir 600 mg/ritonavir 100 mg 2 times a day, 7 days | 10 mg once a day, 7 days | 1.5 times magnification |
| Tipranavir 500 mg/ritonavir 200 mg 2 times a day, 11 days | 10 mg once | 1.4x magnification |
| Dronedarone 400 mg twice daily | No data | 1.4x magnification |
| Itraconazole 200 mg once a day, 5 days | 10 mg or 80 mg once | 1.4x magnification |
| Ezetimibe 10 mg once daily, 14 days | 10 mg once a day, 14 days | 1.2 times magnification |
| Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days | once | Without changes |
| Aleglitazar 0.3 mg, 7 days | 40 mg, 7 days | Without changes |
| Silymarin 140 mg 3 times a day, 5 days | 10 mg once | Without changes |
| Fenofibrate 67 mg 3 times a day, 7 days | 10 mg, 7 days | Without changes |
| Rifampicin 450 mg once a day, 7 days | 20 mg once | Without changes |
| Ketoconazole 200 mg 2 times a day, 7 days | 80 mg once | Without changes |
| Fluconazole 200 mg once a day, 11 days | 80 mg once | Without changes |
| Erythromycin 500 mg 4 times a day, 7 days | 80 mg once | 28% reduction |
| Baikalin 50 mg 3 times a day, 14 days | 20 mg once | 47% reduction |
The effect of rosuvastatin on other drugs
Vitamin K antagonists:
Initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (eg, warfarin) may lead to an increase in the international normalized ratio (INR). Discontinuation of rosuvastatin or reduction in its dose may lead to a decrease in INR. In such cases, INR monitoring is recommended.
Oral contraceptives/hormone replacement therapy:
simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUC of norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives. There are no pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy; therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.
Other medicines:
No clinically significant interaction between rosuvastatin and digoxin is expected.
