Crestor, 28 pcs., 5 mg, film-coated tablets
Renal effects
In patients receiving high doses of Crestor® (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. This proteinuria did not indicate acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.
From the musculoskeletal system
The following effects on the musculoskeletal system have been reported when using Crestor® at all dosages, and especially when taking doses of the drug exceeding 20 mg: myalgia, myopathy, and in rare cases, rhabdomyolysis.
Determination of creatine phosphokinase
The determination of CPK should not be carried out after intense physical activity or in the presence of other possible reasons for the increase in CPK, which may lead to incorrect interpretation of the results obtained. If the initial CPK level is significantly elevated (5 times higher than ULN), a repeat measurement should be taken after 5–7 days. Therapy should not be started if a repeat test confirms the initial CPK level (more than 5 times higher than the ULN).
Before starting therapy
When prescribing Crestor®, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see “Contraindications”, With caution
), it is necessary to consider the balance of risk and possible benefit of therapy and conduct clinical monitoring.
During therapy
The patient should be informed to immediately report to the doctor the unexpected onset of muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, CPK levels should be determined. Therapy should be discontinued if CPK levels are significantly increased (more than 5 times the ULN) or if muscle symptoms are severe and cause daily discomfort (even if the CPK level is less than 5 times the ULN). If symptoms disappear and CPK levels return to normal, re-prescribing Crestor® or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient.
Routine monitoring of CPK in the absence of symptoms is impractical.
Very rare cases of immune-mediated necrotizing myopathy have been reported with clinical manifestations in the form of persistent weakness of the proximal muscles and an increase in serum CPK levels during treatment or upon discontinuation of statins, incl. rosuvastatin. Additional studies of the muscular and nervous system, serological studies, and therapy with immunosuppressive drugs may be required.
There were no signs of increased effects on skeletal muscles when taking Crestor® and concomitant therapy. However, an increased incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, niacin, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used together with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of Crestor® and gemfibrozil is not recommended. The risk/benefit ratio should be carefully weighed when using Crestor® together with fibrates or lipid-lowering doses of nicotinic acid. Taking Crestor® at a dose of 40 mg together with fibrates is contraindicated (see “Contraindications”, “Interaction”).
2-4 weeks after the start of treatment and/or when increasing the dose of Crestor®, monitoring of lipid metabolism parameters is necessary (dose adjustment is required if necessary).
Liver
It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. Taking Crestor® should be discontinued or the dose reduced if the level of transaminase activity in the blood serum is 3 times higher than the ULN.
In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment for underlying diseases should be carried out before starting treatment with Crestor®.
Special populations
Ethnic groups.
During pharmacokinetic studies among Chinese and Japanese patients, an increase in systemic concentrations of rosuvastatin was noted compared with values obtained among European patients (see “Dosage and Administration”, “Pharmacokinetics”).
Protease inhibitors
Concomitant use of the drug with protease inhibitors is not recommended (see “Interaction”).
Lactose
The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.
Interstitial lung disease
Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, non-productive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Diabetes mellitus type 2
In patients with glucose concentrations between 5.6 and 6.9 mmol/L, therapy with Crestor® was associated with an increased risk of developing type 2 diabetes mellitus.
Impact on the ability to drive a car or perform work that requires increased speed of physical and mental reactions.
No studies have been conducted to study the effect of Crestor® on the ability to drive a vehicle and use machinery. However, based on pharmacodynamic properties, Crestor® should not have such an effect. Caution should be exercised when driving a vehicle or doing work that requires increased concentration and psychomotor reaction (dizziness may occur during therapy).
Crestor®
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 3 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 3). Does not affect plasma concentrations of cyclosporine. Krsstor® is contraindicated in patients taking cyclosporine (see section "Contraindications").
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 3). A pharmacokinetic study of the simultaneous use 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 3).
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 of administration and dosage", "Special instructions").
Ezetimibe:
simultaneous use of Crestor® 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 3). An increased risk of side effects due to the pharmacodynamic interaction between Crestor® and ezetimibe cannot be excluded.
Antacids:
simultaneous use of rosuvastatin and antacid suspensions containing magnesium and aluminum 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.
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, there have been post-marketing reports of rhabdomyolysis with co-administration of rosuvastatin and fusidic acid. Patients must be closely monitored. If necessary, it is possible to temporarily stop taking rosuvastatin.
Interactions with drugs that require dose adjustment of rosuvastatin
(see table 3)
The dose of Crestor® should be adjusted if it is necessary to use it together with drugs that increase exposure to rosuvastatin. You should read the instructions for use of these drugs before prescribing them together with Crestor®.
If an increase in exposure by 2 times or more is expected, the initial dose of Crestor® should be 5 mg once daily. The maximum daily dose of Crestor should also be adjusted so that the expected exposure to rosuvastatin does not exceed that for a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin. For example, the maximum daily dose of Crestor® when used simultaneously with gemfibrozil is 20 mg (increased exposure by 1.9 times), with ritonavir/atazanavir - 10 mg (increased exposure by 3.1 times).
Table 3. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data given in descending order) - results of published clinical studies
| Concomitant therapy regimen | Rosuvastatin dosage regimen | Change in AUC of rosuvastatin |
| Cyclosporine 75-200 mg 2 times a day, 6 months. | 10 mg 1 time per day, 10 days | 7.1x magnification |
| Atazanavir 300 mg/ritonavir 100 mg once a day, 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 2 times a day, 17 days | 20 mg 1 time per 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 |
| Darunavnr 600 mg/ritonavir 100 mg once a day, 7 days | 10 mg 1 time per 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 2 times a day. | 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 a day, 14 days | 10 mg once a day, 14 days | 1.2 times magnification |
| Fosamprenavir 700 mg/ritonavir 100 mg 2 times a day, 8 days | 10 mg 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 |
| Rifamiin 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 of the drug dose may lead to a decrease in INR. In such cases, INR monitoring is recommended.
Oral
contraceptives/hormone replacement therapy:
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.
There are no pharmacokinetic data on the simultaneous use of Crestor® 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.
