ROSUVASTATIN
Interaction
Cyclosporine:
Cyclosporine enhances the effect of rosuvastatin. 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 section "Contraindications"). Simultaneous use leads to an 11-fold increase in the concentration of rosuvastatin in the blood plasma, while the concentration of cyclosporine in the blood plasma does not change.
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 prothrombin time (International Normalized Ratio - IHO). Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in MHO. In such cases, MHO monitoring is recommended.
Gemfibrozil and other lipid-lowering drugs:
Gemfibrozil enhances the effect of rosuvastatin. The simultaneous use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax in blood plasma and AUC of rosuvastatin (see section “Special instructions”).
Based on specific interaction data, no pharmacokinetically significant interaction with fenofibrates is expected; pharmacodynamic interaction is possible.
Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (greater than or equivalent to 1 g/day) increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used in monotherapy (see section "Special instructions"). When taking the drug simultaneously with gemfibrozil and other lipid-lowering drugs, patients are recommended to start with an initial dose of 5 mg.
Ezetimibe:
The simultaneous use of rosuvastatin and ezetimibe was not accompanied by changes in the AUC and Cmax of both drugs.
Antacids:
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.
Protease inhibitors:
Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may lead to a significant increase in rosuvastatin exposure. A pharmacokinetic study of the simultaneous use of 20 mg rosuvastatin with a combination drug containing two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers resulted in approximately two-fold and four-fold increases in AUC0-24 and Cmax of rosuvastatin, respectively. Therefore, simultaneous use of rosuvastatin and protease inhibitors in the treatment of patients with HIV is not recommended.
Erythromycin:
The simultaneous use of rosuvastatin and erythromycin leads to a decrease in AUC(0-t) of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by erythromycin.
Oral contraceptives/hormone replacement therapy:
Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUC of norgestril 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.
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 non-core 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). The simultaneous use of rosuvastatin and itraconazole (CYP3A4 inhibitor) increases the AUC of rosuvastatin by 28% (clinically insignificant). Thus, interactions related to cytochrome P 450 metabolism are not expected.
Other medicines:
No clinically significant interaction between rosuvastatin and digoxin is expected. Concomitant use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of a decrease in endogenous steroid hormones.
Rosuvastatin
Renal dysfunction
In patients receiving high doses of rosuvastatin (particularly 40 mg/day), tubular proteinuria was observed, which was detected using test strips and in most cases was intermittent or short-term. Such proteinuria does not indicate acute illness or progression of concomitant renal disease. The incidence of serious renal dysfunction observed in post-marketing studies of rosuvastatin is higher when taking a dose of 40 mg/day. In patients taking Rosuvastatin at a dose of 30 or 40 mg/day, it is recommended to monitor renal function during treatment (at least once every 3 months).
Effect on the musculoskeletal system
The following musculoskeletal effects have been reported with rosuvastatin at all doses, but particularly at doses greater than 20 mg/day: myalgia, myopathy, and in rare cases, rhabdomyolysis. Very rare cases of rhabdomyolysis have been reported with the simultaneous use of HMG-CoA reductase inhibitors and ezetimibe. This combination should be used with caution, as pharmacodynamic interactions cannot be excluded.
As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis with post-marketing use of rosuvastatin is higher when using a dose of 40 mg/day.
Determination of serum CPK activity
Serum CPK activity cannot be determined after intense physical exercise and in the presence of other possible reasons for an increase in its activity; this may lead to incorrect interpretation of the results obtained. If the initial serum CPK activity is significantly exceeded (5 times higher than the upper limit of normal), a repeat analysis should be performed after 5-7 days. Therapy should not be started if the results of a repeat analysis confirm the initial high serum CPK activity (more than 5 times the upper limit of normal).
Before starting therapy
Depending on the daily dose, Rosuvastatin should be administered with caution to patients with existing risk factors for myopathy/rhabdomyolysis.
These factors include:
- renal dysfunction,
- hypothyroidism,
- history of muscle diseases (including family history),
- history of myotoxic effects when taking other HMG-CoA reductase inhibitors or fibrates,
- excessive alcohol consumption,
- age over 65 years,
- conditions in which the concentration of rosuvastatin in the blood plasma may increase,
- simultaneous use of fibrates.
In such patients, it is necessary to evaluate the risks and possible benefits of therapy. Clinical monitoring is also recommended. If the initial serum CK activity is higher than 5 times the upper limit of normal, therapy with Rosuvastatin cannot be started.
During drug therapy
The patient should be informed to immediately report to the doctor if muscle pain, muscle weakness or spasms occur unexpectedly, especially in combination with malaise and fever. In such patients, serum CPK activity should be determined. Therapy should be discontinued if serum CPK activity is significantly increased (more than 5 times the upper limit of normal), or if muscle symptoms are severe and cause daily discomfort (even if serum CPK activity is no more than 5 times the upper limit of normal). exceeds the upper limit of normal). If symptoms disappear and serum CPK activity returns to normal, resumption of use of Rosuvastatin or other HMG-CoA reductase inhibitors in lower doses should be considered under close medical supervision. Monitoring serum CPK activity 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 increased CPK activity in the blood serum during therapy or upon discontinuation of the use of HMG-CoA reductase inhibitors, including 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 rosuvastatin and concomitant therapy. However, an increase in the number of cases of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives (for example, gemfibrozil), cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g / day), antifungals - azole derivatives, HIV protease inhibitors and macrolide antibiotics.
When used simultaneously with certain HMG-CoA reductase inhibitors, gemfibrozil increases the risk of developing myopathy. Thus, the simultaneous use of Rosuvastatin and gemfibrozil is not recommended. The benefits of further changes in plasma lipid concentrations when using the drug Rosuvastatin in combination with fibrates or nicotinic acid in lipid-lowering doses must be carefully weighed against the possible risks. The drug Rosuvastatin at a dose of 40 mg/day is contraindicated for combination therapy with fibrates.
Rosuvastatin should not be used simultaneously or within 7 days after discontinuation of systemic fusidic acid therapy. In patients in whom the use of fusidic acid is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid therapy. There have been reports of rhabdomyolysis (including death in some cases) in patients receiving fusidic acid concomitantly with statins. The patient should seek immediate medical attention if any symptoms of muscle weakness, pain, or tenderness occur.
Therapy with Rosuvastatin can be resumed 7 days after the last dose of fusidic acid.
In exceptional cases, when long-term use of systemic fusidic acid is required, for example, in the treatment of severe infections, the need for simultaneous use of Rosuvastatin and fusidic acid should be considered individually and subject to careful medical supervision.
Due to the increased risk of rhabdomyolysis, Rosuvastatin should not be used in patients with acute conditions that may lead to myopathy or conditions predisposing to the development of renal failure (for example, sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances , uncontrollable seizures).
2-4 weeks after the start of treatment and/or when the dose of Rosuvastatin is increased, monitoring of lipid metabolism parameters is necessary (dose adjustment is required if necessary).
Liver
Depending on the daily dose, Rosuvastatin should be used with caution in patients with excessive alcohol consumption and/or in patients with a history of liver disease, or its use is contraindicated (see sections "Contraindications" and "Precautions").
It is recommended to determine liver function tests before the start of therapy and 3 months after its start. The use of the drug Rosuvastatin should be discontinued or the dose of the drug should be reduced if the activity of “liver” transaminases in the blood serum is 3 times higher than the upper limit of normal.
In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, underlying diseases should be treated before starting treatment with Rosuvastatin.
Ethnic characteristics
During pharmacokinetic studies, an increase in the plasma concentration of rosuvastatin was noted in representatives of the Mongoloid race compared to representatives of the Caucasian race.
Interstitial lung disease
Isolated cases of interstitial lung disease have been reported with the use of certain HMG-CoA reductase inhibitors, especially over long periods of time. 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, therapy with HMG-CoA reductase inhibitors should be discontinued.
Diabetes mellitus type 2
In patients with glucose concentrations between 5.6 and 6.9 mmol/L, rosuvastatin therapy was associated with an increased risk of developing type 2 diabetes mellitus.
HIV protease inhibitors
Concomitant use of the drug with HIV protease inhibitors is not recommended (see section “Interaction with other drugs”).
Special information on excipients
The drug Rosuvastatin contains lactose and is therefore contraindicated in patients with lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.
