Instructions for use TULIP® (TULIP)
The risk of developing myopathy increases with concomitant use of HMG-CoA reductase inhibitors and cyclosporine, fibrates, macrolide antibiotics (including erythromycin), azole antifungals or nicotinic acid. In rare cases, rhabdomyolysis has developed as a result of the concomitant use of these drugs, accompanied by renal failure caused by myoglobinuria. Therefore, the potential benefits of combination therapy must be carefully weighed against the risks.
Atorvastatin is metabolized by the CYP3A4 isoenzyme. With the concomitant use of atorvastatin and inhibitors of the CYP3A4 isoenzyme (for example, cyclosporine, macrolide antibiotics, including erythromycin and clarithromycin, nefazodone, azole antifungals, including itraconazole, and HIV protease inhibitors), an increase in plasma levels of atorvastatin is possible. Therefore, with the concomitant use of atorvastatin and the drugs listed above, special caution must be exercised.
Atorvastatin and its metabolites are substrates of P-glycoprotein. P-glycoprotein inhibitors (eg, cyclosporine) may increase the bioavailability of atorvastatin.
Concomitant use of atorvastatin (10 mg 1 time / day) and erythromycin (500 mg 4 times / day) or clarithromycin (50 mg 2 times / day), which are known to be inhibitors of the CYP3A4 isoenzyme, is associated with increased plasma levels of atorvastatin. Clarithromycin increases atorvastatin Cmax by 56% and AUC by 80%.
As a result of concomitant use of atorvastatin at a dose of 40 mg and itraconazole (200 mg 1 time / day), the AUC values of atorvastatin increase 3 times.
With the concomitant use of atorvastatin and protease inhibitors (inhibitors of the CYP3A4 isoenzyme), an increase in plasma levels of atorvastatin was observed.
There is no known interaction between drugs that induce the CYP3A4 isoenzyme (for example, rifampicin or phenytoin) and atorvastatin. There is also no known interaction between atorvastatin and other substrates of this isoenzyme, but this possibility must be taken into account when using drugs with a narrow therapeutic index, for example, class III antiarrhythmic drugs (amiodarone).
The risk of developing myopathy in connection with the use of atorvastatin may be increased by fibrates. Based on in vitro studies, gemfibrozil inhibits the glucuronidation metabolism of atorvastatin, which may lead to increased plasma levels of atorvastatin.
Repeated simultaneous administration of 10 mg of atorvastatin and digoxin does not affect the plasma concentration of digoxin at steady state. But when taking digoxin and atorvastatin 80 mg daily, digoxin concentrations increased by about 20%. This interaction is explained by the inhibition of glycoprotein P, a transport protein of the cell membrane. In this regard, patients taking digoxin should be under medical supervision.
With the simultaneous use of atorvastatin and oral contraceptives, an increase in plasma levels of norethisterone and ethinyl estradiol was observed. This should be taken into account when selecting the dose of contraceptives.
With simultaneous use of atorvastatin and colestipol, the plasma concentrations of atorvastatin and its active metabolites decreased by approximately 25%, while the degree of cholesterol reduction exceeded that when taking each drug separately.
With the simultaneous use of atorvastatin and antacids containing magnesium and aluminum hydroxides, the concentration of atorvastatin and its active metabolites in plasma is reduced by approximately 35%, but the degree of reduction in LDL-C levels remains unchanged.
In the first days of therapy, with the simultaneous use of atorvastatin and warfarin, the slightly reduced prothrombin time increased, although after 15 days this indicator returned to normal. Patients receiving warfarin should be closely monitored when atorvastatin is added to treatment.
Repeated simultaneous administration of phenazone and atorvastatin has little effect on the clearance of phenazone.
During a study of the combined use of cimetidine and atorvastatin, no interaction was observed between the drugs.
Co-administration of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg does not affect the pharmacokinetics of atorvastatin in a stable state.
In studies of concomitant use of atorvastatin and antihypertensive or hypoglycemic agents, no clinically significant interactions were found.
Grapefruit juice contains one or more components that inhibit CYP3A4 and may cause increased plasma concentrations of drugs if they are metabolized by CYP3A4. Daily consumption of 240 ml of grapefruit juice caused an increase in the AUC values of atorvastatin by 37% and a decrease in the AUC values of its active orthohydroxy metabolite by 20.4%. As a result of consuming large amounts of grapefruit juice (more than 1.2 liters per day for 5 days), the AUC values of atorvastatin increased by 2.5 times and the AUC of HMG-CoA reductase inhibitors (atorvastatin and its metabolites) by 1.3 times. In this regard, during treatment with atorvastatin, consumption of large quantities of grapefruit juice is not recommended.
Tulip
The risk of myopathy during treatment with HMG-CoA reductase inhibitors increases with simultaneous use with cyclosporine, erythromycin, clarithromycin, immunosuppressive, antifungal drugs (azole derivatives)
due to a possible increase in serum concentrations of atorvastatin.
When used simultaneously with HIV protease inhibitors - indinavir, ritonavir -
the risk of developing myopathy increases.
A similar interaction is possible with simultaneous use of atorvastatin with fibrates and nicotinic acid
in lipid-lowering doses (more than 1 g/day).
Inhibitors of the
CYP3A4 isoenzyme
Since atorvastatin is metabolized by the CYP3A4 isoenzyme, concomitant use of the drug Tulip
with inhibitors of this isoenzyme may lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of increasing the concentration of atorvastatin is determined by the variability of the effect on the CYP3A4 isoenzyme.
OATP1B1 transport protein inhibitors
Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. OATP1B1 inhibitors (eg, cyclosporine) may increase the bioavailability of atorvastatin. Thus, the use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day leads to an increase in the concentration of atorvastatin in the blood plasma by 7.7 times.
Erythromycin/clarithromycin
With the simultaneous use of atorvastatin 10 mg and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), which inhibit the cytochrome CYP3A4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma is observed (by 40% when used with erythromycin and by 56% when used with clarithromycin).
Protease inhibitors
The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the cytochrome CYP3A4 isoenzyme, is accompanied by an increase in the concentration of atorvastatin in the blood plasma (when used simultaneously with erythromycin, the Cmax of atorvastatin increases by 40%).
Diltiazem
Co-administration of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma.
Cimetidine
No clinically significant interaction of atorvastatin with cimetidine has been identified. Itraconazole
The simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole in a dose of 200 mg leads to a 3-fold increase in the AUC value of atorvastatin.
Grapefruit juice
Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, excessive consumption (more than 1.2 L per day for 5 days) may cause an increase in plasma concentrations of atorvastatin.
Inducers of the CYP3A4 isoenzyme
: Concomitant CYP3A4 )
may lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), the simultaneous use of atorvastatin and rifampicin is not recommended, since delayed administration of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma.
Antacids
With simultaneous oral administration of atorvastatin and a suspension containing magnesium and aluminum hydroxides, the plasma concentration of atorvastatin is reduced by approximately 35%, but the degree of reduction in LDL-cholesterol concentration does not change.
Phenazone
Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same isoenzymes is not expected.
Colestipol
The lipid-lowering effect of the combination with colestipol is superior to that of each drug separately, despite a 25% decrease in the concentration of atorvastatin when used simultaneously with colestipol.
Fusidic acid
No interaction studies have been conducted between atorvastatin and fusidic acid. As with other statins, muscle side effects, including rhabdomyolysis, have been reported in post-marketing studies of concomitant use of atorvastatin and fusidic acid. The mechanism of interaction is unknown. Such patients require careful monitoring and, possibly, temporary discontinuation of atorvastatin.
Colchicine
Although interaction studies between atorvastatin and colchicine have not been conducted, cases of myopathy have been reported when coadministered with colchicine, and caution should be used when atorvastatin and colchicine are coadministered.
Digoxin
With repeated use of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma do not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day. The concentration of digoxin in the blood plasma increases by approximately 20%. Patients taking digoxin in combination with atorvastatin require monitoring of digoxin plasma concentrations.
Azithromycin
With simultaneous use of atorvastatin at a dose of 10 mg 1 time / day and azithromycin at a dose of 500 mg 1 time / day, the concentration of atorvastatin in the blood plasma does not change.
Oral contraceptives
When atorvastatin is used concomitantly with an oral contraceptive containing norethisterone and ethinyl estradiol, there is a significant increase in the AUC of norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively, which should be taken into account when choosing an oral contraceptive.
Terfenadine
Atorvastatin, when used simultaneously with terfenadine, does not have a clinically significant effect on the pharmacokinetics of terfenadine.
Warfarin
In patients who take warfarin for a long time, atorvastatin at a dose of 80 mg per day slightly shortens the prothrombin time in the first days of joint use. This effect disappears after 15 days of simultaneous use of these drugs. Although clinically significant changes in the anticoagulant effect have been reported very rarely, the prothrombin time should be determined in patients taking coumarin anticoagulants before and frequently during the initiation of treatment with atorvastatin to ensure that there are no significant changes in the prothrombin time. Once a stable prothrombin time has been recorded, it can be checked at intervals usual for patients taking coumarin anticoagulants. If the dose is changed or treatment is stopped, these measures should be repeated. There was no association between atorvastatin use and bleeding or changes in prothrombin time in patients not taking anticoagulants.
Amlodipine
With simultaneous use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin at steady state does not change.
Other lipid-lowering drugs
When atorvastatin is used simultaneously with other lipid-lowering drugs (for example, ezetimibe, gemfibrozil, fibric acid derivative)
in lipid-lowering doses, the risk of developing rhabdomyolysis increases.
Other concomitant therapy
When atorvastatin is used together with antihypertensive drugs and estrogens (as replacement therapy), no clinically significant interaction has been identified.
Tulip, 90 pcs., 20 mg, film-coated tablets
The risk of myopathy during treatment with HMG-CoA reductase inhibitors increases when used simultaneously with cyclosporine, erythromycin, clarithromycin, immunosuppressive, antifungal drugs (azole derivatives) due to a possible increase in the concentration of atorvastatin in the blood serum.
When used simultaneously with HIV protease inhibitors - indinavir, ritonavir - the risk of developing myopathy increases. A similar interaction is possible with simultaneous use of atorvastatin with fibrates and nicotinic acid in lipid-lowering doses (>1 g/day).
Inhibitors of the CYP3A4 isoenzyme.
Since atorvastatin is metabolized by the CYP3A4 isoenzyme, the combined use of Tulip® with inhibitors of this isoenzyme may lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of increasing the concentration of atorvastatin is determined by the variability of the effect on the CYP3A4 isoenzyme.
Inhibitors of the transport protein OATP1B1.
Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. OATP1B1 inhibitors (eg cyclosporine) may increase the bioavailability of atorvastatin. Thus, the use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day leads to an increase in the concentration of atorvastatin in the blood plasma by 7.7 times.
Erythromycin/clarithromycin.
With simultaneous use of atorvastatin (10 mg) and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), which inhibit the cytochrome CYP3A4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma is observed (by 40% when used with erythromycin and by 56% when used with clarithromycin).
Protease inhibitors.
The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the cytochrome CYP3A4 isoenzyme, is accompanied by an increase in the concentration of atorvastatin in the blood plasma (when used simultaneously with erythromycin, the Cmax of atorvastatin increases by 40%).
Diltiazem.
Co-administration of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma.
Cimetidine.
No clinically significant interaction of atorvastatin with cimetidine has been identified.
Itraconazole
The simultaneous use of atorvastatin in doses of 20 to 40 mg and itraconazole in a dose of 200 mg leads to a 3-fold increase in the AUC value of atorvastatin.
Grapefruit juice.
Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, excessive consumption (more than 1.2 L per day for 5 days) may cause an increase in plasma concentrations of atorvastatin.
Inducers of the CYP3A4 isoenzyme.
Concomitant use of atorvastatin with inducers of the CYP3A4 isoenzyme (for example, efavirenz or rifampicin) may lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), the simultaneous use of atorvastatin and rifampicin is not recommended, since delayed administration of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma.
Antacids.
With simultaneous oral administration of atorvastatin and a suspension containing magnesium and aluminum hydroxides, the concentration of atorvastatin in plasma is reduced by approximately 35%, but the degree of reduction in the concentration of LDL-C does not change.
Phenazone.
Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same isoenzymes is not expected.
Colestipol.
The lipid-lowering effect of the combination with colestipol is superior to that of each drug separately, despite a 25% decrease in the concentration of atorvastatin when used simultaneously with colestipol.
Fusidic acid.
No interaction studies have been conducted between atorvastatin and fusidic acid. As with other statins, muscle side effects, including rhabdomyolysis, have been reported in post-marketing studies of concomitant use of atorvastatin and fusidic acid. The mechanism of interaction is unknown. Such patients require careful monitoring and, possibly, temporary discontinuation of atorvastatin.
Colchicine.
Although interaction studies between atorvastatin and colchicine have not been conducted, cases of myopathy have been reported when coadministered with colchicine, and caution should be used when atorvastatin and colchicine are coadministered.
Digoxin.
With repeated use of digoxin and atorvastatin at a dose of 10 mg, the Css of digoxin in the blood plasma do not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day, the concentration of digoxin in the blood plasma increases by approximately 20%. Patients taking digoxin in combination with atorvastatin require monitoring of digoxin plasma concentrations.
Azithromycin.
With simultaneous use of atorvastatin at a dose of 10 mg 1 time / day and azithromycin at a dose of 500 mg 1 time / day, the concentration of atorvastatin in the blood plasma does not change.
Oral contraceptives.
With simultaneous use of atorvastatin and an oral contraceptive containing norethisterone and ethinyl estradiol, there is a significant increase in the AUC of norethisterone and ethinyl estradiol by approximately 30 and 20%, respectively, which should be taken into account when choosing an oral contraceptive.
Terfenadine.
Atorvastatin, when used simultaneously with terfenadine, does not have a clinically significant effect on the pharmacokinetics of terfenadine.
Warfarin.
In patients taking warfarin for a long time, atorvastatin at a dose of 80 mg/day slightly shortens the PT in the first days of co-administration. This effect disappears after 15 days of simultaneous use of these drugs. Although clinically significant changes in the anticoagulant effect have been reported very rarely, the PT should be determined in patients taking coumarin anticoagulants before and frequently during the initiation of treatment with atorvastatin to ensure that there are no significant changes in PT. Once a stable PT has been recorded, it can be monitored at intervals usual for patients taking coumarin anticoagulants. If the dose is changed or treatment is stopped, these measures should be repeated. There was no association between atorvastatin use and bleeding or changes in PT in patients not taking anticoagulants.
Amlodipine.
With simultaneous use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin at steady state does not change.
Other lipid-lowering drugs.
When atorvastatin is used simultaneously with other lipid-lowering drugs (for example, ezetimibe, gemfibrozil, fibric acid derivative) in lipid-lowering doses, the risk of developing rhabdomyolysis increases.
Other concomitant therapy.
When atorvastatin is used together with antihypertensive drugs and estrogens (as replacement therapy), no clinically significant interaction has been identified.
