During treatment with HMG-CoA-rare cytase inhibitors, while using cyclosporine, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day) or inhibitors of the isoenzyme CYP3A4 (for example, erythromycin, clarithromycin, antifungal agents - azole derivatives) increases the risk of myopathy.
Inhibitor inhibitors CYP3A4
Because the atorvastatin is metabolized by isoenzyme CYP3A4, the combined use of atorvastatin with isozyme inhibitors CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of potentiation is determined by the variability of the effect on the isoenzyme CYP3A4.
It was found that potent inhibitors of isoenzyme CYP3A4 lead to a significant increase in the concentration of atorvastatin in blood plasma. If possible, simultaneous use of potent inhibitors of isoenzyme should be avoided CYP3A4 (e.g., ciclosporin, telithromycin, clarithromycin, delavirdine, styipentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir and etc.). If simultaneous administration of these drugs is necessary, consideration should be given to initiating therapy with a minimal dose, and the possibility of reducing the maximum dose of atorvastatin should be evaluated.
Moderate inhibitors of isoenzyme CYP3A4 (e.g., erythromycin, diltiazem, verapamil and fluconazole) can lead to an increase in the concentration of atorvastatin in the blood plasma. Against the background of simultaneous application of HMG-CoA-Rarecutase (statins) and erythromycin, there was an increased risk of myopathy. Studies of the interaction of amiodarone or verapamil and atorvastatin have not been conducted. It is known that u amiodarone and verapamil inhibit isoenzyme activity CYP3A4 and simultaneous use of these drugs with atorvastatin may lead to an increase in exposure to atorvastatin. In this regard, it is recommended to reduce the maximum dose of atorvastatin and to conduct appropriate monitoring of the patient's condition while using with moderate isoenzyme inhibitors CYP3A4. The control should be carried out after the initiation of therapy and against the background of a change in the dose of the inhibitor.
Inhibitors of transport protein OATP1B1
Atorvastatin and its metabolites are transport protein substrates OATP1BJ. Inhibitors OADP1 B1 (nFor example, ciclosporin) may increase the bioavailability of atorvastatin. Thus, the combined use of atorvastatin 10 mg and cyclosporine at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in blood plasma by 7.7 times. The effect of inhibition of hepatic transport function on the concentration of atorvastatin in hepatocytes is unknown. In the event that it is impossible to avoid the simultaneous use of such drugs, it is recommended to reduce the dose and control the effectiveness of therapy.
Gemfibrosil / Fibrates
Against the background of the use of fibrates in monotherapy, undesirable reactions, including rhabdomyolysis, concerning the musculoskeletal system were periodically noted.The risk of developing such reactions increases with the simultaneous use of fibrates and atorvastatin. If simultaneous application of these drugs can not be avoided, then a minimum effective dose of atorvastatin should be used, and regular monitoring of patients' condition should be carried out.
Ezetimibe
The use of ezetimibe is associated with the development of unwanted reactions, including rhabdomyolysis, from the musculoskeletal system. The risk of developing such reactions increases with the simultaneous use of ezetimibe and atorvastatin. Careful observation is recommended for such patients.
Erythromycin / clarithromycin
With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times per day) or clarithromycin (500 mg twice a day), inhibitors of isoenzyme CYP3A4, an increase in the concentration of atorvastatin in blood plasma was observed.
Inhibitors of proteases
The simultaneous use of atorvastatin with protease inhibitors, known as isoenzyme inhibitors CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.
Diltiazem
Joint use of atorvastatin in a dose of 40 mg with diltiazem at a dose of 240 mg, leads to an increase in the concentration of atorvastatin in blood plasma.
Cimetidine
Clinically significant interaction of atorvastatin with cimetidine was not detected.
Itraconazole
Simultaneous use of atorvastatin in doses of 20 to 40 mg and itraconazole at a dose of 200 mg resulted in an increase AUC atorvastatin.
Grapefruit juice
Because grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4, its excessive use (more than 1.2 per day) can cause an increase in the concentration of atorvastatin in the blood plasma.
Inductors of isoenzyme CYP3A4
Combined use of atorvastatin with isoenzyme inducers CYP3A4 (eg, efavirenz, rifampicin, or preparations of St. John's wort) can lead to a decrease in the concentration of atorvastatin in the blood plasma.
Due to the dual mechanism of interaction with rifampicin (isoenzyme inducer CYP3A4 and inhibitor of hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin results in a significant reduction in the concentration of atorvastatin in the blood plasma. However, the effect of rifampicin on the concentration of atorvastatin in hepatocytes is unknown, and if simultaneous application can not be avoided,should carefully monitor the effectiveness of such therapy.
Antacids
Simultaneous ingestion of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the concentration of atorvastatin in the blood plasma by approximately 35%, but the degree of decrease in the concentration of LDL-C was not changed.
Fenazone
Atorvastatin does not affect the pharmacokinetics of phenazone, therefore interaction with other drugs metabolized by the same isoenzymes of cytochrome is not expected.
Kolestypol
With simultaneous use with colestipol, the concentration of atorvastatin in the blood plasma decreased by about 25%. However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.
Digoxin
With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increased by about 20%. Patients receiving digoxin in combination with atorvastatin, require appropriate monitoring.
Azithromycin
With the simultaneous use of atorvastatin 10 mg once a day and azithromycin 500 mg once a day, the concentration of atorvastatin in the blood plasma did not change.
Oral contraceptives
The administration of atorvastatin in combination with an oral contraceptive containing norethisterone and ethinyl estradiol, caused a significant increase AUC norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.
Terfenadine
With the simultaneous use of atorvastatin and terfenadine, clinically significant changes in the pharmacokinetics of terfenadine have not been identified.
Warfarin
In clinical studies, patients regularly receiving warfarin therapy with simultaneous use of atorvastatin at a dose of 80 mg per day resulted in a slight increase in prothrombin time by approximately 1.7 seconds. during the first 4 days of therapy. The indicator returned to normal within 15 days of therapy with atorvastatin. Despite the fact that only in rare cases there was a significant interaction affecting the anticoagulant function,it should be determined prothrombin time before initiation of therapy with atorvastatin in patients receiving coumarin anticoagulant therapy and often enough during therapy to prevent a significant change in prothrombin time. Once a stable prothrombin time is noted, it can be monitored as recommended for patients receiving coumarin anticoagulants. When changing the dose of atorvastatin or stopping therapy, prothrombin time should be monitored according to the same principles as described above. Therapy with atorvastatin was not associated with the development of bleeding or changes in prothrombin time in patients who did not receive anticoagulant treatment.
Colchicine
Despite the fact that no simultaneous application of colchicine and atorvastatin has been performed, there are reports of myopathy developing with this combination. Care should be taken when using atorvastatin and colchicine concomitantly.
Amlodipine
With simultaneous use of atorvastatin in a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin did not change in the equilibrium state.
Fusidic acid
With the simultaneous use of atorvastatin and fusidic acid, cases of rhabdomyolysis have been noted. The mechanism of this interaction is unknown. If further treatment with fusidic acid is necessary, then treatment with statins should be stopped for the entire period of treatment with fusidic acid. Therapy with statins can be resumed 7 days after the last intake of fusidic acid. In exceptional cases where prolonged systemic therapy with fusidic acid is required, for example for the treatment of severe infections, the need for simultaneous use of atorvastatin and fusidic acid should be considered in each case and under strict medical supervision. The patient should immediately seek medical help if symptoms of muscle weakness of sensitivity or pain appear.
Other concomitant therapy
In clinical trials atorvastatin were used in combination with antihypertensive drugs and estrogens within the framework of hormone replacement therapy. There were no signs of clinically significant undesirable interaction. Studies of interaction with specific drugs have not been conducted.In addition, there was an increase in the concentration of atorvastatin when used simultaneously with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole. Caution should be exercised when these drugs are used concomitantly, and the lowest effective dose of atorvastatin should be used.
Table 1. Effect of simultaneous use of drugs on the pharmacokinetics of atorvastatin
| A drug | Atorvastatin |
| Dose (mg) | Change AUC& | Change FROMmax& |
| Cyclosporine 5.2 mg / kg / day, a constant dose | 10 mg once a day, for 28 days | ↑ 8,7 | ↑ 10,7 |
| Tipranavir 500 mg twice daily / ritonavir 200 mg 2 times a day for 7 days | 10 mg, once | ↑ 9,4 | ↑ 8,6 |
| Telaprevir 750 mg every 8 hours, for 10 days | 20 mg, once | ↑ 7,88 | ↑ 10,6 |
| Boceprevir 800 mg 3 times a day, for 7 days | 40 mg, once | ↑ 2,30 | ↑ 2,66 |
| Lopinavir 400 mg twice daily / ritonavir 100 mg 2 times a day for 14 days | 20 mg once a day, for 4 days | ↑ 5,9 | ↑ 4,7 |
| ‡ Saquinavir 400 mg twice a day / ritonavir 400 mg twice a day, for 15 days | 40 mg once a day, for 4 days | ↑ 3,9 | ↑ 4,3 |
| Clarithromycin 500 mg 2 times a day, for 9 days | 80 mg once a day, for 8 days | ↑ 4,4 | ↑ 5,4 |
| Darunavir 300 mg twice daily / ritonavir 100 mg 2 times a day for 9 days | 10 mg once a day, for 4 days | ↑ 3,4 | ↑ 2,25 |
| Itraconazole 200 mg once daily for 4 days | 40 mg, once | ↑ 3,3 | ↑ 20% |
| Fosamprenavir 700 mg twice daily / ritonavir 100 mg 2 times a day, for 14 days | 10 mg once a day, for 4 days | ↑ 2,53 | ↑ 2,84 |
| Fosamprenavir 1400 mg 2 times a day, for 14 days | 10 mg once a day, for 4 days | ↑ 2,3 | ↑ 4,04 |
| Nelfinavir 1250 mg 2 times a day, for 14 days | 10 mg once a day, for 28 days | ↑ 0,74 | ↑ 2,2 |
| grapefruit juice, 240 ml once a day * | 40 mg, once | ↑ 0,37 | ↑ 0,16 |
| diltiazem 240 mg once a day, for 28 days | 40 mg, once | ↑ 0,51 | 0 |
| erythromycin 500 mg 4 times a day, for 7 days | 10 mg, once | ↑ 0,33 | ↑ 0,38 |
| amlodipine 10 mg, once | 80 mg, once | ↑ 0,15 | ↓0,12 |
| cimetidine 300 mg 4 times a day, for 2 weeks | 10 mg once a day, for 2 weeks | ↓0,001 | ↓0,11 |
| Colestipol 10 mg twice a day for 28 weeks | 40 mg once a day, for 28 weeks | not installed | ↓ 0,26 ** |
| maalox tc® 30 ml once a day, for 17 days | 10 mg once a day, for 15 days | ↓ 0,33 | ↓0,34 |
| efavirenz 600 mg once a day, for 14 days | 10 mg, for 3 days | ↓0,41 | ↓0,01 |
| rifampicin 600 mg once daily for 7 days (simultaneous use)† | 40 mg, once | ↑ 0,30 | ↑ 2,7 |
| rifampicin 600 mg once daily for 5 days (separate intake)† | 40 mg, once | ↓ 0,80 | ↓0,40 |
| gemfibrozil 600 mg 2 times a day, for 7 days | 40 mg, once | ↑ 0,35 | ↓ less than 1% |
| fenofibrate 160 mg once a day, for 7 days | 40 mg, once | ↑ 0,03 | ↑ 0,02 |
& coefficient of change [(1-in) / in], where i = pharmacokinetic values during the interaction and in = pharmacokinetic values are normal;
* with a significant consumption of grapefruit juice (> 750 ml - 1.2 liters per day) noted a larger increase auc (up to 1.5 times) and / or withmOh (up to 0.71 times);
** The sample was taken only once 8-16 hours after taking the drug.
†as rifampicin has a dual mechanism of interaction, it is recommended to introduce atorvastatin and rifampicin Simultaneously. the later use of atorvastatin after rifampicin is associated with a significant decrease in the concentration of atorvastatin in the blood plasma;
‡ doses of saquinavir and ritonavir used in this study differ from those used in clinical practice. it should be borne in mind that the increase in exposure to atorvastatin in clinical use is likely to be higher than observed in this study. therefore, the lowest dose of atorvastatin should be used.
table 2.the effect of atorvastatin on the pharmacokinetics of other drugs
| atorvastatin | a drug used concomitantly with atorvastatin, dosage |
| preparation / dose (mg) | change auc& | change frommax& |
| 80 mg once a day, for 15 days | antipyrine, 600 mg, once | ↑0,03 | ↑0,11 |
| 80 mg once a day, for 14 days | digoxin 0.25 mg once daily for 20 days | ↑ 0,15 | ↑ 0,20 |
| 40 mg once a day, for 22 days | oral contraceptives once a day, for 2 months - norethindrone 1 mg - ethinylestradiol 35 μg | ↑ 0,28 ↑ 0,19 | ↑ 0,23 ↑ 0,30 |
| 10 mg once a day, for 4 days | fosamprenavir 1400 mg 2 times a day, for 14 days | ↓0,27 | ↓0,18 |
| 10 mg once a day, for 4 days | fosamprenavir 700 mg twice daily / ritonavir 100 mg 2 times a day, for 14 days | does not change | does not change |
| 10 mg, once | tipranavir 500 mg 2 times a day, for 7 days | does not change | does not change |
&coefficient of change [(1-in) / in], where i = pharmacokinetic values during the interaction and in = pharmacokinetic values are normal.