Emend® (Emend®)

Aprepitant is a substrate. a moderate inhibitor and inducer of the isoenzyme CYP3A4. Aprepitant is also an inducer of the isoenzyme CYP2C9.

With simultaneous appointment aprepitant can increase the concentration in the plasma of drugs, the metabolism of which occurs under the action of the isoenzyme CYP3A4. Emend® should not be used concomitantly with pimozide, terfenadine, astemizole, cisapride, or ergot alkaloid derivatives. Inhibition of isoenzyme CYP3A4 aprepitant may lead to an increase in the concentration of these drugs in plasma and potentially serious and life-threatening phenomena.

Aprepitant induces the metabolism of warfarin and tolbutamide. Simultaneous administration of Emend® with these or other drugs that are metabolized by isoenzyme CYP2C9 (eg, phenytoin), can lead to a decrease in their concentration in the plasma. There was no effect of Emend® on the area under the concentration-time curve R (+) - or S (-) - warfarin, however, when combined, a decrease in the minimum concentration S (-) - warfarin, which was accompanied by a decrease in INR by 14% 5 days after the end of the Emend® drug. In patients receiving warfarin therapy for a long period of time, the level of INR should be carefully monitored within 2 weeks,and especially on 7-10 days after the start of the drug Emend® on 3-day schedule, during each cycle of chemotherapy. Emend® reduces the area under the concentration-time curve of tolbutamide, which is the substrate of the isoenzyme CYP2C9, by 23% on the 4th day, by 28% on the 8th day and by 15% on the 15th day. In this case, tolbutamide in a single dose of 500 mg was taken before the start of the 3-day therapy with Emend® on days 4, 8 and 15. The interaction of Emend® with preparations that are carrier substrates P-glycoprotein is unlikely because of the lack of interaction between Emend® and digoxin.

Aprepitant does not have a clinically significant effect on the pharmacokinetics of antagonists of 5-HT3 receptors: ondansetron, granisetron and hydrodolasetron (active metabolite of dolasetron).

With concomitant administration of Emend® and glucocorticosteroids, there was an increase in the area under the concentration-time curve for dexamethasone ingested 2.2-fold, for methyl-prednisolone administered intravenously 1.3-fold and methylprednisolone taken internally at 2, 5 times. In this regard, in order to achieve the desired effect, the standard dose of dexamethasone when administered in combination with aprepitant is reduced by 50%When administered intravenously, the dose of methylprednisolone is reduced by approximately 25%, when administered intravenously, by 50%.

When using the drug Emend® together with chemotherapeutic drugs, the metabolism of which mainly or partially occurs with the participation of the isoenzyme CYP3A4 (etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel), the doses of these drugs can not be adjusted. However, it is recommended that care should be taken with regard to patients receiving these medications and follow-up with them. Post-registration studies have documented cases of neurotoxicity, which can be considered as a possible side effect of ifosfamide, used in conjunction with aprepitant.

Effects of the drug Emend® on the pharmacokinetics of docetaxel have not been revealed. The effectiveness of hormonal contraceptives during the intake and within 28 days after the end of the drug Emend® can be reduced. During treatment with Emend® and within 1 month after the last dose of Emend®, alternative or reserve methods of contraception should be used.

With the simultaneous oral administration of midazolam and Emend®, an increase in the area under the concentration-time curve of midazolam was noted. The potential effect of increasing plasma concentrations of midazolam or other benzodiazepines metabolized through an isoenzyme CYP3A4 (alprazolam, triazolam), should be taken into account when these drugs are simultaneously prescribed with Emend®.

Simultaneous administration of Emend® with drugs that inhibit isoenzyme activity CYP3A4, can lead to an increase in the concentration of aprepitant in the plasma. Therefore, caution should be given to the preparation Emend® in combination with strong inhibitors of the isoenzyme CYP3A4 (e.g., ketoconazole). However, concurrent administration of Emend® with moderate isoenzyme inhibitors CYP3A4 (for example, diltiazem, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin and protease inhibitors) does not cause clinically significant changes in the concentration of aprepitant in plasma.

Simultaneous reception of the drug Emend® with drugs that are strong inducers of isoenzyme CYP3A4 (for example, rifampicin, phenytoin, carbamazepine, phenobarbital), can lead to a decrease in the concentration of aprepitant in the plasma and, thus, to a decrease in the effectiveness of the Emend® preparation. Also, the simultaneous use of aprepitant with preparations of St. John's wort is not recommended.

In patients with mild to moderate hypertension, the aprepitant tablet is taken. containing a dose comparable to 230 mg of the drug in capsules, in combination with diltiazem at a dose of 120 mg 3 times a day for 5 days led to an increase in the area under the concentration-time curve of aprepitant by a factor of 2 and a simultaneous increase in the area under the concentration curve - time "diltiazem in 1,7 times. These pharmacokinetic effects did not lead to clinically significant changes in the ECG, heart rate or blood pressure compared to changes in these indices when only diltiazem was taken.

Simultaneous reception of aprepitant once a day in the form of a tablet in a dose comparable to 85 mg or 170 mg of the drug in capsules and paroxetine at a dose of 20 mg once a day led to a decrease in the area under the concentration-time curve by approximately 25% and C_max approximately 20% for both the aprepitant and paroxetine.