Aprepitant

As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes within two weeks following initiation and treatment. This effect may become apparent only after the end of a 3-day treatment with aprepitant. For CYP2C9 and CYP3A4 substrates, the induction is transient with a maximum effect reached 3-5 days after end of the aprepitant 3-day treatment. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after end of aprepitant treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant given for 7 days. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known to be metabolised by CYP2C9 are administered during this time period.

Concomitant administration of aprepitant with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination results in reductions of the plasma concentrations of aprepitant that may result in decreased efficacy of aprepitant. Concomitant administration of aprepitant with herbal preparations containing St. John’s Wort (Hypericum perforatum) is not recommended.

No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. Aprepitant should be used with caution in these patients.

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of aprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with aprepitant and for 2 months following the last dose of aprepitant.

In a clinical study, single doses of an oral contraceptive containing ethinyl estradiol and norethindrone were administered on Days 1 through 21 with aprepitant, given as a regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg intravenously on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. During days 9 through 21 in this study, there was as much as a 64% decrease in ethinyl estradiol trough concentrations and as much as a 60% decrease in norethindrone trough concentrations.

In pharmacokinetic studies, aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel administered intravenously on Day 1 or vinorelbine administered intravenously on Day 1 or Day 8. Because the effect of aprepitant on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of aprepitant on the pharmacokinetics of intravenously administered CYP3A4 substrates, an interaction with orally administered chemotherapeutic medicinal products metabolised primarily or partly by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4. Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration.

During the 3-day CINV regimen, a transient moderate increase followed by a mild decrease in exposure of immunosuppressants metabolised by CYP3A4 (e.g. cyclosporine, tacrolimus, everolimus and sirolimus) is expected. Given the short duration of the 3-day regimen and the time-dependent limited changes in exposure, dose reduction of the immunosuppressant is not recommended during the 3 days of co-administration with aprepitant.

Concomitant administration of EMEND with active substances that inhibit CYP3A4 activity (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors) should be approached cautiously, as the combination is expected to result several-fold in increased plasma concentrations of aprepitant.

As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 3-fold during the 3-day treatment with aprepitant; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. Aprepitant must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of aprepitant and orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine.

The usual oral dexamethasone dose should be reduced by approximately 50% when co-administered with aprepitant 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy induced nausea and vomiting clinical trials was chosen to account for active substance interactions. Aprepitant, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and aprepitant when given as 80 mg/day with dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5.

When a single 125 mg dose of aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold.

The usual intravenously administered methylprednisolone dose should be reduced approximately 25%, and the usual oral methylprednisolone dose should be reduced approximately 50% when co-administered with aprepitant 125 mg/80 mg regimen. Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was co-administered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.

During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease at later time points within 2 weeks following initiation of the aprepitant dose, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.

The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products with aprepitant (125 mg/80 mg).

Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of 2 mg midazolam was co-administered on Days 1 and 5 of a regimen of aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 to 5.

In another study with intravenous administration of midazolam, aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and 2 mg midazolam was given intravenously prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15. Aprepitant increased the AUC of midazolam 25% on Day 4 and decreased the AUC of midazolam 19% on Day 8 and 4% on Day 15. These effects were not considered clinically important.

In a third study with intravenous and oral administration of midazolam, aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, together with ondansetron 32 mg Day 1, dexamethasone 12 mg Day 1 and 8 mg Days 2-4. This combination (i.e. Aprepitant, ondansetron and dexamethasone) decreased the AUC of oral midazolam 16% on Day 6, 9% on Day 8, 7% on Day 15 and 17% on Day 22. These effects were not considered clinically important.

An additional study was completed with intravenous administration of midazolam and aprepitant. Intravenous 2 mg midazolam was given 1 hour after oral administration of a single dose of aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.

When a single 375 mg dose of aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased 91% and the mean terminal half-life decreased 68%.

Aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15.

In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with aprepitant and for 2 weeks following each 3-day course of aprepitant for chemotherapy induced nausea and vomiting. When a single 125 mg dose of aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilised on chronic warfarin therapy, there was no effect of aprepitant on the plasma AUC of R(+) or S() warfarin determined on Day 3; however, there was a 34% decrease in S() warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in INR 5 days after completion of treatment with aprepitant.

For aprepitant no clinical data on exposed pregnancies are available. In animal studies there was no indication of direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. The potential effects on reproduction of alterations in neurokinin regulation are unknown. Aprepitant should not be used during pregnancy unless clearly necessary.

Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with aprepitant.

Contraception in males and females

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of aprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with aprepitant and for 2 months following the last dose of aprepitant.

Fertility

Fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility.

Aprepitant may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of aprepitant.