Emend Tri-Pack Drug Interactions

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.
Effect of aprepitant on the pharmacokinetics of other agents: As a moderate (125 mg/80 mg) inhibitor of CYP3A4, aprepitant can increase plasma concentrations of orally coadministered medicinal products that are metabolized through CYP3A4. Aprepitant (125 mg/80 mg) can increase plasma concentrations of intravenously coadministered medicinal products metabolized through CYP3A4 to a lesser extent.
EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Dose-independent inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see Contraindications).
Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.
EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.
5-HT₃ antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).
Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate by 2.2-fold, on Days 1 and 5. The usual oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone (see Dosage & Administration).
Methylprednisolone: EMEND, 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 coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The usual IV methylprednisolone dose should be reduced by approximately 25%, and the usual oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen), to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND.
Chemotherapeutic agents: In clinical studies, EMEND (125 mg/80 mg regimen) was administered with the following chemotherapeutic agents metabolized primarily or in part by CYP3A4: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan, and paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. Caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4. Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide coadministration (see Precautions).
Docetaxel: In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel.
Vinorelbine: In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine.
Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle.
Tolbutamide: EMEND, 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 EMEND and on Days 4, 8, and 15.
Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.
In another study, a single dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21 with EMEND, given as a regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.
The efficacy of hormonal contraceptives during and for 28 days after administration of EMEND may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND.
Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg).
In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.
An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.
Effect of other agents on the pharmacokinetics of aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g., ketoconazole) should be approached cautiously; but concomitant administration of EMEND with moderate CYP3A4 inhibitors (e.g., diltiazem) does not result in clinically meaningful changes in plasma concentrations of aprepitant.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND.
Ketoconazole: When a single 125-mg dose of EMEND 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. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.
Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND.
Additional interactions: Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone.
Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C_max by approximately 20% of both aprepitant and paroxetine.