Fosemred Drug Interactions

When administered intravenously, fosaprepitant is rapidly converted to aprepitant. Therefore, drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. The following information was derived from data of oral aprepitant and data of fosaprepitant coadministered with dexamethasone, midazolam or diltiazem.
Aprepitant is a substrate, a weak to moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.
As a weak inhibitor of CYP3A4, the fosaprepitant 150 mg single dose can cause a transient increase in plasma concentrations of co-administered active substances that are metabolized through CYP3A4. The total exposure of CYP3A4 substrates may increase on Days 1 and 2 after coadministration with a single 150 mg fosaprepitant dose. Fosaprepitant must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by fosaprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions (see Contraindications). Caution is advised during concomitant administration of fosaprepitant and active substances that are metabolized primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see Precautions).
Effect of fosaprepitant/aprepitant on the pharmacokinetics of other agents: Aprepitant, as a weak to moderate inhibitor of CYP3A4, and fosaprepitant, as a weak inhibitor of CYP3A4, can increase plasma concentrations of orally coadministered medicinal products that are metabolized through CYP3A4.
Fosaprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. 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 fosaprepitant 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.
Fosaprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin.
5-HT3 antagonists: Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg on Days 2 and 3, did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).
Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, a CYP3A4 substrate on Days 1 and 2 when dexamethasone was coadministered as a single 8 mg oral dose on Days 1, 2, and 3. The oral dexamethasone dose on Days 1 and 2 should be reduced when coadministered with fosaprepitant 150 mg I.V. on Day 1 to achieve exposures of dexamethasone similar to those obtained when given without fosaprepitant 150 mg (see Dosage & Administration).
Methylprednisolone: Oral 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 on Day 1 and Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.
Chemotherapeutic agents: The oral aprepitant 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: Oral aprepitant, (CINV regimen) did not influence the pharmacokinetics of docetaxel.
Vinorelbine: Oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine.
Warfarin: A single 125 mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy patient who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant. 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 fosaprepitant with each chemotherapy cycle.
Tolbutamide: Oral 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) on Day 4, Day 8, and Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant 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, and decreased the AUC of norethindrone.
A single dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21 with oral aprepitant, 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. The AUC of ethinyl estradiol decreased on Day 10 and there was a decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of oral aprepitant on the AUC of norethindrone on Day 10, there was a decrease in norethindrone trough concentrations during Days 9 through 21.
The efficacy of hormonal contraceptives during and for 28 days after administration of fosaprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 1 month following administration of fosaprepitant.
Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-∞ of midazolam on Day 1 and had no effect on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days 1 and 4. Fosaprepitant 150 mg I.V. is a weak CYP3A4 inhibitor as a single dose on Day 1 with no evidence of inhibition or induction of CYP3A4 observed on Day 4.
Effect of other agents on the pharmacokinetics of aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached cautiously. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.
Ketoconazole: When a single 125 mg dose of oral 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 and the mean terminal half-life of aprepitant increased. Concomitant administration of fosaprepitant with strong CYP3A4 inhibitors should be approached cautiously.
Rifampin: When a single 375 mg dose of oral aprepitant 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 and the mean terminal half-life decreased. Coadministration of fosaprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.
Additional interactions: Diltiazem: In patients with mild to moderate hypertension, infusion of 100 mg of fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in an increase of aprepitant AUC and an increase in diltiazem AUC. The pharmacokinetic effects resulted in a small but clinically meaningful decrease in diastolic blood pressure (decrease of 16.8 mm Hg with fosaprepitant versus 10.5 mm Hg without fosaprepitant) and may result in a small but clinically meaningful decrease in systolic blood pressure (decrease of 24.4 mm Hg with fosaprepitant versus 18.8 mm Hg without fosaprepitant), but did not result in a clinically meaningful change in heart rate, or PR interval, 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 and Cmax of both aprepitant and paroxetine.