IVEMEND 115 mg powder for solution for infusion.

Each vial contains fosaprepitant dimeglumine equivalent to 115 mg fosaprepitant. After reconstitution and dilution 1 ml of solution contains 1 mg fosaprepitant (see section 6.6).

For a full list of excipients, see section 6.1.

Powder for solution for infusion.

White to off-white amorphous powder.

Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adults.

Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults.

IVEMEND 115 mg is given as part of a combination therapy (see section 4.2).

IVEMEND is a lyophilized prodrug of aprepitant for intravenous administration. Aprepitant is available as capsules for oral administration.

Since IVEMEND is also available as a 150 mg vial, it is important to note that the preparation (volume for dilution), infusion rate and doses of concomitant therapy for IVEMEND 115 mg are different from those for IVEMEND 150 mg. See also section 6.6 for preparation. Oral aprepitant on Days 2 and 3 is only administered in combination with IVEMEND 115 mg on Day 1. No aprepitant is administered orally in combination with IVEMEND 150 mg.

The recommended dose of dexamethasone with IVEMEND 115 mg differs from the recommended dose of dexamethasone with IVEMEND 150 mg on Days 3 and 4.

Posology

IVEMEND (115 mg) can replace aprepitant (125 mg) prior to chemotherapy, on Day 1 only of the chemotherapy induced nausea and vomiting (CINV) regimen as an infusion administered over 15 minutes (see section 6.6).

The 3-day CINV regimen includes IVEMEND (115 mg) 30 minutes prior to chemotherapy treatment or aprepitant (125 mg) PO once daily one hour prior to chemotherapy treatment on Day 1; aprepitant (80 mg) PO on Days 2 and 3; in addition to a corticosteroid and a 5-HT₃ antagonist.

The following regimen is recommended, based on clinical studies with aprepitant, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

Highly Emetogenic Chemotherapy Regimen

In clinical studies:

Aprepitant was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. The dose of dexamethasone was chosen to account for active substance interactions.

Ondansetron was administered intravenously 30 minutes prior to chemotherapy treatment on Day 1.

Moderately Emetogenic Chemotherapy Regimen

In clinical studies:

Aprepitant was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone was chosen to account for active substance interactions.

One 8 mg capsule of ondansetron was administered 30 to 60 minutes prior to chemotherapy treatment and one 8 mg capsule was administered 8 hours after first dose on Day 1.

Efficacy data on combination with other corticosteroids and 5-HT₃ antagonists are limited. For additional information on the co-administration with corticosteroids, see section 4.5.

Refer to the Summary of Product Characteristics of co-administered antiemetic medicinal products.

Special Populations

Elderly (65 years)

No dose adjustment is necessary for the elderly (see section 5.2).

Gender

No dose adjustment is necessary based on gender (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2).

Hepatic impairment

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. IVEMEND should be used with caution in these patients (see sections 4.4 and 5.2).

Paediatric population

IVEMEND is not recommended for use in children below the age of 18 years of age due to insufficient data on safety and efficacy.

Method of Administration

IVEMEND should be administered intravenously and should not be given by the intramuscular or subcutaneous route. Intravenous administration occurs preferably through a running intravenous infusion over 15 minutes (see section 6.6). Do not administer IVEMEND as a bolus injection or undiluted solution.

Hypersensitivity to fosaprepitant, aprepitant, or to polysorbate 80 or any of the other excipients.

Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).

Patients with moderate to severe hepatic impairment

There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. IVEMEND should be used with caution in these patients (see section 5.2).

CYP3A4 interactions

IVEMEND and oral aprepitant should be used with caution in patients receiving concomitant 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 (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity.

Co-administration of fosaprepitant with ergot alkaloid derivatives, which are CYP3A4 substrates, may result in elevated plasma concentrations of these active substances. Therefore, caution is advised due to the potential risk of ergot-related toxicity.

Concomitant administration of fosaprepitant 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 (see section 4.5). Concomitant administration of fosaprepitant with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended.

Concomitant administration of fosaprepitant 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 in increased plasma concentrations of aprepitant (see section 4.5).

Co-administration with warfarin (a CYP2C9 substrate)

Co-administration of oral aprepitant with warfarin results in decreased prothrombin time, reported as International Normalised Ratio (INR). In patients on chronic warfarin therapy, the INR should be monitored closely during treatment with oral aprepitant and for 2 weeks following each 3-day regimen of fosaprepitant followed by oral aprepitant for chemotherapy induced nausea and vomiting (see section 4.5).

Co-administration with hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of aprepitant. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant or aprepitant and for 2 months following the last dose of aprepitant (see section 4.5).

Hypersensitivity reactions

Isolated reports of immediate hypersensitivity reactions including flushing, erythema, and dyspnea have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.

Administration and infusion site reactions

IVEMEND should not be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see section 4.2). IVEMEND should not be administered intramuscularly or subcutaneously (see section 5.3). Mild injection site thrombosis has been observed at higher doses (see section 4.9). If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.

When administered intravenously fosaprepitant is rapidly converted to aprepitant.

Drug interactions following administration of fosaprepitant are likely to occur with active substances that interact with oral aprepitant. The following information was derived from data with oral aprepitant and studies conducted with fosaprepitant and midazolam or diltiazem.

Aprepitant (125 mg/ 80 mg) is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with oral aprepitant, CYP3A4 is inhibited. After the end of treatment, oral aprepitant causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Fosaprepitant or aprepitant does not seem to interact with the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin. It is anticipated that fosaprepitant 115 mg as part of the 3-day regimen with aprepitant would cause similar induction of CYP2C9, CYP3A4 and glucuronidation as that caused by the administration of the 3-day regimen of oral aprepitant. Data are lacking regarding effects on CYP2C8 and CYP2C19.

Effect of fosaprepitant / aprepitant on the pharmacokinetics of other active substances

CYP3A4 inhibition

As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of orally 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 fosaprepitant followed by oral aprepitant; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. Fosaprepitant 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 (see section 4.3). Caution is advised during concomitant administration of fosaprepitant 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 (see section 4.4).

Corticosteroids:

Dexamethasone: The usual oral dexamethasone dose should be reduced by approximately 50 % when co-administered with a regimen of fosaprepitant followed by aprepitant. The dose of dexamethasone in chemotherapy induced nausea and vomiting clinical trials was chosen to account for active substance interactions (see section 4.2). Oral aprepitant, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and oral 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.

Methylprednisolone: 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 a regimen of fosaprepitant followed by aprepitant. 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, 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 dosing with oral aprepitant, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.

Chemotherapeutic medicinal products: In pharmacokinetic studies, oral 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 agents metabolised primarily or in part by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving such agents (see section 4.4).

Immunosuppressants:

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 immunosuppressants is not recommended during the 3 days of co-administration with aprepitant.

Midazolam: The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-admin