IVEMEND 150 mg powder for solution for infusion.

Each vial contains fosaprepitant dimeglumine equivalent to 150 mg fosaprepitant. After reconstitution and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml) (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 150 mg is given as part of a combination therapy (see section 4.2).

IVEMEND is a lyophilised prodrug of aprepitant for intravenous administration.

Since IVEMEND is also available as a 115 mg vial, it is important to note that the preparation (volume for dilution), infusion rate and doses of concomitant therapy for IVEMEND 150 mg are different from those for IVEMEND 115 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 150 mg differs from the recommended dose of dexamethasone with IVEMEND 115 mg on Days 3 and 4.

Posology

IVEMEND 150 mg is administered as an infusion over 20-30 minutes on Day 1 only, initiated approximately 30 minutes prior to chemotherapy (see section 6.6). IVEMEND should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in the tables below.

The following regimen is recommended for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

Highly Emetogenic Chemotherapy Regimen

Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. Dexamethasone should also be administered in the evenings on Days 3 and 4. The dose of dexamethasone accounts for active substance interactions.

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

Moderately Emetogenic Chemotherapy Regimen

Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions.

One 8 mg capsule of ondansetron should be administered 30 to 60 minutes prior to chemotherapy treatment and one 8 mg capsule should be 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

The safety and efficacy of IVEMEND in children and adolescents below the age of 18 years of age has not yet been established. No data are available.

Method of administration

IVEMEND 150 mg 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 20-30 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 should be used with caution in patients receiving concomitant 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 could result 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 for 2 weeks following the use of fosaprepitant for the prevention of 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 fosaprepitant. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 2 months following the use of fosaprepitant (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.

Interactions with other medicinal products following administration of intravenous fosaprepitant are likely to occur with active substances that interact with oral aprepitant. The following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous fosaprepitant coadministered with dexamethasone, midazolam, or diltiazem.

Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4. 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 would cause less or no greater induction of CYP2C9, CYP3A4 and glucuronidation than that caused by the administration of oral aprepitant. Data are lacking regarding effects on CYP2C8 and CYP2C19.

Effect of fosaprepitant on the pharmacokinetics of other active substances

CYP3A4 inhibition

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 metabolised through CYP3A4. The total exposure of CYP3A4 substrates may increase up to 2-fold on Days 1 and 2 after co-administration 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 section 4.3). Caution is advised during concomitant administration of fosaprepitant and 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 oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50 % when coadministered with fosaprepitant 150 mg on Day 1 to achieve exposures of dexamethasone similar to those obtained when given without fosaprepitant 150 mg. Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC_0-24hr of dexamethasone, a CYP3A4 substrate, by 100 % on Day 1 86 % on Day 2 and 18 % on Day 3 when dexamethasone was coadministered as a single 8 mg oral dose on Days 1, 2, and 3.

Chemotherapeutic medicinal products

Interaction studies with fosaprepitant 150 mg and chemotherapeutic medicinal products have not been conducted; however, based on studies with oral aprepitant and docetaxel and vinorelbine, IVEMEND 150 mg is not expected to have a clinically relevant interaction with intravenously administered docetaxel and vinorelbine. An interaction with orally administered chemotherapeutic medicinal products 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 medicinal products (see section 4.4).

Immunosuppressants

Following a single 150 mg fosaprepitant dose, a transient moderate increase for two days possibly 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 increased exposure, dose reduction of the immunosuppressant based on Therapeutic Dose Monitoring is not recommended on the day of and the day after administration of IVEMEND.

Midazolam

Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC_0- of midazolam by 77 % 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 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.

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