IVEMEND 150 mg powder for solution for infusion.

Each vial contains fosaprepitant dimeglumine equivalent to 150 mg fosaprepitant, which corresponds to 130.5 mg of aprepitant. After reconstitution and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml) (see section 6.6).

For the 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).

Posology

The recommended dose is 150 mg administered as an infusion over 20-30 minutes on Day 1, 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 regimens are 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.

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.

Efficacy data in 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 5-HT₃ antagonist 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 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.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to polysorbate 80 or any of the other excipients listed in section 6.1.

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 14 days following the use of fosaprepitant (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 non-hormonal 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 dyspnoea 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. 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 co-administered with dexamethasone, midazolam, or diltiazem.

Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4. Fosaprepitant 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 dexame