Ivemend · 4.3 Contraindications · 1

HOS-094616 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile In clinical studies, various formulations of fosaprepitant have been administered to a total of 2,687 adults including 371 healthy subjects and 2,084 patients, and 299 children and adolescents with chemotherapy induced nausea and vomiting (CINV). Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. The safety profile of aprepitant was evaluated in approximately 6,500 adults and 184 children and adolescents. Oral aprepitant The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving HEC were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving MEC was fatigue (1.4 % versus 0.9 %). The most common adverse reactions reported at a greater incidence in paediatric patients treated with the aprepitant regimen than with the control regimen while receiving emetogenic cancer chemotherapy were hiccups (3.3 % versus 0.0 %) and flushing (1.1 % versus 0.0 %). Tabulated list of adverse reactions - aprepitant The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with oral aprepitant than with standard therapy in adults or paediatric patients or in post-marketing use. The frequency categories given in the table are based on the studies in adults; the observed frequencies in the paediatric studies were similar or lower, unless shown in the table. Some less common ADRs in the adult population were not observed in the paediatric studies. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data). Table 5: Tabulated list of adverse reactions – aprepitant System organ class Adverse reaction Frequency Infection and infestations candidiasis, staphylococcal infection rare Blood and lymphatic system febrile neutr

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HOS-094612 · has-contraindication-information · PDF-Seite 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).

HOS-094611 · has-indication-information · PDF-Seite 2

Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and paediatric patients aged 6 months and older. IVEMEND 150 mg is given as part of a combination therapy (see section 4.2).

HOS-094614 · has-interaction-information · PDF-Seite 7

When administered intravenously fosaprepitant is rapidly converted to aprepitant. 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. Interactions with other medicinal products following administration of intravenous fosaprepitant are likely to occur with active substances that interact with oral aprepitant. The potential for interactions with multi-day fosaprepitant regimens are anticipated to be no greater than those for oral aprepitant regimens. Therefore, the recommendations for use of IVEMEND with other medicinal products in paediatric patients are based upon adult data from fosaprepitant and aprepitant studies. When using combined IVEMEND and EMEND regimens, please refer to the Summary of Product Characteristics (SmPC) section 4.5 for EMEND capsules or EMEND for oral suspension. The following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous single dose fosaprepitant co-administered with dexamethasone, midazolam, or diltiazem. 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 ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4). Corticosteroids Dexamethasone: The oral

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HOS-094615 · has-pregnancy-information · PDF-Seite 9

Contraception in males and females 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 last dose of fosaprepitant (see sections 4.4 and 4.5). Pregnancy For fosaprepitant and aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicities of fosaprepitant and aprepitant have not been fully characterised, since exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokinin regulation are unknown. IVEMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats after intravenous administration of fosaprepitant as well as after oral administration of aprepitant. It is not known whether aprepitant is excreted in human milk. Therefore, breast-feeding is not recommended during treatment with IVEMEND. Fertility The potential for effects of fosaprepitant and aprepitant on fertility has not been fully characterised because exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3).

HOS-094613 · has-warning-information · PDF-Seite 6

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 ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, 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 with warfarin (a CYP2C9 substrate) In patients on chronic warfarin therapy, the International Normalised Ratio (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 Immediate hypersensitivity reactions including flushing, erythema, dyspnoea, and anaphylaxis/anaphylactic shock have occurred during or soon after 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 Infusion site reactions (ISRs) have been reported with the use of IVEMEND (see section 4.8). The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (e.g., anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Mild injection site thrombosis has been observed at higher doses without concomitant vesicant chemotherapy. 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 subcu

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