Emend · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-093704 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials. The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (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 Moderately Emetogenic Chemotherapy (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 The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with 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). System organ class Adverse reaction Frequency Infection and infestations candidiasis, staphylococcal infection rare Blood and lymphatic system febrile neutropenia, anaemia uncommon disorders Immune system disorders hypersensitivity reactions including not known anaphylactic reactions Metabolism and nutrition decreased appetite common disorders

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HOS-093710 · has-adverse-reaction-information · PDF-Seite 25

Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials. The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (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 adults receiving Moderately Emetogenic Chemotherapy (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 The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy 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. 25 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). System organ class Adverse reaction Frequency Infection and infestations candidiasis, staphylococcal infection rare Blood and lymphatic system febrile neutropenia, anaemia uncommon disorders Immune system disorders hypersensitivity reactions including not known anaphylactic reactions Metabolism and nutrition decreased appetite common disorders

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HOS-093706 · has-contraindication-information · PDF-Seite 21

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).

HOS-093700 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).

HOS-093699 · has-indication-information · PDF-Seite 2

Prevention nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and adolescents from the age of 12. EMEND 125 mg/80 mg is given as part of combination therapy (see section 4.2).

HOS-093705 · has-indication-information · PDF-Seite 20

Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in children, toddlers and infants from the age of 6 months to less than 12 years. EMEND powder for oral suspension is given as part of combination therapy (see section 4.2).

HOS-093708 · has-interaction-information · PDF-Seite 22

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 EMEND, CYP3A4 is inhibited. After the end of treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin. Effect of aprepitant on the pharmacokinetics of other active substances CYP3A4 inhibition As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of 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 EMEND; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of EMEND 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 EMEND 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy induced nausea and vomiting (CINV) clinical trials was chosen to account for active substance interactions (see section 4.2). EMEND, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and EMEND 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 EMEND 125 mg/80 mg regimen. EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on D

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HOS-093702 · has-interaction-information · PDF-Seite 4

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 EMEND, CYP3A4 is inhibited. After the end of treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. 4 Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin. Effect aprepitant on the pharmacokinetics of other active substances CYP3A4 inhibition As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of 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 EMEND; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of EMEND 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 EMEND 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy induced nausea and vomiting (CINV) clinical trials was chosen to account for active substance interactions (see section 4.2). EMEND, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and EMEND 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 EMEND 125 mg/80 mg regimen. EMEND, when

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HOS-093703 · has-pregnancy-information · PDF-Seite 7

Contraception in males and females The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5). Pregnancy For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose 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 7 reproduction of alterations in neurokinin regulation are unknown. EMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND. Fertility The potential for effects of 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-093709 · has-pregnancy-information · PDF-Seite 25

Contraception in males and females The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5). Pregnancy For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose 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. EMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND. Fertility The potential for effects of 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-093701 · has-warning-information · PDF-Seite 4

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. EMEND should be used with caution in these patients (see section 5.2). CYP3A4 interactions EMEND 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, 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 during treatment with EMEND and for 14 days following each 3-day course of EMEND (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 EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5). Excipients EMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

HOS-093707 · has-warning-information · PDF-Seite 21

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. EMEND should be used with caution in these patients (see section 5.2). CYP3A4 interactions EMEND 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, 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 during treatment with EMEND and for 14 days following each 3-day course of EMEND (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 EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5). 21 Excipients EMEND powder for oral suspension contains sucrose and lactose. Patients with rare hereditary problems of fructose or galactose intolerance, glucose-galactose malabsorption, total lactase deficiency, or sucrase-isomaltase insufficiency should not take this medicine. Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’.