IVEMEND 115mg 1mg / ml powder infusion solution medication leaflet

IVEMEND 150 mg powder for solution for infusion.

Each vial contains fosaprepitant dimeglumine equivalent to 150 mg fosaprepitant, which correspondsto 130.5 mg of aprepitant. After reconstitution and dilution 1 ml of solution contains 1 mgfosaprepitant (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 nausea and vomiting associated with highly and moderately emetogenic cancerchemotherapy 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).

The recommended dose is 150 mg administered as an infusion over 20-30 minutes on Day 1, initiatedapproximately 30 minutes prior to chemotherapy (see section 6.6). IVEMEND should be administeredin 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 withemetogenic cancer chemotherapy.

Table 1: Recommended dosing for the prevention of nausea and vomiting associatedwith highly emetogenic chemotherapy regimen in adults

Day 1 Day 2 Day 3 Day 4

IVEMEND 150 mg none none noneintravenously

Dexamethasone 12 mg orally 8 mg orally 8 mg orally twice 8 mg orally twicedaily daily5-HT3 Standard dose of none none noneantagonists 5-HT3 antagonists.

See the productinformation for theselected 5-HT3antagonist forappropriate dosinginformation

Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and inthe 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.

Table 2: Recommended dosing for the prevention of nausea and vomiting associatedwith moderately emetogenic chemotherapy regimen in adults

Day 1

IVEMEND 150 mg intravenously

Dexamethasone 12 mg orally5-HT3 antagonists Standard dose of 5-HT3antagonists. See theproduct information for theselected 5-HT3 antagonistfor appropriate dosinginformation

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

Paediatric patients aged 6 months and older, and not less than 6 kg

The recommended dose regimen of IVEMEND, to be administered with a 5-HT3 antagonist, with orwithout a corticosteroid, for the prevention of nausea and vomiting associated with administration ofsingle or multi-day chemotherapy regimens of Highly Emetogenic Chemotherapy (HEC) or

Moderately Emetogenic Chemotherapy (MEC), is shown in Table 3. Single day chemotherapyregimens include those regimens in which HEC or MEC is administered for a single day only.

Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC isadministered for 2 or more days.

An alternative dose regimen that may be used with single day chemotherapy regimens is shown in

Table 4.

Dosing for Single or Multi-Day Chemotherapy Regimens

For paediatric patients receiving single or multi-day regimens of HEC or MEC, administer IVEMENDas an intravenous infusion through a central venous catheter on Days 1, 2, and 3. EMEND capsules or

EMEND for oral suspension may be used on Days 2 and 3 instead of IVEMEND, as shown in

Table 3. See the Summary of Product Characteristics (SmPC) for EMEND capsules or EMEND fororal suspension for appropriate dosing instructions.

Table 3: Recommended dosing for the prevention of nausea and vomiting associatedwith single or multi-day regimens of HEC or MEC in paediatric patients

Population Day 1 Day 2 Day 3

IVEMEND* Paediatric 115 mg 80 mg 80 mgpatients 12 years intravenously intravenously intravenouslyand older OR OR80 mg orally 80 mg orally(EMEND (EMENDcapsules) capsules)

Paediatric 3 mg/kg 2 mg/kg 2 mg/kgpatients 6 months intravenously intravenously intravenouslyto less than OR OR12 years and not Maximum dose 2 mg/kg orally 2 mg/kg orallyless than 6 kg 115 mg (EMEND oral (EMEND oralsuspension) suspension)

Maximum Maximum dosedose 80 mg 80 mg

Dexamethasone** All paediatric If a corticosteroid, such as dexamethasone, ispatients co-administered, administer 50% of therecommended corticosteroid dose on days 1 through5-HT3 antagonist All paediatric See selected 5-HT3 antagonist prescribingpatients information for the recommended dosage

* For paediatric patients 12 years and older, administer IVEMEND intravenously over 30 minutes,completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients lessthan 12 years, administer IVEMEND intravenously over 60 minutes, completing the infusionapproximately 30 minutes prior to chemotherapy.

** Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1.

Alternative Dosing for Single Day Chemotherapy Regimens

For paediatric patients receiving single day HEC or MEC, IVEMEND may be administered as anintravenous infusion through a central venous catheter on Day 1.

Table 4: Alternative dosing for the prevention of nausea and vomiting associated withsingle day regimens of HEC or MEC in paediatric patients

Population Day 1

IVEMEND* Paediatric patients 12 years and 150 mgolder intravenously

Paediatric patients 2 to less than 4 mg/kg12 years intravenously

Maximum dose 150 mg

Paediatric patients 6 months to 5 mg/kgless than 2 years and not less than intravenously6 kg

Maximum dose 150 mg

Dexamethasone** All paediatric patients If a corticosteroid, such asdexamethasone, is co-administered,administer 50% of therecommended corticosteroid doseon days 1 and 2.

5-HT3 antagonist All paediatric patients See selected 5-HT3 antagonistprescribing information for therecommended dosage

* For paediatric patients 12 years and older, administer IVEMEND intravenously over 30 minutes,completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients lessthan 12 years, administer IVEMEND intravenously over 60 minutes, completing the infusionapproximately 30 minutes prior to chemotherapy.

** Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1.

The safety and efficacy of IVEMEND in infants below 6 months of age have not been established. Nodata are available.

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

Refer to the Summary of Product Characteristics of co-administered 5-HT3 antagonist medicinalproducts.

Elderly (≥65 years)

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

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

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

No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data inpatients 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).

IVEMEND 150 mg should be administered intravenously and should not be given by theintramuscular or subcutaneous route. Intravenous administration in adults occurs preferably through arunning intravenous infusion over 20-30 minutes. Intravenous administration in paediatric patientsaged 6 months and older is recommended through a central venous catheter and should beadministered over 30 minutes in patients aged 12 years and older or over 60 minutes in patients lessthan 12 years of age (see section 6.6). Do not administer IVEMEND as a bolus injection or undilutedsolution.

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

Hypersensitivity to the active substance or to polysorbate 80 or any of the other excipients listed insection 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 withsevere 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 aremetabolised primarily through CYP3A4 and with a narrow therapeutic range, such as ciclosporin,tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (seesection 4.5). Additionally, concomitant administration with irinotecan should be approached withparticular 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 bemonitored 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 administrationof fosaprepitant. Alternative non-hormonal back-up methods of contraception should be used duringtreatment with fosaprepitant and for 2 months following the use of fosaprepitant (see section 4.5).

Immediate hypersensitivity reactions including flushing, erythema, dyspnoea, andanaphylaxis/anaphylactic shock have occurred during or soon after infusion of fosaprepitant. Thesehypersensitivity reactions have generally responded to discontinuation of the infusion andadministration of appropriate therapy. It is not recommended to reinitiate the infusion in patients whoexperience hypersensitivity reactions.

Administration and infusion site reactions

Infusion site reactions (ISRs) have been reported with the use of IVEMEND (see section 4.8). Themajority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitantvesicant (e.g., anthracycline-based) chemotherapy administration, particularly when associated withextravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy.

Mild injection site thrombosis has been observed at higher doses without concomitant vesicantchemotherapy.

IVEMEND should not be given as a bolus injection, but should always be diluted and given as a slowintravenous infusion (see section 4.2). IVEMEND should not be administered intramuscularly orsubcutaneously (see section 5.3). If signs or symptoms of local irritation occur, the injection orinfusion should be terminated and restarted in another vein.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

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 notseem to interact with the P-glycoprotein transporter, as demonstrated by the lack of interaction of oralaprepitant 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. Dataare lacking regarding effects on CYP2C8 and CYP2C19.

Interactions with other medicinal products following administration of intravenous fosaprepitant arelikely to occur with active substances that interact with oral aprepitant. The potential for interactionswith multi-day fosaprepitant regimens are anticipated to be no greater than those for oral aprepitantregimens. Therefore, the recommendations for use of IVEMEND with other medicinal products inpaediatric patients are based upon adult data from fosaprepitant and aprepitant studies. When usingcombined 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 studiesconducted 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 increasein 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 concurrentlywith pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by fosaprepitant couldresult 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 offosaprepitant and active substances that are metabolised primarily through CYP3A4 and with anarrow therapeutic range, such as ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil,diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4).

Dexamethasone: The oral dexamethasone dose should be reduced by approximately 50 % whenco-administered with fosaprepitant (see section 4.2). Fosaprepitant 150 mg administered as a singleintravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, a CYP3A4 substrate, by 100 %on Day 1, 86 % on Day 2 and 18 % on Day 3 when dexamethasone was co-administered as a single8 mg oral dose on Days 1, 2, and 3.

Chemotherapeutic medicinal products

Interaction studies with fosaprepitant 150 mg and chemotherapeutic medicinal products have not beenconducted; however, based on studies with oral aprepitant and docetaxel and vinorelbine, IVEMEND150 mg is not expected to have a clinically relevant interaction with intravenously administereddocetaxel and vinorelbine. An interaction with orally administered chemotherapeutic medicinalproducts metabolised primarily or partly by CYP3A4 (e.g., etoposide, vinorelbine) cannot beexcluded. Caution is advised and additional monitoring may be appropriate in patients receivingmedicinal products metabolised primarily or partly by CYP3A4 (see section 4.4). Postmarketingevents of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitantand ifosfamide co-administration.

Immunosuppressants

Following a single 150 mg fosaprepitant dose, a transient moderate increase for two days possiblyfollowed by a mild decrease in exposure of immunosuppressants metabolised by CYP3A4 (e.g.,ciclosporin, tacrolimus, everolimus and sirolimus) is expected. Given the short duration of increasedexposure, dose reduction of the immunosuppressant based on Therapeutic Dose Monitoring is notrecommended 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 AUC0-∞ ofmidazolam by 77 % on Day 1 and had no effect on Day 4 when midazolam was co-administered as asingle oral dose of 2 mg on Days 1 and 4. Fosaprepitant 150 mg is a weak CYP3A4 inhibitor as asingle 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 benzodiazepinesmetabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering thesemedicinal products with IVEMEND.

Diltiazem

Interaction studies with fosaprepitant 150 mg and diltiazem have not been conducted; however, thefollowing study with 100 mg of fosaprepitant should be considered when using IVEMEND 150 mgwith diltiazem. In patients with mild to moderate hypertension, infusion of 100 mg of fosaprepitantover 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.4-fold increase in diltiazem AUCand a small but clinically meaningful decrease in blood pressure, but did not result in a clinicallymeaningful change in heart rate, or PR interval.

Induction

The fosaprepitant 150 mg single dose did not induce CYP3A4 on Days 1 and 4 in the midazolaminteraction study. It is anticipated that IVEMEND would cause less or no greater induction of

CYP2C9, CYP3A4, and glucuronidation than that caused by the administration of the 3-day oralaprepitant regimen, for which a transient induction with its maximum effect 6-8 days after firstaprepitant dose has been observed. The 3-day oral aprepitant regimen resulted in an about 30-35 %reduction in AUC of CYP2C9 substrates and up to a 64 % decrease in ethinyl estradiol troughconcentrations. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advisedwhen warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known tobe metabolised by CYP2C9 are administered with IVEMEND.

In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closelyduring treatment with and for 14 days following the use of IVEMEND for the prevention ofchemotherapy induced nausea and vomiting (see section 4.4).

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administrationof fosaprepitant. Alternative non-hormonal back-up methods of contraception should be used duringtreatment with fosaprepitant and for 2 months following the use of fosaprepitant.

5-HT3 antagonists

Interaction studies with fosaprepitant 150 mg and 5-HT3 antagonists have not been conducted;however, in clinical interaction studies, the oral aprepitant regimen did not have clinically importanteffects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metaboliteof dolasetron). Therefore, there is no evidence of interaction with the use of IVEMEND 150 mg and5-HT3 antagonists.

Effect of other medicinal products on the pharmacokinetics of aprepitant resulting fromadministration of fosaprepitant 150 mg

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 expectedto result in several-fold increased plasma concentrations of aprepitant (see section 4.4). Ketoconazoleincreased the terminal half-life of oral aprepitant about 3-fold.

Concomitant administration of fosaprepitant with active substances that strongly induce CYP3A4activity (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as thecombination could result in reductions of the plasma concentrations of aprepitant that may result indecreased efficacy. Concomitant administration of fosaprepitant with herbal preparations containing

St. John’s Wort (Hypericum perforatum) is not recommended. Rifampicin decreased the meanterminal half-life of oral aprepitant by 68 %.

Diltiazem

Interaction studies with fosaprepitant 150 mg and diltiazem have not been conducted; however, thefollowing study with 100 mg of fosaprepitant should be considered when using IVEMEND 150 mgwith diltiazem. Infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily,resulted in a 1.5-fold increase of aprepitant AUC. This effect was not considered clinically important.

Interaction studies have only been performed in adults.

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administrationof fosaprepitant. Alternative non-hormonal back-up methods of contraception should be used duringtreatment with fosaprepitant and for 2 months following the last dose of fosaprepitant (seesections 4.4 and 4.5).

For fosaprepitant and aprepitant no clinical data on exposed pregnancies are available. The potentialfor reproductive toxicities of fosaprepitant and aprepitant have not been fully characterised, sinceexposure 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 potentialeffects on reproduction of alterations in neurokinin regulation are unknown. IVEMEND should not beused during pregnancy unless clearly necessary.

Aprepitant is excreted in the milk of lactating rats after intravenous administration of fosaprepitant aswell as after oral administration of aprepitant. It is not known whether aprepitant is excreted in humanmilk. Therefore, breast-feeding is not recommended during treatment with IVEMEND.

The potential for effects of fosaprepitant and aprepitant on fertility has not been fully characterisedbecause exposure levels above the therapeutic exposure in humans could not be attained in animalstudies. These fertility studies did not indicate direct or indirect harmful effects with respect to matingperformance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3).

IVEMEND may have minor influence on the ability to drive and use machines. Dizziness and fatiguemay occur following administration of IVEMEND (see section 4.8).

In clinical studies, various formulations of fosaprepitant have been administered to a total of2,687 adults including 371 healthy subjects and 2,084 patients, and 299 children and adolescents withchemotherapy induced nausea and vomiting (CINV). Since fosaprepitant is converted to aprepitant,those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. The safetyprofile 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 theaprepitant regimen than with standard therapy in patients receiving HEC were: hiccups (4.6 % versus2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus2.0 %), 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 patientstreated 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 withthe aprepitant regimen than with the control regimen while receiving emetogenic cancerchemotherapy 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 agreater incidence with oral aprepitant than with standard therapy in adults or paediatric patients or inpost-marketing use.

The frequency categories given in the table are based on the studies in adults; the observedfrequencies in the paediatric studies were similar or lower, unless shown in the table. Some lesscommon 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 (≥1/1,000to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimatedfrom 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 neutropenia, anaemia uncommondisorders

Immune system disorders hypersensitivity reactions including not knownanaphylactic reactions

Metabolism and nutrition decreased appetite commondisorders polydipsia rare

Psychiatric disorders anxiety uncommondisorientation, euphoric mood rare

Nervous system disorders headache common

System organ class Adverse reaction Frequencydizziness, somnolence uncommoncognitive disorder, lethargy, dysgeusia rare

Eye disorders conjunctivitis rare

Ear and labyrinth disorders tinnitus rare

Cardiac disorders palpitations uncommonbradycardia, cardiovascular disorder rare

Vascular disorders hot flush/flushing uncommon

Respiratory, thoracic and hiccups commonmediastinal disorders oropharyngeal pain, sneezing, cough, rarepostnasal drip, throat irritation

Gastrointestinal disorders constipation, dyspepsia commoneructation, nausea*, vomiting*, uncommongastroesophageal reflux disease, abdominalpain, dry mouth, flatulenceduodenal ulcer perforation, stomatitis, rareabdominal distension, faeces hard,neutropenic colitis

Skin and subcutaneous tissue rash, acne uncommondisorders photosensitivity reaction, hyperhidrosis, rareseborrhoea, skin lesion, rash pruritic,

Stevens-Johnson syndrome/toxic epidermalnecrolysispruritus, urticaria not known

Musculoskeletal and connective muscular weakness, muscle spasms raretissue disorders

Renal and urinary disorders dysuria uncommonpollakisuria rare

General disorders and fatigue commonadministration site conditions asthenia, malaise uncommonoedema, chest discomfort, gait disturbance rare

Investigations ALT increased common

AST increased, blood alkaline phosphatase uncommonincreasedred blood cells urine positive, blood sodium raredecreased, weight decreased, neutrophil countdecreased, glucose urine present, urine outputincreased

*Nausea and vomiting were efficacy parameters in the first 5-days of post-chemotherapy treatment and werereported as adverse reactions only thereafter.

The adverse reactions profiles in the Multiple-Cycle extension of HEC and MEC studies in adults forup to 6 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.

In an additional active-controlled clinical study in 1,169 adult patients receiving aprepitant and HEC,the adverse reactions profile was generally similar to that seen in the other HEC studies withaprepitant.

Non-CINV studies

Additional adverse reactions were observed in adult patients treated with aprepitant for post-operativenausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper,bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea,sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.

*Reported in patients taking a higher dose of aprepitant.

Fosaprepitant

In an active-controlled clinical study in adult patients receiving HEC, safety was evaluated for1,143 patients receiving the 1-day regimen of IVEMEND 150 mg compared to 1,169 patientsreceiving the 3-day regimen of aprepitant. Additionally, in a placebo-controlled clinical trial in adultpatients receiving MEC, safety was evaluated for 504 patients receiving a single dose of IVEMEND150 mg compared to 497 patients receiving the control regimen.

The safety of the 1-day IV regimen was supported by a pooled analysis of 3 active-controlled clinicalstudies in 139 paediatric patients (aged 6 months to 17 years) receiving either HEC or MEC and asingle dose of IVEMEND at or above the recommended 1-day regimen dose.

The safety of the 3-day IV regimen is supported by a single arm clinical study in 100 paediatricpatients (aged 6 months to 17 years) receiving either HEC or MEC and a 3-day regimen of IVEMENDat the recommended dose (see section 4.2). The safety profile of the 3-day IV fosaprepitant regimen inpaediatric patients is similar to that of the 1-day fosaprepitant regimen.

The safety profile of fosaprepitant in adult and paediatric patients was generally similar to thatobserved with aprepitant.

Tabulated list of adverse reactions - fosaprepitant

The following are adverse reactions reported in adult patients receiving fosaprepitant in clinicalstudies or post-marketing that have not been reported with aprepitant as described above. Thefrequency categories in the table are based on studies in adults; the observed frequencies in thepaediatric studies were similar or lower. Some adverse reactions that are commonly observed in theadult population were not observed in the paediatric studies. Infusion site reactions (ISRs) have beenreported with the use of IVEMEND (see section 4.4).

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimatedfrom the available data).

Table 6: Tabulated list of adverse reactions - fosaprepitant

System organ class Adverse reaction Frequency

Vascular disorders flushing, thrombophlebitis (predominantly, uncommoninfusion site thrombophlebitis)

Skin and subcutaneous tissue erythema uncommondisorders

General disorders and infusion site erythema, infusion site pain, uncommonadministration site conditions infusion site pruritusinfusion site induration rareimmediate hypersensitivity reactions not knownincluding flushing, erythema, dyspnoea,anaphylactic reactions/anaphylactic shock

Investigations blood pressure increased uncommon

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, fosaprepitant should be discontinued and general supportive treatment andmonitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by amedicinal product may not be effective.

Aprepitant cannot be removed by haemodialysis.

Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12.

Fosaprepitant is the prodrug of aprepitant and when administered intravenously is converted rapidlyto aprepitant (see section 5.2). The contribution of fosaprepitant to the overall antiemetic effect hasnot fully been characterised, but a transient contribution during the initial phase cannot be ruled out.

Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors.

The pharmacological effect of fosaprepitant is attributed to aprepitant.

1-Day Regimen of Fosaprepitant in Adults

Highly Emetogenic Chemotherapy (HEC)

In a randomised, parallel, double-blind, active-controlled study, IVEMEND 150 mg (N=1,147) wascompared with a 3-day aprepitant regimen (N=1,175) in adult patients receiving a HEC regimen thatincluded cisplatin (≥ 70 mg/m2). The fosaprepitant regimen consisted of fosaprepitant 150 mg on

Day 1 in combination with ondansetron 32 mg IV on Day 1 and dexamethasone 12 mg on Day 1, 8 mgon Day 2, and 8 mg twice daily on Days 3 and 4. The aprepitant regimen consisted of aprepitant125 mg on Day 1 and 80 mg/day on Days 2 and 3 in combination with ondansetron 32 mg IV on

Day 1 and dexamethasone 12 mg on Day 1 and 8 mg daily on Days 2 through 4. Fosaprepitantplacebo, aprepitant placebo, and dexamethasone placebo (in the evenings on Days 3 and 4) were usedto maintain blinding (see section 4.2). Although a 32 mg intravenous dose of ondansetron was used inclinical trials, this is no longer the recommended dose. See the product information for the selected5-HT3 antagonist for appropriate dosing information.

Efficacy was based on evaluation of the following composite measures: complete response in both theoverall and delayed phases and no vomiting in the overall phase. IVEMEND 150 mg was shown to benon-inferior to that of the 3-day regimen of aprepitant. A summary of the primary and secondaryendpoints is shown in Table 7.

Table 7: Percent of adult patients receiving Highly Emetogenic Chemotherapyresponding by treatment group and phase — Cycle 1

ENDPOINTS* Fosaprepitant Aprepitant Difference†regimen regimen (95 % CI)(N =1,106)** (N =1,134)**% %

Complete response‡

Overall§ 71.9 72.3 -0.4 (-4.1, 3.3)

Delayed phase§§ 74.3 74.2 0.1 (-3.5, 3.7)

No vomiting

Overall§ 72.9 74.6 -1.7 (-5.3, 2.0)

*Primary endpoint is bolded.

**N: Number of adult patients included in the primary analysis of complete response.†Difference and confidence interval (CI) were calculated using the method proposed by Miettinenand Nurminen and adjusted for gender.‡Complete response = no vomiting and no use of rescue therapy.§Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy.§§Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.

Moderately Emetogenic Chemotherapy (MEC)

In a randomised, parallel, double-blind, placebo-controlled study, IVEMEND 150 mg (N=502) incombination with ondansetron and dexamethasone was compared with ondansetron anddexamethasone alone (control regimen) (N=498) in adult patients receiving a moderately emetogenicchemotherapy regimen. The fosaprepitant regimen consisted of fosaprepitant 150 mg on Day 1 incombination with oral ondansetron 8 mg for 2 doses and oral dexamethasone 12 mg. On Days 2 and 3,patients in the fosaprepitant group received placebo for ondansetron every 12 hours. The controlregimen consisted of fosaprepitant placebo 150 mg IV on Day 1 in combination with oral ondansetron8 mg for 2 doses and oral dexamethasone 20 mg. On Days 2 and 3, patients in the control groupreceived 8 mg oral ondansetron every 12 hours. Fosaprepitant placebo and dexamethasone placebo(on Day 1) were used to maintain blinding.

The efficacy of fosaprepitant was evaluated based on the primary and secondary endpoints listed in

Table 8 and was shown to be superior to the control regimen with regard to complete response in thedelayed and overall phases.

Table 8: Percent of adult patients receiving Moderately Emetogenic Chemotherapyresponding by treatment group and phase

ENDPOINTS* Fosaprepitant Control P-Valueregimen regimen(N =502)** (N =498)**% %

Complete response†

Delayed phase‡ 78.9 68.5 < 0.001

Complete response†

Overall§ 77.1 66.9 < 0.001

Acute phase§§ 93.2 91 0.184

*Primary endpoint is bolded.

**N: Number of adult patients included in the intention to treat population.†Complete response = no vomiting and no use of rescue therapy.‡Delayed phase = 25 to 120 hours post-initiation of chemotherapy.§Overall = 0 to 120 hours post-initiation of chemotherapy.§§Acute= 0 to 24 hours post-initiation of chemotherapy.

The estimated time to first emesis is depicted by the Kaplan-Meier plot in Figure 1.

Figure 1: Percent of adult patients receiving Moderately Emetogenic Chemotherapywho remain emesis free over time20 Fosaprepitant Regimen(N=502)

Control Regimen(N=498)0 12 24 36 48 60 72 84 96 108 120

Time(hours) Since the First MEC Administration

In 3 active-controlled, open-label clinical studies, paediatric patients aged 6 months to 17 yearsreceived either highly or moderately emetogenic chemotherapy and a single dose of fosaprepitant at orabove the recommended 1-day regimen dose (139 patients) or 3-day regimen (199 patients), incombination with ondansetron with or without dexamethasone.

Percent of Patients

Paediatric Patients Receiving 1-Day Fosaprepitant Regimen

The efficacy of the 1-day fosaprepitant regimen in paediatric patients was extrapolated from thatdemonstrated in adults receiving the 1-day fosaprepitant regimen as described in the 1-Day Regimenof Fosaprepitant in Adults subsection.

The efficacy of a 1-day fosaprepitant regimen in paediatric patients is expected to be similar to that ofthe 1-day adult fosaprepitant regimen.

Paediatric Patients Receiving 3-Day Fosaprepitant Regimen

The efficacy of the 3-day fosaprepitant regimen in paediatric patients was based on that demonstratedin paediatric patients receiving the 3-day oral aprepitant regimen.

The efficacy of a 3-day fosaprepitant regimen in paediatric patients is expected to be similar to that ofthe 3-day oral aprepitant regimen. See the summary of product characteristics for EMEND capsulesand EMEND powder for oral suspension for complete clinical information regarding studiesperformed with oral aprepitant.

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted toaprepitant. Plasma concentrations of fosaprepitant are below quantifiable levels within 30 minutes ofthe completion of infusion.

Aprepitant after fosaprepitant administration

Following a single intravenous 150 mg dose of fosaprepitant administered as a 20-minute infusion tohealthy adult volunteers, the mean AUC0-∞ of aprepitant was 35.0 µg-hr/ml and the mean maximalaprepitant concentration was 4.01 µg/ml.

Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean volume of distributionat steady state (Vdss) of aprepitant estimated from a single 150 mg intravenous dose of fosaprepitant isapproximately 82 l in humans.

Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations fromhumans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in

S9 preparations from other human tissues including kidney, lung and ileum. Thus, it appears that theconversion of fosaprepitant to aprepitant can occur in multiple tissues. In humans, fosaprepitantadministered intravenously was rapidly converted to aprepitant within 30 minutes following the endof infusion.

Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts forapproximately 19 % of the radioactivity in plasma over 72 hours following a single intravenousadministration 100 mg dose of [14C]- fosaprepitant, a prodrug for aprepitant, indicating a substantialpresence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified inhuman plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring andits side chains and the resultant metabolites were only weakly active. In vitro studies using humanliver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially withminor contribution by CYP1A2 and CYP2C19.

All metabolites observed in urine, faeces and plasma following an intravenous 100 mg [14C]-fosaprepitant dose were also observed following an oral dose of [14C]-aprepitant. Upon conversion of245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant) to aprepitant, 23.9 mg ofphosphoric acid and 95.3 mg of meglumine are liberated.

Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliaryexcretion in faeces. Following a single intravenously administered 100 mg dose of [14C]- fosaprepitantto healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces.

The pharmacokinetics of aprepitant is non-linear across the clinical dose range. The terminal half-lifeof aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 11 hours. Thegeometric mean plasma clearance of aprepitant following a 150 mg intravenous dose of fosaprepitantwas approximately 73 ml/min.

Hepatic impairment: Fosaprepitant is metabolised in various extrahepatic tissues; therefore hepaticimpairment is not expected to alter the conversion of fosaprepitant to aprepitant. Mild hepaticimpairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinicallyrelevant extent. No dose adjustment is necessary for patients with mild hepatic impairment.

Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) onaprepitant pharmacokinetics cannot be drawn from available data. There are no clinical orpharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment: A single 240 mg dose of oral aprepitant was administered to patients with severerenal impairment (CrCl< 30 ml/min) and to patients with end stage renal disease (ESRD) requiringhaemodialysis.

In patients with severe renal impairment, the AUC0- of total aprepitant (unbound and protein bound)decreased by 21 % and Cmax decreased by 32 %, relative to healthy subjects. In patients with ESRDundergoing haemodialysis, the AUC0- of total aprepitant decreased by 42 % and Cmax decreased by32 %. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the

AUC of pharmacologically active unbound aprepitant was not significantly affected in patients withrenal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours afterdosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2 % of the dosewas recovered in the dialysate.

No dose adjustment is necessary for patients with renal impairment or for patients with ESRDundergoing haemodialysis.

Paediatric population: As part of a 3-day IV/IV/IV regimen, simulated median AUC0-24hr of aprepitantwith median peak plasma concentration (Cmax) on Day 1 and the median concentrations at the end of

Day 1, Day 2 and Day 3 in paediatric patients (6 months to 17 years old) are shown in Table 9.

Table 9: Pharmacokinetic parameters of aprepitant for 3-day IV fosaprepitant regimen inpaediatric patients

Population 3-day IV/IV/IV AUC 0-24 hr. Cmax C24 C48 C72dose (ng*hr/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL)12 - 17 years old 115 mg, 80 mg, 21,172 2,475 454 424 41780 mg6 - < 12 years old 25,901 2,719 518 438 4182 - < 6 years old 3 mg/kg, 2 mg/kg, 20,568 2,335 336 248 2322 mg/kg6 months - 16,979 1,916 256 179 167< 2 years old

In the 1-day IV fosaprepitant setting, simulated median AUC0-24hr of aprepitant with median peakplasma concentration (Cmax) on Day 1 and the median concentrations at the end of Day 1, Day 2and Day 3 in paediatric patients (6 months to < 12 years old) and observed mean AUC0-24hr withmedian peak plasma concentration (Cmax) on Day 1 and mean concentrations at the end of Day 1, Day2 and Day 3 in paediatric patients (12 to 17 years old) are shown in Table 10.

Table 10: Pharmacokinetic parameters of aprepitant for 1-day IV fosaprepitant regimen inpaediatric patients

Population 1-day IV AUC 0-24 hr. Cmax C24 C48 C72dose (ng*hr/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL)12 - 17 years old 150 mg 30,400 3,500 735 NR NR6 - < 12 years old 35,766 3,637 746 227 69.24 mg/kg2 - < 6 years old 28,655 3,150 494 108 23.56 months - 5 mg/kg 30,484 3,191 522 112 24.4<2 years old

NR = Not Reported

A population pharmacokinetic analysis of aprepitant in paediatric patients (aged 6 months through17 years) suggests that gender and race have no clinically meaningful effect on the pharmacokineticsof aprepitant.

Relationship between concentration and effect

Positron emission tomography (PET) imaging studies, using a highly specific NK1 receptor tracer, inhealthy young men administered a single intravenous dose of 150 mg fosaprepitant (N=8)demonstrated brain NK1 receptor occupancy of ≥ 100 % at Tmax, and 24 hours, ≥ 97 % at 48 hours, andbetween 41 % and 75 % at 120 hours, following dosing. Occupancy of brain NK1 receptors, in thisstudy, correlate well with aprepitant plasma concentrations.

Pre-clinical data obtained with intravenous administration of fosaprepitant and oral administration ofaprepitant reveal no special hazard for humans based on conventional studies of single and repeateddose toxicity, genotoxicity (including in vitro tests), and toxicity to reproduction and development.

Carcinogenic potential in rodents was only investigated with orally administered aprepitant. However,it should be noted that the value of the toxicity studies carried out with rodents, rabbits and monkeys,including the reproduction toxicity studies, are limited since systemic exposures to fosaprepitant andaprepitant were only similar or even lower than therapeutic exposure in adult humans. In theperformed safety pharmacology and repeated dose toxicity studies with dogs, fosaprepitant Cmax andaprepitant AUC values were up to 3 times and 40 times, respectively, higher than clinical values.

In a toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 to day 42, adecreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increaseduterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen infemales from 4 mg/kg/day. In a juvenile toxicity study in rats treated with aprepitant from postnatalday 10 to day 63, earlier vaginal opening in females from 250 mg/kg b.i.d. and delayed preputialseparation in males from 10 mg/kg b.i.d was seen. There were no treatment-related effects on mating,fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. Therewere no margins to clinically relevant exposure of aprepitant. For short term treatment, these findingsare considered unlikely to be clinically relevant.

In laboratory animals, fosaprepitant in non-commercial formulations caused vascular toxicity andhaemolysis at concentrations below 1 mg/ml and higher, dependent on the formulation. In humanwashed blood cells also evidence of haemolysis was found with non-commercial formulations atfosaprepitant concentrations of 2.3 mg/ml and higher, although tests in human whole blood werenegative. No haemolysis was found with the commercial formulation up to a fosaprepitantconcentration of 1 mg/ml in human whole blood and washed human erythrocytes.

In rabbits, fosaprepitant caused initial transient local acute inflammation following paravenous,subcutaneous and intramuscular administration. At the end of the follow-up period (post-dose day 8),up to slight local subacute inflammation was noted following paravenous and intramuscularadministration and additional up to moderate focal muscle degeneration/necrosis with muscleregeneration following intramuscular administration.

Disodium edetate (E386)

Polysorbate 80 (E433)

Lactose anhydrous

Sodium hydroxide (E524) (for pH adjustment) and/or

Hydrochloric acid diluted (E507) (for pH adjustment)

IVEMEND is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+),including Hartman’s and lactated Ringer’s solutions. This medicinal product must not be mixed withother medicinal products except those mentioned in section 6.6.

2 years.

After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for24 hours at 25°C.

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8°C.

Store in a refrigerator (2°C - 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

10 ml Type I clear glass vial with a chlorobutyl or bromobutyl rubber stopper and an aluminium sealwith a grey plastic flip off cap.

Pack sizes: 1 or 10 vials.

Not all pack sizes may be marketed.

IVEMEND must be reconstituted and then diluted prior to administration.

Preparation of IVEMEND 150 mg for intravenous administration:

1. Inject 5 ml sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial. Assure thatsodium chloride 9 mg/ml (0.9 %) solution for injection is added to the vial along the vial wallin order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting sodium chloride9 mg/ml (0.9 %) solution for injection into the vial.

2. Prepare an infusion bag filled with 145 ml of sodium chloride 9 mg/ml (0.9 %) solution forinjection (for example, by removing 105 ml of sodium chloride 9 mg/ml (0.9 %) solution forinjection from a 250 ml sodium chloride 9 mg/ml (0.9 %) solution for injection infusion bag).

3. Withdraw the entire volume from the vial and transfer it into an infusion bag containing 145 mlof sodium chloride 9 mg/ml (0.9 %) solution for injection to yield a total volume of 150 mland final concentration of 1 mg/ml. Gently invert the bag 2-3 times.

4. Determine the volume to be administered from this prepared infusion bag, based on therecommended dose (see section 4.2).

The entire volume of the prepared infusion bag (150 ml) should be administered.

Paediatrics

In patients 12 years and older, the volume to be administered is calculated as follows:

- Volume to administer (ml) equals the recommended dose (mg)

In patients 6 months to less than 12 years, the volume to be administered is calculated asfollows:

- Volume to administer (ml) = recommended dose (mg/kg) x weight (kg)o Note: Do not exceed maximum doses (see section 4.2).

5. If necessary, for volumes less than 150 ml, the calculated volume can be transferred to anappropriate size bag or syringe prior to administration by infusion.

The appearance of the reconstituted solution is the same as the appearance of the diluent.

The reconstituted and diluted medicinal product should be inspected visually for particulate matterand discoloration before administration.

Discard any remaining solution and waste material. Any unused medicinal product or waste materialshould be disposed of in accordance with local requirements.

The medicinal product must not be reconstituted or mixed with solutions for which physical andchemical compatibility has not been established (see section 6.2).

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/07/437/003

EU/1/07/437/004

Date of first authorisation: 11 January 2008

Date of latest renewal: 12 November 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.