Drug Class Description
Anti-emetics

Drug Description
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).

Presentation
Powder for solution for infusion.White to off-white amorphous powder

Indications
Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatinbased 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

Adult Dosage
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.* Ivemend 115 mg is no longer available in the UKOral 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.PosologyIVEMEND 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 RegimenDay 1Day 2Day 3Day 4IVEMEND150 mg intravenouslynonenonenoneDexamethasone12 mg orally8 mg orally8 mg orally twice daily8 mg orally twice dailyOndansetron32 mg intravenouslynonenonenoneDexamethasone 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 RegimenDay 1IVEMEND150 mg intravenouslyDexamethasone12 mg orallyOndansetron2 x 8 mg orallyDexamethasone 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 coadministration with corticosteroids, see section 4.5.Refer to the Summary of Product Characteristics of coadministered antiemetic medicinal products.Special populationsElderly (65 years)No dose adjustment is necessary for the elderly (see section 5.2).GenderNo dose adjustment is necessary based on gender (see section 5.2).Renal impairmentNo dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2).Hepatic impairmentNo 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 populationThe 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 administrationIVEMEND 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.

Contra Indications
Hypersensitivity to fosaprepitant, aprepitant, or to polysorbate 80 or any of the other excipients.Coadministration with pimozide, terfenadine, astemizole or cisapride.

Special Precautions
Patients with moderate to severe hepatic impairmentThere 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.CYP3A4 interactionsIVEMEND 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. Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity.Coadministration 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. 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.Coadministration with warfarin (a CYP2C9 substrate)Coadministration 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.Coadministration with hormonal contraceptivesThe 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.Hypersensitivity reactionsIsolated 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 reactionsIVEMEND should not be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion. IVEMEND should not be administered intramuscularly or subcutaneously. 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.

Interactions
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 substancesCYP3A4 inhibitionAs a weak inhibitor of CYP3A4, the fosaprepitant 150 mg single dose can cause a transient increase in plasma concentrations of coadministered active substances that are metabolised through CYP3A4. The total exposure of CYP3A4 substrates may increase up to 2fold 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. 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.CorticosteroidsDexamethasone: 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 AUC0-24hr 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 productsInteraction 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.ImmunosuppressantsFollowing 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.MidazolamFosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0- 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 coadministering these medicinal products with IVEMEND.DiltiazemInteraction studies with fosaprepitant 150 mg and diltiazem have not been conducted; however, the following study with 100 mg of fosaprepitant should be considered when using IVEMEND 150 mg with diltiazem. In patients with mild to moderate hypertension, infusion of 100 mg of fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.4fold increase in diltiazem AUC and a small but clinically meaningful decrease in blood pressure, but did not result in a clinically meaningful change in heart rate, or PR interval.InductionThe fosaprepitant 150 mg single dose did not induce CYP3A4 on Days 1 and 4 in the midazolam interaction 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 3day oral aprepitant regimen, for which a transient induction with its maximum effect 6-8 days after first aprepitant 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 trough concentrations. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known to be metabolised by CYP2C9 are administered with IVEMEND.WarfarinIn patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with and for 2 weeks following the use of IVEMEND for the prevention of chemotherapy induced nausea and vomiting.Hormonal contraceptivesThe 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.5-HT3 antagonistsInteraction 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 important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Therefore, there is no evidence of interaction with the use of IVEMEND 150 mg and 5-HT3 antagonists.Effect of other medicinal products on the pharmacokinetics of aprepitant resulting from administration of fosaprepitant 150 mgConcomitant 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 severalfold increased plasma concentrations of aprepitant. Ketoconazole increased the terminal half-life of oral aprepitant about 3fold.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 that may result in decreased efficacy. Concomitant administration of fosaprepitant with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended. Rifampicin decreased the mean terminal half-life of oral aprepitant by 68 %.DiltiazemInteraction studies with fosaprepitant 150 mg and diltiazem have not been conducted; however, the following study with 100 mg of fosaprepitant should be considered when using IVEMEND 150 mg with diltiazem. Infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5fold increase of aprepitant AUC. This effect was not considered clinically important.

Adverse Reactions
Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. Prior to approval of fosaprepitant 150 mg, the safety profiles of fosaprepitant and aprepitant were eva luated in approximately 1,100 individuals and 6,500 individuals, respectively. In clinical studies, various formulations of fosaprepitant have been administered to a total of 2,183 individuals including 371 healthy subjects and 1,579 patients with CINV.Oral aprepitantAdverse reactions were reported in approximately 17 % of patients treated with the aprepitant regimen compared with approximately 13 % of patients treated with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC). Aprepitant was discontinued due to adverse reactions in 0.6 % of patients treated with the aprepitant regimen compared with 0.4 % of patients treated with standard therapy. In a combined analysis of 2 clinical studies of patients receiving Moderately Emetogenic Chemotherapy (MEC), clinical adverse reactions were reported in approximately 14 % of patients treated with the aprepitant regimen compared with approximately 15 % of patients treated with standard therapy. Aprepitant was discontinued due to adverse reactions in 0.7 % of patients treated with the aprepitant regimen compared with 0.2 % of patients treated with standard therapy.The most common adverse reactions reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving HEC were: hiccups (4.6 % versus 2.9 %), asthenia/fatigue (2.9 % versus 1.6 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.5 %), constipation (2.2 % versus 2.0 %), headache (2.2 % versus 1.8 %), and anorexia (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 following adverse reactions were observed in either HEC or MEC studies or postmarketing in patients treated with the aprepitant regimen.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 classAdverse reactionFrequencyInfection and infestationscandidiasis, staphylococcal infectionuncommonBlood and lymphatic system disordersfebrile neutropenia, anaemiauncommonImmune system disordershypersensitivity reactions including anaphylactic reactionsnot knownMetabolism and nutrition disordersanorexiaweight gain, polydipsiacommonuncommonPsychiatric disordersdisorientation, euphoria, anxietyuncommonNervous system disordersheadache, dizzinessdream abnormality, cognitive disorder, lethargy, somnolencecommonuncommonEye disordersconjunctivitisuncommonEar and labyrinth disorderstinnitusuncommonCardiac disordersbradycardia, palpitations, cardiovascular disorderuncommonVascular disordersflushing/hot flushuncommonRespiratory, thoracic and mediastinal disordershiccupspharyngitis, sneezing, cough, postnasal drip, throat irritationcommonuncommonGastrointestinal disordersconstipation, diarrhoea, dyspepsia, eructationperforating duodenal ulcer, nausea*, vomiting*, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, abdominal pain, dry mouth, enterocolitis, flatulence, stomatitis, abdominal distension, faeces hard, neutropenic colitiscommonuncommonSkin and subcutaneous tissue disordersrash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion, rash pruriticurticariauncommonnot knownMusculoskeletal and connective tissue disordersmuscle cramp, myalgia, muscular weaknessuncommonRenal and urinary disorderspolyuria, dysuria, pollakiuriauncommonGeneral disorders and administration site conditionsasthaenia, fatigueoedema, chest discomfort, malaise, thirst, chills, gait disturbancecommonuncommonInvestigationsALT increased, AST increasedalkaline phosphatase increased, hyperglycaemia, microscopic haematuria, hyponatraemia, weight decreased, neutrophil count decreasedcommonuncommon*Nausea and vomiting were efficacy parameters in the first 5days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.The adverse reactions profiles in the Multiple-Cycle extension of HEC and MEC studies for up 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 patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.Additional adverse reactions were observed in patients treated with aprepitant (40 mg) for postoperative nausea and vomiting and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, visual acuity reduced, wheezing.In addition, two serious adverse reactions were reported in clinical studies in postoperative nausea and vomiting (PONV) in patients taking a higher dose of aprepitant: one case of constipation, and one case of subileus.One case of Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy.One case of angioedema and urticaria was reported as a serious adverse reaction in a patient receiving aprepitant in a non-CINV/non-PONV study.FosaprepitantIn an active-controlled clinical study in patients receiving HEC, safety was eva luated for 1,143 patients receiving the 1day regimen of IVEMEND 150 mg compared to 1,169 patients receiving the 3day regimen of aprepitant. The safety profile was generally similar to that seen in the aprepitant table above.The following are clinically important adverse reactions reported in patients receiving fosaprepitant in clinical studies or postmarketing that have not been reported with aprepitant as described above. 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 classAdverse reactionFrequencyVascular disordersflushing, thrombophlebitis (predominantly, infusion-site thrombophlebitis)uncommonSkin and subcutaneous tissue disorderserythemauncommonGeneral disorders and administration site conditionsinfusion site erythema, infusion site pain, infusion site pruritus, infusion site indurationimmediate hypersensitivity reactions including flushing, erythema, dyspneauncommonnot knownInvestigationsblood pressure increaseduncommon

Owner
Merck Sharp & Dohme Limited

Drug Availability
POM – Prescription Only Medicine - Black Triangle

Updated
06 April 2011