Drug Class Description
Antiemetics and Antinauseants

Generic Name
Aprepitant

Drug Description
Each 125 mg capsule contains 125 mg of aprepitant. Each 80 mg capsule contains 80 mg of aprepitant.Excipient: 125 mg sucrose (in the 125 mg capsule).Excipient: 80 mg sucrose (in the 80 mg capsule).

Presentation
Hard capsuleThe 125 mg capsule is opaque with a white body and pink cap with “462” and “125 mg” printed radially in black ink on the body. The 80 mg capsules are opaque with a white body and cap with “461” and “80 mg” printed radially in black ink on the body.

Indications
Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adultsPrevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.EMEND 125/80mg is given as part of combination therapy

Adult Dosage
PosologyEMEND is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended posology of EMEND is 125 mg orally (PO) once daily one hour before start of chemotherapy on Day 1 and 80 mg PO once daily on Days 2 and 3. Fosaprepitant 115mg, a lyophilized prodrug of aprepitant may be substituted for oral EMEND (125mg), 30 minutes prior to chemotherapy, on Day 1 only of the chemotherapy –induced nausea and vomiting (CINV) regimen as an intravenous infusion administered over 15minutes. Please refer to the Summary of Product Characteristics for fosaprepitant.In clinical studies with EMEND, the following regimens were used for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy:Highly Emetogenic Chemotherapy RegimenDay 1Day 2Day 3Day 4EMEND125 mg PO80 mg PO80 mg POnoneDexamethasone12 mg PO8 mg PO8 mg PO8 mg POOndansetron32 mg IVnonenonenoneEMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. The dose of dexamethasone was chosen to account for active substance interactions.Ondansetron was administered intravenously 30 minutes prior to chemotherapy treatment on Day 1.Moderately Emetogenic Chemotherapy RegimenDay 1Day 2Day 3EMEND125 mg PO80 mg PO80 mg PODexamethasone12 mg POnonenoneOndansetron2 x 8 mg POnonenoneEMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone was chosen to account for active substance interactions.One 8 mg capsule of ondansetron was administered 30 to 60 minutes prior to chemotherapy treatment and one 8 mg capsule was 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 co-administration with corticosteroids.GenderNo dosage adjustment is necessary based on gender.Renal impairmentNo dosage adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis.Hepatic impairmentNo dosage 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.Children and adolescentsEMEND is not recommended for use in children below 18 years due to insufficient data on safety and efficacy.Method of administrationThe hard capsule should be swallowed whole.EMEND may be taken with or without food.

Child Dosage
Safety and efficacy have not been established in children and adolescents. Therefore, use in patients under 18 years of age is not recommended.

Elderly Dosage
Elderly (65 years)No dosage adjustment is necessary for the elderly.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Co-administration with pimozide, terfenadine, astemizole or cisapride.

Special Precautions
There are limited data in patients with moderate hepatic insufficiency and no data in patients with severe hepatic impairment. EMEND should be used with caution in these patients.EMEND should be used with caution in patients receiving concomitant orally administered active substances that are metabolised primarily through CYP3A4. Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity.Co-administration of EMEND 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.Co-administration of EMEND 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 during treatment with EMEND and for 2 weeks following each 3-day course of EMEND for chemotherapy induced nausea and vomiting.The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND.Concomitant administration of EMEND with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination results in reductions of the plasma concentrations of aprepitant. Concomitant administration of EMEND with herbal prepartions containing St. John's Wort (Hypericum perforatum) is not recommended.Concomitant administration of EMEND with active substances that inhibit CYP3A4 activity (e.g. ritonavir, ketoconazole, clarithromycin, telithromycin) should be approached cautiously as the combination results in increased plasma concentrations of aprepitant.EMEND contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Interactions
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 moderate induction of CYP2C9 and a transient mild induction of CYP3A4 and glucuronidation.Effect of CYP3A4 inhibition by aprepitant on the pharmacokinetics of other active substances 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 area under the curve (AUC) 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. Caution is advised during concomitant administration of EMEND and CYP3A4 substrates.EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisaprideInhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions.InductionAs a moderate inducer of CYP2C9 and a mild inducer of CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes. This effect may become apparent only after the end of treatment with EMEND. For CYP2C9 and CYP3A4 substrates, the induction is transient with a maximum effect reached 3-5 days after end of the EMEND 3-day treatment. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after end of EMEND treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant given for 7 days. 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 during this time period.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 clinical trials was chosen to account for active substance interactions. 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 coadministered 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 coadministered with EMEND 125 mg/80 mg regimen. EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was co-administered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease at later time points within 2 weeks following initiation of dosing with EMEND, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.Chemotherapeutic agents: In pharmacokinetic studies, EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel administered intravenously on Day 1 or vinorelbine administered intravenously on Day 1 or Day 8. Because the effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of EMEND on the pharmacokinetics of intravenously administered CYP3A4 substrates, an interaction with orally administered chemotherapeutic agents 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 agents orally.Midazolam: The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg).EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of 2mg midazolam was co-administered on Days 1 and 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 to 5.In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and 2mg midazolam was given intravenously prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam 25 % on Day 4 and decreased the AUC of midazolam 19 % on Day 8 and 4 % on Day 15. These effects were not considered clinically important.In a third study with intravenous and oral administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, together with ondansetron 32 mg Day 1, dexamethasone 12 mg Day 1 and 8 mg Days 2-4. This combination (i.e. EMEND, ondansetron and dexamethasone) decreased the AUC of oral midazolam 16 % on Day 6, 9 % on Day 8, 7 % on Day 15 and 17 % on Day 22. These effects were not considered clinically important.An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous 2mg midazolam was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.Warfarin: In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with EMEND and for 2 weeks following each 3-day course of EMEND for chemotherapy induced nausea and vomiting. When a single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilised on chronic warfarin therapy, there was no effect of EMEND on the plasma AUC of R(+) or S(-) warfarin determined on Day 3; however, there was a 34 % decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14 % decrease in INR 5 days after completion of dosing with EMEND.Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23 % on Day 4, 28 % on Day 8, and 15 % on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.Oral contraceptives: The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND. Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 μg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43 %, and decreased the AUC of norethindrone by 8 %.In another study, single doses of an oral contraceptive containing ethinyl estradiol and norethindrone were administered on Days 1 through 21 with EMEND, given as a regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg intravenously on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. During days 9 through 21 in this study, there was as much as a 64% decrease in ethinyl estradiol trough concentrations and as much as a 60% decrease in norethindrone trough concentrations.5 -HT 3 antagonists: In clinical interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of EMEND with digoxin.Effect of other agents on the pharmacokinetics of aprepitantConcomitant administration of EMEND with active substances that inhibit CYP3A4 activity (e.g., ritonavir, ketoconazole, clarithromycin, telithromycin) should be approached cautiously, as the combination results in increased plasma concentrations of aprepitant.Concomitant administration of EMEND with active substancesthat strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination results in reductions of the plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Concomitant administration of EMEND with herbal prepartions containing St. John's Wort (Hypericum perforatum) is not recommended.Ketoconazole: When a single 125-mg dose of aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold.Rifampicin: When a single 375-mg dose of aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased 91 % and the mean terminal half-life decreased 68 %.

Adverse Reactions
The safety profile of aprepitant was eva luated in approximately 4,900 individuals.Adverse reactions considered as drug-related by the investigator 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. 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 clinical study of patients receiving moderately emetogenic chemotherapy, clinical adverse reactions were reported in approximately 21% of patients treated with the aprepitant regimen compared with approximately 20% of patients treated with standard therapy. Aprepitant was discontinued due to adverse reactions in 1.1% of patients treated with the aprepitant regimen compared with 0.5% 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 highly emetogenic chemotherapy were: hiccups (4.6 % versus 2.9%), asthenia/fatigue (2.9 % versus 1.6%), alanine transferase (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 moderately emetogenic chemotherapy was fatigue (2.5 % versus 1.6%).The following adverse reactions were observed in patients treated with the aprepitant regimen and at a greater incidence than with standard therapy: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 reactionFrequencyInvestigationsALT increased, AST increased alkaline phosphatase increased, hyperglycaemia, microscopic haematuria, hyponatraemia, weight decreasedcommon uncommonCardiac disordersbradycardiauncommonBlood and lymphatic system disordersfebrile neutropenia, anaemiauncommonNervous system disordersheadache, dizziness dream abnormality, cognitive disordercommon uncommonEye disordersconjunctivitisuncommonEar and labyrinth disorderstinnitusuncommonRespiratory, thoracic and mediastinal disordershiccups< pharyngitis, sneezing, cough, postnasal drip, throat irritationcommon uncommoGastrointestinal disordersconstipation, diarrhoea, dyspepsia, eructation perforating duodenal ulcer, nausea*, vomiting*, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, abdominal pain, dry mouth, enterocolitis, flatulence, stomatitiscommon uncommonRenal and urinary disorderspolyuria, dysuria, pollakiuriauncommonSkin and subcutaneous tissue disordersrash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesionuncommonMusculoskeletal and connective tissue disordersmuscle cramp, myalgiauncommonMetabolism and nutrition disordersanorexia weight gain, polydipsiacommon uncommonInfection and infestationscandidiasis, staphylococcal infectionuncommonVascular disordersflushing/hot flushuncommonGeneral disorders and administration site conditionsasthaenia/fatigue oedema, chest discomfort, lethargy, thirstcommon uncommonPsychiatric disordersdisorientation, euphoria, anxietyuncommon*Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.The adverse reactions profiles in the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.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 experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.One case of Stevens-Johnson syndrome was reported as a serious adverse event in a patient receiving aprepitant with cancer chemotherapy.One case of angioedema and urticaria was reported as a serious adverse event in a patient receiving aprepitant in a non-CINV/non-PONV study.Post-marketing experienceDuring post-marketing experience the following side effects have been reported (frequency not known):Skin and subcutaneous tissue disorders: pruritus, rash, urticariaImmune system disorders: hypersensitivity reactions including anaphylactic reactions

Manufacturer
Merck Sharp & Dohme Limited

Drug Availability
(POM)

Updated
11 August 2009