ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT EMEND 40 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains 40 mg of aprepitant. Excipient with known effect Each capsule contains 40 mg of sucrose. For the full list of excipients, see section PHARMACEUTICAL FORM Hard capsule. Capsules are opaque with a white body and mustard yellow cap with 464 and 40 mg printed radially in black ink on the body. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications EMEND 40 mg is indicated for the prevention of postoperative nausea and vomiting (PONV) in adults. 4.2 Posology and method of administration Posology Clinical treatment guidelines should be considered as regards the need for prophylactic treatment against postoperative nausea and vomiting (PONV). The recommended oral dose of EMEND is a single 40 mg dose within 3 hours prior to induction of anaesthesia. Special populations Elderly ( 65 years) No dose adjustment is necessary for the elderly (see section 5.2). Gender No dose adjustment is necessary based on gender (see section 5.2). Renal impairment No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2). Hepatic impairment No 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. Aprepitant should be used with caution in these patients (see sections 4.4 and 5.2). 2

3 Paediatric population The safety and efficacy of EMEND 40 mg in children and adolescents below 18 years of age has not yet been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made. Method of administration The hard capsule should be swallowed whole. EMEND may be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section Special warnings and precautions for use Patients with moderate to severe hepatic impairment There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. EMEND should be used with caution in these patients (see section 5.2). CYP3A4 interactions EMEND (40 mg) should be used with caution in patients receiving concomitant administration of pimozide, terfenadine, astemizole, cisapride or ergot alkaloid derivatives. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious adverse reactions (see section 4.5). Co-administration with hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5). For further information on interaction potential of aprepitant at higher and multiple doses, please refer to the Summary of Product Characteristics for EMEND 80 mg hard capsules and EMEND 125 mg hard capsules. Excipients EMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Aprepitant is a substrate, and a dose-dependent inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment, the single 40 mg dose of aprepitant recommended for PONV results in a weak inhibition of CYP3A4. After the treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant has been studied at higher doses. During treatment for chemotherapy induced nausea and vomiting (CINV), the 3-day 125 mg/80 mg regimen of aprepitant is a moderate inhibitor of CYP3A4. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin. Effect of aprepitant on the pharmacokinetics of other active substances CYP3A4 inhibition As a weak inhibitor of CYP3A4, aprepitant (40 mg) can increase plasma concentrations of orally co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 1.5-fold after a single 40 mg dose of aprepitant; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. 3

4 EMEND 40 mg should be used with caution in patients receiving pimozide, terfenadine, astemizole, cisapride, or ergot alkaloid derivatives. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious reactions. Corticosteroids Dexamethasone: A single 40 mg dose of aprepitant, when co-administered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. No dose adjustment is recommended. Methylprednisolone: Although the concomitant administration of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a single 40 mg dose of aprepitant produces a weak inhibition of CYP3A4 and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. Midazolam The AUC of orally administrated midazolam increased by 1.2-fold when a single dose of 40 mg aprepitant was co-administered with a single oral dose of 2 mg midazolam; this effect was not considered clinically important. Induction As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes within two weeks following initiation of treatment. For CYP2C9 and CYP3A4 substrates the induction is transient with a maximum effect reached after 3-5 days. The effect may be maintained for a few days, and is expected to be clinically insignificant by two weeks after the end of treatment with EMEND. Data are lacking regarding effects of CYP2C8 and CYP2C19. Co-administration of EMEND with active substances that are known to be metabolized by CYP2C9 (e.g., phenytoin, warfarin), may result in lower plasma concentrations of these active substances. Based on interaction studies with tolbutamide and oral contraceptives, total exposure of concomitantly administered active substances metabolised by CYP2C9 or CYP3A4 may be reduced up to %. Hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND. 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). Effect of other medicinal products on the pharmacokinetics of aprepitant Concomitant administration of EMEND 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 several-fold increased plasma concentrations of aprepitant (see section 4.4). 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 that may result in decreased efficacy of EMEND. Concomitant administration of EMEND with herbal preparations 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. 4

5 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 %. 4.6 Fertility, pregnancy and lactation Contraception in males and females The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5). Pregnancy For aprepitant no clinical data on exposed pregnancies are available. In animal studies there was no indication of direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokinin regulation are unknown. EMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND. Fertility Fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3). 4.7 Effects on ability to drive and use machines EMEND may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of EMEND (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults. Adverse reactions were reported in approximately 4 % of adults treated with 40 mg aprepitant compared with approximately 6 % of patients treated with 4 mg ondansetron intravenously. In controlled clinical studies in adults receiving general anaesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron intravenously. Most adverse reactions reported in these clinical studies were described as mild to moderate in intensity. The most common adverse reaction reported at a greater incidence in adults treated with 40 mg aprepitant (1.1 %) than with ondansetron (1.0 %) was ALT increased. Tabulated list of adverse reactions The following adverse reactions were observed in PONV studies in adults treated with aprepitant at a greater incidence than with ondansetron or in postmarketing use: 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). 5

6 System organ class Adverse reaction Frequency Immune system disorders hypersensitivity reactions including not known anaphylactic reactions Psychiatric disorders insomnia uncommon Nervous system disorders dysarthria, hypoaesthesia, sensory disturbance uncommon Eye disorders miosis, visual acuity reduced uncommon Cardiac disorders bradycardia uncommon Respiratory, thoracic and dyspnoea, wheezing uncommon mediastinal disorders Gastrointestinal disorders abdominal pain upper, bowel sounds uncommon abnormal, dry mouth, nausea, stomach discomfort, constipation*, sub-ileus* Skin and subcutaneous tissue pruritus, rash, urticaria, Stevens-Johnson not known disorders syndrome/toxic epidermal necrolysis Investigations ALT increased common *Reported in patients taking a higher dose of aprepitant. Description of selected adverse reactions Additional adverse reactions were observed in adults treated with the aprepitant (125 mg/80 mg) regimen for chemotherapy induced nausea and vomiting (CINV) and at a greater incidence than with standard therapy: abdominal distension, abdominal pain, acne, anaemia, anxiety, AST increased, asthenia, blood alkaline phosphatase increased, blood sodium decreased, candidiasis, cardiovascular disorder, chest discomfort, cognitive disorder, conjunctivitis, cough, decreased appetite, disorientation, dizziness, duodenal ulcer perforation, dysgeusia, dyspepsia, dysuria, eructation, euphoric mood, faeces hard, fatigue, febrile neutropenia, flatulence, gait disturbance, gastroesophageal reflux disease, glucose urine present, hiccups, hot flush, hyperhidrosis, lethargy, malaise, muscle spasms, muscular weakness, nausea*, neutropenic colitis, neutrophil count decreased, oedema, oropharyngeal pain, palpitations, photosensitivity reaction, pollakiuria, polydipsia, postnasal drip, rash pruritic, red blood cells urine positive, seborrhoea, skin lesion, sneezing, somnolence, staphylococcal infection, stomatitis, throat irritation, tinnitus, urine output increased, vomiting*, weight decreased. *Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as reactions only thereafter. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a medicinal product may not be effective. Aprepitant cannot be removed by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12 Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK 1 ) receptors. 6

7 In 2 multicentre, randomised, double-blind, active comparator-controlled, parallel-group phase III clinical studies in adults, aprepitant was compared with ondansetron for the prevention of PONV in 1,658 patients undergoing open abdominal surgery. The majority of adults were women (> 90 %), mainly undergoing gynaecological surgery. Patients were randomised to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron. Aprepitant was given orally with 50 ml of water 1 to 3 hours before anaesthesia. Ondansetron was given intravenously immediately before induction of anaesthesia. The antiemetic activity of aprepitant was evaluated during the 0 to 48 hour period following the end of surgery. The results show that a higher percentage of post-surgical adults experienced complete response (no emesis and no use of rescue) with aprepitant 40 mg than with ondansetron 4 mg (lower bound of C.I. is 0.0 indicating borderline significance) as described in Table 1. Table 1 Percent of post-operative adults responding by treatment group Combined results from 2 Phase III trials Aprepitant 40 mg orally (N=541) Ondansetron 4 mg intravenously (N=526) Percentage point difference (%) and 95 % C.I. # n/m (%) n/m (%) % 95 % C.I. Complete response ( /541 (55.1) 258/526 (49.0) 5.9 (0.0, 11.8) hours) # Complete response: No emesis and no use of rescue Difference (%) calculated as Aprepitant 40 mg minus Ondansetron 4 mg Difference (%) and 95 % C.I. calculated using stratified Miettinen-Nurminen method using Cochran- Mantel-Haenszel weights The reduction in risk for a vomiting episode over the 0 to 24 hour period with aprepitant 40 mg relative to ondansetron 4 mg was 53.3 % (95 % C.I.: 35.3 to 66.3) in an analysis that censors patients at the time of rescue use. Paediatric population The safety and exploratory efficacy of aprepitant were evaluated in a Phase I clinical study (n=50) using a 40 mg powder for oral suspension. The percentage of subjects reporting no vomiting over the first 24 hours following surgery was similar for subjects receiving aprepitant versus ondansetron. No new safety concerns were identified. However, the data from this small study do not support a conclusion on the optimal dosing regimen. Further studies evaluating the use of aprepitant in paediatric patients are on-going (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose. Absorption The mean absolute oral bioavailability of aprepitant is 67 % for the 80 mg capsule and 59 % for the 125 mg capsule. The mean peak plasma concentration (C max ) of aprepitant occurred at approximately 4 hours (t max ). Following oral administration of a single 40 mg dose of EMEND in the fasted state, the AUC 0- (mean ± SD) was 8.0 ± 2.1 µg h/ml and the C max was 0.7 ± 0.24 µg/ml. The median t max was 3.0 hours. Concomitant intake of a 40 mg dose with a standard breakfast decreased the aprepitant C max by 18 % but did not affect AUC. This is not considered to be clinically important. 7

8 Distribution Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean apparent volume of distribution at steady state (Vd ss ) is approximately 66 L in humans. Biotransformation Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100 mg dose of [ 14 C]-fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19. Elimination Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [ 14 C]-fosaprepitant, a prodrug for aprepitant to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces. The plasma clearance of aprepitant is dose-dependent, decreasing with increased dose and ranged from approximately 60 to 72 ml/min in the therapeutic dose range. The terminal half-life is approximately 9 hours after administration of a single 40 mg dose. Pharmacokinetics in special populations Elderly: Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21 % higher on Day 1 and 36 % higher on Day 5 in elderly ( 65 years) relative to younger adults. The C max was 10 % higher on Day 1 and 24 % higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary in elderly patients. Gender: Following oral administration of a single 125 mg dose of aprepitant, the C max for aprepitant is 16 % higher in females as compared with males. The half-life of aprepitant is 25 % lower in females as compared with males and its t max occurs at approximately the same time. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary based on gender. Hepatic impairment: Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment. Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C). Renal impairment: A single 240 mg dose of aprepitant was administered to patients with severe renal impairment (CrCl < 30 ml/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis. In patients with severe renal impairment, the AUC 0- of total aprepitant (unbound and protein bound) decreased by 21 % and C max decreased by 32 %, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC 0- of total aprepitant decreased by 42 % and C max decreased by 32 %. 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 with renal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2 % of the dose was recovered in the dialysate. 8

9 No dose adjustment for EMEND is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis. Paediatric population: In a study using a powder for oral suspension formulation, a single dose of 40 mg aprepitant administered to adolescent patients (aged 12 through 17 years) resulted in a mean AUC 0-48hr of 6 µg/ml with a mean peak plasma concentration (C max ) of 0.5 µg/ml occurring at approximately 4 hours. Administration of body surface area adjusted doses to patients 6 months to less than 12 years achieved a mean AUC 0-48hr above 4 µg/ml with a mean C max above 0.5 µg/ml occurring at approximately 3 hours. Relationship between concentration and effect Using a highly specific NK 1 -receptor tracer, positron emission tomography (PET) studies in healthy young men have shown that aprepitant penetrates into the brain and occupies NK 1 receptors in a doseand plasma-concentration-dependent manner. Aprepitant plasma concentrations achieved with the 3-day regimen of EMEND are predicted to provide greater than 95 % occupancy of brain NK 1 receptors. 5.3 Preclinical safety data Pre-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. It should be noted that systemic exposure in adult male rats was lower than the therapeutic exposure in humans at 40 mg. Consequently, no adequate assessment of potential effects on male fertility in rats can be made. However, in a 9 month study in dogs, no organ weight changes nor gross or histomorphologic findings were present in male reproductive organs at systemic exposures 35-fold above the therapeutic exposure in humans at 40 mg. Although no adverse effects were noted in reproduction studies when adult female animals were exposed 3.5-to 4-fold above the therapeutic exposure in humans at 40 mg, the potential effects on reproduction of alterations in neurokinin regulation are unknown. In a juvenile toxicity study in rats treated from post natal day 10 to day 63 aprepitant led to an earlier vaginal opening in females from 250 mg/kg b.i.d. and to a delayed preputial separation in males, from 10 mg/kg b.i.d. There were no margins to clinically relevant exposure. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. In a juvenile toxicity study in dogs treated from post natal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. There were no margins to clinically relevant exposure of aprepitant. For short term treatment according to recommended dose regimen these findings are considered unlikely to be clinically relevant. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content Sucrose Microcrystalline cellulose (E 460) Hydroxypropylcellulose (E 463) Sodium laurilsulfate Capsule shell Gelatin Titanium dioxide (E 171) Yellow iron oxide (E 172) 9

10 Printing ink Shellac Potassium hydroxide Black iron oxide (E 172) 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 4 years 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Different pack sizes are available: Aluminium blister containing one 40 mg capsule. 5 Aluminium blisters each containing one 40 mg capsule. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements for disposal. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg BN Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER EU/1/03/262/007 EU/1/03/262/ DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION Date of first authorisation: 11 November 2003 Date of latest renewal: 22 September DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency 10

11 1. NAME OF THE MEDICINAL PRODUCT EMEND 165 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains 165 mg of aprepitant. Excipient with known effect Each capsule contains 165 mg of sucrose. For the full list of excipients, see section PHARMACEUTICAL FORM Hard capsule. Capsules are opaque with a light blue cap and a white body with 466 and 165 mg printed radially in black ink on one side of the body and the Merck logo on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adults. Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults. EMEND 165 mg is given as part of combination therapy (see section 4.2). 4.2 Posology and method of administration Posology EMEND 165 mg is given on Day 1 only, approximately one hour before the start of chemotherapy, as part of a regimen that includes a corticosteroid and a 5-HT 3 antagonist. The following regimens are recommended in adults for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy: 11

12 Highly Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 Day 4 EMEND 165 mg orally none none none Dexamethasone 12 mg orally 8 mg orally 8 mg orally 8 mg orally 5-HT 3 antagonists Standard dose of 5-HT 3 antagonists. See the product information for the selected 5-HT 3 antagonist for the appropriate dosing information twice daily twice daily none none none Dexamethasone 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. Moderately Emetogenic Chemotherapy Regimen Day 1 EMEND 165 mg orally Dexamethasone 12 mg orally 5-HT 3 antagonists Standard dose of 5-HT 3 antagonists. See the product information for the selected 5-HT 3 antagonist for the appropriate dosing information Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions. Efficacy data in combination with other corticosteroids and 5-HT 3 antagonists are limited. For additional information on the co-administration with corticosteroids, see section 4.5. Please refer to the Summary of Product Characteristics of co-administered 5-HT 3 antagonist medicinal products. Fosaprepitant 150 mg, a lyophilised prodrug of aprepitant for intravenous administration, is also available as a single dose and may be used as an alternative to oral EMEND 165 mg. Special populations Elderly ( 65 years) No dose adjustment is necessary for the elderly (see section 5.2). Gender No dose adjustment is necessary based on gender (see section 5.2). Renal impairment No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2). Hepatic impairment No 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. Aprepitant should be used with caution in these patients (see sections 4.4 and 5.2). 12

13 Paediatric population The safety and efficacy of EMEND 165 mg in children and adolescents below 18 years of age has not been established. No data are available. Other pharmaceutical forms/strengths may be more appropriate for administration to this population. Method of administration The hard capsule should be swallowed whole. EMEND may be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5). 4.4 Special warnings and precautions for use Patients with moderate to severe hepatic impairment There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. EMEND should be used with caution in these patients (see section 5.2). CYP3A4 interactions EMEND should be used with caution in patients receiving concomitant active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity. Co-administration with warfarin (a CYP2C9 substrate) In patients on chronic warfarin therapy, the International Normalised Ratio (INR) should be monitored closely during treatment with EMEND and for 14 days following the use of EMEND (see section 4.5). Co-administration with hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5). Excipients EMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Aprepitant 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 for up to 4 days. EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation approximately one week after treatment. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin. Effect of aprepitant on the pharmacokinetics of other active substances CYP3A4 inhibition As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 3-fold for 2 days following a single 165 mg dose of EMEND and decreasing to baseline approximately 4 days after dosing of 165 mg EMEND. The effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. EMEND must not be used concurrently with pimozide, 13

14 terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or lifethreatening reactions. Caution is advised during concomitant administration of EMEND 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 (see section 4.4). Corticosteroids Dexamethasone: Interaction studies with aprepitant 165 mg and dexamethasone have not been conducted; however, the following study with 200 mg of aprepitant should be considered when using EMEND 165 mg with oral dexamethasone. Aprepitant, when given as a single dose of 200 mg in the fed state (standard light breakfast) on Day 1 with oral dexamethasone, co-administered orally as 12 mg on Day 1 and 8 mg on Days 2 through 4, increased the AUC 0-24hr of dexamethasone by 2.1- and 2.3-fold on Days 1 and 2, to a lesser extent (1.4-fold increase) on Day 3, and had no effect on Day 4 (1.1-fold). The daily dose of dexamethasone on Days 1 and 2 should be reduced by approximately 50 % when co-administered with EMEND 165 mg on Day 1 to achieve exposures of dexamethasone similar to those obtained when given without EMEND 165 mg. Methylprednisolone: Interaction studies with aprepitant 165 mg and methylprednisolone have not been conducted; however, the following study with the aprepitant 125 mg/80 mg regimen should be considered when using EMEND 165 mg with methylprednisolone. 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 14 days following initiation of the EMEND dose, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone. Chemotherapeutic medicinal products Interaction studies with aprepitant 165 mg and chemotherapeutic medicinal products have not been conducted; however, based on studies with 3-day regimen of oral aprepitant and docetaxel and vinorelbine, EMEND 165 mg is not expected to have a clinically relevant interaction with intravenously administered docetaxel and vinorelbine. 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 medicinal products metabolised primarily or partly by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration. Immunosuppressants Following a single 165 mg aprepitant 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 EMEND 165 mg. Midazolam Interaction studies with aprepitant 165 mg and midazolam have not been conducted; however, the following study with 200 mg of aprepitant should be considered when using EMEND 165 mg with medicinal products metabolised via CYP3A4. In a study with 2 mg midazolam orally co-administered 14

15 with 200 mg aprepitant in the fed state (standard light breakfast), the AUC 0- of midazolam, a sensitive CYP3A4 substrate, was increased 3.2-fold on Day 1. No clinically important effect resulted on Day 4 (midazolam AUC fold increase) and a slight change in midazolam AUC 0- was observed on Day 8 (35 % decrease). The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products with EMEND 165 mg. Induction As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes. This effect may become apparent approximately 7 days following the single dose administration of EMEND 165 mg. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant within 14 days after end of EMEND treatment. A single dose of aprepitant 200 mg on Day 1 co-administered with midazolam, a sensitive CYP3A4 substrate, on Days 1, 4 and 8 resulted in a 35 % reduction of midazolam AUC 0- on Day 8. It is anticipated that EMEND 165 mg would cause similar induction of CYP2C9, CYP3A4, and glucuronidation than that caused by the administration of the 3-day oral aprepitant regimen, for which a transient induction with its maximum effect 6 to 8 days after first aprepitant dose has been observed. The 3-day oral aprepitant regimen resulted in an about % 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 EMEND 165 mg. Warfarin In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment and for 14 days following the use of EMEND 165 mg for chemotherapy induced nausea and vomiting (see section 4.4). 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 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. Hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND. In a clinical 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, when given as a regimen of 125 mg on Day 1 and 80 mg on Days 2 and 3, did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). 15

16 Effect of other medicinal products on the pharmacokinetics of aprepitant Concomitant administration of EMEND 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 several-fold increased plasma concentrations of aprepitant (see section 4.4). 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 that may result in decreased efficacy of EMEND. Concomitant administration of EMEND with herbal preparations 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 %. 4.6 Fertility, pregnancy and lactation Contraception in males and females The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5). Pregnancy For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg and 165 mg doses could not be attained in animal studies. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokinin regulation are unknown. EMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND. Fertility The potential for effects of aprepitant on fertility has not been fully characterised because exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3). 4.7 Effects on ability to drive and use machines EMEND may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of EMEND (see section 4.8). 16

17 4.8 Undesirable effects Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults. Based on a comparable pharmacokinetic/pharmacodynamic profile, the 1-day oral regimen of EMEND 165 mg is anticipated to have a similar safety and tolerability profile to that of the 1-day regimen of fosaprepitant 150 mg and the 3-day oral aprepitant regimen in chemotherapy patients (see section 5.2). The most common adverse reactions reported at a greater incidence in adults treated with the 3-day oral aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the 3-day oral aprepitant regimen than with standard therapy in patients receiving Moderately Emetogenic Chemotherapy (MEC) was fatigue (1.4 % versus 0.9 %). Tabulated list of adverse reactions The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy in adults or postmarketing use: Frequencies are defined as: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000) and very rare (< 1/10,000), not known (cannot be estimated from the available data). System organ class Adverse reaction Frequency Infection and infestations candidiasis, staphylococcal infection rare Blood and lymphatic system febrile neutropenia, anaemia uncommon disorders Immune system disorders hypersensitivity reactions including not known anaphylactic reactions Metabolism and nutrition decreased appetite common disorders polydipsia rare Psychiatric disorders anxiety uncommon disorientation, euphoric mood rare Nervous system disorders headache common dizziness, somnolence uncommon cognitive disorder, lethargy, dysgeusia rare Eye disorders conjunctivitis rare Ear and labyrinth disorders tinnitus rare Cardiac disorders palpitations uncommon bradycardia, cardiovascular disorder rare Vascular disorders hot flush uncommon Respiratory, thoracic and hiccups common mediastinal disorders oropharyngeal pain, sneezing, cough, rare postnasal drip, throat irritation Gastrointestinal disorders constipation, dyspepsia common eructation, nausea*, vomiting*, uncommon gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence duodenal ulcer perforation, stomatitis, rare abdominal distension, faeces hard, neutropenic colitis Skin and subcutaneous tissue rash, acne uncommon 17

18 System organ class Adverse reaction Frequency disorders photosensitivity reaction, hyperhidrosis, rare seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis pruritus, urticaria not known Musculoskeletal and connective muscular weakness, muscle spasms rare tissue disorders Renal and urinary disorders dysuria uncommon pollakiuria rare General disorders and fatigue common administration site conditions asthenia, malaise uncommon oedema, chest discomfort, gait disturbance rare Investigations ALT increased common AST increased, blood alkaline phosphatase uncommon increased red blood cells urine positive, blood sodium decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increased rare *Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter. Description of selected adverse reactions The adverse reactions profiles in adults 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 adult patients receiving the 3-day oral aprepitant regimen and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with the 3-day oral aprepitant regimen. Additional adverse reactions were observed in patients treated with aprepitant for postoperative nausea 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. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a medicinal product may not be effective. Aprepitant cannot be removed by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12 18

19 Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK 1 ) receptors. Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant. Based on a comparable pharmacokinetic/pharmacodynamic profile, the 1-day oral regimen of EMEND 165 mg is anticipated to have a similar efficacy profile to that of the 1-day regimen of fosaprepitant 150 mg and 3-day regimen of oral aprepitant (see section 5.2) 3-day regimen of aprepitant in adults In 2 randomised, double-blind studies encompassing a total of 1,094 adult patients receiving chemotherapy that included cisplatin 70 mg/m 2, aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT 3 antagonist for appropriate dosing information. Efficacy was based on evaluation of the following composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined. A summary of the key study results from the combined analysis is shown in Table 1. Table 1 Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase Cycle 1 COMPOSITE MEASURES Aprepitant regimen (N= 521) % Standard therapy (N= 524) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) 0-24 hours hours (14.0, 25.8) (7.9, 17.6) (14.5, 26.1) INDIVIDUAL MEASURES No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours (16.4, 28.0) (8.0, 17.5) (17.0, 28.2) No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) hours (1.6, 12.8) (1.5, 12.6) * The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models. One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses. 19

20 The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1. Figure 1 Percent of adult patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time Cycle 1 100% 90% Aprepitant Regimen (N=520) Standard Therapy (N=523) Percent of Patients 80% 70% 60% 50% 40% Time (hours) Statistically significant differences in efficacy were also observed in each of the 2 individual studies. In the same 2 clinical studies, 851 adult patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles. In a randomised, double-blind study in a total of 866 adult patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m 2 ; or cyclophosphamide 500-1,500 mg/m 2 and doxorubicin (< 60 mg/m 2 ) or epirubicin (< 100 mg/m 2 ), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. 20

21 A summary of the key study results is shown in Table 2. Table 2 Percent of adult patients responding by treatment group and phase Cycle 1 Moderately Emetogenic Chemotherapy COMPOSITE MEASURES Aprepitant regimen (N= 433) % Standard therapy (N= 424) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) 0-24 hours hours (1.6, 15.0) (0.7, 12.7) (-0.4, 13.0) INDIVIDUAL MEASURES No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) 0-24 hours hours (10.8, 23.2) (5.1, 15.3) (5.9, 17.5) 5.3 (-1.3, 11.9) 1.3 (-4.2, 6.8) 3.9 (-2.6, 10.3) * The confidence intervals were calculated with no adjustment for age category (< 55 years, 55 years) and investigator group, which were included in the primary analysis of odds ratios and logistic models. One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses. In the same clinical study, 744 adult patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles. In a second multicentre, randomised, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 adult patients (652 females, 196 males) receiving a chemotherapy regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenously (< 1,500 mg/m 2 ); or cytarabine intravenously (> 1 g/m 2 ). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumour types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynaecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on the evaluation of the following primary and key secondary endpoints: No vomiting in the overall period (0 to 120 hours post-chemotherapy), evaluation of safety and tolerability of the aprepitant regimen for chemotherapy induced nausea and vomiting (CINV), and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to 120 hours post-chemotherapy). Additionally, no significant nausea in the overall period (0 to 120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis. A summary of the key study results is shown in Table 3. 21

22 Table 3 Percent of adult patients responding by treatment group and phase for Study 2 Cycle 1 Moderately Emetogenic Chemotherapy Aprepitant regimen (N= 425) % Standard therapy (N= 406) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) 0-24 hours hours No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) hours hours No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) 0-24 hours hours (5.9, 18.9) (4.0, 13.8) (3.5, 16.3) (7.9, 20.3) (3.9, 12.7) (5.1, 17.1) (1.0, 13.4) (0.2, 9.0) (-0.7, 11.5) *The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models. The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men. 1-day regimen of fosaprepitant 150 mg in adults In a randomised, parallel, double-blind, active-controlled study, fosaprepitant 150 mg (N=1,147) was compared with a 3-day aprepitant regimen (N=1,175) in adult patients receiving a HEC regimen that included cisplatin ( 70 mg/m 2 ). The fosaprepitant regimen consisted of fosaprepitant 150 mg on Day 1 in combination with intravenous ondansetron 32 mg on Day 1 and dexamethasone 12 mg on Day 1, 8 mg on Day 2, and 8 mg twice daily on Days 3 and 4. The aprepitant regimen consisted of aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 and 3 in combination with intravenous ondansetron 32 mg on Day 1 and dexamethasone 12 mg on Day 1 and 8 mg daily on Days 2 through 4. Fosaprepitant placebo, aprepitant placebo, and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding (see section 4.2). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT 3 antagonist for appropriate dosing information. Efficacy was based on evaluation of the following composite measures: complete response in both the overall and delayed phases and no vomiting in the overall phase. Fosaprepitant 150 mg was shown to be non-inferior to that of the 3-day regimen of aprepitant. A summary of the primary and secondary endpoints is shown in Table 4. 22

23 Table 4 Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase Cycle 1 ENDPOINTS* Fosaprepitant regimen (N =1,106) ** % Aprepitant regimen (N =1,134) ** % Difference (95 % CI) Complete response Overall (-4.1, 3.3) Delayed phase (-3.5, 3.7) No vomiting Overall (-5.3, 2.0) *Primary endpoint is bolded. **N: Number of patients included in the primary analysis of complete response. Difference and confidence interval (CI) were calculated using the method proposed by Miettinen and 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. Paediatric population Studies evaluating the use of aprepitant in paediatric patients are on-going (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose. Absorption The AUC 0- of aprepitant following oral administration of 165 mg was equivalent to the AUC 0- of 150 mg fosaprepitant administered intravenously, while the C max was 2.4-fold lower. Following a single oral dose of aprepitant 165 mg to healthy volunteers, the mean AUC 0- of aprepitant was 32.5 µg hr/ml and the mean maximal aprepitant concentration was 1.67 µg/ml. The mean peak plasma concentration (C max ) of aprepitant occurred at approximately 4 hours (T max ). Oral administration of the capsule with a standard light breakfast and a high-fat breakfast resulted in an up to an 8 % and a 47 % increase in AUC 0- of aprepitant, respectively. This increase is not considered clinically relevant. Distribution Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean apparent volume of distribution at steady state (Vd ss ) is approximately 66 L in humans. Biotransformation Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100 mg dose of [ 14 C]-fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19. 23

24 Elimination Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [ 14 C]-fosaprepitant, a prodrug for aprepitant, to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces. The plasma clearance of aprepitant is dose-dependent, decreasing with increased dose and ranged from approximately 60 to 72 ml/min in the therapeutic dose range. The terminal half-life ranged from approximately 9 to 13 hours. Pharmacokinetics in special populations Elderly: Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21 % higher on Day 1 and 36 % higher on Day 5 in elderly ( 65 years) relative to younger adults. The C max was 10 % higher on Day 1 and 24 % higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary in elderly patients. Gender: Following oral administration of a single 125 mg dose of aprepitant, the C max for aprepitant is 16 % higher in females as compared with males. The half-life of aprepitant is 25 % lower in females as compared with males and its t max occurs at approximately the same time. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary based on gender. Hepatic impairment: Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment. Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C). Renal impairment: A single 240 mg dose of aprepitant was administered to patients with severe renal impairment (CrCl < 30 ml/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis. In patients with severe renal impairment, the AUC 0- of total aprepitant (unbound and protein bound) decreased by 21 % and C max decreased by 32 %, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC 0- of total aprepitant decreased by 42 % and C max decreased by 32 %. 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 with renal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2 % of the dose was recovered in the dialysate. No dose adjustment for EMEND is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis. Relationship between concentration and effect Using a highly specific NK 1 -receptor tracer, positron emission tomography (PET) studies in healthy young men have shown that aprepitant penetrates into the brain and occupies NK 1 receptors in a doseand plasma-concentration-dependent manner. Aprepitant plasma concentrations achieved with the 3-day regimen of EMEND are predicted to provide greater than 95 % occupancy of brain NK 1 receptors. A PET study in healthy young men administered a single oral dose of 165 mg aprepitant or a single intravenous dose of 150 mg fosaprepitant demonstrated similar brain NK 1 receptor occupancy at T max, ( 99 %), 24 hours ( 99 %), 48 hours ( 97 %), and 120 hours (37 to 76 %) following dosing. Occupancy of brain NK 1 receptors by aprepitant correlate well with aprepitant plasma concentrations. 24

25 5.3 Preclinical safety data Pre-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. However, it should be noted that systemic exposure in rodents was similar or even lower than therapeutic exposure in humans at the 125 mg/80 mg and 165 mg doses. In particular, although no adverse effects were noted in reproduction studies at human exposure levels, the animal exposures are not sufficient to make an adequate risk assessment in man. In a juvenile toxicity study in rats treated from post natal day 10 to day 63 aprepitant led to an earlier vaginal opening in females from 250 mg/kg b.i.d. and to a delayed preputial separation in males, from 10 mg/kg b.i.d. There were no margins to clinically relevant exposure. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. In a juvenile toxicity study in dogs treated from post natal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. There were no margins to clinically relevant exposure of aprepitant. For short term treatment according to recommended dose regimen these findings are considered unlikely to be clinically relevant. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content Sucrose Microcrystalline cellulose (E 460) Hydroxypropylcellulose (E 463) Sodium laurilsulfate Capsule shell Gelatin Titanium dioxide (E 171) Indigo carmine (E 132) Printing ink Shellac Potassium hydroxide Black iron oxide (E 172) 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 4 years 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 25

26 6.5 Nature and contents of container Aluminium blister containing one 165 mg capsule. 6 Aluminium blisters each containing one 165 mg capsule. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements for disposal. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg BN Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER EU/1/03/262/009 EU/1/03/262/ DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION Date of first authorisation: 11 November 2003 Date of latest renewal: 22 September DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency 26

27 1. NAME OF THE MEDICINAL PRODUCT EMEND 125 mg hard capsules EMEND 80 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 125 mg capsule contains 125 mg of aprepitant. Each 80 mg capsule contains 80 mg of aprepitant. Excipient with known effect Each capsule contains 125 mg of sucrose (in the 125 mg capsule). Excipient with known effect Each capsule contains 80 mg of sucrose (in the 80 mg capsule). For the full list of excipients, see section PHARMACEUTICAL FORM Hard capsule. The 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. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and adolescents from the age of 12. EMEND 125 mg/80 mg is given as part of combination therapy (see section 4.2). 4.2 Posology and method of administration Posology Adults EMEND is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT 3 antagonist. The recommended dose is 125 mg orally once daily one hour before start of chemotherapy on Day 1 and 80 mg orally once daily on Days 2 and 3 in the morning. 27

28 The following regimens are recommended in adults for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy: Highly Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 Day 4 EMEND 125 mg orally 80 mg orally 80 mg orally none Dexamethasone 12 mg orally 8 mg orally 8 mg orally 8 mg orally 5-HT 3 antagonists Standard dose of 5-HT 3 antagonists. See the product information for the selected 5-HT 3 antagonist for appropriate dosing information none none none Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. The dose of dexamethasone accounts for active substance interactions. Moderately Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 EMEND 125 mg orally 80 mg orally 80 mg orally Dexamethasone 12 mg orally none none 5-HT 3 antagonists Standard dose of 5-HT 3 antagonists. See the product information for the selected 5-HT 3 antagonist for appropriate dosing information none none Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions. Paediatric population Adolescents (aged 12 through 17 years) EMEND is given for 3 days as part of a regimen that includes a 5-HT 3 antagonist. The recommended dose of capsules of EMEND is 125 mg orally on Day 1 and 80 mg orally on Days 2 and 3. EMEND is administered orally 1 hour prior to chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3, EMEND should be administered in the morning. See the Summary of Product Characteristics (SmPC) for the selected 5-HT 3 antagonist for appropriate dosing information. If a corticosteroid, such as dexamethasone, is co-administered with EMEND, the dose of the corticosteroid should be administered at 50 % of the usual dose (see sections 4.5 and 5.1). The safety and efficacy of the 80 mg and 125 mg capsules have not been demonstrated in children less than 12 years of age. No data are available. Refer to the powder for oral suspension SmPC for appropriate dosing in infants, toddlers and children aged 6 months to less than 12 years. General Efficacy data in combination with other corticosteroids and 5-HT 3 antagonists are limited. For additional information on the co-administration with corticosteroids, see section 4.5. Please refer to the SmPC of co-administered 5-HT 3 antagonist medicinal products. Special populations Elderly ( 65 years) No dose adjustment is necessary for the elderly (see section 5.2). Gender No dose adjustment is necessary based on gender (see section 5.2). 28

29 Renal impairment No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2). Hepatic impairment No 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. Aprepitant should be used with caution in these patients (see sections 4.4 and 5.2). Method of administration The hard capsule should be swallowed whole. EMEND may be taken with or without food. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5). 4.4 Special warnings and precautions for use Patients with moderate to severe hepatic impairment There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. EMEND should be used with caution in these patients (see section 5.2). CYP3A4 interactions EMEND should be used with caution in patients receiving concomitant orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity. Co-administration with warfarin (a CYP2C9 substrate) In patients on chronic warfarin therapy, the International Normalised Ratio (INR) should be monitored closely during treatment with EMEND and for 14 days following each 3-day course of EMEND (see section 4.5). Co-administration with hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5). Excipients EMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Aprepitant (125 mg/80 mg) is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with EMEND, CYP3A4 is inhibited. After the end of treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin. 29

30 Effect aprepitant on the pharmacokinetics of other active substances CYP3A4 inhibition As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 3-fold during the 3-day treatment with EMEND; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of EMEND and orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4). Corticosteroids Dexamethasone: The usual oral dexamethasone dose should be reduced by approximately 50 % when co-administered with EMEND 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy induced nausea and vomiting clinical trials was chosen to account for active substance interactions (see section 4.2). EMEND, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5. Methylprednisolone: The usual intravenously administered methylprednisolone dose should be reduced approximately 25 %, and the usual oral methylprednisolone dose should be reduced approximately 50 % when co-administered with EMEND 125 mg/80 mg regimen. EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on 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 the EMEND dose, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone. Chemotherapeutic medicinal products 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 medicinal products metabolised primarily or partly by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration. Immunosuppressants During the 3-day CINV regimen, a transient moderate increase 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 the 3-day regimen and the time-dependent limited changes in exposure, dose reduction of the immunosuppressant is not recommended during the 3 days of co-administration with EMEND. 30

31 Midazolam The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products 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 2 mg 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 2 mg 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 2 mg 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. Induction As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes within two weeks following initiation and treatment. This effect may become apparent only after the end of a 3-day 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. 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 (see section 4.4). 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 treatment 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

32 Hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND. In a clinical 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). Effect of other medicinal products on the pharmacokinetics of aprepitant Concomitant administration of EMEND 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 several-fold in increased plasma concentrations of aprepitant (see section 4.4). 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 that may result in decreased efficacy of EMEND. Concomitant administration of EMEND with herbal preparations 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 %. Paediatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Contraception in males and females The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5). Pregnancy For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose could not be attained in animal studies. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on 32

33 reproduction of alterations in neurokinin regulation are unknown. EMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND. Fertility The potential for effects of aprepitant on fertility has not been fully characterised because exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3). 4.7 Effects on ability to drive and use machines EMEND may have minor influence on the ability to drive, cycle and use machines. Dizziness and fatigue may occur following administration of EMEND (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials. The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving Moderately Emetogenic Chemotherapy (MEC) was fatigue (1.4 % versus 0.9 %). The most common adverse reactions reported at a greater incidence in paediatric patients treated with the aprepitant regimen than with the control regimen while receiving emetogenic cancer chemotherapy were hiccups (3.3 % versus 0.0 %) and flushing (1.1 % versus 0.0 %). Tabulated list of adverse reactions The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy in adults or paediatric patients or in postmarketing use. The frequency categories given in the table are based on the studies in adults; the observed frequencies in the paediatric studies were similar or lower, unless shown in the table. Some less common ADRs in the adult population were not observed in the paediatric studies. Frequencies are defined as: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000) and very rare (< 1/10,000), not known (cannot be estimated from the available data). System organ class Adverse reaction Frequency Infection and infestations candidiasis, staphylococcal infection rare Blood and lymphatic system febrile neutropenia, anaemia uncommon disorders Immune system disorders hypersensitivity reactions including not known anaphylactic reactions Metabolism and nutrition decreased appetite common disorders polydipsia rare 33

34 System organ class Adverse reaction Frequency Psychiatric disorders anxiety uncommon disorientation, euphoric mood Nervous system disorders headache common rare dizziness, somnolence uncommon cognitive disorder, lethargy, dysgeusia Eye disorders conjunctivitis rare Ear and labyrinth disorders tinnitus rare Cardiac disorders palpitations uncommon bradycardia, cardiovascular disorder Vascular disorders hot flush/flushing uncommon Respiratory, thoracic and hiccups common mediastinal disorders oropharyngeal pain, sneezing, cough, rare postnasal drip, throat irritation Gastrointestinal disorders constipation, dyspepsia common rare rare Skin and subcutaneous tissue disorders eructation, nausea, vomiting, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitis rash, acne photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis pruritus, urticaria uncommon rare uncommon rare not known Musculoskeletal and connective muscular weakness, muscle spasms rare tissue disorders Renal and urinary disorders dysuria uncommon pollakiuria rare 34

35 System organ class Adverse reaction Frequency General disorders and fatigue common administration site conditions asthenia, malaise uncommon oedema, chest discomfort, gait disturbance rare Investigations ALT increased common AST increased, blood alkaline phosphatase increased uncommon red blood cells urine positive, blood sodium rare decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increased Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter. Description of selected adverse reactions The adverse reactions profiles in adults 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 adult 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 adult patients treated with aprepitant for postoperative nausea 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. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a medicinal product may not be effective. Aprepitant cannot be removed by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12 Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK 1 ) receptors. 35

36 3-day regimen of aprepitant in adults In 2 randomised, double-blind studies encompassing a total of 1,094 adult patients receiving chemotherapy that included cisplatin 70 mg/m 2, aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT 3 antagonist for appropriate dosing information. Efficacy was based on evaluation of the following composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined. A summary of the key study results from the combined analysis is shown in Table 1. Table 1 Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase Cycle 1 COMPOSITE MEASURES Aprepitant regimen (N= 521) % Standard therapy (N= 524) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) 0-24 hours hours (14.0, 25.8) (7.9, 17.6) (14.5, 26.1) INDIVIDUAL MEASURES No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours (16.4, 28.0) (8.0, 17.5) (17.0, 28.2) No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) hours (1.6, 12.8) (1.5, 12.6) * The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models. One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses. 36

37 The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1. Figure 1 Percent of adult patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time Cycle 1 100% 90% Aprepitant Regimen (N=520) Standard Therapy (N=523) Percent of Patients 80% 70% 60% 50% 40% Time (hours) Statistically significant differences in efficacy were also observed in each of the 2 individual studies. In the same 2 clinical studies, 851 adult patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles. In a randomised, double-blind study in a total of 866 adult patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m 2 ; or cyclophosphamide 500-1,500 mg/m 2 and doxorubicin (< 60 mg/m 2 ) or epirubicin (< 100 mg/m 2 ), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. 37

38 A summary of the key study results is shown in Table 2. Table 2 Percent of adult patients responding by treatment group and phase Cycle 1 Moderately Emetogenic Chemotherapy COMPOSITE MEASURES Aprepitant regimen (N= 433) % Standard therapy (N= 424) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) hours hours (1.6, 15.0) (0.7, 12.7) (-0.4, 13.0) INDIVIDUAL MEASURES No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) 0-24 hours hours (10.8, 23.2) (5.1, 15.3) (5.9, 17.5) 5.3 (-1.3, 11.9) 1.3 (-4.2, 6.8) 3.9 (-2.6, 10.3) * The confidence intervals were calculated with no adjustment for age category (< 55 years, 55 years) and investigator group, which were included in the primary analysis of odds ratios and logistic models. One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses. In the same clinical study, 744 adult patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles. In a second multicentre, randomised, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 adult patients (652 females, 196 males) receiving a chemotherapy regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenously (< 1,500 mg/m 2 ); or cytarabine intravenously (> 1 g/m 2 ). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumour types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynaecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on the evaluation of the following primary and key secondary endpoints: No vomiting in the overall period (0 to 120 hours post-chemotherapy), evaluation of safety and tolerability of the aprepitant regimen for chemotherapy induced nausea and vomiting (CINV), and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to 120 hours post-chemotherapy). Additionally, no significant nausea in the overall period (0 to 120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis. A summary of the key study results is shown in Table 3. 38

39 Table 3 Percent of adult patients responding by treatment group and phase for Study 2 Cycle 1 Moderately Emetogenic Chemotherapy Aprepitant regimen (N= 425) % Standard therapy (N= 406) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) hours hours No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) 0-24 hours hours (5.9, 18.9) (4.0, 13.8) (3.5, 16.3) (7.9, 20.3) (3.9, 12.7) (5.1, 17.1) (1.0, 13.4) (0.2, 9.0) (-0.7, 11.5) *The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models. The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men. Paediatric population In a randomised, double-blind, active comparator-controlled clinical study that included 302 children and adolescents (aged 6 months to 17 years) receiving moderately or highly emetogenic chemotherapy, the aprepitant regimen was compared to a control regimen for the prevention of CINV. The efficacy of the aprepitant regimen was evaluated in a single cycle (Cycle 1). Patients had the opportunity to receive open-label aprepitant in subsequent cycles (Optional Cycles 2-6); however efficacy was not assessed in these optional cycles. The aprepitant regimen for adolescents aged 12 through 17 years (n=47) consisted of EMEND capsules 125 mg orally on Day 1 and 80 mg/day on Days 2 and 3 in combination with ondansetron on Day 1. The aprepitant regimen for children aged 6 months to less than 12 years (n=105) consisted of EMEND powder for oral suspension 3.0 mg/kg (up to 125 mg) orally on Day 1 and 2.0 mg/kg (up to 80 mg) orally on Days 2 and 3 in combination with ondansetron on Day 1. The control regimen in adolescents aged 12 through 17 years (n=48) and children aged 6 months to less than 12 years (n=102) consisted of placebo for aprepitant on Days 1, 2 and 3 in combination with ondansetron on Day 1. EMEND or placebo and ondansetron were administered 1 hour and 30 minutes prior to initiation of chemotherapy, respectively. Intravenous dexamethasone was permitted as part of the antiemetic regimen for paediatric patients in both age groups, at the discretion of the physician. A dose reduction (50 %) of dexamethasone was required for paediatric patients receiving aprepitant. No dose reduction was required for paediatric patients receiving the control regimen. Of the paediatric patients, 29 % in the aprepitant regimen and 28 % in the control regimen used dexamethasone as part of the regimen in Cycle 1. The antiemetic activity of EMEND was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint was complete response in the delayed phase (25 to 120 hours following initiation of chemotherapy) in Cycle 1. A summary of the key study results are shown in Table 4. 39

40 Table 4 Number (%) of paediatric patients with complete response and no vomiting by treatment group and phase Cycle 1 (Intent to treat population) Aprepitant regimen n/m (%) Control regimen n/m (%) PRIMARY ENDPOINT Complete response * Delayed phase 77/152 (50.7) 39/150 (26.0) OTHER PRESPECIFIED ENDPOINTS Complete response * Acute phase 101/152 (66.4) 78/150 (52.0) Complete response * Overall phase 61/152 (40.1) 30/150 (20.0) No vomiting Overall phase 71/152 (46.7) 32/150 (21.3) * Complete response = No vomiting or retching or dry heaves and no use of rescue medication. p < 0.01 when compared to control regimen p < 0.05 when compared to control regimen No vomiting = No vomiting or retching or dry heaves n/m = Number of patients with desired response/number of patients included in time point. Acute phase: 0 to 24 hours following initiation of chemotherapy. Delayed phase: 25 to 120 hours following initiation of chemotherapy. Overall phase: 0 to 120 hours following initiation of chemotherapy. The estimated time to first vomiting after initiation of chemotherapy treatment was longer with the aprepitant regimen (estimated median time to first vomiting was 94.5 hours) compared with the control regimen group (estimated median time to first vomiting was 26.0 hours) as depicted in the Kaplan-Meier curves in Figure 2. Figure 2 Time to first vomiting episode from start of chemotherapy administration - paediatric patients in the overall phase-cycle 1 (Intent to treat population) An analysis of efficacy in subpopulations in Cycle 1 demonstrated that, regardless of age category, gender, use of dexamethasone for antiemetic prophylaxis, and emetogenicity of chemotherapy, the aprepitant regimen provided better control than the control regimen with respect to the complete response endpoints. 5.2 Pharmacokinetic properties Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose. 40

41 Absorption The mean absolute oral bioavailability of aprepitant is 67 % for the 80 mg capsule and 59 % for the 125 mg capsule. The mean peak plasma concentration (C max ) of aprepitant occurred at approximately 4 hours (t max ). Oral administration of the capsule with an approximately 800 Kcal standard breakfast resulted in an up to 40 % increase in AUC of aprepitant. This increase is not considered clinically relevant. The pharmacokinetics of aprepitant is non-linear across the clinical dose range. In healthy young adults, the increase in AUC 0- was 26 % greater than dose proportional between 80 mg and 125 mg single doses administered in the fed state. Following oral administration of a single 125 mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUC 0-24hr (mean±sd) was 19.6 ± 2.5 µg h/ml and 21.2 ± 6.3 µg h/ml on Days 1 and 3, respectively. C max was 1.6 ± 0.36 µg/ml and 1.4 ± 0.22 µg/ml on Days 1 and 3, respectively. Distribution Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean apparent volume of distribution at steady state (Vd ss ) is approximately 66 L in humans. Biotransformation Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100-mg dose of [ 14 C]-fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19. Elimination Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [ 14 C]-fosaprepitant, a prodrug for aprepitant, to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces. The plasma clearance of aprepitant is dose-dependent, decreasing with increased dose and ranged from approximately 60 to 72 ml/min in the therapeutic dose range. The terminal half-life ranged from approximately 9 to 13 hours. Pharmacokinetics in special populations Elderly: Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21 % higher on Day 1 and 36 % higher on Day 5 in elderly ( 65 years) relative to younger adults. The C max was 10 % higher on Day 1 and 24 % higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary in elderly patients. Gender: Following oral administration of a single 125 mg dose of aprepitant, the C max for aprepitant is 16 % higher in females as compared with males. The half-life of aprepitant is 25 % lower in females as compared with males and its t max occurs at approximately the same time. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary based on gender. Hepatic impairment: Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment. Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data. 41

42 There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C). Renal impairment: A single 240 mg dose of aprepitant was administered to patients with severe renal impairment (CrCl < 30 ml/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis. In patients with severe renal impairment, the AUC 0- of total aprepitant (unbound and protein bound) decreased by 21 % and C max decreased by 32 %, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC 0- of total aprepitant decreased by 42 % and C max decreased by 32 %. 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 with renal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2 % of the dose was recovered in the dialysate. No dose adjustment for EMEND is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis. Paediatric population: As part of a 3-day regimen, dosing of aprepitant capsules (125/80/80-mg) in adolescent patients (aged 12 through 17 years) achieved an AUC 0-24hr above 17 µg hr/ml on Day 1 with concentrations (C min ) at the end of Days 2 and 3 above 0.4 µg/ml in a majority of patients. The median peak plasma concentration (C max ) was approximately 1.3 µg/ml on Day 1, occurring at approximately 4 hours. As part of a 3-day regimen, dosing of aprepitant powder for oral suspension (3/2/2-mg/kg) in patients aged 6 months to less than12 years achieved an AUC 0-24hr above 17 µg hr/ml on Day 1 with concentrations (C min ) at the end of Days 2 and 3 above 0.1 µg/ml in a majority of patients. The median peak plasma concentration (C max ) was approximately 1.2 µg/ml on Day 1, occurring between 5 and 7 hours. A population pharmacokinetic analysis of aprepitant in paediatric patients (aged 6 months through 17 years) suggests that gender and race have no clinically meaningful effect on the pharmacokinetics of aprepitant. Relationship between concentration and effect Using a highly specific NK 1 -receptor tracer, positron emission tomography (PET) studies in healthy young men have shown that aprepitant penetrates into the brain and occupies NK 1 receptors in a doseand plasma-concentration-dependent manner. Aprepitant plasma concentrations achieved with the 3-day regimen of EMEND in adults are predicted to provide greater than 95 % occupancy of brain NK 1 receptors. 5.3 Preclinical safety data Pre-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. However, it should be noted that systemic exposure in rodents was similar or even lower than therapeutic exposure in humans at the 125 mg/80 mg dose. In particular, although no adverse effects were noted in reproduction studies at human exposure levels, the animal exposures are not sufficient to make an adequate risk assessment in man. In a juvenile toxicity study in rats treated from post natal day 10 to day 63 aprepitant led to an earlier vaginal opening in females from 250 mg/kg b.i.d. and to a delayed preputial separation in males, from 10 mg/kg b.i.d. There were no margins to clinically relevant exposure. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. In a juvenile toxicity study in dogs treated from post natal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. There were no margins to clinically relevant exposure of 42

43 aprepitant. For short term treatment according to recommended dose regimen these findings are considered unlikely to be clinically relevant. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule content Sucrose Microcrystalline cellulose (E 460) Hydroxypropylcellulose (E 463) Sodium laurilsulfate Capsule shell (125 mg) Gelatin Titanium dioxide (E 171) Red iron oxide (E 172) Yellow iron oxide (E 172) Capsule shell (80 mg) Gelatin Titanium dioxide (E 171) Printing ink Shellac Potassium hydroxide Black iron oxide (E 172) 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 4 years 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Different pack sizes including different strengths are available. Aluminium blister containing one 80 mg capsule. Aluminium blister containing two 80 mg capsules. 5 Aluminium blisters each containing one 80 mg capsule. Aluminium blister containing one 125 mg capsule. 5 Aluminium blisters each containing one 125 mg capsule. Aluminium blister containing one 125 mg capsule and two 80 mg capsules. Not all pack sizes may be marketed. 43

44 6.6 Special precautions for disposal No special requirements for disposal. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg BN Haarlem The Netherlands 8. MARKETING AUTHORISATION NUMBER EU/1/03/262/001 EU/1/03/262/002 EU/1/03/262/003 EU/1/03/262/004 EU/1/03/262/005 EU/1/03/262/ DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION Date of first authorisation: 11 November 2003 Date of latest renewal: 22 September DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency 44

45 1. NAME OF THE MEDICINAL PRODUCT EMEND 125 mg powder for oral suspension 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each sachet contains 125 mg of aprepitant. After reconstitution, 1 ml oral suspension contains 25 mg of aprepitant. Excipients with known effect Each sachet contains approximately 125 mg of sucrose and mg lactose (as anhydrous). For the full list of excipients, see section PHARMACEUTICAL FORM Powder for oral suspension. Pink to light pink powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in children, toddlers and infants from the age of 6 months to less than 12 years. EMEND powder for oral suspension is given as part of combination therapy (see section 4.2). 4.2 Posology and method of administration The oral suspension should be prepared and the dose measured by healthcare professionals only. Posology Paediatric population Infants, toddlers and children (aged 6 months to less than 12 years, and not less than 6 kg) EMEND is given for 3 days as part of a regimen that includes a 5-HT 3 antagonist. The recommended dose of EMEND powder for oral suspension is based on weight, as specified in the table below. EMEND is administered orally 1 hour prior to chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3, EMEND should be administered in the morning. See the Summary of Product Characteristics (SmPC) for the selected 5-HT 3 antagonist for appropriate dosing information. If a corticosteroid, such as dexamethasone, is co-administered with EMEND, the dose of the corticosteroid should be administered at 50 % of the usual dose (see sections 4.5 and 5.1). Recommended dose of EMEND oral suspension in paediatric patients aged 6 months to less than 12 years EMEND oral suspension Day 1 Day 2 Day 3 2 mg/kg orally Maximum dose 80 mg 3 mg/kg orally Maximum dose 125 mg 2 mg/kg orally Maximum dose 80 mg 25 mg/ml 45

46 The efficacy of the 125 mg powder for oral suspension has not been established in children 12 years of age and older. For adolescents aged years, EMEND is available as capsules containing 80 mg, or 125 mg of aprepitant. The safety and efficacy of EMEND powder for oral suspension in infants below 6 months of age or weighing less than 6 kg has not been established. No data are available. General Efficacy data in combination with other corticosteroids and 5-HT 3 antagonists are limited. For additional information on the co-administration with corticosteroids, see section 4.5. Please refer to the SmPC of co-administered 5-HT 3 antagonist medicinal products. Special populations Gender No dose adjustment is necessary based on gender (see section 5.2). Renal impairment No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2). Hepatic impairment No 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. Aprepitant should be used with caution in these patients (see sections 4.4 and 5.2). Method of administration The oral suspension may be taken with or without food. For details on preparation and administration of the suspension, see section Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5). 4.4 Special warnings and precautions for use Patients with moderate to severe hepatic impairment There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. EMEND should be used with caution in these patients (see section 5.2). CYP3A4 interactions EMEND should be used with caution in patients receiving concomitant orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity. Co-administration with warfarin (a CYP2C9 substrate) In patients on chronic warfarin therapy, the International Normalised Ratio (INR) should be monitored closely during treatment with EMEND and for 14 days following each 3-day course of EMEND (see section 4.5). Co-administration with hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5). 46

47 Excipients EMEND powder for oral suspension contains sucrose and lactose. Patients with rare hereditary problems of fructose or galactose intolerance, glucose-galactose malabsorption, Lapp lactase deficiency, or sucrase-isomaltase insufficiency should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Aprepitant (125 mg/80 mg) is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with EMEND, CYP3A4 is inhibited. After the end of treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin. Effect of aprepitant on the pharmacokinetics of other active substances CYP3A4 inhibition As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 3-fold during the 3-day treatment with EMEND; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of EMEND and orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4). Corticosteroids Dexamethasone: The usual oral dexamethasone dose should be reduced by approximately 50 % when co-administered with EMEND 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy induced nausea and vomiting clinical trials was chosen to account for active substance interactions (see section 4.2). EMEND, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5. Methylprednisolone: The usual intravenously administered methylprednisolone dose should be reduced approximately 25 %, and the usual oral methylprednisolone dose should be reduced approximately 50 % when co-administered with EMEND 125 mg/80 mg regimen. EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on 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 the EMEND dose, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone. Chemotherapeutic medicinal products 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 medicinal products metabolised primarily or partly by CYP3A4 (e.g., 47

48 etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration. Immunosuppressants During the 3-day CINV regimen, a transient moderate increase 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 the 3-day regimen and the time-dependent limited changes in exposure, dose reduction of the immunosuppressant is not recommended during the 3 days of co-administration with EMEND. Midazolam The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products 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 2 mg 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 2 mg 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 2 mg 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. Induction As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes within two weeks following initiation and treatment. This effect may become apparent only after the end of a 3-day 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. 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 (see section 4.4). 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) 48

49 trough concentration accompanied by a 14 % decrease in INR 5 days after completion of treatment 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. Hormonal contraceptives The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND. In a clinical 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). Effect of other medicinal products on the pharmacokinetics of aprepitant Concomitant administration of EMEND 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 several-fold in increased plasma concentrations of aprepitant (see section 4.4). 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 that may result in decreased efficacy of EMEND. Concomitant administration of EMEND with herbal preparations 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 %. Paediatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Contraception in males and females The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during 49

50 treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5). Pregnancy For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose could not be attained in animal studies. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokinin regulation are unknown. EMEND should not be used during pregnancy unless clearly necessary. Breast-feeding Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND. Fertility The potential for effects of aprepitant on fertility has not been fully characterised because exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3). 4.7 Effects on ability to drive and use machines EMEND may have minor influence on the ability to ride a bicycle and use machines. Dizziness and fatigue may occur following administration of EMEND (see section 4.8). 4.8 Undesirable effects Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials. The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in adults receiving Moderately Emetogenic Chemotherapy (MEC) was fatigue (1.4 % versus 0.9 %). The most common adverse reactions reported at a greater incidence in paediatric patients treated with the aprepitant regimen than with the control regimen while receiving emetogenic cancer chemotherapy were hiccups (3.3 % versus 0.0 %) and flushing (1.1 % versus 0.0 %). Tabulated list of adverse reactions The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy or in postmarketing use. The frequency categories given in the table are based on the studies in adults; the observed frequencies in the paediatric studies were similar or lower, unless shown in the table. Some less common ADRs in the adult population were not observed in the paediatric studies. Frequencies are defined as: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000) and very rare (< 1/10,000), not known (cannot be estimated from the available data). 50

51 System organ class Adverse reaction Frequency Infection and infestations candidiasis, staphylococcal infection rare Blood and lymphatic system febrile neutropenia, anaemia uncommon disorders Immune system disorders hypersensitivity reactions including not known anaphylactic reactions Metabolism and nutrition decreased appetite common disorders polydipsia rare Psychiatric disorders anxiety uncommon disorientation, euphoric mood Nervous system disorders headache common rare dizziness, somnolence uncommon cognitive disorder, lethargy, dysgeusia Eye disorders conjunctivitis rare Ear and labyrinth disorders tinnitus rare Cardiac disorders palpitations uncommon bradycardia, cardiovascular disorder Vascular disorders hot flush/flushing uncommon Respiratory, thoracic and hiccups common mediastinal disorders oropharyngeal pain, sneezing, cough, rare postnasal drip, throat irritation Gastrointestinal disorders constipation, dyspepsia common rare rare Skin and subcutaneous tissue disorders eructation, nausea, vomiting, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitis rash, acne photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis pruritus, urticaria uncommon rare uncommon rare not known Musculoskeletal and connective muscular weakness, muscle spasms rare tissue disorders Renal and urinary disorders dysuria uncommon pollakiuria rare 51

52 System organ class Adverse reaction Frequency General disorders and fatigue common administration site conditions asthenia, malaise uncommon oedema, chest discomfort, gait disturbance rare Investigations ALT increased common AST increased, blood alkaline phosphatase increased uncommon red blood cells urine positive, blood sodium rare decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increased Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter. Description of selected adverse reactions The adverse reactions profiles in adults 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 adult patients treated with aprepitant for postoperative nausea 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. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a medicinal product may not be effective. Aprepitant cannot be removed by haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12 Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK 1 ) receptors. 52

53 3-day regimen of aprepitant in adults In 2 randomised, double-blind studies encompassing a total of 1,094 adult patients receiving chemotherapy that included cisplatin 70 mg/m 2, aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT 3 antagonist for appropriate dosing information. Efficacy was based on evaluation of the following composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined. A summary of the key study results from the combined analysis is shown in Table 1. Table 1 Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase Cycle 1 COMPOSITE MEASURES Aprepitant regimen (N= 521) % Standard therapy (N= 524) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) hours hours (14.0, 25.8) (7.9, 17.6) (14.5, 26.1) INDIVIDUAL MEASURES No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours (16.4, 28.0) (8.0, 17.5) (17.0, 28.2) No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) hours (1.6, 12.8) (1.5, 12.6) * The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models. One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses. 53

54 The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1. Figure 1 Percent of adult patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time Cycle 1 100% 90% Aprepitant Regimen (N=520) Standard Therapy (N=523) Percent of Patients 80% 70% 60% 50% 40% Time (hours) Statistically significant differences in efficacy were also observed in each of the 2 individual studies. In the same 2 clinical studies, 851 adult patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles. In a randomised, double-blind study in a total of 866 adult patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m 2 ; or cyclophosphamide 500-1,500 mg/m 2 and doxorubicin (< 60 mg/m 2 ) or epirubicin (< 100 mg/m 2 ), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. 54

55 A summary of the key study results is shown in Table 2. Table 2 Percent of adult patients responding by treatment group and phase Cycle 1 Moderately Emetogenic Chemotherapy COMPOSITE MEASURES Aprepitant regimen (N= 433) % Standard therapy (N= 424) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) hours hours (1.6, 15.0) (0.7, 12.7) (-0.4, 13.0) INDIVIDUAL MEASURES No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) 0-24 hours hours (10.8, 23.2) (5.1, 15.3) (5.9, 17.5) (-1.3, 11.9) (-4.2, 6.8) (-2.6, 10.3) * The confidence intervals were calculated with no adjustment for age category (< 55 years, 55 years) and investigator group, which were included in the primary analysis of odds ratios and logistic models. One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses. In the same clinical study, 744 adult patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles. In a second multicentre, randomised, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 adult patients (652 females, 196 males) receiving a chemotherapy regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenously (< 1,500 mg/m 2 ); or cytarabine intravenously (> 1 g/m 2 ). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumour types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynaecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on the evaluation of the following primary and key secondary endpoints: No vomiting in the overall period (0 to 120 hours post-chemotherapy), evaluation of safety and tolerability of the aprepitant regimen for chemotherapy induced nausea and vomiting (CINV), and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to 120 hours post-chemotherapy). Additionally, no significant nausea in the overall period (0 to 120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis. A summary of the key study results is shown in Table 3. 55

56 Table 3 Percent of adult patients responding by treatment group and phase for Study 2 Cycle 1 Moderately Emetogenic Chemotherapy Aprepitant regimen (N= 425) % Standard therapy (N= 406) % Differences* % (95 % CI) Complete response (no emesis and no rescue therapy) Overall (0-120 hours) hours hours No emesis (no emetic episodes regardless of use of rescue therapy) Overall (0-120 hours) 0-24 hours hours No significant nausea (maximum VAS < 25 mm on a scale of mm) Overall (0-120 hours) 0-24 hours hours (5.9, 18.9) (4.0, 13.8) (3.5, 16.3) (7.9, 20.3) (3.9, 12.7) (5.1, 17.1) (1.0, 13.4) (0.2, 9.0) (-0.7, 11.5) *The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models. The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men. Paediatric population In a randomised, double-blind, active comparator-controlled clinical study that included 302 children and adolescents (aged 6 months to 17 years) receiving moderately or highly emetogenic chemotherapy, the aprepitant regimen was compared to a control regimen for the prevention of CINV. The efficacy of the aprepitant regimen was evaluated in a single cycle (Cycle 1). Patients had the opportunity to receive open-label aprepitant in subsequent cycles (Optional Cycles 2-6); however efficacy was not assessed in these optional cycles. The aprepitant regimen for adolescents aged 12 through 17 years (n=47) consisted of EMEND capsules 125 mg orally on Day 1 and 80 mg/day on Days 2 and 3 in combination with ondansetron on Day 1. The aprepitant regimen for children aged 6 months to less than 12 years (n=105) consisted of EMEND powder for oral suspension 3.0 mg/kg (up to 125 mg) orally on Day 1 and 2.0 mg/kg (up to 80 mg) orally on Days 2 and 3 in combination with ondansetron on Day 1. The control regimen in adolescents aged 12 through 17 years (n=48) and children aged 6 months to less than 12 years (n=102) consisted of placebo for aprepitant on Days 1, 2 and 3 in combination with ondansetron on Day 1. EMEND or placebo and ondansetron were administered 1 hour and 30 minutes prior to initiation of chemotherapy, respectively. Intravenous dexamethasone was permitted as part of the antiemetic regimen for paediatric patients in both age groups, at the discretion of the physician. A dose reduction (50 %) of dexamethasone was required for paediatric patients receiving aprepitant. No dose reduction was required for paediatric patients receiving the control regimen. Of the paediatric patients, 29 % in the aprepitant regimen and 28 % in the control regimen used dexamethasone as part of the regimen in Cycle 1. The antiemetic activity of EMEND was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint was complete response in the delayed phase (25 to 120 hours following initiation of chemotherapy) in Cycle 1. A summary of the key study results are shown in Table 4. 56

57 Table 4 Number (%) of paediatric patients with complete response and no vomiting by treatment group and phase Cycle 1 (Intent to treat population) Aprepitant regimen n/m (%) Control regimen n/m (%) PRIMARY ENDPOINT Complete response * Delayed phase 77/152 (50.7) 39/150 (26.0) OTHER PRESPECIFIED ENDPOINTS Complete response * Acute phase 101/152 (66.4) 78/150 (52.0) Complete response * Overall phase 61/152 (40.1) 30/150 (20.0) No vomiting Overall phase 71/152 (46.7) 32/150 (21.3) * Complete response = No vomiting or retching or dry heaves and no use of rescue medication. p < 0.01 when compared to control regimen p < 0.05 when compared to control regimen No vomiting = No vomiting or retching or dry heaves n/m = Number of patients with desired response/number of patients included in time point. Acute phase: 0 to 24 hours following initiation of chemotherapy. Delayed phase: 25 to 120 hours following initiation of chemotherapy. Overall phase: 0 to 120 hours following initiation of chemotherapy. The estimated time to first vomiting after initiation of chemotherapy treatment was longer with the aprepitant regimen (estimated median time to first vomiting was 94.5 hours) compared with the control regimen group (estimated median time to first vomiting was 26.0 hours) as depicted in the Kaplan-Meier curves in Figure 2. Figure 2 Time to first vomiting episode from start of chemotherapy administration - paediatric patients in the overall phase-cycle 1 (Intent to treat population) An analysis of efficacy in subpopulations in Cycle 1 demonstrated that, regardless of age category, gender, use of dexamethasone for antiemetic prophylaxis, and emetogenicity of chemotherapy, the aprepitant regimen provided better control than the control regimen with respect to the complete response endpoints. 5.2 Pharmacokinetic properties Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose. 57