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 6.1.

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.

CLINICAL PARTICULARS

Posology and method of administration

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 Older people (>= 65 years) No dose adjustment is necessary for the elderly (see section 5.2).

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

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).

The safety and efficacy of EMEND in children and adolescents below 18 years of age has not yet been established. No data are available.

The hard capsule should be swallowed whole. EMEND may be taken with or without food.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Special warnings and precautions for use

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).

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). 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 (see section 4.5). Concomitant administration of EMEND with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended. 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 increased plasma concentrations of aprepitant (see section 4.5).

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.

EMEND contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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.

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. 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.

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.

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.

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 15-30 %.

5-HT3 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).

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. Concomitant administration of EMEND with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended.

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.

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 %.

Fertility, pregnancy and lactation

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.

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 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).

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).

Undesirable effects

Summary of the safety profile

The safety profile of aprepitant was evaluated in approximately 6,500 individuals. Adverse reactions were reported in approximately 4 % of patients treated with 40 mg aprepitant compared with approximately 6 % of patients treated with 4 mg ondansetron intravenously. In controlled clinical studies in patients 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 patients 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 patients 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).

System organ class		Adverse reaction	Frequency
Immune system disorders	hypersensitivity reactions including anaphylactic reactions		not known
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 mediastinal disorders	dyspnoea, wheezing		uncommon
Gastrointestinal disorders	abdominal pain upper, bowel sounds abnormal, dry mouth, nausea, stomach discomfort, constipation , sub-ileus		uncommon
Skin and subcutaneous tissue disorders	pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis		not known
Investigations	ALT increased		common

*Reported in patients taking a higher dose of aprepitant.

Description of selected adverse reactions

Additional adverse reactions were observed in patients 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, asthaenia, 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.

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.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12 Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors. In 2 multicenter, randomized, double-blind, active comparator-controlled, parallel-group phase III clinical studies, aprepitant was compared with ondansetron for the prevention of PONV in 1,658 patients undergoing open abdominal surgery. The majority of patients were women (> 90 %), mainly undergoing gynaecological surgery. Patients were randomized 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 patients 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 patients responding by treatment group Combined results from 2 Phase III trials

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.

Studies evaluating the use of aprepitant in paediatric patients are on-going (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose.

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 (Cmax) of aprepitant occurred at approximately 4 hours (tmax). Following oral administration of a single 40 mg dose of EMEND in the fasted state, the AUC0-[?] (mean +- SD) was 8.0 +- 2.1 ug * h/ml and the Cmax was 0.7 +- 0.24 ug/ml. The median tmax was 3.0 hours. Concomitant intake of a 40 mg dose with a standard breakfast decreased the aprepitant Cmax by 18 % but did not affect AUC. This is not considered to be clinically important.

Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean apparent volume of distribution at steady state (Vdss) is approximately 66 l in humans.

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 [14C]-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.

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 [14C]-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.

Older people: 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 AUC0-24hr of aprepitant was 21 % higher on Day 1 and 36 % higher on Day 5 in elderly (>= 65 years) relative to younger adults. The Cmax 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 Cmax 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 tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dose adjustment for EMEND is necessary based on gender.

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).

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 AUC0-[?] of total aprepitant (unbound and protein bound) decreased by 21 % and Cmax decreased by 32 %, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC0-[?] of total aprepitant decreased by 42 % and Cmax 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.

Using a highly specific NK1-receptor tracer, positron emission tomography (PET) studies in healthy young men have shown that aprepitant penetrates into the brain and occupies NK1 receptors in a dose- and 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 NK1 receptors.

Pre-clinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. It should be noted that systemic exposure in 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 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.

PHARMACEUTICAL PARTICULARS

List of excipients

Microcrystalline cellulose (E 460) Hydroxypropyl cellulose (E 463) Sodium laurilsulfate

Incompatibilities

Shelf-life

Special precautions for storage

Nature and contents of container

Different pack sizes are available: Aluminium blister containing one 40 mg capsule.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd. Hertford Road, Hoddesdon Hertfordshire EN 11 9BU United Kingdom

MARKETING AUTHORISATION NUMBER

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 11 November 2003 Date of latest renewal: 11 November 2008

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

	Aprepitant 40 mg orally (N=541)		Ondansetron 4 mg intravenously (N=526)		Percentage point difference (%) SS and 95 % C.I. #
	n/m	(%)	n/m	(%)	%	95 % C.I.
Complete response (0-24 hours) +	298/541	(55.1)	258/526	(49.0)	5.9	(0.0, 11.8)

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION