EMEND 125 mg hard capsules

EMEND 80 mg hard capsules

Each 125 mg capsule contains 125 mg of aprepitant. Each 80 mg capsule contains 80 mg of aprepitant.

Excipient: 125 mg sucrose (in the 125 mg capsule).

Excipient: 80 mg sucrose (in the 80 mg capsule).

For a full list of excipients, see section 6.1.

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.

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.

EMEND 125/80mg is given as part of combination therapy (see section 4.2).

Posology

EMEND is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT₃ antagonist. The recommended posology of EMEND is 125 mg orally (PO) once daily one hour before start of chemotherapy on Day 1 and 80 mg PO once daily on Days 2 and 3. Fosaprepitant 115mg, a lyophilized prodrug of aprepitant may be substituted for oral EMEND (125mg), 30 minutes prior to chemotherapy, on Day 1 only of the chemotherapy –induced nausea and vomiting (CINV) regimen as an intravenous infusion administered over 15 minutes. Please refer to the Summary of Product Characteristics for fosaprepitant.

In clinical studies with EMEND, the following regimens were used for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy:

Highly Emetogenic Chemotherapy Regimen

EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. The dose of dexamethasone was chosen to account for active substance interactions.

Ondansetron was administered intravenously 30 minutes prior to chemotherapy treatment on Day 1.

Moderately Emetogenic Chemotherapy Regimen

EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone was chosen to account for active substance interactions.

One 8 mg capsule of ondansetron was administered 30 to 60 minutes prior to chemotherapy treatment and one 8 mg capsule was administered 8 hours after first dose on Day 1.

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

Please refer to the Summary of Product Characterisitics of coadministered antiemetics.

Elderly (65 years)

No dosage adjustment is necessary for the elderly. (see Section 5.2)

Gender

No dosage adjustment is necessary based on gender (see Section 5.2).

Renal impairment

No dosage 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 dosage adjustment is necessary for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. (see sections 4.4 and 5.2).

Children and adolescents

EMEND is not recommended for use in children below 18 years due to insufficient data on safety and efficacy (see section 5.2).

Method of administration

The hard capsule should be swallowed whole.

EMEND may be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients.

Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).

There are limited data in patients with moderate hepatic insufficiency and no data in patients with severe hepatic impairment. EMEND should be used with caution in these patients (see section 5.2).

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 ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, 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 of EMEND with ergot alkaloid derivatives, which are CYP3A4 substrates, may result in elevated plasma concentrations of these active substances.. Therefore, caution is advised due to the potential risk of ergot-related toxicity.

Co-administration of EMEND with warfarin results in decreased prothrombin time, reported as International Normalised Ratio (INR). In patients on chronic warfarin therapy, the INR should be monitored closely during treatment with EMEND and for 2 weeks following each 3-day course of EMEND for chemotherapy induced nausea and vomiting (see section 4.5).

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (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 prepartions 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).

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

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 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, terfanadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevatated 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 metabolized primarily through CYP3A4 and with a narrow therapeutic range, such as ciclosporin, tacrolimus, sirolimus, everolimus, aflentanil, 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 coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5.

Methylprednisolone: The usual intravenously administered methylprednisolone dose should be reduced approximately 25 %, and the usual oral methylprednisolone dose should be reduced approximately 50 % when coadministered with EMEND 125 mg/80 mg regimen. EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was co-administered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.

During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease at later time points within 2 weeks following initiation of dosing with EMEND, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.

Chemotherapeutic agents : In pharmacokinetic studies, EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel administered intravenously on Day 1 or vinorelbine administered intravenously on Day 1 or Day 8. Because the effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of EMEND on the pharmacokinetics of intravenously administered CYP3A4 substrates, an interaction with orally administered chemotherapeutic agents metabolised primarily or in part by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving such agents orally (see section 4.4).

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 immunosuppressants 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 coadministering these agents with EMEND (125 mg/80 mg).

EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of 2mg midazolam was co-administered on Days 1 and 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 to 5.

In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and 2mg midazolam was given intravenously prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam 25 % on Day 4 and decreased the AUC of midazolam 19 % on Day 8 and 4 % on Day 15. These effects were not considered clinically important.

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 only after the end of treatment with EMEND. For CYP2C9 and CYP3A4 substrates, the induction is transient with a maximum effect reached 35 days after end of the EMEND 3day 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.

In a third study with intravenous and oral administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, together with ondansetron 32 mg Day 1, dexamethasone 12 mg Day 1 and 8 mg Days 2-4. This combination (i.e. EMEND, ondansetron and dexamethasone) decreased the AUC of oral midazolam 16 % on Day 6, 9 % on Day 8, 7 % on Day 15 and 17 % on Day 22. These effects were not considered clinically important.

An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous 2mg midazolam was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.

Warfarin: In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with EMEND and for 2 weeks following each 3-day course of EMEND for chemotherapy induced nausea and vomiting (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 dosing with EMEND.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23 % on Day 4, 28 % on Day 8, and 15 % on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.

Hormonal contraceptives :The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND.

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 -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).

Effect of other agents 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 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 prepartions containing St. John's Wort (Hypericum perforatum) is not recommended.

Ketoconazole: When a single 125-mg dose of aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold.

Rifampicin: When a single 375-mg dose of aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased 91 % and the mean terminal half-life decreased 68 %.

The potential for reproductive toxicity of aprepitant has not been fully characterized, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose were not 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.

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.

No studies on the effects of EMEND on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness and fatigue have been reported after taking EMEND (see section 4.8).

The safety profile of aprepitant was evaluated in approximately 4,900 individuals.

Adverse reactions considered as drug-related by the investigator were reported in approximately 17 % of patients treated with the aprepitant regimen compared with approximately 13 % of patients treated with standard therapy in patients receiving highly emetogenic chemotherapy. Aprepitant was discontinued due to adverse reactions in 0.6 % of patients treated with the aprepitant regimen compared with 0.4 % of patients treated with standard therapy. In a clinical study of patients receiving moderately emetogenic chemotherapy, clinical adverse reactions were reported in approximately 21% of patients treated with the aprepitant regimen compared with approximately 20% of patients treated with standard therapy. Aprepitant was discontinued due to adverse reactions in 1.1% of patients treated with the aprepitant regimen compared with 0.5% of patients treated with standard therapy.

The most common adverse reactions reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving highly emetogenic chemotherapy were: hiccups (4.6 % versus 2.9%), asthenia/fatigue (2.9 % versus 1.6%), alanine aminotransferase (ALT) increased (2.8 % versus 1.5%), constipation (2.2 % versus 2.0%), headache (2.2 % versus 1.8%), and anorexia (2.0 % versus 0.5%). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving moderately emetogenic chemotherapy was fatigue (2.5 % versus 1.6%).

The following adverse reactions were observed in patients treated with the aprepitant regimen and at a greater incidence than with standard therapy:

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

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

The adverse reactions profiles in the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.

Additional adverse reactions were observed in patients treated with aprepitant (40 mg) for postoperative nausea and vomiting and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, visual acuity reduced, wheezing.

In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.

One case of Stevens-Johnson syndrome was reported as a serious adverse event in a patient receiving aprepitant with cancer chemotherapy.

One case of angioedema and urticaria was reported as a serious adverse event in a patient receiving aprepitant in a non-CINV/non-PONV study.

Post-marketing experience

During post-marketing experience the following side effects have been reported (frequency not known):

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria

Immune system disorders: hypersensitivity reactions including anaphylactic reactions

No specific information is available on the treatment of overdose with EMEND.

Drowsiness and headache were reported in one patient who ingested 1,440 mg of aprepitant.

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, drug-induced emesis may not be effective.

Aprepitant cannot be removed by haemodialysis.

Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04A D12

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

In 2 randomised, double-blind studies encompassing a total of 1,094 patients receiving chemotherapy that included cisplatin 70 mg/m², 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).

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 Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group and Phase — Cycle 1

• 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.

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

Figure 1

Percent of Patients Receiving Highly Emetogenic Chemotherapy

Who Remain Emesis Free Over Time – Cycle 1

Statistically significant differences in efficacy were also observed in each of the 2 individual studies.

In the same 2 clinical studies, 851 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 patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1500 mg/m²; or cyclophosphamide 500-1500 mg/m² and doxorubicin ( 60 mg/m²) or epirubicin ( 100 mg/m²), 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.

A summary of the key study results is shown in Table 2.

Table 2

Percent of Patients Responding by Treatment Group and Phase —Cycle 1

Moderately Emetogenic Chemotherapy

• 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 Regiment only had data in the acute phase and was excluded from the overall and delayed phase analyses.

The estimated time to first emesis in the study is depicted by the Kaplan-Meier plot in Figure 2.

Figure 2

Percent of Patients Receiving Moderately Emetogenic Chemotherapy

Who Remain Emesis Free Over Time – Cycle 1

In the same clinical study, 744 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.

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). 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 microgram x hr/ml and 21.2±6.3 microgram x hr/ml on Days 1 and 3, respectively. C_max was 1.6±0.36 microgram/ml and 1.4±0.22 microgram/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.

Metabolism

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.

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 [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 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 dosage 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 dosage adjustment for EMEND is necessary based on gender.

Hepatic insufficiency : 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 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 data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. 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.

Capsule content

Sucrose

Microcrystalline cellulose (E 460)

Hydroxypropyl cellulose (E 463)

Sodium laurilsulfate

Capsule shell (125 mg)

Gelatin

Sodium laurilsulfate and silica colloidal anhydrous may be used

Titanium dioxide (E 171)

Red iron oxide (E 172)

Yellow iron oxide (E 172)

Capsule shell (80 mg)

Gelatin

Sodium laurilsulfate and silica colloidal anhydrous may be used

Titanium dioxide (E 171)

Printing ink

Shellac

Potassium hydroxide

Black iron oxide (E 172)

Not applicable.

4 years

Store in the original package in order to protect from moisture.

Different pack sizes including different strengths are available.

Alminium blister containing one 125 mg capsule.

Aluminium blister containing one 80 mg capsule.

Aluminium blister containing two 80 mg capsules.

5 Aluminium blisters each containing one 80 mg capsule.

5 Aluminium blisters each containing one 125mg capsule.

Aluminium blister containing one 125 mg capsule and two 80 mg capsules.

Not all pack sizes may be marketed.

No special requirements.

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN 11 9BU

United Kingdom

125 mg x1: EU/1/03/262/004

125 mg x 5: EU/1/03/262/005

80 mg x1: EU/1/03/262/001

80 mg x2: EU/1/03/262/002

80 mg x5: EU/1/03/262/003

80 mg x2 and 125 mg x1: EU/1/03/262/006

Date of first authorization: 11^th November 2003

Date of latest renewal: 22 September 2008

31 July 2009

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

SPC.EMD.09.UK.3116 (022+023)

® denotes registered trademark of Merck & Co. Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited, 2009. All rights reserved.