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APREPITANT ETHYPHARM 125 MG HARD CAPSULES - summary of medicine characteristics

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Summary of medicine characteristics - APREPITANT ETHYPHARM 125 MG HARD CAPSULES

SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Aprepitant Ethypharm 125 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 125 mg capsule contains 125 mg of aprepitant.

Excipient with known effect

Each capsule contains 125 mg of sucrose (in the 125 mg capsule).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule.

The 125 mg capsule is size 1 capsule and has an opaque pink cap and an opaque white body printed with “125 mg” in black ink.

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.

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

4.2 Posology and method of administration

Posology

Adults

Aprepitant Ethypharm is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 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.

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

aprepitant

125 mg orally

80 mg orally

80 mg orally

none

Dexamethason

12 mg orally

8 mg orally

8 mg orally

8 mg orally

5-HT3 antagonists

Standard dose of 5-HT3 antagonists.

See the product information for the selected 5-HT3 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

aprepitant

125 mg orally

80 mg orally

80 mg orally

Dexamethasone

12 mg orally

none

none

5-HT3 antagonists

Standard dose of 5-HT3 antagonists. See the product information for the selected 5-HT3 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)

Aprepitant Ethypharm is given for 3 days as part of a regimen that includes a 5-HT3 antagonist. The recommended dose of capsules of Aprepitant Ethypharm is 125 mg orally on Day 1 and 80 mg orally on Days 2 and 3. Aprepitant Ethypharm is administered orally 1 hour prior to chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3, Aprepitant Ethypharm should be administered in the morning. See the Summary of Product Characteristics (SmPC) for the selected 5-HT3 antagonist for appropriate dosing information. If a corticosteroid, such as dexamethasone, is co-administered with Aprepitant Ethypharm, 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.

General

Efficacy data in 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 SmPC of co-administered 5-HT3 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).

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.

Aprepitant Ethypharm 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. Aprepitant Ethypharm should be used with caution in these patients (see section 5.2).

CYP3A4 interactions

Aprepitant Ethypharm 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 Aprepitant Ethypharm and for 14 days following each 3-day course of Aprepitant Ethypharm (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 Aprepitant Ethypharm. Alternative non-hormonal back-up methods of contraception should be used during treatment with Aprepitant Ethypharm and for 2 months following the last dose of Aprepitant Ethypharm (see section 4.5).

Excipients

Aprepitant Ethypharm capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucroseisomaltase 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 aprepitant, CYP3A4 is inhibited. After the end of treatment, aprepitant 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 Aprepitant Ethypharm; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. Aprepitant Ethypharm 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 Aprepitant Ethypharm 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 aprepitant 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). Aprepitant, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and aprepitant 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 aprepitant 125 mg/80 mg regimen. aprepitant, 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 aprepitant 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, aprepitant, 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 aprepitant on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of aprepitant 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). Postmarketing 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 aprepitant.

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 aprepitant (125 mg/80 mg).

Aprepitant 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 coadministered on Days 1 and 5 of a regimen of aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 to 5.

In another study with intravenous administration of midazolam, aprepitant 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 aprepitant and on Days 4, 8, and 15. Aprepitant 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, aprepitant 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. aprepitant, 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 aprepitant. Intravenous 2 mg midazolam was given 1 hour after oral administration of a single dose of aprepitant 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 aprepitant. For CYP2C9 and CYP3A4 substrates, the induction is transient with a maximum effect reached 3–5 days after end of the aprepitant 3-day treatment. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after end of aprepitant 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 aprepitant and for 2 weeks following each 3-day course of aprepitant for chemotherapy induced nausea and vomiting (see section 4.4). When a single 125 mg dose of aprepitant 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 aprepitant 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 aprepitant.

Tolbutamide

Aprepitant, 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 aprepitant 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 aprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with aprepitant and for 2 months following the last dose of aprepitant.

In a clinical study, single doses of an oral contraceptive containing ethinyl estradiol and norethindrone were administered on Days 1 through 21 with aprepitant, 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 medicinal products on the pharmacokinetics of aprepitant

Concomitant administration of aprepitant 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 aprepitant 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 aprepitant. Concomitant administration of aprepitant 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 aprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with aprepitant and for 2 months following the last dose of aprepitant (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. Aprepitant 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 Aprepitant Ethypharm.

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

Aprepitant Ethypharm may have minor influence on the ability to drive, cycle and use machines. Dizziness and fatigue may occur following administration of Aprepitant Ethypharm (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 disorders

febrile neutropenia, anaemia

uncommon

Immune system disorders

hypersensitivity reactions including anaphylactic reactions

not known

Metabolism and nutrition disorders

decreased appetite

common

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

tinnitus

rare

Cardiac disorders

palpitations

uncommon

bradycardia, cardiovascular disorder

rare

Vascular disorders

hot flush/flushing

uncommon

Respiratory, thoracic and mediastinal disorders

hiccups

common

oropharyngeal pain, sneezing, cough, postnasal drip, throat irritation

rare

Gastrointestinal disorders

constipation, dyspepsia

common

eructation, nausea*, vomiting*, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence

uncommon

duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitis

rare

Skin and subcutaneous tissue disorders

rash, acne

uncommon

photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis

rare

pruritus, urticaria

not known

Musculoskeletal and connective tissue

muscular weakness, muscle spasms

rare

Renal and urinary disorders

dysuria

uncommon

pollakiuria

rare

General disorders and administration site conditions

fatigue

common

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 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 postchemotherapy 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

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 (Cmax) of aprepitant occurred at approximately 4 hours (tmax). 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 AUC0-co 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 aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0–24hr (mean±SD) was

19.6 ± 2.5 pg»h/mL and 21.2 ± 6.3 pg»h/mL on Days 1 and 3, respectively. Cmax was 1.6 ± 0.36 pg/mL and 1.4 ± 0.22 pg/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 (Vdss) 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 [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 population

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 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 aprepitant 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 aprepitant 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 AUC0-co 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-co 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 aprepitant 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 AUC0–24hr above 17 gg^hr/mL on Day 1 with concentrations (Cmin) at the end of Days 2 and 3 above 0.4 jig/mL in a majority of patients. The median peak plasma concentration (Cmax) was approximately 1.3 jig/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 AUC0–24hr above 17 gg^hr/mL on Day 1 with concentrations (Cmin) at the end of Days 2 and 3 above 0.1 jig/mL in a majority of patients. The median peak plasma concentration (Cmax) was approximately 1.2 jig/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 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 aprepitant in adults are predicted to provide greater than 95% occupancy of brain NK1 receptors.

5.3 Preclinical safety data

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 aprepitant. For short term treatment according to recommended dose regimen these findings are considered unlikely to be clinically relevant.

6

6.1

PHARMACEUTICAL PARTICULARSPHARMACEUTICAL PARTICULARS

List of excipients

Capsule content

hydroxypropyl­cellulose

sodium laurilsulfate

sucrose

cellulose, microcrystalline.

Capsule shell (125 mg)

Titanium dioxide (E 171)

Red iron oxide (E 172)

Gelatin

Printink ink:

Shellac

Ammonia solution, concentrated

Propylene glycol

Potassium hydroxide

Black iron oxide (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Different pack sizes including different strengths are available.

PA/Aluminium/PVC/A­luminium blister containing one 125 mg capsule.

PA/Aluminium/PVC/A­luminium blister containing five 125 mg capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Ethypharm

194, Bureaux de la Colline, Bâtiment D

92213 Saint-Cloud cedex

France