ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
EMEND 40 mg hard capsules
2.
Each capsule contains 40 mg of aprepitant.
Excipient: 40 mg sucrose.
For a full list of excipients, see section 6.1.
3.
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.
EMEND 40 mg is indicated for the prevention of postoperative nausea and vomiting (PONV) in
adults.
Posology
Clinical treatment guidelines should be considered as regards the need for prophylactic treatment
against postoperative nausea and vomiting (PONV).
The recommended oral dosage of EMEND is a single 40 mg dose within 3 hours prior to induction of
anesthesia.
Elderly
(≥
65 years)
No dose 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 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 (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.
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.
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).
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 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).
EMEND contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-
galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
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.
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
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. 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. Coadministration 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%.
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.
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 active substances on the pharmacokinetics of aprepitant
C
YP3A4 inhibitors
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).
C
YP3A4 inducers
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.
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
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 %.
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.
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 5,300 individuals.
Adverse reactions considered as drug-related by the investigator were reported in approximately 4 %
of patients treated with 40 mg aprepitant compared with approximately 6 % of patients treated with 4
mg ondansetron IV. In controlled clinical studies in patients receiving general anesthesia, 564 patients
were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron IV.
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 aprepitant
(1.1 %) than with ondansetron (1.0 %) was ALT increased.
The following adverse reactions were observed in patients treated with aprepitant and at a greater
incidence than with ondansetron:
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
Investigations
ALT increased
common
Cardiac disorders
bradycardia
uncommon
Nervous system disorders
dysarthria, hypoaesthesia, sensory disturbance
uncommon
Eye disorders
miosis, visual acuity reduced
uncommon
Respiratory, thoracic and
mediastinal disorders
dyspnoea, wheezing
uncommon
Gastrointestinal disorders
abdominal pain upper, bowel sounds
abnormal, dry mouth, nausea, stomach
discomfort
uncommon
Psychiatric disorders
insomnia
uncommon
In addition, two serious reactions were reported in clinical studies in postoperative nausea and
vomiting (PONV) in patients taking a higher dose of aprepitant: one case of constipation, and one case
of sub-ileus.
5
Additional adverse reactions were observed in patients treated with the aprepitant (125 mg/80 mg)
regimen for chemotherapy induced nausea and vomiting and at a greater incidence than with standard
therapy: abdominal distension, abdominal pain, acid reflux, acne, alkaline phosphatase increased,
anaemia, anorexia, anxiety, AST increased, asthaenia/fatigue, candidiasis, cardiovascular disorder,
chest discomfort, chills, cognitive disorder, conjunctivitis, constipation, cough, diarrhoea,
disorientation, dizziness, dream abnormality, dysgeusia, dyspepsia, dysuria, enterocolitis, epigastric
discomfort, eructation,
euphoria, faeces hard, febrile neutropenia, flatulence, flushing, gait
disturbance, gastroesophageal reflux disease, headache, hiccups, hot flush, hyperglycaemia,
hyperhidrosis, hyponatraemia, lethargy, malaise, microscopic haematuria, muscle cramp, muscular
weakness, myalgia, nausea*, neutropenic colitis, neutrophil count decreased, obstipation, oedema, oily
skin, perforating duodenal ulcer, palpitations, pharyngitis, photosensitivity, pollakiuria, polydipsia,
polyuria, postnasal drip, pruritus, rash, rash pruritic, skin lesion, sneezing, somnolence, staphylococcal
infection, stomatitis, thirst, throat irritation, tinnitus, vomiting*, weight decreased, weight gain.
*Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and
were reported as reactions only thereafter.
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.
5.
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.
In 2 multicenter, randomized, double-blind, active comparator-controlled, parallel-group phase III
clinical studies, aprepitant was compared with ondansetron for the prevention of postoperative nausea
and vomiting 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 (PO) with 50
ml of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before
induction of anesthesia. The antiemetic activity of aprepitant was evaluated during the 0 to 48 hour
period following the end of surgery.
6
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
Aprepitant
40 mg PO
(N=541)
Ondansetron
4 mg IV
(N=526)
Percentage Point
Difference (%)
§
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)
†
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.
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 microgram x h/ml and the C
max
was 0.7 ± 0.24 microgram/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.
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 [
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,
7
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 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 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 (PK/PD)
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 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 NK
1
receptors.
5.3 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
8
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.
6.
6.1 List of excipients
Capsule content
Sucrose
Microcrystalline cellulose (E 460)
Hydroxypropyl cellulose (E 463)
Sodium laurilsulfate
Capsule shell
Gelatin
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Sodium laurilsulfate and silica colloidal anhydrous may be used
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
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.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN 11 9BU
United Kingdom
9
8.
EU/1/03/262/007
EU/1/03/262/008
9.
Date of first authorisation: 11 November 2003
Date of latest renewal: 11 November 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/.
10
1.
EMEND 80 mg hard capsules
2.
Each capsule contains 80 mg of aprepitant.
Excipient: 80 mg sucrose.
For a full list of excipients, see section 6.1.
3.
Hard capsule
Capsules are opaque with a white body and cap with “461” and “80 mg” printed radially in black ink
on the body.
4.
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 80 mg 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-HT
3
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 115 mg, a
lyophilized prodrug of aprepitant, may be substituted for oral EMEND (125 mg), 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:
11
Highly Emetogenic Chemotherapy Regimen
Day 1 Day 2 Day 3 Day 4
EMEND 125 mg PO 80 mg PO 80 mg PO none
Dexamethasone 12 mg PO 8 mg PO 8 mg PO 8 mg PO
Ondansetron 32 mg IV none none none
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
Day 1 Day 2 Day 3
EMEND 125 mg PO 80 mg PO 80 mg PO
Dexamethasone 12 mg PO none none
Ondansetron 2 x 8 mg PO none none
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-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 co-administered antiemetics.
Elderly
(≥
65 years)
No dose 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 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 (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.
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).
12
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 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, 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 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).
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 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
13
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 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
co-administering 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 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.
14
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. This effect may become apparent only after
the end of treatment with EMEND. For CYP2C9 and CYP3A4 substrates, the induction is transient
with a maximum effect reached 3-5 days after end of the EMEND 3-day treatment. The effect is
maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after
end of EMEND treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant
given for 7 days. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advised
when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known to be
metabolised by CYP2C9 are administered during this time period.
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 intravenouslyon 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 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).
15
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 %.
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 5,300 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 (HEC). 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 combined analysis of 2 clinical
studies of patients receiving moderately emetogenic chemotherapy (MEC), clinical adverse reactions
were reported in approximately 14 % of patients treated with the aprepitant regimen compared with
approximately 15 % of patients treated with standard therapy. Aprepitant was discontinued due to
adverse reactions in 0.7 % of patients treated with the aprepitant regimen compared with 0.2 % 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 (1.4 % versus 0.9 %).
16
The following adverse reactions were observed in either HEC or MEC studies in patients treated with
the aprepitant regimen and at a greater incidence than with standard therapy:
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000
to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated
from the available data).
System Organ Class
Adverse reaction
Frequency
Investigations
ALT increased, AST increased
common
uncommon
alkaline phosphatase increased,
hyperglycaemia, microscopic haematuria,
hyponatraemia, weight decreased, neutrophil
count decreased
Cardiac disorders
bradycardia, palpitations, cardiovascular
disorder
uncommon
Blood and lymphatic system
disorders
febrile neutropenia, anaemia
uncommon
Nervous system disorders
headache, dizziness
common
uncommon
dream abnormality, cognitive disorder,
lethargy, somnolence
Eye disorders
conjunctivitis
uncommon
Ear and labyrinth disorders
tinnitus
uncommon
Respiratory, thoracic and
mediastinal disorders
hiccups
common
uncommon
pharyngitis, sneezing, cough, postnasal drip,
throat irritation
Gastrointestinal disorders
constipation, diarrhoea, dyspepsia, eructation
common
uncommon
perforating duodenal ulcer, nausea*,
vomiting*, acid reflux, dysgeusia, epigastric
discomfort, obstipation, gastroesophageal
reflux disease, abdominal pain, dry mouth,
enterocolitis, flatulence, stomatitis, abdominal
distension, faeces hard, neutropenic colitis
Renal and urinary disorders
polyuria, dysuria, pollakiuria
uncommon
Skin and subcutaneous tissue
disorders
rash, acne, photosensitivity, hyperhidrosis,
oily skin, pruritus, skin lesion, rash pruritic
uncommon
Musculoskeletal and connective
tissue disorders
muscle cramp, myalgia, muscular weakness
uncommon
Metabolism and nutrition
disorders
anorexia
common
uncommon
weight gain, polydipsia
Infection and infestations
candidiasis, staphylococcal infection
uncommon
Vascular disorders
flushing/hot flush
uncommon
General disorders and
administration site conditions
asthaenia/fatigue
common
uncommon
oedema, chest discomfort, malaise, thirst,
chills, gait disturbance
Psychiatric disorders disorientation, euphoria, anxiety uncommon
*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 of HEC and MEC studies for up to
6 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.
17
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 reactions were reported in clinical studies in postoperative nausea and
vomiting (PONV) 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04A D12
Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK
1
) receptors.
In 2 randomised, double-blind studies encompassing a total of 1,094 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).
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.
18
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
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
25-120 hours
67.7
86.0
71.5
47.8
73.2
51.2
19.9
12.7
20.3
(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
25-120 hours
71.9
86.8
76.2
49.7
74.0
53.5
22.2
12.7
22.6
(16.4, 28.0)
(8.0, 17.5)
(17.0, 28.2)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
(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.
72.1
74.0
64.9
66.9
7.2
7.1
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
100%
Aprepitant Regimen (N=520)
Standard Therapy (N=523)
90%
80%
70%
60%
50%
40%
0
0 2468024680
Time (hours)
Statistically significant differences in efficacy were also observed in each of the 2 individual studies.
19
Overall (0-120 hours)
25-120 hours
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/m
2
; or cyclophosphamide 500-
1500 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.
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
Aprepitant
Regimen
(N= 433)
†
%
Standard
Therapy
(N= 424)
%
Differences*
COMPOSITE MEASURES
% (95 % CI)
Complete Response (no emesis and no rescue therapy)
Overall (0-120 hours)
0-24 hours
25-120 hours
50.8
75.7
55.4
42.5
69.0
49.1
8.3
6.7
6.3
(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
25-120 hours
75.7
87.5
80.8
58.7
77.3
69.1
17.0
10.2
11.7
(10.8, 23.2)
(5.1, 15.3)
(5.9, 17.5)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
(-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.
60.9
79.5
65.3
55.7
78.3
61.5
5.3
1.3
3.9
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.
In a second multicenter, randomized, double-blind, parallel-group, clinical study, the aprepitant
regimen was compared with standard therapy in 848 patients (652 females, 196 males) receiving a
chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin,
ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1500 mg/m
2
); or
cytarabine IV (>1 g/m
2
). Patients receiving the aprepitant regimen were receiving chemotherapy for a
variety of tumor types including 52 % with breast cancer, 21 % with gastrointestinal cancers including
colorectal cancer, 13 % with lung cancer and 6 % with gynecological 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).
20
Overall (0-120 hours)
0-24 hours
25-120 hours
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 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.
Table 3
Percent of Patients Responding by TreatmentGroup 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
25-120 hours
68.7
89.2
70.8
56.3
80.3
60.9
12.4
8.9
9.9
(5.9, 18.9)
(4.0, 13.8)
(3.5, 16.3)
No Emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)
0-24 hours
25-120 hours
76.2
92.0
77.9
62.1
83.7
66.8
14.1
8.3
11.1
(7.9, 20.3)
(3.9, 12.7)
(5.1, 17.1)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
Overall (0-120 hours)
0-24 hours
25-120 hours
73.6
90.9
74.9
66.4
86.3
69.5
7.2
4.6
5.4
(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.
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
). 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.
21
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 h/ml and 21.2±6.3 microgram x
h/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 [
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 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 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
22
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 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 NK
1
receptors.
5.3 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. 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.
6.
6.1 List of excipients
Capsule content
Sucrose
Microcrystalline cellulose (E 460)
Hydroxypropyl cellulose (E 463)
Sodium laurilsulfate
Capsule shell
Gelatin
Sodium laurilsulfate and silica colloidal anhydrous may be used
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.
23
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.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN 11 9BU
United Kingdom
8.
EU/1/03/262/001
EU/1/03/262/002
EU/1/03/262/003
9.
Date of first authorisation: 11 November 2003
Date of latest renewal: 11 November 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/.
24
1.
EMEND 125 mg hard capsules
2.
Each capsule contains 125 mg of aprepitant.
Excipient: 125 mg sucrose.
For a full list of excipients, see section 6.1.
3.
Hard capsule
Capsules are opaque with a white body and pink cap with “462” and “125 mg” printed radially in
black ink on the body.
4.
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 125 mg 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-HT
3
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 115 mg, a
lyophilized prodrug of aprepitant, may be substituted for oral EMEND (125 mg), 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:
25
Highly Emetogenic Chemotherapy Regimen
Day 1 Day 2 Day 3 Day 4
EMEND 125 mg PO 80 mg PO 80 mg PO none
Dexamethasone 12 mg PO 8 mg PO 8 mg PO 8 mg PO
Ondansetron 32 mg IV none none none
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
Day 1 Day 2 Day 3
EMEND 125 mg PO 80 mg PO 80 mg PO
Dexamethasone 12 mg PO none none
Ondansetron 2 x 8 mg PO none none
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-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 antiemetic agents.
Elderly (≥65 years)
No dose 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 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 (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.
Method of administration
The hard capsule should be swallowed whole.
EMEND may be taken with or without food.
26
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 impairment 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 cyclosporine, 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 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).
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
27
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 foractive 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 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
co-administering 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 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
28
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. This effect may become apparent only after
the end of treatment with EMEND. For CYP2C9 and CYP3A4 substrates, the induction is transient
with a maximum effect reached 3-5 days after end of the EMEND 3-day treatment. The effect is
maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after
end of EMEND treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant
given for 7 days. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advised
when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known to be
metabolised by CYP2C9 are administered during this time period.
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 intravenouslyon 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).
29
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 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 %.
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 5,300 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 (HEC). 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 combined analysis of 2 clinical
studies of patients receiving moderately emetogenic chemotherapy (MEC), clinical adverse reactions
were reported in approximately 14 % of patients treated with the aprepitant regimen compared with
approximately 15 % of patients treated with standard therapy. Aprepitant was discontinued due to
adverse reactions in 0.7 % of patients treated with the aprepitant regimen compared with 0.2 % 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
30
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 (1.4 % versus 0.9 %).
The following adverse reactions were observed in either HEC or MEC studies in patients treated with
the aprepitant regimen and at a greater incidence than with standard therapy:
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000
to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated
from the available data).
System Organ Class
Adverse reaction
Frequency
Investigations
ALT increased, AST increased
common
uncommon
alkaline phosphatase increased,
hyperglycaemia, microscopic haematuria,
hyponatraemia, weight decreased, neutrophil
count decreased
Cardiac disorders
bradycardia, palpitations, cardiovascular
disorder
uncommon
Blood and lymphatic system
disorders
febrile neutropenia, anaemia
uncommon
Nervous system disorders
headache, dizziness
common
uncommon
dream abnormality, cognitive disorder,
lethargy, somnolence
Eye disorders
conjunctivitis
uncommon
Ear and labyrinth disorders
tinnitus
uncommon
Respiratory, thoracic and
mediastinal disorders
hiccups
common
uncommon
pharyngitis, sneezing, cough, postnasal drip,
throat irritation
Gastrointestinal disorders
constipation, diarrhoea, dyspepsia, eructation
common
uncommon
perforating duodenal ulcer, nausea*,
vomiting*, acid reflux, dysgeusia, epigastric
discomfort, obstipation, gastroesophageal
reflux disease, abdominal pain, dry mouth,
enterocolitis, flatulence, stomatitis, abdominal
distension, faeces hard, neutropenic colitis
Renal and urinary disorders
polyuria, dysuria, pollakiuria
uncommon
Skin and subcutaneous tissue
disorders
rash, acne, photosensitivity, hyperhidrosis,
oily skin, pruritus, skin lesion, rash pruritic
uncommon
Musculoskeletal and connective
tissue disorders
muscle cramp, myalgia, muscular weakness
uncommon
Metabolism and nutrition
disorders
anorexia
common
uncommon
weight gain, polydipsia
Infection and infestations
candidiasis, staphylococcal infection
uncommon
Vascular disorders
flushing/hot flush
uncommon
General disorders and
administration site conditions
asthaenia/fatigue
common
uncommon
oedema, chest discomfort, malaise, thirst,
chills, gait disturbance
Psychiatric disorders disorientation, euphoria, anxiety uncommon
*Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were
reported as adverse reactions only thereafter.
31
The adverse reactions profiles 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.
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 reactions were reported in clinical studies in postoperative nausea and
vomiting (PONV) 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04A D12
Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK
1
) receptors.
In 2 randomised, double-blind studies encompassing a total of 1,094 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).
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.
32
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
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
25-120 hours
67.7
86.0
71.5
47.8
73.2
51.2
19.9
12.7
20.3
(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
25-120 hours
71.9
86.8
76.2
49.7
74.0
53.5
22.2
12.7
22.6
(16.4, 28.0)
(8.0, 17.5)
(17.0, 28.2)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
(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.
72.1
74.0
64.9
66.9
7.2
7.1
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
100%
Aprepitant Regimen (N=520)
Standard Therapy (N=523)
90%
80%
70%
60%
50%
40%
0
0 2468024680
Time (hours)
Statistically significant differences in efficacy were also observed in each of the 2 individual studies.
33
Overall (0-120 hours)
25-120 hours
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/m
2
; or cyclophosphamide 500-
1500 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.
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
Aprepitant
Regimen
(N= 433)
†
%
Standard
Therapy
(N= 424)
%
Differences*
COMPOSITE MEASURES
% (95 % CI)
Complete Response (no emesis and no rescue therapy)
Overall (0-120 hours)
0-24 hours
25-120 hours
50.8
75.7
55.4
42.5
69.0
49.1
8.3
6.7
6.3
(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
25-120 hours
75.7
87.5
80.8
58.7
77.3
69.1
17.0
10.2
11.7
(10.8, 23.2)
(5.1, 15.3)
(5.9, 17.5)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
(-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.
60.9
79.5
65.3
55.7
78.3
61.5
5.3
1.3
3.9
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.
In a second multicenter, randomized, double-blind, parallel-group, clinical study, the aprepitant
regimen was compared with standard therapy in 848 patients (652 females, 196 males) receiving a
chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin,
ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1500 mg/m
2
); or
cytarabine IV (>1 g/m
2
). Patients receiving the aprepitant regimen were receiving chemotherapy for a
variety of tumor types including 52% with breast cancer, 21% with gastrointestinal cancers including
colorectal cancer, 13% with lung cancer and 6% with gynecological 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).
34
Overall (0-120 hours)
0-24 hours
25-120 hours
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 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.
Table 3
Percent of Patients Responding by TreatmentGroup 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
25-120 hours
68.7
89.2
70.8
56.3
80.3
60.9
12.4
8.9
9.9
(5.9, 18.9)
(4.0, 13.8)
(3.5, 16.3)
No Emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)
0-24 hours
25-120 hours
76.2
92.0
77.9
62.1
83.7
66.8
14.1
8.3
11.1
(7.9, 20.3)
(3.9, 12.7)
(5.1, 17.1)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
Overall (0-120 hours)
0-24 hours
25-120 hours
73.6
90.9
74.9
66.4
86.3
69.5
7.2
4.6
5.4
(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.
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
). 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.
35
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 h/ml and 21.2±6.3 microgram x
h/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 [
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 dosage adjustment for EMEND is necessary in elderly patients.
Gender:
Following oral administration of a single 125 mg dose ofaprepitant, 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 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
36
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 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 NK
1
receptors.
5.3 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. 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.
6.
6.1 List of excipients
Capsule content
Sucrose
Microcrystalline cellulose (E 460)
Hydroxypropyl cellulose (E 463)
Sodium laurilsulfate
Capsule shell
Gelatin
Sodium laurilsulfate and silica colloidal anhydrous may be used
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
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.
37
6.5 Nature and contents of container
Different pack sizes including different strengths are available.
Aluminium blister containing one 125 mg capsule.
5 Aluminium blisters each containing one 125 mg capsule.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN 11 9BU
United Kingdom
8.
EU/1/03/262/004
EU/1/03/262/005
9.
Date of first authorisation: 11 November 2003
Date of latest renewal: 11 November 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/.
38
1.
FURTHER INFORMATION
What EMEND contains
The active substance is aprepitant. Each 125 mg hard capsule contains 125 mg of aprepitant. Each
80 mg hard capsule contains 80 mg of aprepitant.
The other ingredients are: sucrose, microcrystalline cellulose (E 460), hydroxypropyl cellulose
(E 463), sodium laurilsulfate, gelatin, titanium dioxide (E 171), shellac, potassium hydroxide, and
black iron oxide (E 172); the 125 mg hard capsule also contains red iron oxide (E 172) and yellow iron
oxide (E 172). The capsule shell may also contain sodium laurilsulfate and silica colloidal anhydrous.
95
What EMEND looks like and contents of the pack
The 125 mg hard 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 hard capsule is opaque with a white cap and body with “461” and “80 mg” printed radially
in black ink on the body.
EMEND 125 mg and 80 mg hard capsules are supplied in the following pack sizes:
•
Not all pack sizes may be marketed.
Marketing Authorisation
Holder
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
UK - Hertfordshire EN11 9BU
United Kingdom
Manufacturer
Merck Sharp & Dohme B. V.
Waarderweg 39, Postbus 581
NL-2003 PC Haarlem
The Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme, IDEA, Inc. org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme (Middle East) Limited
Tel: +357 22866700
info_cyprus@merck.com
Ċipru
96
3-day treatment pack containing one 125 mg capsule and two 80 mg capsules
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
Emend@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.Simi: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East)
LimitedΤηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
97
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.emea.europa.eu/
.
98
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/emend.html
Copyright © 1995-2021 ITA all rights reserved.