ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
IVEMEND 115 mg powder for solution for infusion.
2.
Each vial contains fosaprepitant dimeglumine equivalent to 115 mg fosaprepitant. After reconstitution
and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml) (see section 6.6).
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
White to off-white amorphous powder.
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.
IVEMEND 115 mg is given as part of a combination therapy (see section 4.2).
IVEMEND is a lyophilised prodrug of aprepitant for intravenous administration. Aprepitant is
available as capsules for oral administration.
Since IVEMEND is also available as a 150 mg vial, it is important to note that the preparation (volume
for dilution), infusion rate and doses of concomitant therapy for IVEMEND 115 mg are different from
those for IVEMEND 150 mg. See also section 6.6 for preparation.
Oral aprepitant on Days 2 and 3 is only administered in combination with IVEMEND 115 mg on
Day 1. No aprepitant is administered orally in combination with IVEMEND 150 mg.
The recommended dose of dexamethasone with IVEMEND 115 mg differs from the recommended
dose of dexamethasone with IVEMEND 150 mg on Days 3 and 4.
Posology
IVEMEND
115 mg can replace aprepitant (125 mg) prior to chemotherapy, on Day 1 only of the
chemotherapy induced nausea and vomiting (CINV) regimen, as an infusion administered
over
15 minutes
(see section 6.6).
The 3-day CINV regimen includes IVEMEND 115 mg 30 minutes prior to chemotherapy treatment or
oral aprepitant (125 mg) once daily one hour prior to chemotherapy treatment on Day 1; oral
aprepitant (80 mg) on Days 2 and 3; in addition to a corticosteroid and a 5-HT
3
antagonist.
2
The following regimens are recommended, based on what was used in clinical studies with aprepitant,
for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.
Highly Emetogenic Chemotherapy Regimen
Day 1
Day 2
Day 3
Day 4
IVEMEND
115 mg
intravenously
none
none
none
Aprepitant
none
80 mg orally
80 mg orally
none
Dexamethasone
12 mg orally
8 mg orally
8 mg orally
8 mg orally
Ondansetron
32 mg intravenously
none
none
none
In clinical studies:
Aprepitant
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
IVEMEND
115 mg intravenously
none
none
Aprepitant
none
80 mg orally
80 mg orally
Dexamethasone
12 mg orally
none
none
Ondansetron
2 x 8 mg PO
none
none
In clinical studies:
Aprepitant
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.
Refer to the Summary of Product Characteristics of co-administered antiemetic medicinal products.
Special Populations
Elderly (≥65 years)
No dose adjustment is necessary for the elderly (see section 5.2).
Gender
No dose adjustment is necessary based on gender (see section 5.2).
Renal impairment
No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal
disease undergoing haemodialysis (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data in
patients with moderate hepatic impairment and no data in patients with severe hepatic impairment.
IVEMEND should be used with caution in these patients (see sections 4.4 and 5.2).
3
Paediatric population
The safety and efficacy of IVEMEND in children and adolescents below 18 years of age has not yet
been established. No data are available.
Method of administration
IVEMEND 115 mg should be administered intravenously and should not be given by the
intramuscular or subcutaneous route. Intravenous administration occurs preferably through a running
intravenous infusion over 15 minutes (see section 6.6). Do not administer IVEMEND as a bolus
injection or undiluted solution.
Hypersensitivity to fosaprepitant, aprepitant, or to polysorbate 80 or any of the other excipients.
Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).
Patients with moderate to severe hepatic impairment
There are limited data in patients with moderate hepatic impairment and no data in patients with severe
hepatic impairment. IVEMEND should be used with caution in
these patients (see section 5.2).
CYP3A4 interactions
IVEMEND and oral aprepitant 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 fosaprepitant 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.
Concomitant administration of fosaprepitant 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 fosaprepitant with herbal preparations containing St. John’s Wort
(
Hypericum perforatum
) is not recommended.
Concomitant administration of fosaprepitant 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).
Co-administration with warfarin (a CYP2C9 substrate)
Co-administration of oral aprepitant 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 oral aprepitant and for 2 weeks following each 3-day regimen
of fosaprepitant followed by oral aprepitant for chemotherapy induced nausea and vomiting (see
section 4.5).
Coadministration with hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration
of fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during
treatment with fosaprepitant or aprepitant and for 2 months following the last dose of aprepitant (see
section
4.5).
4
Hypersensitivity reactions
Isolated reports of immediate hypersensitivity reactions including flushing, erythema, and dyspnea
have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally
responded to discontinuation of the infusion and administration of appropriate therapy. It is not
recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.
Administration and infusion site reactions
IVEMEND should not be given as a bolus injection, but should always be diluted and given as a slow
intravenous infusion (see section 4.2). IVEMEND should not be administered intramuscularly or
subcutaneously (see section 5.3). Mild injection site thrombosis has been observed at higher doses (see
section 4.9). If signs or symptoms of local irritation occur, the injection or infusion should be
terminated and restarted in another vein.
When administered intravenously fosaprepitant is rapidly converted to aprepitant.
Interactions with other medicinal products following administration of fosaprepitant are likely to occur
with active substances that interact with oral aprepitant. The following information was derived from
data with oral aprepitant and studies conducted with fosaprepitant and midazolam or diltiazem.
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 oral aprepitant, CYP3A4 is inhibited.
After the end of treatment, oral aprepitant causes a transient mild induction of CYP2C9, CYP3A4 and
glucuronidation. Fosaprepitant or aprepitant does not seem to interact with the P-glycoprotein
transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin. It is anticipated
that fosaprepitant 115 mg as part of the 3-day regimen with aprepitant would cause similar induction
of CYP2C9, CYP3A4 and glucuronidation as that caused by the administration of the 3-day regimen
of oral aprepitant. Data are lacking regarding effects on CYP2C8 and CYP2C19.
Effect of fosaprepitant / aprepitant on the pharmacokinetics of other active substances
CYP3A4 inhibition
As a moderate inhibitor of CYP3A4, aprepitant 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 3-fold during the 3-day treatment
with fosaprepitant followed by oral aprepitant; the effect of aprepitant on the plasma concentrations of
intravenously administered CYP3A4 substrates is expected to be smaller. Fosaprepitant must not be
used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by
aprepitant could result in elevated plasma concentrations of these active substances, potentially
causing serious or life-threatening reactions (see section 4.3). Caution is advised during concomitant
administration of fosaprepitant 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 a regimen of fosaprepitant followed by aprepitant. The dose of dexamethasone in
chemotherapy induced nausea and vomiting clinical trials was chosen to account for active substance
interactions (see section 4.2). Oral aprepitant, when given as a regimen of 125 mg with dexamethasone
co-administered orally as 20 mg on Day 1, and oral aprepitant when given as 80 mg/day with
dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of
dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5.
Methylprednisolone
:
The usual intravenously administered methylprednisolone dose should be
reduced approximately 25 %, and the usual oral methylprednisolone dose should be reduced
approximately 50 % when co-administered with a regimen of fosaprepitant followed by aprepitant.
5
Oral aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3,
increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on Day 1 and by 2.5-fold
on Day 3, when methylprednisolone was co-administered intravenously as 125 mg on Day 1 and
orally as 40 mg on Days 2 and 3.
During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease
at later time points within 2 weeks following initiation of the oral aprepitant dose, due to the inducing
effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally
administered methylprednisolone.
Chemotherapeutic medicinal products
In pharmacokinetic studies, oral aprepitant, when given as a regimen of 125 mg on Day 1 and
80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel administered
intravenously on Day 1 or vinorelbine administered intravenously on Day 1 or Day 8. Because the
effect of aprepitant on the pharmacokinetics of orally administered CYP3A4 substrates is greater than
the effect of aprepitant on the pharmacokinetics of intravenously administered CYP3A4 substrates, an
interaction with orally administered chemotherapeutic medicinal products metabolised primarily or in
part by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution is advised and additional
monitoring may be appropriate in patients receiving such medicinal products (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 immunosuppressant is not recommended during the
3 days of co-administration with aprepitant.
Midazolam
The potential effects of increased plasma concentrations of midazolam or other benzodiazepines
metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these
medicinal products with a 3-day regimen of fosaprepitant followed by aprepitant.
Fosaprepitant given at a dose of 100 mg over 15 minutes with a single dose of midazolam 2 mg
increased the
AUC of midazolam
1.6-fold. This effect was not considered clinically important.
Oral aprepitant increased the AUC of midazolam 2.3-fold on Day 1 and 3.3 fold on Day 5, when a
single oral dose of midazolam 2 mg was co-administered on Days 1 and 5 of a regimen of oral
aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 to 5.
In another study with intravenous administration of midazolam, oral aprepitant was given as 125 mg
on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg was given intravenously prior to the
administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Oral aprepitant
increased the AUC of midazolam 25 % on Day 4 and decreased the AUC of midazolam 19 % on
Day 8 and 4 % on Day 15. These effects were not considered clinically important.
In a third study with intravenous and oral administration of midazolam, oral aprepitant was given as
125 mg on Day 1 and 80 mg/day on Days 2 and 3, together with ondansetron 32 mg Day 1,
dexamethasone, 12 mg Day 1 and 8 mg Days 2-4. This combination (i.e. oral aprepitant, ondansetron
and dexamethasone)
decreased the AUC of oral midazolam 16 % on Day 6, 9 % on Day 8, 7 % on
Day 15 and 17 % on Day 22. These effects were not considered clinically important.
A fourth study was completed with intravenous administration of midazolam and oral aprepitant.
Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of oral
aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not
considered clinically important.
6
Diltiazem
In patients with mild to moderate hypertension, infusion of 100 mg fosaprepitant over 15 minutes with
diltiazem 120 mg 3 times daily, resulted in a 1.4-fold increase in diltiazem AUC and a small but
clinically meaningful decrease in blood pressure, but did not result in a clinically meaningful change
in heart rate, or PR interval.
Induction
As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma
concentrations of substrates eliminated by these routes within two weeks following initiation of
treatment. This effect may become apparent only after the end of a 3-day regimen of fosaprepitant
followed by aprepitant. For CYP2C9 and CYP3A4 substrates, the induction is transient with a
maximum effect reached 3-5 days after end of the oral aprepitant 3-day treatment. The effect is
maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after
end of oral aprepitant treatment. Mild induction of glucuronidation is also seen with 80 mg oral
aprepitant given for 7 days. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is
advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are
known to be metabolised by CYP2C9 are administered during this time period.
Warfarin
In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely
during treatment with fosaprepitant or aprepitant and for 2 weeks following each 3-day regimen for
chemotherapy induced nausea and vomiting (see section 4.4). When a single 125 mg dose of oral
aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were
stabilised on chronic warfarin therapy, there was no effect of oral aprepitant on the plasma AUC of
R(+) or S(-) warfarin determined on Day 3; however, there was a 34 % decrease in S(-) warfarin (a
CYP2C9 substrate) trough concentration accompanied by a 14 % decrease in INR 5 days after
completion of oral aprepitant.
Tolbutamide
Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC
of tolbutamide (a CYP2C9 substrate) by 23 % on Day 4, 28 % on Day 8, and 15 % on Day 15, when a
single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day
regimen of oral aprepitant and on Days 4, 8, and 15.
Hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration
of fosaprepitant or oral aprepitant. Alternative or back-up methods of contraception should be used
during treatment with fosaprepitant or oral aprepitant and for 2 months following the last dose of
aprepitant.
In a clinical study, single doses of an oral contraceptive containing ethinyl estradiol and norethindrone
were administered on Days 1 through 21 with oral aprepitant, given as a regimen of 125 mg on Day 8
and 80 mg/day on Days 9 and 10 with ondansetron 32 mg intravenously on Day 8 and oral
dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. During days 9
through 21 in this study, there was as much as a 64 % decrease in ethinyl estradiol trough
concentrations and as much as a 60 % decrease in norethindrone trough concentrations.
5-HT
3
antagonists
In clinical interaction studies, aprepitant did not have clinically important effects on the
pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of
dolasetron).
Effect of other medicinal products on the pharmacokinetics of aprepitant
Concomitant administration of fosaprepitant or aprepitant with active substances that inhibit CYP3A4
activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin,
nefazodone, and protease inhibitors) should be approached cautiously, as the combination is expected
to result in several-fold increased plasma concentrations of aprepitant (see section 4.4).
7
Concomitant administration of fosaprepitant or aprepitant with active substances that strongly induce
CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the
combination results in reductions of the plasma concentrations of aprepitant that may result in
decreased efficacy. Concomitant administration of fosaprepitant with herbal preparations containing
St. John’s Wort (
Hypericum perforatum
) is not recommended.
Ketoconazole
When a single 125 mg dose of oral 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.
Diltiazem
Infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a
1.5-fold increase of aprepitant AUC. This effect was not considered clinically important.
Rifampicin
When a single 375 mg dose of oral 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 %.
Pregnancy
For fosaprepitant and aprepitant no clinical data on exposed pregnancies are available.
The potential for reproductive toxicities of fosaprepitant and aprepitant have not been fully
characterised, since exposure levels above the therapeutic exposure in humans could not be attained in
animal studies. These studies did not indicate direct or indirect harmful effects with respect to
pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The
potential effects on reproduction of alterations in neurokinin regulation are unknown. IVEMEND
should not be used during pregnancy unless clearly necessary.
Breast-feeding
Aprepitant is excreted in the milk of lactating rats after intravenous administration of fosaprepitant as
well as after oral administration of aprepitant
.
It is not known whether aprepitant is excreted in human
milk. Therefore, breast-feeding is not recommended during treatment with IVEMEND and oral
aprepitant.
Fertility
The potential for effects of fosaprepitant and aprepitant on fertility has not been fully characterised
because exposure levels above the therapeutic exposure in humans could not be attained in animal
studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating
performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3).
No studies on the effects of IVEMEND on the ability to drive and use machines have been performed.
However, when driving or operating machines, it should be taken into account that dizziness and
fatigue have been reported after using IVEMEND (see section 4.8).
Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are
expected to occur with fosaprepitant. Prior to approval of fosaprepitant 150 mg the safety profiles of
fosaprepitant and aprepitant were evaluated in approximately 1,100 individualsand 6,500 individuals,
respectively. In clinical studies, various formulations of fosaprepitant have been administered to a total
of 2,183 individuals including 371 healthy subjects and 1,579 patients with CINV.
8
Oral aprepitant
Adverse reactions 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 HEC 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 MEC was fatigue (1.4 % versus
0.9 %).
The following adverse reactions were observed in either HEC or MEC studies or postmarketing in
patients treated with the aprepitant regimen.
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000
to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated
from the available data).
System organ class
Adverse reaction
Frequency
Infection and infestations
candidiasis, staphylococcal infection
uncommon
Blood and lymphatic system
disorders
febrile neutropenia, anaemia
uncommon
Immune system disorders
hypersensitivity reactions including
anaphylactic reactions
not known
Metabolism and nutrition
disorders
anorexia
common
uncommon
weight gain, polydipsia
Psychiatric disorders
disorientation, euphoria, anxiety
uncommon
Nervous system disorders
headache, dizziness
common
uncommon
dream abnormality, cognitive disorder,
lethargy, somnolence
Eye disorders
conjunctivitis
uncommon
Ear and labyrinth disorders
tinnitus
uncommon
Cardiac disorders
bradycardia, palpitations, cardiovascular
disorder
uncommon
Vascular disorders
flushing/hot flush
uncommon
Respiratory, thoracic and
mediastinal disorders
hiccups
common
uncommon
pharyngitis, sneezing, cough, postnasal drip,
throat irritation
9
System organ class
Adverse reaction
Frequency
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
Skin and subcutaneous tissue
disorders
rash, acne, photosensitivity, hyperhidrosis,
oily skin, pruritus, skin lesion, rash pruritic
uncommon
not known
urticaria
Musculoskeletal and connective
tissue disorders
muscle cramp, myalgia, muscular weakness
uncommon
Renal and urinary disorders
polyuria, dysuria, pollakiuria
uncommon
General disorders and
administration site conditions
asthaenia, fatigue
common
uncommon
oedema, chest discomfort, malaise, thirst,
chills, gait disturbance
Investigations
ALT increased, AST increased
common
uncommon
alkaline phosphatase increased,
hyperglycaemia, microscopic haematuria,
hyponatraemia, weight decreased, neutrophil
count decreased
*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.
In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the
adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.
Additional adverse reactions were observed in 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 reaction in a patient
receiving aprepitant with cancer chemotherapy.
One case of angioedema and urticaria was reported as a serious adverse reaction in a patient receiving
aprepitant in a non-CINV/non-PONV study.
Fosaprepitant
In an active-controlled clinical study in patients receiving HEC, safety was evaluated for
1,143 patients receiving the 1-day regimen of fosaprepitant 150 mg compared to 1,169 patients
receiving the 3-day regimen of aprepitant. The safety profile was generally similar to that seen in the
aprepitant table above.
10
The following are clinically important adverse reactions reported in patients receiving fosaprepitant in
clinical studies or postmarketing that have not been reported with aprepitant as described above.
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
Vascular disorders
flushing, thrombophlebitis (predominantly,
infusion-site thrombophlebitis)
uncommon
Skin and subcutaneous tissue
disorders
erythema
uncommon
General disorders and
administration site conditions
infusion site erythema, infusion site pain,
infusion site pruritus, infusion site induration
uncommon
not known
immediate hypersensitivity reactions including
flushing, erythema, dyspnea
Investigations
blood pressure increased
uncommon
In the event of overdose, fosaprepitant should be discontinued and general supportive treatment and
monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a
medicinal product may not be effective.
Aprepitant cannot be removed by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04A D12.
Fosaprepitant is the prodrug of aprepitant and when administered intravenously is converted rapidly to
aprepitant (see section 5.2). The contribution of fosaprepitant to the overall antiemetic effect has not
fully been characterised, but a transient contribution during the initial phase cannot be ruled out.
Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK
1
) receptors.
The pharmacological effect of fosaprepitant is attributed to aprepitant.
3-Day regimen of aprepitant
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.
11
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
Aprepitant
regimen
(N= 521)
†
%
Standard
therapy
(N= 524)
†
%
Differences*
COMPOSITE MEASURES
% (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)
Overall (0-120 hours)
25-120 hours
(1.6, 12.8)
(1.5, 12.6)
* The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which
were included in the primary analysis of odds ratios and logistic models.
†
One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and
delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was
excluded from the overall and acute phase analyses.
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.
12
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 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 750-1,500 mg/m
2
; or cyclophosphamide 500-
1,500 mg/m
2
and doxorubicin (≤60 mg/m
2
) or epirubicin (≤100 mg/m
2
),
aprepitant in combination
with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy
(placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus
dexamethasone 20 mg orally on Day 1).
Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic
episodes and no use of rescue therapy) primarily during Cycle 1.
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
COMPOSITE MEASURES
Aprepitant
regimen
(N= 433)
†
%
Standard
therapy
(N= 424)
%
Differences*
% (95 % CI)
Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)
0-24 hours
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)
(-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 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 (<1,500 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 gynaecological cancers. The aprepitant regimen
in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with
standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every
12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).
13
No significant nausea (maximum VAS <25 mm on a scale of 0-100 mm)
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 treatment group and phase for Study 2 – Cycle 1
Moderately Emetogenic Chemotherapy
Aprepitant
regimen
(N= 425)
%
Standard
therapy
(N= 406)
%
Differences*
% (95 % CI)
Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)
0-24 hours
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)
(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.
73.6
90.9
74.9
66.4
86.3
69.5
7.2
4.6
5.4
Paediatric population
Studies evaluating the use of fosaprepitant in paediatric patients are on-going (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to
aprepitant. Plasma concentrations of fosaprepitant are below quantifiable levels within 30 minutes
of the completion of infusion.
Aprepitant after fosaprepitant administration
The AUC of aprepitant following 115 mg of fosaprepitant was equivalent to the AUC of 125 mg of
oral aprepitant, while C
max
was 2.5-fold higher.
Following a single intravenous 115 mg dose of fosaprepitant administered as a 15-minute infusion to
healthy volunteers the mean AUC
0-24h
of aprepitant was 19.8 μg•h/ml and the mean maximal
aprepitant concentration was 3.26 μg/ml. The mean aprepitant plasma concentrations from 4 hours
14
Overall (0-120 hours)
0-24 hours
25-120 hours
after dosing (including the concentration at 24 hours postdose) were similar between the 125 mg oral
aprepitant dose and the 115 mg intravenous fosaprepitant dose.
Distribution
Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean apparent volume of
distribution at steady state (Vd
ss
) is approximately 66 l in humans.
Biotransformation
Fosaprepitant was rapidly converted to aprepitant in
in vitro
incubations with liver preparations from
humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in
S9 preparations from other human tissues including kidney, lung and ileum. Thus, it appears that the
conversion of fosaprepitant to aprepitant can occur in multiple tissues. In humans, fosaprepitant
administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of
infusion.
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.
All metabolites observed in urine, faeces and plasma following an intravenous 100 mg
[
14
C]-fosaprepitant dose were also observed following an oral dose of [
14
C]-aprepitant. Upon
conversion of 115 mg of fosaprepitant to aprepitant, 18.3 mg of phosphate is liberated from
fosaprepitant.
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
to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces.
The pharmacokinetics of aprepitant is non-linear across the clinical dose range. The terminal half-life
of aprepitant after oral administration ranged from approximately 9 to 13 hours.
Pharmacokinetics in special populations
Fosaprepitant pharmacokinetics has not been evaluated in special populations. No clinically relevant
differences in aprepitant pharmacokinetics is expected due to age and gender.
Hepatic impairment:
Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic
impairment is not expected to alter the conversion of fosaprepitant to aprepitant. 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 oral 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
15
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 is necessary for patients with renal impairment or for patients with ESRD
undergoing haemodialysis.
Relationship between concentration and effect
Fosaprepitant is a prodrug of aprepitant. Positron emission tomography (PET) imaging studies, using a
highly specific NK
1
-receptor tracer, in healthy young men after administration of oral aprepitant 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 oral aprepitant are predicted to provide greater than 95 % occupancy of brain NK
1
receptors. The
relationship between concentration and effect has not been evaluated after administration of
fosaprepitant.
5.3 Pre-clinical safety data
Pre-clinical data
obtained with intravenous administration of fosaprepitant and oral administration of
aprepitant reveal no special hazard for humans based on conventional studies of single and repeated
dose toxicity, genotoxicity (including
in vitro
tests), and toxicity to reproduction. In laboratory
animals, fosaprepitant in non-commercial formulations caused vascular toxicity and hemolysis at
concentrations below 1 mg/ml and higher, dependent on the formulation. In human washed blood cells
also evidence of hemolysis was found with non-commercial formulations at fosaprepitant
concentrations of 2.3 mg/ml and higher, although tests in human whole blood were negative. No
hemolysis was found with the commercial formulation up to a fosaprepitant concentration of 1 mg/ml
in human whole blood and washed human erythrocytes.
Carcinogenic potential in rodents was only investigated with orally administered aprepitant. However,
it should be noted that the value of the toxicity studies carried out with rodents, rabbit and monkey,
including the reproduction toxicity studies, are limited since systemic exposures to fosaprepitant and
aprepitant were only similar or even lower than therapeutic exposure in humans. In the performed
safety pharmacology and repeated dose toxicity studies with dogs, fosaprepitant C
max
and aprepitant
AUC values were 4-7 times and 60-70 times, respectively, higher than clinical values.
In rabbits, IVEMEND caused initial transient local acute inflammation following paravenous,
subcutaneous and intramuscular administration. At the end of the follow-up period (post-dose day 8),
up to slight local subacute inflammation was noted following paravenous and intramuscular
administration and additional up to moderate focal muscle degeneration/necrosis with muscle
regeneration following intramuscular administration.
6.
6.1 List of excipients
Disodium edetate (E386)
Polysorbate 80 (E433)
Lactose anhydrous
Sodium hydroxide (E524) (for pH adjustment) and/or
Hydrochloric acid diluted (E507) (for pH adjustment)
16
6.2 Incompatibilities
IVEMEND is incompatible with any solutions containing divalent cations (e.g., Ca
2+
, Mg
2+
), including
Hartman’s and lactated Ringer’s solutions. This medicinal product must not be mixed with other
medicinal products except those mentioned in section 6.6.
6.3 Shelf-life
2 years.
After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 24
hours at 25°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2 to 8°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
10 ml Type I clear glass vial with a chlorobutyl or bromobutyl rubber
stopper and an aluminum seal
with a blue plastic flip off cap.
Each vial contains 115 mg of fosaprepitant. Pack sizes: 1 or 10 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
IVEMEND must be reconstituted and then diluted prior to administration.
Note that the preparation (volume for dilution), infusion rate and doses of concomitant therapy
for IVEMEND 115 mg are different from those for IVEMEND 150 mg. See also section 4.2 for
posology and method of administration.
Preparation of IVEMEND 115 mg for intravenous administration:
1.
Inject 5 ml sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial. Assure that
sodium chloride 9 mg/ml (0.9 %) solution for injection is added to the vial along the vial wall in
order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting sodium chloride
9 mg/ml (0.9 %) solution for injection into the vial.
2.
Prepare an infusion bag filled with
110 ml
of sodium chloride 9 mg/ml (0.9 %) solution for
injection (for example, by adding 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for
injection to a 100 ml sodium chloride 9 mg/ml (0.9 %) solution for injection infusion bag).
3.
Withdraw the entire volume from the vial and transfer it into an infusion bag containing 110 ml
of sodium chloride 9 mg/ml (0.9 %) solution for injection to
yield a total volume of 115 ml
.
Gently invert the bag 2-3 times.
The medicinal product
must not be reconstituted or mixed with solutions for which physical and
chemical compatibility has not been established (see section 6.2).
17
The appearance of the reconstituted solution is the same as the appearance of the diluent.
The reconstituted and diluted medicinal product should be inspected visually for particulate matter and
discoloration before administration.
No special requirements for disposal.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN 11 9BU
United Kingdom
8.
EU/1/07/437/001
EU/1/07/437/002
9.
11 January 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
18
1.
IVEMEND 115 mg powder for solution for infusion
Fosaprepitant
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains fosaprepitant dimeglumine equivalent to 115 mg fosaprepitant. After reconstitution
and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml).
3.
LIST OF EXCIPIENTS
Disodium edetate, polysorbate 80, lactose anhydrous, NaOH and/or HCl diluted (for pH adjustment)
4.
1 vial
10 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Single use only.
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
40
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
After reconstitution and dilution
:
24 hours at 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/07/437/001 1 x 1 vial
EU/1/07/437/002 1 x 10 vials
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
IVEMEND 115 mg
41
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
115 mg
1.
FURTHER INFORMATION
What IVEMEND contains
•
The active substance is fosaprepitant. Each vial contains fosaprepitant dimeglumine equivalent
to 150 mg fosaprepitant. After reconstitution and dilution 1 ml of solution contains 1 mg
fosaprepitant (1 mg/ml).
•
The other ingredients are: disodium edetate (E386), polysorbate 80 (E433), lactose anhydrous,
sodium hydroxide (E524) (for pH adjustment) and/or hydrochloric acid diluted (E507) (for pH
adjustment).
What IVEMEND looks like and contents of the pack
IVEMEND is a white to off-white powder for solution for infusion.
The powder is contained in a clear glass vial with a rubber stopper and an aluminum seal with a grey
plastic flip off cap.
Each vial contains 150 mg of fosaprepitant. Pack sizes: 1 or 10 vials.
Not all pack sizes may be marketed.
57
Marketing Authorisation Holder and Manufacturer
Manufacturer
Merck Sharp & Dohme B.V.
Waarderweg 39,
2031 BN Haarlem
Nederland
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
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800 99 99 000
medicalinfo.nl@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
Ivemend@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
58
Marketing Authorisation Holder
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
Merck Sharp & Dohme Ísland ehf.
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
MSD Italia S.r.l.
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) Limited.
Τηλ: +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
medicalinformationuk@merck.com
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 web site:
http://www.ema.europa.eu/.
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Note that the preparation (volume for dilution), infusion rate and doses of concomitant therapy for
IVEMEND 150 mg are different from those for IVEMEND 115 mg.
Oral aprepitant on Days 2 and 3 is only administered in combination with IVEMEND 115 mg on
Day 1. No aprepitant is administered orally in combination with IVEMEND 150 mg.
The recommended dose of dexamethasone with IVEMEND 150 mg differs from the recommended
dose of dexamethasone with IVEMEND 115 mg on Days 3 and 4.
59
Instructions of how to reconstitute and dilute IVEMEND 150 mg
1.
Inject 5 ml sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial. Assure that
sodium chloride 9 mg/ml (0.9 %) solution for injection is added to the vial along the vial wall in
order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting sodium chloride
9 mg/ml (0.9 %) solution for injection into the vial.
2.
Prepare an infusion bag filled with
145 ml
of sodium chloride 9 mg/ml (0.9 %) solution for
injection (for example, by removing 105 ml of sodium chloride 9 mg/ml (0.9 %) solution for
injection from a 250 ml sodium chloride 9 mg/ml (0.9 %) solution for injection infusion bag).
3.
Withdraw the entire volume from the vial and transfer it into an infusion bag containing 145 ml
of sodium chloride 9 mg/ml (0.9 %) solution for injection to
yield a total volume of 150 ml
.
Gently invert the bag 2-3 times (see HOW TO USE IVEMEND).
The reconstituted and diluted final solution is stable for 24 hours at 25°C.
Parenteral medicines should be inspected visually for particulate matter and discoloration before
administration whenever solution and container permit.
The appearance of the reconstituted solution is the same as the appearance of the diluent.
60
Source: European Medicines Agency
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