Aprepitant Capsules Taj Pharma-SMPC

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pitant 80 mg Caps ules Taj P harma D osage & Rx I nfo | Aprepitant 80 mg Capsules Taj Phar ma Uses, Side Effects, A prepitant 80 mg Capsules Taj Pharma : Indi cations , Side Effects , Warning s, Aprepitant 80 mg Ca psules Taj P harma - Drug Infor mation - TajPhar ma, Apre pitant 80mg Caps ules Taj Phar ma dose Taj pharma ceuti cals Aprepitant 80 mg Ca psule s Taj Phar ma interactions, Taj P harma ceutical Apre pitant 80 mg Caps ules Taj P harma contraindications, Apre pitant 80mg Caps ules Taj Phar ma pri ce, Aprepitant 8 0mg Ca psules Taj Phar maTajPhar ma Aprepitant 80 mg Ca psule s Taj Phar ma PI L- TajP harma Stay conne cted to all updated on Aprepitant 8 0mg Ca psul es Taj Phar maTaj Phar ma ceuticals Taj phar mace uticals. Patie nt Information Lea flets, PI L.
4.2 Posology and method of

Rx administration
Posology
Aprepitant 80mg Capsules Adults
Taj Pharma Aprepitant capsules are given for 3 days as
part of a regimen that includes a
1. NAME OF THE MEDICINAL corticosteroid and a 5-HT3 antagonist.
PRODUCT The recommended dose is 125 mg orally
Aprepitant 80mg hard capsules Taj Pharma once daily one hour before start of
Aprepitant 125mg hard capsules Taj Pharma chemotherapy on Day 1 and 80 mg orally
once daily on Days 2 and 3 in the morning.
2. QUALITATIVE AND
QUANTITATIVE COMPOSITION The following regimens are recommended
in adults for the prevention of nausea and
a) Each hard gelatin capsule contains: vomiting associated with emetogenic cancer
Aprepitant 80mg chemotherapy:
Excipients q.s
Empty gelatin capsule contains approved Highly Emetogenic Chemotherapy Regimen
colours. Day Day Day Day 1
2 3 4
b) Each hard gelatin capsule contains:
Aprepitant 125mg Aprepitant 125 mg orally 80 80 none
Excipients q.s capsules mg mg
Empty gelatin capsule contains approved orall orall
colours. y y
Dexamethaso 12 mg orally 8 8 8
For the full list of excipients, see section 6.1. ne mg mg mg
3. PHARMACEUTICAL FORM orall orall orall
y y y
Hard capsule (capsule)
5- Standard dose none none none
The 80 mg hard capsules are presented as HT3 antagoni of 5-
opaque hard gelatin capsules of size No 2, sts HT3 antagoni
with a white cap and white body, imprinted sts.
in black ink with “80mg” on the body. See the
4. CLINICAL PARTICULARS product
information
4.1 Therapeutic indications for the
Prevention of nausea and vomiting selected 5-
associated with highly and moderately HT3 antagoni
emetogenic cancer chemotherapy in adults st for
and adolescents from the age of 12. appropriate
Aprepitant 125 mg/80 mg capsules are given dosing
as part of combination therapy (see section information
4.2).
Aprepitant 80mg Caps ules Taj P harma: Uses, Side E ffects, I nteractions, Pict ures, War nings, Apre pitant 80 mg Caps ules Taj P harma D osage & Rx I nfo | Aprepitant 80 mg Capsules Taj Phar ma Uses, Side Effects, A prepitant 80 mg Capsules Taj Pharma : Indi cations , Side Effects , Warning s, Aprepitant 80 mg Ca psules Taj P harma - Drug Infor mation - TajPhar ma, Apre pitant 80mg Caps ules Taj Phar ma dose Taj pharma ceuti cals Aprepitant 80 mg Ca psule s Taj Phar ma interactions, Taj P harma ceutical Apre pitant 80 mg Caps ules Taj P harma contraindications, Apre pitant 80mg Caps ules Taj Phar ma pri ce, Aprepitant 8 0mg Ca psules Taj Phar maTajPhar ma Aprepitant 80 mg Ca psule s Taj Phar ma PI L- TajP harma Stay conne cted to all updated on Aprepitant 8 0mg Ca psul es Taj Phar maTaj Phar ma ceuticals Taj phar mace uticals. Patie nt Information Lea flets, PI L.
Dexamethasone should be administered 30 Summary of Product Characteristics (SmPC)

minutes prior to chemotherapy treatment on for the selected 5-HT3 antagonist for
Day 1 and in the morning on Days 2 to 4. appropriate dosing information. If a
The dose of dexamethasone accounts for corticosteroid, such as dexamethasone, is
active substance interactions. co-administered with Aprepitant capsules
the dose of the corticosteroid should be
Moderately Emetogenic Chemotherapy
administered at 50 % of the usual dose (see
Regimen
sections 4.5 and 5.1).
Day Day Day 1 The safety and efficacy of the 80 mg and
2 3 125 mg capsules have not been
Aprepitant 125 mg orally 80 80 demonstrated in children less than 12 years
capsules mg mg of age. No data are available.
orall orall
General
y y
Dexamethason 12 mg orally none none Efficacy data in combination with other
e corticosteroids and 5-HT3 antagonists are
limited. For
5- Standard dose none none
HT3 antagonist of 5- additional information on the co-
s HT3 antagonists administration with corticosteroids, see
. section 4.5. Please refer to the SmPC of co-
See the product administered 5-HT3 antagonist medicinal
information for products.
the selected 5-
Special populations
HT3 antagonist
for appropriate Elderly (≥ 65 years)
dosing
No dose adjustment is necessary for the
information
elderly (see section 5.2).
Dexamethasone should be administered 30
minutes prior to chemotherapy treatment on Gender
Day 1. The dose of dexamethasone accounts No dose adjustment is necessary based on
for active substance interactions. gender (see section 5.2).
Paediatric population Renal impairment
Adolescents (aged 12 through 17 years) No dose adjustment is necessary for patients
Aprepitant capsules are given for 3 days as with renal impairment or for patients with
part of a regimen that includes a 5- end stage renal disease undergoing
HT3 antagonist. The recommended dose of haemodialysis (see section 5.2).
capsules of Aprepitant capsules is 125 mg Hepatic impairment
orally on Day 1 and 80 mg orally on Days 2
and 3. Aprepitant capsules are administered No dose adjustment is necessary for patients
orally 1 hour prior to chemotherapy on Days with mild hepatic impairment. There are
1, 2 and 3. If no chemotherapy is given on limited data in patients with moderate
Days 2 and 3, Aprepitant capsules should be hepatic impairment and no data in patients
administered in the morning. See the with severe hepatic impairment.
Aprepitant should be used with caution in In patients on chronic warfarin therapy, the
these patients (see sections 4.4 and 5.2). International Normalised Ratio (INR) should
be monitored closely during treatment with
Method of administration
Aprepitant capsules and for 14 days
For oral use. following each 3-day course of Aprepitant
capsules (see section 4.5).
The hard capsule should be swallowed
whole. Co-administration with hormonal
contraceptives
Aprepitant capsules may be taken with or
without food. The efficacy of hormonal contraceptives
may be reduced during and for 28 days after
4.3 Contraindications
administration of Aprepitant capsules .
Hypersensitivity to the active substance or to
Alternative non-hormonal back-up methods
any of the excipients listed in section 6.1.
of contraception should be used during
Co-administration with pimozide, treatment with Aprepitant capsules and for 2
terfenadine, astemizole or cisapride (see months following the last dose of Aprepitant
section 4.5). capsules (see section 4.5).
4.4 Special warnings and precautions for Excipients
use
Aprepitant capsules capsules contain
Patients with moderate to severe hepatic
sucrose. Patients with rare hereditary
impairment
problems of fructose intolerance, glucose-
There are limited data in patients with galactose malabsorption or sucrase-
moderate hepatic impairment and no data in isomaltase insufficiency should not take this
patients with severe hepatic impairment. medicinal product.
Aprepitant capsules should be used with
Aprepitant capsules capsules contain
caution in these patients (see section 5.2).
sodium. This medicinal product contains
CYP3A4 interactions less than 1 mmol sodium (23 mg) per
Aprepitant capsules should be used with capsule, that is to say essentially 'sodium-
caution in patients receiving concomitant free'.
orally administered active substances that 4.5 Interaction with other medicinal
are metabolised primarily through CYP3A4 products and other forms of interaction
and with a narrow therapeutic range, such as Aprepitant (125 mg/80 mg) is a substrate, a
cyclosporine, tacrolimus, sirolimus, moderate inhibitor and an inducer of
everolimus, alfentanil, ergot alkaloid CYP3A4. Aprepitant is also an inducer of
derivatives, fentanyl, and quinidine (see CYP2C9. During treatment with Aprepitant
section 4.5). Additionally, concomitant capsules , CYP3A4 is inhibited. After the
administration with irinotecan should be end of treatment, Aprepitant capsules cause
approached with particular caution as the a transient mild induction of CYP2C9,
combination might result in increased CYP3A4 and glucuronidation. Aprepitant
toxicity. does not seem to interact with the P-
Co-administration with warfarin (a CYP2C9 glycoprotein transporter, as suggested by the
substrate) lack of interaction of aprepitant with
digoxin.
Effect of aprepitant on the pharmacokinetics aprepitant, when given as 80 mg/day with

of other active substances dexamethasone co-administered orally as 8
mg on Days 2 through 5, increased the AUC
CYP3A4 inhibition
of dexamethasone, a CYP3A4 substrate, 2.2-
As a moderate inhibitor of CYP3A4, fold on Days 1 and 5.
aprepitant (125 mg/80 mg) can increase
Methylprednisolone: The usual
plasma concentrations of co-administered
intravenously administered
active substances that are metabolised
methylprednisolone dose should be reduced
through CYP3A4. The total exposure of
approximately 25 %, and the usual oral
orally administered CYP3A4 substrates may
methylprednisolone dose should be reduced
increase up to approximately 3-fold during
approximately 50 % when co-administered
the 3-day treatment with Aprepitant capsules
with Aprepitant capsules 125 mg/80 mg
; the effect of aprepitant on the plasma
regimen. Aprepitant, when given as a
concentrations of intravenously
regimen of 125 mg on Day 1 and 80 mg/day
administered CYP3A4 substrates is expected
on Days 2 and 3, increased the AUC of
to be smaller. Aprepitant capsules must not
methylprednisolone, a CYP3A4 substrate,
be used concurrently with pimozide,
by 1.3-fold on Day 1 and by 2.5-fold on Day
terfenadine, astemizole, or cisapride (see
3, when methylprednisolone was co-
section 4.3). Inhibition of CYP3A4 by
administered intravenously as 125 mg on
aprepitant could result in elevated plasma
Day 1 and orally as 40 mg on Days 2 and 3.
concentrations of these active substances,
potentially causing serious or life- During continuous treatment with
threatening reactions. Caution is advised methylprednisolone, the AUC of
during concomitant administration of methylprednisolone may decrease at later
Aprepitant capsules and orally administered time points within 2 weeks following
active substances that are metabolised initiation of the aprepitant dose, due to the
primarily through CYP3A4 and with a inducing effect of aprepitant on CYP3A4.
narrow therapeutic range, such as This effect may be expected to be more
cyclosporine, tacrolimus, sirolimus, pronounced for orally administered
everolimus, alfentanil, diergotamine, methylprednisolone.
ergotamine, fentanyl, and quinidine (see
Chemotherapeutic medicinal products
section 4.4).
In pharmacokinetic studies, aprepitant, when
Corticosteroids
given as a regimen of 125 mg on Day 1 and
Dexamethasone: The usual oral 80 mg/day on Days 2 and 3, did not
dexamethasone dose should be reduced by influence the pharmacokinetics of docetaxel
approximately 50 % when co-administered administered intravenously on Day 1 or
with Aprepitant capsules 125 mg/80 mg vinorelbine administered intravenously on
regimen. The dose of dexamethasone in Day 1 or Day 8. Because the effect of
chemotherapy-induced nausea and vomiting aprepitant on the pharmacokinetics of orally
clinical trials was chosen to account for administered CYP3A4 substrates is greater
active substance interactions (see section than the effect of aprepitant on the
4.2). Aprepitant, when given as a regimen of pharmacokinetics of intravenously
125 mg with dexamethasone co- administered CYP3A4 substrates, an
administered orally as 20 mg on Day 1, and interaction with orally administered
chemotherapeutic medicinal products Days 2 and 3, and 2 mg midazolam was

metabolised primarily or partly by CYP3A4 given intravenously prior to the
(e.g. etoposide, vinorelbine) cannot be administration of the 3-day regimen of
excluded. Caution is advised and additional aprepitant and on Days 4, 8, and 15.
monitoring may be appropriate in patients Aprepitant increased the AUC of midazolam
receiving medicinal products metabolized 25 % on Day 4 and decreased the AUC of
primarily or partly by CYP3A4 (see section midazolam 19 % on Day 8 and 4 % on Day
4.4). Post-marketing events of neurotoxicity, 15. These effects were not considered
a potential adverse reaction of ifosfamide, clinically important.
have been reported after aprepitant and
In a third study with intravenous and oral
ifosfamide co-administration.
administration of midazolam, aprepitant was
Immunosuppressants given as 125 mg on Day 1 and 80 mg/day on
Days 2 and 3, together with ondansetron 32
During the 3-day CINV regimen, a transient
mg Day 1, dexamethasone 12 mg Day 1 and
moderate increase followed by a mild
8 mg Days 2-4. This combination (i.e.
decrease in exposure of
aprepitant, ondansetron and dexamethasone)
immunosuppressants metabolised by
decreased the AUC of oral midazolam 16 %
CYP3A4 (e.g. cyclosporine, tacrolimus,
on Day 6, 9 % on Day 8, 7 % on Day 15 and
everolimus and sirolimus) is expected.
17 % on Day 22. These effects were not
Given the short duration of the 3-day
considered clinically important.
regimen and the time-dependent limited
changes in exposure, dose reduction of the An additional study was completed with
immunosuppressant is not recommended intravenous administration of midazolam
during the 3 days of co-administration with and aprepitant. Intravenous 2 mg midazolam
Aprepitant capsules. was given 1 hour after oral administration of
a single dose of aprepitant 125 mg. The
Midazolam
plasma AUC of midazolam was increased
The potential effects of increased plasma by 1.5-fold. This effect was not considered
concentrations of midazolam or other clinically important.
benzodiazepines metabolised via CYP3A4
Induction
(alprazolam, triazolam) should be
considered when co-administering these As a mild inducer of CYP2C9, CYP3A4 and
medicinal products with Aprepitant capsules glucuronidation, aprepitant can decrease
(125 mg/80 mg). plasma concentrations of substrates
eliminated by these routes within two weeks
Aprepitant increased the AUC of
following initiation of treatment. This effect
midazolam, a sensitive CYP3A4 substrate,
may become apparent only after the end of a
2.3-fold on Day 1 and 3.3-fold on Day 5,
3-day treatment with Aprepitant capsules .
when a single oral dose of 2 mg midazolam
For CYP2C9 and CYP3A4 substrates the
was co-administered on Days 1 and 5 of a
induction is transient with a maximum effect
regimen of aprepitant 125 mg on Day 1 and
reached after 3-5 days after the end of the
80 mg/day on Days 2 to 5.
Aprepitant capsules 3-day treatment. The
In another study with intravenous effect is maintained for a few days,
administration of midazolam, aprepitant was thereafter slowly declines and is clinically
given as 125 mg on Day 1 and 80 mg/day on insignificant by two weeks after the end of
Aprepitant capsules treatment. Mild Alternative non-hormonal back-up methods

induction of glucuronidation is also seen of contraception should be used during
with 80 mg oral aprepitant given for 7 days. treatment with Aprepitant capsules and for 2
Data are lacking regarding effects on months following the last dose of Aprepitant
CYP2C8 and CYP2C19. Caution is advised capsules.
when warfarin, acenocoumarol, tolbutamide,
In a clinical study, single doses of an oral
phenytoin or other active substances that are
contraceptive containing ethinyl estradiol
known to be metabolised by CYP2C9 are
and norethindrone were administered on
administered during this time period.
Days 1 through 21 with aprepitant, given as
Warfarin a regimen of 125 mg on Day 8 and 80
mg/day on Days 9 and 10 with ondansetron
In patients on chronic warfarin therapy, the
32 mg intravenously on Day 8 and oral
prothrombin time (INR) should be
dexamethasone given as 12 mg on Day 8
monitored closely during treatment with
and 8 mg/day on Days 9, 10, and 11. During
Aprepitant capsules and for 2 weeks
days 9 through 21 in this study, there was as
following each 3-day course of Aprepitant
much as a 64 % decrease in ethinyl estradiol
capsules for chemotherapy-induced nausea
trough concentrations and as much as a 60
and vomiting (see section 4.4). When a
% decrease in norethindrone trough
single 125 mg dose of aprepitant was
concentrations.
administered on Day 1 and 80 mg/day on
Days 2 and 3 to healthy subjects who were 5-HT3 antagonists
stabilised on chronic warfarin therapy, there
In clinical interaction studies, aprepitant did
was no effect of aprepitant on the plasma
not have clinically important effects on the
AUC of R(+) or S(-) warfarin determined on
pharmacokinetics of ondansetron,
Day 3; however, there was a 34 % decrease
granisetron, or hydrodolasetron (the active
in S(-) warfarin (a CYP2C9 substrate)
metabolite of dolasetron).
trough concentration accompanied by a 14
% decrease in INR 5 days after completion Effect of other medicinal products on the
of treatment with aprepitant. pharmacokinetics of aprepitant
Tolbutamide Concomitant administration of Aprepitant
capsules with active substances that inhibit
Aprepitant, when given as 125 mg on Day 1
CYP3A4 activity (e.g. ketoconazole,
and 80 mg/day on Days 2 and 3, decreased
itraconazole, voriconazole, posaconazole,
the AUC of tolbutamide (a CYP2C9
clarithromycin, telithromycin, nefazodone
substrate) by 23 % on Day 4, 28 % on Day
and protease inhibitors) should be
8, and 15 % on Day 15, when a single dose
approached cautiously, as the combination is
of tolbutamide 500 mg was administered
expected to result in several-fold increased
orally prior to the administration of the 3-
plasma concentrations of aprepitant (see
day regimen of aprepitant and on Days 4, 8,
section 4.4).
and 15.
Concomitant administration of Aprepitant
Hormonal contraceptives
capsules with active substances that strongly
The efficacy of hormonal contraceptives induce CYP3A4 activity (e.g. rifampicin,
may be reduced during and for 28 days after phenytoin, carbamazepine, phenobarbital)
administration of Aprepitant capsules. should be avoided as the combination results
in reductions of the plasma concentrations of levels above the therapeutic exposure in

aprepitant that may result in decreased humans at the 125 mg/80 mg dose could not
efficacy of Aprepitant capsules. be attained in animal studies. These studies
did not indicate direct or indirect harmful
Concomitant administration of Aprepitant
effects with respect to pregnancy,
capsules with herbal preparations containing
embryonal/foetal development, parturition
St. John's Wort (Hypericum perforatum) is
or postnatal development (see section 5.3).
not recommended.
The potential effects on reproduction of
Ketoconazole alterations in neurokinin regulation are
unknown. Aprepitant capsules should not be
When a single 125 mg dose of aprepitant
used during pregnancy unless clearly
was administered on Day 5 of a 10-day
necessary.
regimen of 400 mg/day of ketoconazole, a
strong CYP3A4 inhibitor, the AUC of Breast-feeding
aprepitant increased approximately 5-fold
Aprepitant is excreted in the milk of
and the mean terminal half-life of aprepitant
lactating rats. It is not known whether
increased approximately 3-fold.
aprepitant is excreted in human milk;
Rifampicin therefore, breast-feeding is not
recommended during treatment with
When a single 375 mg dose of aprepitant
Aprepitant capsules.
was administered on Day 9 of a 14-day
regimen of 600 mg/day of rifampicin, a Fertility
strong CYP3A4 inducer, the AUC of
The potential for effects of aprepitant on
aprepitant decreased 91 % and the mean
fertility has not been fully characterised
terminal half-life decreased 68%.
because exposure levels above the
Paediatric population therapeutic exposure in humans could not be
attained in animal studies. These fertility
Interaction studies have only been
studies did not indicate direct or indirect
performed in adults.
harmful effects with respect to mating
4.6 Fertility, pregnancy and lactation performance, fertility, embryonic/foetal
Contraception in males and females development, or sperm count and motility
The efficacy of hormonal contraceptives (see section 5.3).
may be reduced during and for 28 days after 4.7 Effects on ability to drive and use
administration of Aprepitant capsules. machines
Alternative non-hormonal back-up methods Aprepitant capsules may have minor
of contraception should be used during influence on the ability to drive, cycle and
treatment with Aprepitant capsules and for 2 use machines. Dizziness and fatigue may
months following the last dose of Aprepitant occur following administration of Aprepitant
capsules (see sections 4.4 and 4.5). capsules (see section 4.8).
Pregnancy 4.8 Undesirable effects
For aprepitant no clinical data on exposed Summary of the safety profile
pregnancies are available. The potential for The safety profile of aprepitant was
reproductive toxicity of aprepitant has not evaluated in approximately 6,500 adults in
been fully characterised, since exposure more than 50 studies and 184 children and
adolescents in 2 pivotal paediatric clinical 1/10,000), not known (cannot be estimated

trials. from the available data).
The most common adverse reactions System organ Adverse Frequenc
reported at a greater incidence in adults class reaction y
treated with the aprepitant regimen than with Infection and candidiasis, rare
standard therapy in patients receiving infestations staphylococcal
Highly Emetogenic Chemotherapy (HEC) infection
were: hiccups (4.6 % versus 2.9 %), alanine
aminotransferase (ALT) increased (2.8 % Blood and febrile uncommo
versus 1.1 %), dyspepsia (2.6 % versus 2.0 lymphatic neutropenia, n
%), constipation (2.4 % versus 2.0 %), system anaemia
headache (2.0 % versus 1.8 %), and disorders
decreased appetite (2.0 % versus 0.5 %). Immune system hypersensitivity not known
The most common adverse reaction reported disorders reactions
at a greater incidence in patients treated with including
the aprepitant regimen than with standard anaphylactic
therapy in patients receiving Moderately reactions
Emetogenic Chemotherapy (MEC) was Metabolism decreased common
fatigue (1.4 % versus 0.9 %). and nutrition appetite
The most common adverse reactions disorders polydipsia rare
reported at a greater incidence in paediatric Psychiatric anxiety uncommo
patients treated with the aprepitant regimen disorders n
than with the control regimen while
disorientation, rare
receiving emetogenic cancer chemotherapy
euphoric mood
were hiccups (3.3 % versus 0.0 %) and
flushing (1.1 % versus 0.0 %). Nervous headache common
system dizziness, uncommo
Tabulated list of adverse reactions disorders somnolence n
The following adverse reactions were cognitive rare
observed in a pooled analysis of the HEC disorder,
and MEC studies at a greater incidence with lethargy,
aprepitant than with standard therapy in dysgeusia
adults or paediatric patients or in post-
marketing use. The frequency categories Eye disorders conjunctivitis rare
given in the table are based on the studies in Ear and tinnitus rare
adults; the observed frequencies in the labyrinth
paediatric studies were similar or lower, disorders
unless shown in the table. Some less Cardiac palpitations uncommo
common ADRs in the adult population were disorders n
not observed in the paediatric studies. bradycardia, rare
Frequencies are defined as: very common (≥ cardiovascular
1/10); common (≥ 1/100 to < 1/10); disorder
uncommon ( ≥ 1/ 1,000 to < 1/100); rare (≥ Vascular hot uncommo
1/10,000 to < 1/1,000) and very rare (<
disorders flush/flushing n connective muscle spasms

Respiratory, hiccups common tissue disorders
thoracic and oropharyngeal rare Renal and dysuria uncommo
mediastinal pain, sneezing, urinary n
disorders cough, postnasal disorders pollakiuria rare
drip, throat General fatigue common
irritation disorders and asthenia, uncommo
Gastrointestinal constipation, common administration malaise n
disorders dyspepsia site conditions
oedema, chest rare
eructation, uncommo discomfort, gait
†
nausea , n disturbance
vomiting†,
Investigations ALT increased common
gastroesophagea
l reflux disease, AST increased, uncommo
abdominal pain, blood alkaline n
dry mouth, phosphatase
flatulence increased
duodenal ulcer rare red blood cells rare
perforation, urine positive,
stomatitis, blood sodium
abdominal decreased,
distension, weight
faeces hard, decreased,
neutropenic neutrophil count
colitis decreased,
glucose urine
Skin and rash, acne uncommo
present, urine
subcutaneous n
output increased
tissue disorders photosensitivity rare †
Nausea and vomiting were efficacy
reaction, parameters in the first 5 days of post-
hyperhidrosis, chemotherapy treatment and were reported
seborrhoea, skin as adverse reactions only thereafter.
lesion, rash
pruritic, Description of selected adverse reactions
Stevens- The adverse reactions profiles in adults in
Johnson the Multiple-Cycle extension of HEC and
syndrome/toxic MEC studies for up to 6 additional cycles of
epidermal chemotherapy were generally similar to
necrolysis those observed in Cycle 1.
pruritus, not known
urticaria In an additional active-controlled clinical
study in 1,169 adult patients receiving
Musculoskeleta muscular rare aprepitant and HEC, the adverse reactions
l and weakness,
profile was generally similar to that seen in combination with an

the other HEC studies with aprepitant. ondansetron/dexamethasone regimen (see
section 4.2) was compared with a standard
Additional adverse reactions were observed
regimen (placebo plus ondansetron 32 mg
in adult patients treated with aprepitant for
intravenously administered on Day 1 plus
postoperative nausea and vomiting (PONV)
dexamethasone 20 mg orally on Day 1 and 8
and a greater incidence than with
mg orally twice daily on Days 2 to 4).
ondansetron: abdominal pain upper, bowel
Although a 32 mg intravenous dose of
sounds abnormal, constipation*, dysarthria,
ondansetron was used in clinical trials, this
dyspnoea, hypoaesthesia, insomnia, miosis,
is no longer the recommended dose. See the
nausea, sensory disturbance, stomach
product information for the selected 5-
discomfort, sub-ileus*, visual acuity
HT3 antagonist for appropriate dosing
reduced, wheezing.
information.
*Reported in patients taking a higher dose of
Efficacy was based on evaluation of the
aprepitant.
following composite measure: complete
Reporting of suspected adverse reactions response (defined as no emetic episodes and
no use of rescue therapy) primarily during
Reporting suspected adverse reactions after
Cycle 1. The results were evaluated for each
authorisation of the medicinal product is
individual study and for the 2 studies
important.
combined.
4.9 Overdose
A summary of the key study results from the
In the event of overdose, Aprepitant
combined analysis is shown in Table 1.
capsules should be discontinued and general
supportive treatment and monitoring should Table 1
be provided. Because of the antiemetic
Percent of adult patients receiving Highly
activity of aprepitant, emesis induced by a
Emetogenic Chemotherapy responding by
medicinal product may not be effective.
treatment group and phase — Cycle 1
Aprepitant cannot be removed by
haemodialysis. Aprepitant Standard
regimen therapy
5. PHARMACOLOGICAL Differences*
(N= (N=
PROPERTIES 521) † 524) †
5.1 Pharmacodynamic properties (95 %
% % %
Pharmacotherapeutic group: Antiemetics CI)
and antinauseants, Other antiemetics COMPOSITE MEASURES
Aprepitant is a selective high-affinity Complete response (no emesis and no
antagonist at human substance P neurokinin rescue therapy)
1 (NK1) receptors. Overall
(14.0,
3-day regimen of aprepitant in adults (0-120 67.7 47.8 19.9
25.8)
hours)
In 2 randomised, double-blind studies
encompassing a total of 1,094 adult patients 0-24 (7.9,
86.0 73.2 12.7
receiving chemotherapy that included hours 17.6)
cisplatin ≥ 70 mg/m2, aprepitant in 25-120 71.5 51.2 20.3 (14.5,
hours 26.1)
INDIVIDUAL MEASURES
No emesis (no emetic episodes regardless
of use of rescue therapy)
Overall
(16.4,
(0-120 71.9 49.7 22.2
28.0)
hours)
0-24 (8.0,
86.8 74.0 12.7
hours 17.5)
25-120 (17.0,
76.2 53.5 22.6 Statistically significant differences in
hours 28.2)
efficacy were also observed in each of the 2
No significant nausea (maximum VAS < individual studies.
25 mm on a scale of 0-100 mm)
Overall In the same 2 clinical studies, 851 adult
(1.6, patients continued into the Multiple-Cycle
(0-120 72.1 64.9 7.2
12.8) extension for up to 5 additional cycles of
hours)
chemotherapy. The efficacy of the aprepitant
25-120 (1.5, regimen was apparently maintained during
74.0 66.9 7.1
hours 12.6) all cycles.
*
The confidence intervals were calculated
with no adjustment for gender and In a randomised, double-blind study in a
concomitant chemotherapy, which were total of 866 adult patients (864 females, 2
included in the primary analysis of odds males) receiving chemotherapy that included
ratios and logistic models. cyclophosphamide 750-1,500 mg/m2; or
cyclophosphamide 500-1,500 mg/m2 and
One patient in the Aprepitant regimen only doxorubicin (< 60 mg/m2) or epirubicin (<
had data in the acute phase and was 100 mg/m2), aprepitant in combination with
excluded from the overall and delayed phase an ondansetron/dexamethasone regimen (see
analyses; one patient in the Standard section 4.2) was compared with standard
regimen only had data in the delayed phase therapy (placebo plus ondansetron 8 mg
and was excluded from the overall and acute orally (twice on Day 1, and every 12 hours
phase analyses. on Days 2 and 3) plus dexamethasone 20 mg
The estimated time to first emesis in the orally on Day 1).
combined analysis is depicted by the Efficacy was based on evaluation of the
Kaplan-Meier plot in Figure 1. composite measure: complete response
Figure 1 (defined as no emetic episodes and no use of
rescue therapy) primarily during Cycle 1.
Percent of adult patients receiving Highly
Emetogenic Chemotherapy who remain A summary of the key study results is shown
emesis free over time – Cycle 1 in Table 2.
Table 2
Percent of adult patients responding by
treatment group and phase — Cycle 1
Moderately Emetogenic Chemotherapy which were included in the primary analysis

of odds ratios and logistic models.
Aprepitant
Standard †
One patient in the Aprepitant regimen only
regimen
therapy Differences* had data in the acute phase and was
(N=
(N=424)
433) † excluded from the overall and delayed phase
analyses.
(95 %
% % %
CI) In the same clinical study, 744 adult patients
COMPOSITE MEASURES continued into the Multiple-Cycle extension
for up to 3 additional cycles of
Complete response (no emesis and no
chemotherapy. The efficacy of the aprepitant
rescue therapy)
regimen was apparently maintained during
Overall all cycles.
(1.6,
(0-120 50.8 42.5 8.3
15.0) In a second multicentre, randomised,
hours)
double-blind, parallel-group, clinical study,
0-24 (0.7,
75.7 69.0 6.7 the aprepitant regimen was compared with
hours 12.7)
standard therapy in 848 adult patients (652
25-120 (-0.4, females, 196 males) receiving a
55.4 49.1 6.3
hours 13.0) chemotherapy regimen that included any
INDIVIDUAL MEASURES intravenous dose of oxaliplatin, carboplatin,
No emesis (no emetic episodes regardless epirubicin, idarubicin, ifosfamide,
of use of rescue therapy) irinotecan, daunorubicin, doxorubicin;
cyclophosphamide intravenously (< 1,500
Overall
(10.8, mg/m2); or cytarabine intravenously (> 1
(0-120 75.7 58.7 17.0
23.2) g/m2). Patients receiving the aprepitant
hours)
regimen were receiving chemotherapy for a
0-24 (5.1, variety of tumour types including 52 % with
87.5 77.3 10.2
hours 15.3) breast cancer, 21 % with gastrointestinal
25-120 (5.9, cancers including colorectal cancer, 13 %
80.8 69.1 11.7
hours 17.5) with lung cancer and 6 % with
No significant nausea (maximum VAS < gynaecological cancers. The aprepitant
25 mm on a scale of 0-100 mm) regimen in combination with an
ondansetron/dexamethasone regimen (see
Overall section 4.2) was compared with standard
(-1.3,
(0-120 60.9 55.7 5.3 therapy (placebo in combination with
11.9)
hours) ondansetron 8 mg orally (twice on Day 1,
0-24 (-4.2, and every 12 hours on Days 2 and 3) plus
79.5 78.3 1.3
hours 6.8) dexamethasone 20 mg orally on Day 1).
25-120 (-2.6, Efficacy was based on the evaluation of the
65.3 61.5 3.9
hours 10.3) following primary and key secondary
*
The confidence intervals were calculated endpoints: No vomiting in the overall period
with no adjustment for age category (< 55 (0 to 120 hours post-chemotherapy),
years, ≥ 55 years) and investigator group, evaluation of safety and tolerability of the
aprepitant regimen for chemotherapy
induced nausea and vomiting (CINV), and 25 mm on a scale of 0-100 mm)

complete response (defined as no vomiting Overall
and no use of rescue therapy) in the overall (1.0,
(0-120 73.6 66.4 7.2
period (0 to120 hours post-chemotherapy). 13.4)
hours)
Additionally, no significant nausea in the
overall period (0 to120 hours post- 0-24 (0.2,
90.9 86.3 4.6
chemotherapy) was evaluated as an hours 9.0)
exploratory endpoint, and in the acute and 25-120 (-0.7,
74.9 69.5 5.4
delayed phases as a post-hoc analysis. hours 11.5)
*
A summary of the key study results is shown The confidence intervals were calculated
in Table 3. with no adjustment for gender and region,
which were included in the primary analysis
Table 3 using logistic models.
Percent of adult patients responding by The benefit of aprepitant combination
treatment group and phase for Study 2 – therapy in the full study population was
Cycle 1 mainly driven by the results observed in
Moderately Emetogenic Chemotherapy patients with poor control with the standard
regimen such as in women, even though the
Aprepitant Standard results were numerically better regardless of
regimen therapy Differences* age, tumour type or gender. Complete
(N= 425) (N=406) response to the aprepitant regimen and
(95 % standard therapy, respectively, was reached
% % % in 209/324 (65 %) and 161/320 (50 %) in
CI)
women and 83/101 (82 %) and 68/87 (78 %)
Complete response (no emesis and no
of men.
rescue therapy)
Overall Paediatric population
(5.9,
(0-120 68.7 56.3 12.4 In a randomised, double-blind, active
18.9)
hours) comparator-controlled clinical study that
0-24 (4.0, included 302 children and adolescents (aged
89.2 80.3 8.9 6 months to 17 years) receiving moderately
hours 13.8)
25-120 (3.5, or highly emetogenic chemotherapy, the
70.8 60.9 9.9 aprepitant regimen was compared to a
hours 16.3)
control regimen for the prevention of CINV.
No emesis (no emetic episodes regardless
of use of rescue therapy) The efficacy of the aprepitant regimen was
Overall evaluated in a single cycle (Cycle 1).
(7.9, Patients had the opportunity to receive open-
(0-120 76.2 62.1 14.1
20.3) label aprepitant in subsequent cycles
hours)
(Optional Cycles 2-6); however efficacy was
0-24 (3.9, not assessed in these optional cycles. The
92.0 83.7 8.3
hours 12.7) aprepitant regimen for adolescents aged 12
25-120 (5.1, through 17 years (n=47) consisted of
77.9 66.8 11.1
hours 17.1) aprepitant capsules 125 mg orally on Day 1
No significant nausea (maximum VAS < and 80 mg/day on Days 2 and 3 in
combination with ondansetron on Day 1. n/m (%) n/m (%)

The aprepitant regimen for children aged 6 PRIMARY ENDPOINT
months to less than 12 years (n=105)
consisted of aprepitant powder for oral Complete
77/152 39/150
response* –
suspension 3.0 mg/kg (up to 125 mg) orally (50.7)† (26.0)
on Day 1 and 2.0 mg/kg (up to 80 mg) orally Delayed phase
on Days 2 and 3 in combination with OTHER PRESPECIFIED ENDPOINTS
ondansetron on Day 1. The control regimen Complete
in adolescents aged 12 through 17 years 101/152 78/150
response* – Acute
(n=48) and children aged 6 months to less (66.4)‡ (52.0)
phase
than 12 years (n=102) consisted of placebo
Complete
for aprepitant on Days 1, 2 and 3 in 61/152 30/150
response* – Overall
combination with ondansetron on Day 1. (40.1)† (20.0)
phase
Aprepitant or placebo and ondansetron were
administered 1 hour and 30 minutes prior to No vomiting§ – 71/152 32/150
†
initiation of chemotherapy, respectively. Overall phase (46.7) (21.3)
*
Intravenous dexamethasone was permitted Complete response = No vomiting or
as part of the antiemetic regimen for retching or dry heaves and no use of rescue
paediatric patients in both age groups, at the medication.
†
discretion of the physician. A dose reduction p < 0.01 when compared to control
(50 %) of dexamethasone was required for regimen
‡
paediatric patients receiving aprepitant. No p < 0.05 when compared to control
dose reduction was required for paediatric regimen
§
patients receiving the control regimen. Of No vomiting = No vomiting or retching or
the paediatric patients, 29 % in the dry heaves
aprepitant regimen and 28 % in the control n/m = Number of patients with desired
regimen used dexamethasone as part of the response/number of patients included in
regimen in Cycle 1. time point.
Acute phase: 0 to 24 hours following
The antiemetic activity of aprepitant was
initiation of chemotherapy.
evaluated over a 5-day (120 hour) period
Delayed phase: 25 to 120 hours following
following the initiation of chemotherapy on
Day 1. The primary endpoint was complete
Overall phase: 0 to 120 hours following
response in the delayed phase (25 to 120
hours following initiation of chemotherapy)
in Cycle 1. A summary of the key study The estimated time to first vomiting after
results are shown in Table 4. initiation of chemotherapy treatment was
longer with the aprepitant regimen
Table 4 (estimated median time to first vomiting was
Number (%) of paediatric patients with 94.5 hours) compared with the control
complete response and no vomiting by regimen group (estimated median time to
treatment group and phase – Cycle 1 (Intent first vomiting was 26.0 hours) as depicted in
to treat population) the Kaplan-Meier curves in Figure 2.
Figure 2
Aprepitant Control
regimen regimen
Time to first vomiting episode from start of mg once daily on Days 2 and 3, the AUC0-
chemotherapy administration - paediatric 24hr (mean±SD) was 19.6 ± 2.5 μg∙h/mL and
patients in the overall phase-Cycle 1 (Intent 21.2 ± 6.3 μg∙h/mL on Days 1 and 3,
to treat population) respectively. Cmax was 1.6 ± 0.36 μg/mL and
1.4 ± 0.22 μg/mL on Days 1 and 3,
respectively.
Distribution
Aprepitant is highly protein bound, with a
mean of 97 %. The geometric mean apparent
volume of distribution at steady state (Vdss)
An analysis of efficacy in subpopulations in is approximately 66 L in humans.
Cycle 1 demonstrated that, regardless of age
category, gender, use of dexamethasone for Biotransformation
antiemetic prophylaxis, and emetogenicity Aprepitant undergoes extensive metabolism.
of chemotherapy, the aprepitant regimen In healthy young adults, aprepitant accounts
provided better control than the control for approximately 19 % of the radioactivity
regimen with respect to the complete in plasma over 72 hours following a single
response endpoints. intravenous administration 100 mg dose of
5.2 Pharmacokinetic properties [14C]-fosaprepitant, a prodrug for aprepitant,
Aprepitant displays non-linear indicating a substantial presence of
pharmacokinetics. Both clearance and metabolites in the plasma. Twelve
absolute bioavailability decrease with metabolites of aprepitant have been
increasing dose. identified in human plasma. The metabolism
of aprepitant occurs largely via oxidation at
Absorption the morpholine ring and its side chains and
The mean absolute oral bioavailability of the resultant metabolites were only weakly
aprepitant is 67 % for the 80 mg capsule and active. In vitro studies using human liver
59 % for the 125 mg capsule. The mean microsomes indicate that aprepitant is
peak plasma concentration (Cmax) of metabolised primarily by CYP3A4 and
aprepitant occurred at approximately 4 hours potentially with minor contribution by
(tmax). Oral administration of the capsule CYP1A2 and CYP2C19.
with an approximately 800 Kcal standard Elimination
breakfast resulted in an up to 40 % increase
in AUC of aprepitant. This increase is not Aprepitant is not excreted unchanged in
considered clinically relevant. urine. Metabolites are excreted in urine
and via biliary excretion in faeces.
The pharmacokinetics of aprepitant is non- Following a single intravenously
linear across the clinical dose range. In administered 100 mg dose of [14C]-
healthy young adults, the increase in AUC0- fosaprepitant, a prodrug for aprepitant, to
∞ was 26 % greater than dose proportional healthy subjects, 57 % of the radioactivity
between 80 mg and 125 mg single doses was recovered in urine and 45 % in faeces.
administered in the fed state.
The plasma clearance of aprepitant is dose-
Following oral administration of a single dependent, decreasing with increased dose
125 mg dose of aprepitant on Day 1 and 80 and ranged from approximately 60 to 72
mL/min in the therapeutic dose range. The Renal impairment: A single 240 mg dose of
terminal half-life ranged from approximately aprepitant was administered to patients with
9 to 13 hours. severe renal impairment (CrCl < 30
mL/min) and to patients with end stage renal
Pharmacokinetics in special populations
disease (ESRD) requiring haemodialysis.
Elderly: Following oral administration of a
In patients with severe renal impairment, the
single 125 mg dose of aprepitant on Day 1
AUC0-∞ of total aprepitant (unbound and
and 80 mg once daily on Days 2 through 5,
protein bound) decreased by 21 % and
the AUC0-24hr of aprepitant was 21 % higher
Cmax decreased by 32 %, relative to healthy
on Day 1 and 36 % higher on Day 5 in
subjects. In patients with ESRD undergoing
elderly (≥ 65 years) relative to younger
haemodialysis, the AUC0-∞ of total
adults. The Cmax was 10 % higher on Day 1
aprepitant decreased by 42 % and
and 24 % higher on Day 5 in elderly relative
Cmax decreased by 32 %. Due to modest
to younger adults. These differences are not
decreases in protein binding of aprepitant in
considered clinically meaningful.
patients with renal disease, the AUC of
No dose adjustment for Aprepitant capsules pharmacologically active unbound
is necessary in elderly patients. aprepitant was not significantly affected in
patients with renal impairment compared
Gender: Following oral administration of a
with healthy subjects. Haemodialysis
single 125 mg dose of aprepitant, the
conducted 4 or 48 hours after dosing had no
Cmax for aprepitant is 16 % higher in females
significant effect on the pharmacokinetics of
as compared with males. The half-life of
aprepitant; less than 0.2 % of the dose was
aprepitant is 25 % lower in females as
recovered in the dialysate.
compared with males and its tmax occurs at
approximately the same time. These No dose adjustment for Aprepitant capsules
differences are not considered clinically is necessary for patients with renal
meaningful. impairment or for patients with ESRD
undergoing haemodialysis.
No dose adjustment for Aprepitant capsules
is necessary based on gender. Paediatric population: As part of a 3-day
regimen, dosing of aprepitant capsules
Hepatic impairment: Mild hepatic
(125/80/80 mg) in adolescent patients (aged
impairment (Child-Pugh class A) does not
12 through 17 years) achieved an AUC0-
affect the
24hr above 17 μg∙hr/mL on Day 1 with
pharmacokinetics of aprepitant to a concentrations (Cmin) at the end of Days 2
clinically relevant extent. No dose and 3 above 0.4 μg/mL in a majority of
adjustment is necessary for patients with patients. The median peak plasma
mild hepatic impairment. Conclusions concentration (Cmax) was approximately 1.3
regarding the influence of moderate hepatic μg/mL on Day 1, occurring at approximately
impairment (Child-Pugh class B) on 4 hours. As part of a 3-day regimen, dosing
aprepitant pharmacokinetics cannot be of aprepitant powder for oral suspension
drawn from available data. There are no (3/2/2-mg/kg) in patients aged 6 months to
clinical or pharmacokinetic data in patients less than12 years achieved an AUC0-
with severe hepatic impairment (Child-Pugh 24hr above 17 μg∙hr/mL on Day 1 with
class C). concentrations (Cmin) at the end of Days 2
and 3 above 0.1 μg/mL in a majority of
patients. The median peak plasma relevant exposure. There were no treatment-
concentration (Cmax) was approximately 1.2 related effects on mating, fertility or
μg/mL on Day 1, occurring between 5 and 7 embryonic/foetal survival, and no
hours. pathological changes in the reproductive
organs. In a juvenile toxicity study in dogs
A population pharmacokinetic analysis of
treated from postnatal day 14 to day 42, a
aprepitant in paediatric patients (aged 6
decreased testicular weight and Leydig cell
months through 17 years) suggests that
size were seen in the males at 6 mg/kg/day
gender and race have no clinically
and increased uterine weight, hypertrophy of
meaningful effect on the pharmacokinetics
the uterus and cervix, and oedema of vaginal
of aprepitant.
tissues were seen in females from 4
Relationship between concentration and mg/kg/day. There were no margins to
effect clinically relevant exposure of aprepitant.
For short term treatment according to
Using a highly specific NK1-receptor tracer,
recommended dose regimen these findings
positron emission tomography (PET) studies
are considered unlikely to be clinically
in healthy young men have shown that
relevant.
aprepitant penetrates into the brain and
occupies NK1 receptors in a dose- and 6. PHARMACEUTICAL
plasma-concentration-dependent manner. PARTICULARS
Aprepitant plasma concentrations achieved
6.1 List of excipients
with the 3-day regimen of Aprepitant
Capsule content
capsules are predicted to provide greater
than 95 % occupancy of brain Hypromellose, Poloxamer
NK1 receptors.
Sucrose, Cellulose, microcrystalline
5.3 Preclinical safety data
Capsule shell (80 mg)
Pre-clinical data reveal no special hazard for
humans based on conventional studies of Gelatin
single and repeated dose toxicity,
Sodium laurilsulfate
genotoxicity, carcinogenic potential, toxicity
to reproduction and development. However, Titanium dioxide
it should be noted that systemic exposure in Black printing ink
rodents was similar or even lower than the
therapeutic exposure in humans at the 125 Shellac
mg/80 mg dose. In particular, although no Iron oxide black
adverse effects were noted in reproduction
studies at human exposure levels, the animal Propylene glycol
exposures are not sufficient to make an 6.2 Incompatibilities
adequate risk assessment in man. Not applicable.
In a juvenile toxicity study in rats treated 6.3 Shelf life
from postnatal day 10 to day 63 aprepitant 30 months
led to an earlier vaginal opening in females
from 250 mg/kg b.i.d. and to a delayed 6.4 Special precautions for storage
preputial separation in males, from10 mg/kg Store in the original package in order to
b.i.d. There were no margins to clinically protect from moisture.
6.5 Nature and contents of container

Tablets are packed in Bottle/Alu-Alu blisters
Pack Size of: 7, 14, 28, 30, 50, 90, 100 or
200 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and
other handling
No special requirements for disposal.
7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210
(INDIA).

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Aprepitant 80mg Caps ules Taj P harma: Uses, Side E ffects, I nteractions, Pict ures, War nings, Apre

4.2 Posology and method of

Dexamethasone should be administered 30 Summary of Product Characteristics (SmPC)

Effect of aprepitant on the pharmacokinetics aprepitant, when given as 80 mg/day with

chemotherapeutic medicinal products Days 2 and 3, and 2 mg midazolam was

Aprepitant capsules treatment. Mild Alternative non-hormonal back-up methods

in reductions of the plasma concentrations of levels above the therapeutic exposure in

adolescents in 2 pivotal paediatric clinical 1/10,000), not known (cannot be estimated

disorders flush/flushing n connective muscle spasms

profile was generally similar to that seen in combination with an

Moderately Emetogenic Chemotherapy which were included in the primary analysis

induced nausea and vomiting (CINV), and 25 mm on a scale of 0-100 mm)

combination with ondansetron on Day 1. n/m (%) n/m (%)

6.5 Nature and contents of container

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