Emend

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Aprepitant 40 mg
Available from:
Merck Sharp & Dohme (New Zealand) Limited
INN (International Name):
Aprepitant 40 mg
Dosage:
40 mg
Pharmaceutical form:
Capsule
Composition:
Active: Aprepitant 40 mg Excipient: Hyprolose Micronised sodium lauryl sulphate Opaque white and mustard yellow hard gelatin capsule (contains titanium dioxide, yellow iron) Microcrystalline cellulose Purified water Sodium laurilsulfate Sucrose
Units in package:
Blister pack, 1 capsule
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Siegfried Evionnaz SA
Therapeutic indications:
Emend, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of: · moderately emetogenic cancer chemotherapy. · highly emetogenic cancer chemotherapy. Emend is indicated for the prevention of postoperative nausea and vomiting.
Product summary:
Package - Contents - Shelf Life: Blister pack, - 1 capsules - 48 months from date of manufacture stored at or below 30°C - Blister pack, - 5 capsules - 48 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-6996c
Authorization date:
2005-10-20

EMEND

EMEND

®

Aprepitant

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about EMEND. It does not

contain all the available information.

It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking EMEND

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What EMEND is used

for

Chemotherapy Induced

Nausea and Vomiting

EMEND, in combination with other

medicines, is used to prevent nausea

(feeling sick) and vomiting

associated with cancer

chemotherapy.

Post-Operative Nausea and

Vomiting

EMEND is used to prevent nausea

(feeling sick) and vomiting which

can occur after surgery.

EMEND belongs to a group of

medicines called neurokinin 1 (NK1)

receptor antagonists. It works by

blocking the actions of substances in

your brain, called substance P

neurokinins, that cause nausea and

vomiting.

Your doctor may have prescribed

EMEND for another reason. Ask

your doctor if you have any questions

about why EMEND has been

prescribed for you.

The safety and effectiveness of

EMEND in children and teenagers

under the age of 18 years have not

been established.

EMEND is not addictive.

Before you take

EMEND

When you must not take it

Do not take EMEND if you have

an allergy to EMEND or any of the

ingredients listed at the end of this

leaflet.

Do not take EMEND if you are

taking:

Cisapride*, used to treat stomach

reflux

pimozide*, used to treat psychotic

conditions

terfenadine (Teldane*) and

astemizole (Hismanal*),

antihistamines used for allergic

conditions, including hayfever

* not available in New Zealand

St Johns Wort - a herb used to

treat depression

Taking EMEND with these

medicines may cause serious or life-

threatening reactions.

Do not take EMEND if you have a

rare hereditary problem of

fructose intolerance, glucose-

galactose malabsorption, or

sucrose-isomaltase insufficiency.

Do not take EMEND if you are

breast-feeding or plan to breast-

feed.

It is not known if EMEND passes

into breast milk. You and your doctor

should discuss whether you should

stop breast-feeding or not take

EMEND.

Do not take EMEND if:

the packaging is torn or shows

signs of tampering

the expiry date on the pack has

passed.

If you take this medicine after the

expiry date has passed, it may not

work.

If you are not sure whether you

should start taking EMEND, talk

to your doctor.

Before you take it

Tell your doctor if:

1.

you have or have had any

medical conditions

2.

you are pregnant or intend to

become pregnant

EMEND has not been studied in

pregnant women. EMEND should

be used during pregnancy only if

clearly needed.

3.

you have any allergies to any

other medicines or any other

substances, such as foods,

preservatives or dyes.

If you have not told your doctor

about any of the above, tell the

doctor before you take any

EMEND.

EMEND

Taking other medicines

Tell your doctor if you are taking

any other medicines, including

medicines that you buy without a

prescription from your pharmacy,

supermarket or health food shop.

Some medicines should not be

taken with EMEND. These

include:

cisapride*, used to treat stomach

reflux

pimozide*, used to treat psychotic

conditions

terfenadine (Teldane*) and

astemizole (Hismanal*),

antihistamines used for allergic

conditions, including hayfever

* not available in New Zealand

St John's Wort - a herb used to

treat depression

Taking EMEND with these

medicines may cause serious or life-

threatening reactions.

Some medicines and EMEND may

interfere with each other. These

include:

warfarin, used to prevent blood

clots. Your doctor may order

additional blood tests to check the

effect of warfarin after you have

taken EMEND.

rifampicin, an antibiotic used to

treat tuberculosis and other

infections

ketoconazole, used to treat fungal

infections

oral contraceptive pills (also

known as the pill). Alternative or

"back-up" measures of

contraception should be used

during treatment with EMEND

and for one month following the

last dose of EMEND

paroxetine, used to treat

depression, and obsessive

compulsive and panic disorders

diltiazem, used to treat angina

and high blood pressure

midazolam, triazolam, or

alprazolam, used as sedatives or

to treat anxiety or panic disorder

dexamethasone or

methylprednisolone, steroid

medicines used for a variety of

conditions

certain cancer chemotherapy

agents, including etoposide,

vinorelbine, paclitaxel

tolbutamide, used to treat diabetes

phenytoin, used to treat epilepsy

These medicines may be affected by

EMEND or may affect how well it

works. You may need different

amounts of your medicine, or you

may need to take different medicines.

Your doctor or pharmacist has more

information on medicines to be

careful with or avoid while taking

EMEND.

How to take EMEND

How much to take

Take EMEND only when

prescribed by your doctor.

Chemotherapy Induced Nausea

and Vomiting

EMEND may be given to you in one

of two ways:

1.

EMEND 1-Day Regimen

Day 1 (day of chemotherapy):

One 165 mg capsule of EMEND will

be given to you to take by mouth 1

hour before you start your

chemotherapy treatment on Day 1

only.

OR

2.

EMEND 3-Day Regimen

Day 1 (day of chemotherapy):

EMEND 125 mg will be given to you

by mouth 1 hour before you start

your chemotherapy treatment on Day

Day 2 and Day 3 (the two days

after chemotherapy):

Take one 80 mg capsule of EMEND

each morning for the 2 days

following your chemotherapy

treatment.

Post-Operative Nausea and

Vomiting

The recommended dose of EMEND

to prevent nausea and vomiting

caused by surgery is one 40 mg

capsule within 3 hours before your

surgery.

Follow all directions given to you

by your doctor carefully.

They may differ from the

information contained in this leaflet.

If you do not understand the

instructions on the carton, ask

your doctor or pharmacist for

help.

How to take it

Chemotherapy Induced Nausea

and Vomiting

Swallow each capsule of EMEND

whole with a glass of water.

It does not matter if you take

EMEND before, with or after food.

However, if you are taking the 165

mg capsule, take it either without

food or with a light meal.

Post-Operative Nausea and

Vomiting

Your doctor will give you one 40 mg

capsule of EMEND 3 hours before

your surgery.

EMEND can be taken with or

without food. Follow your doctor's

instructions about eating or drinking

before surgery.

How long to take it

Chemotherapy Induced Nausea

and Vomiting

EMEND may be given in one of two

ways. EMEND 1-Day regimen is a

165 mg capsule given only on the

day of chemotherapy treatment.

EMEND 3-Day regimen is usually

taken for 3 days.

Post-Operative Nausea and

Vomiting

EMEND is given as 1 dose before

your surgery.

If you are not sure how long to

take EMEND, talk to your doctor.

EMEND

If you forget to take it

If you forget to take your capsules,

contact your doctor for

instructions.

If you take too much

(overdose)

Immediately telephone your doctor

or Poisons Information Centre

(telephone 13 11 26), or go to

accident and emergency at your

nearest hospital, if you think that

you or anyone else may have taken

too much EMEND. Do this even if

there are no signs of discomfort or

poisoning.

While you are using

EMEND

Things you must do

Women taking oral contraceptive

pills for birth control should also

use other methods of contraception

during treatment with EMEND

and for one month following the

last dose of EMEND.

This is because oral contraceptive

pills may not work as well when

taking EMEND.

If you become pregnant while

taking EMEND, tell your doctor

immediately.

If you are about to be started on

any new medicine, tell your doctor

and pharmacist that you are taking

EMEND.

Things you must not do

Do not give EMEND to anyone

else, even if they have the same

condition as you.

Things to be careful of

Be careful driving or operating

machinery until you know how

EMEND affects you.

EMEND generally does not cause

any problems with your ability to

drive a car or operate machinery.

However, as with many medicines, it

may cause certain side effects in

some people, including tiredness and

dizziness. Make sure you know how

you react to EMEND before you

drive a car or operate machinery.

Things that may be helpful

to manage your

chemotherapy induced

nausea and vomiting

Small, frequent meals or eating a

snack before your chemotherapy

treatment may help you to tolerate it

better.

Talk to your doctor, pharmacist or

nurse for more information.

Things that may be helpful

to manage your nausea and

vomiting caused by your

surgery

Talk to your doctor about measures

to manage your nausea and vomiting

after surgery.

Side Effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking EMEND.

EMEND helps most people with

nausea and vomiting associated with

cancer chemotherapy, but it may

have unwanted side effects in a few

people. All medicines can have side

effects. Sometimes they are serious,

most of the time they are not. You

may need medical treatment if you

get some of the side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor if you notice or

have any of the following and they

worry you:

tiredness

generally feeling unwell

muscle weakness

headache, dizziness

constipation, diarrhoea

indigestion, heartburn, loss of

appetite

gas from the stomach or bowel,

wind

hiccups/hiccoughs

vomiting

disorientation

chills

hot flushes

bloating

pain on urination

changes to your walking pattern

acne

Most of these are the more common

side effects of EMEND. For the

most part these have been mild.

Tell your doctor immediately if

you notice any of the following:

slow, fast or irregular heart beat

severe upper stomach pain

symptoms of severe sunburn,

such as redness, itching, pain,

swelling or blistering

signs of anaemia such as, being

short of breath when exercising,

looking pale

frequent signs of infections such

as fever, severe chills, sore throat

or mouth ulcers

These may be serious side effects.

You may need urgent medical

attention. These side effects are rare.

If any of the following happen, tell

your doctor immediately or go to

accident and emergency at your

nearest hospital:

swelling of the face, lips, mouth,

throat or tongue which may cause

difficulty in breathing or

swallowing

pinkish, itchy swellings on the

skin, also called hives or

nettlerash

severe skin reactions, including

the inside of the nose or mouth

These may be serious side effects. If

you have them, you may be having a

serious allergic reaction to EMEND.

EMEND

You may need urgent medical

attention. These side effects are rare.

Other side effects not listed above

may also occur in some patients.

Tell your doctor if you notice any

other effects.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

After using EMEND

Storage

Keep your capsules in the blister

pack until it is time to take them.

If you take them out of the blister

pack, they may not keep well.

Keep EMEND in a cool dry place

where the temperature stays below

30°C. Do not store it or any other

medicine in the bathroom or near a

sink.

Do not leave it in the car or on

window sills.

Heat and dampness can destroy some

medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a-half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking EMEND, or the capsules

have passed their expiry date, ask

your pharmacist what to do with

any that are left over.

Product description

What it looks like

EMEND comes in four types of

capsules:

EMEND 165 mg - white and light

blue coloured, with "466" and

"165 mg" printed in black ink on

the capsule

EMEND 125 mg - white and pink

coloured, with "462" and "125

mg" printed in black ink on the

capsule

EMEND 80 mg - white coloured

with "461" and "80 mg" printed

in black ink on the capsule.

EMEND 40 mg * - white and

mustard coloured, with "464" and

"40 mg" printed in black on the

capsule

The capsules come in:

A box of EMEND 165 mg

containing one capsule*

A box of EMEND 165 mg

containing six capsules *

A 3-day box containing one 125

mg capsule and two 80 mg

capsules

A box of EMEND 125 mg

containing one capsule. *

A box of EMEND 80 mg

containing one capsule *

A box of EMEND 80 mg

containing two capsules. *

* not currently available in New

Zealand

Ingredients

Active ingredient:

EMEND 165 mg - 165 mg

aprepitant per capsule

EMEND 125 mg - 125 mg

aprepitant per capsule

EMEND 80 mg - 80 mg

aprepitant per capsule

EMEND 40 mg - 40 mg

aprepitant per capsule

Inactive ingredients:

sucrose

microcrystalline cellulose

hydroxypropyl cellulose

sodium lauryl sulphate

Capsule shell ingredients:

gelatin

titanium dioxide CI77891

iron oxide red CI 77491 (125 mg

capsules)

iron oxide yellow CI 77492 (40

mg and 125 mg capsules)

iron oxide black CI 77499

indigo carmine (165 mg capsule)

sodium lauryl sulphate

colloidal silicon dioxide

EMEND does not contain gluten,

tartrazine or any other azo dyes.

Supplier

Merck Sharp & Dohme (New

Zealand) Limited

PO Box 99-851

Newmarket, Auckland 1149

This leaflet was prepared in October

2017.

New Zealand Register Numbers:

165 mg - TT50-6996d

125 mg/80mg 3 day pack TT50-

6996b

125 mg - TT50-6996b

80 mg - TT50-6996

40 mg - TT50-6996c

Page 1 of 19

NEW ZEALAND DATA SHEET

1 PRODUCT NAME

EMEND

40 mg, 80 mg, 125 mg, and 165 mg capsule

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 40 mg capsule contains 40 mg of aprepitant

Each 80 mg capsule contains 80 mg of aprepitant

Each 125 mg capsule contains 125 mg of aprepitant

Each 165 mg capsule contains 165 mg of aprepitant

Excipients with known effect

Each 40 mg capsule contains 40 mg of sucrose.

Each 80 mg capsule contains 80 mg of sucrose.

Each 125 mg capsule contains 125 mg sucrose.

Each 165 mg capsule contains 165 mg sucrose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

40 mg: A size #4 opaque, hard gelatin capsule with white body and mustard yellow cap with

“464” and “40 mg” printed radially in black ink. Dimensions are overall length 14.3 mm.

80 mg: A size #2 opaque, hard gelatin capsule with white body and white cap with “461” and

“80 mg” printed radially in black ink. Dimensions are overall length 18.0 mm.

125 mg: A size #1 opaque, hard gelatin capsule with white body and pink cap with “462”

and “125 mg” printed radially in black ink. Dimensions are overall length 19.4 mm.

165 mg: A size #0 opaque. Hard gelatin capsule with a white body and light blue cap with

“466” and “165 mg” printed radially in black ink. Dimensions are overall length 21.7 mm.

4 CLINICAL PARTICULARS

4.1

Therapeutic indications

EMEND, in combination with other antiemetic agents, is indicated for the prevention of acute

and delayed nausea and vomiting associated with initial and repeat courses of:

highly emetogenic cancer chemotherapy (see Section 4.2)

moderately emetogenic cancer chemotherapy (see Section 4.2).

EMEND is indicated for the prevention of postoperative nausea and vomiting.

Page 2 of 19

4.2

Dose and method of administration

PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV)

EMEND (aprepitant) is available as capsules for oral administration.

EMEND is given for 1 day or for 3 days as part of a regimen that includes a corticosteroid

and a 5-HT3 antagonist. The package insert for the co-administered 5-HT3 antagonist (e.g.,

ondansetron) must be consulted prior to initiation of treatment with EMEND.

1-Day Regimen of EMEND

The recommended dose of EMEND for the 1-day oral regimen is 165 mg orally 1 hour prior

to chemotherapy treatment on Day 1 only.

Recommended dosing for the prevention of nausea and vomiting associated with highly

emetogenic cancer chemotherapy:

Day 1

Day 2

Day 3

Day 4

EMEND

165 mg orally

none

none

none

Dexamethasone*

12 mg orally

8 mg orally

8 mg orally bid

8 mg orally bid

5-HT

antagonist

(e.g., ondansetron)

See the package

insert for the selected

5-HT

antagonist for

appropriate dosing

information

none

none

none

* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and

in the morning on Days 2 through 4. Dexamethasone should also be administered in the evenings on

Days 3 and 4. The dose of dexamethasone accounts for drug interactions.

Recommended dosing for the prevention of nausea and vomiting associated with moderately

emetogenic cancer chemotherapy:

Day 1

EMEND

165 mg orally

Dexamethasone*

12 mg orally

5-HT

antagonist (e.g., ondansetron)

See the package insert for the selected 5-HT

antagonist for appropriate dosing information

* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The

dose of dexamethasone accounts for drug interactions.

3-Day Regimen of EMEND

The recommended dose of EMEND for the 3-day oral regimen is 125 mg orally 1 hour prior

to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2

and 3.

Page 3 of 19

Recommended dosing for the prevention of nausea and vomiting associated with highly

emetogenic cancer chemotherapy:

Day 1

Day 2

Day 3

Day 4

EMEND

125 mg orally

80 mg orally

80 mg orally

none

Dexamethasone*

12 mg orally

8 mg orally

8 mg orally

8 mg orally

5-HT

antagonist

(e.g., ondansetron)

See the package insert for

the selected 5-HT

antagonist for appropriate

dosing information

none

none

none

* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and

in the morning on Days 2 through 4. The dose of dexamethasone was chosen to accounts for

Medicine interactions.

Recommended dosing for the prevention of nausea and vomiting associated with moderately

emetogenic cancer chemotherapy:

Day 1

Day 2

Day 3

EMEND

125 mg orally

80 mg orally

80 mg orally

Dexamethasone**

12 mg orally

none

none

5-HT

antagonist

(e.g., ondansetron)

See the package insert for the

selected 5-HT

antagonist for

appropriate dosing information

none

none

* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The

dose of dexamethasone was chosen to accounts for medicine interactions.

PREVENTION OF POSTOPERATIVE NAUSEA AND VOMITING (PONV)

The recommended oral dosage of EMEND is 40 mg within 3 hours prior to induction of

anaesthesia.

Method of administration

Capsules should be swallowed whole.

General information

Section

additional

information

administration

EMEND

with

corticosteroids.

Refer to the full prescribing information for co-administered antiemetic agents.

EMEND may be taken with or without food.

No dosage adjustment is necessary based on age, gender, race or Body Mass Index (BMI).

No dosage adjustment is necessary for patients with severe renal insufficiency (creatinine

clearance

<30

mL/min)

patients

with

stage

renal

disease

undergoing

haemodialysis.

Page 4 of 19

No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency

(Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic

insufficiency (Child-Pugh score >9).

Paediatric patients

The safety and efficacy of EMEND in paediatric patients have not been established.

4.3

Contraindications

EMEND is contraindicated in patients who are hypersensitive to any component of the

product.

EMEND

should

used

concurrently

with

pimozide,

terfenadine,

astemizole,

cisapride. Dose-dependent inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by

aprepitant could result in elevated plasma concentrations of these medicines, potentially

causing serious or life-threatening reactions (see Section 4.5).

4.4

Special warnings and precautions for use

EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients

receiving concomitant orally administered medicinal products that are primarily metabolised

through CYP3A4; some chemotherapy agents are metabolised by CYP3A4 (see Section

4.5). Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg 3-day oral regimen or 165

mg single dose, could result in elevated plasma concentrations of these concomitant

medicinal products administered orally (see Section 4.5). Weak inhibition of CYP3A4 by a

single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of these

concomitant medicinal products to a clinically significant degree. The effect of EMEND on

the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of

EMEND on the pharmacokinetics of intravenously administered CYP3A4 substrates (see

Section 4.5).

Co-administration of EMEND with warfarin may result in a clinically significant decrease in

International Normalised Ratio (INR) of prothrombin time. In patients on chronic warfarin

therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10

days following initiation of the 3-day regimen of EMEND (125 mg/80 mg) or administration of

a single 165 mg dose of EMEND with each chemotherapy cycle or following administration

of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting

(PONV) (see Section 4.5).

The efficacy of hormonal contraceptives during and for 28 days after administration of

EMEND may be reduced. Alternative or back-up methods of contraception should be used

during treatment with EMEND and for one month following the last dose of EMEND (see

Interactions).

Paediatric Use

Safety and effectiveness of EMEND in paediatric patients have not been established.

Use in the Elderly

In clinical studies, the efficacy and safety of EMEND in the elderly (≥65 years) were

comparable to those seen in younger patients (<65 years). No dosage adjustment is

necessary in elderly patients.

Page 5 of 19

4.5

Interaction with other medicines and other forms of interaction

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of

CYP3A4. Aprepitant is also an inducer of CYP2C9.

EFFECT OF APREPITANT ON THE PHARMACOKINETICS OF OTHER AGENTS

As a weak (40 mg) to moderate (125 mg/80 mg, 165 mg) inhibitor of CYP3A4, aprepitant

can increase plasma concentrations of orally co-administered medicinal products that are

metabolised

through

CYP3A4.

Aprepitant

increase

plasma

concentrations

intravenously co-administered medicinal products metabolised through CYP3A4 to a lesser

extent.

EMEND

should

used

concurrently

with

pimozide,

terfenadine,

astemizole,

cisapride. Dose-dependent inhibition of CYP3A4 by aprepitant could result in elevated

plasma concentrations of these medicines, potentially causing serious or life-threatening

reactions (see Section 4.3).

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which

are metabolised through CYP2C9. Co-administration of EMEND with these drugs or other

drugs that are known to be metabolised by CYP2C9, such as phenytoin, may result in lower

plasma concentrations of these medicines.

EMEND is unlikely to interact with medicines that are substrates for the P-glycoprotein

transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical

medicine interaction study.

5-HT3 antagonists

In clinical medicine interaction studies, EMEND, when given as a regimen of 125 mg on Day

Days

have

clinically

important

effects

pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of

dolasetron).

Corticosteroids

Dexamethasone: EMEND when given as a regimen of 125 mg with dexamethasone co-

administered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with

dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of

dexamethasone, a CYP3A4 substrate by 2.2-fold, on Days 1 and 5. The usual

oral

dexamethasone doses should be reduced by approximately 50% when co-administered with

EMEND (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those

obtained when it is given without EMEND. The daily dose of dexamethasone administered in

clinical

chemotherapy

induced

nausea

vomiting

studies

with

EMEND

reflects

approximate 50% reduction of the dose of dexamethasone (see Section 4.2).

Aprepitant, when given as a single dose of 200 mg in the fed state (standard light breakfast)

on Day 1 with oral dexamethasone coadministered orally as 12 mg on Day 1 and 8 mg on

Days 2 through 4, increased the AUC of dexamethasone by 2.1- and 2.3-fold on Days 1 and

2, to a lesser extent (1.4-fold increase) on Day 3, and had no effect on Day 4 (1.1-fold

increase). The daily dose of dexamethasone on Days 1 and 2 should be reduced by

approximately 50% when coadministered with EMEND 165 mg on Day 1 to achieve

exposures of dexamethasone similar to those obtained when given without EMEND 165 mg.

Page 6 of 19

A single dose of EMEND (40 mg), when co-administered with a single oral dose of

dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no

dose adjustment is recommended.

Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day

on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-

fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was co-administered

intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The usual IV

methylprednisolone dose should be reduced by approximately 25%, and the usual oral

methylprednisolone dose should be reduced by approximately 50% when co-administered

with EMEND (125 mg/80 mg regimen), to achieve exposures of methylprednisolone similar

to those obtained when it is given without EMEND. Although the concomitant administration

of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a

single 40 mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam

interaction

study)

expected

alter

plasma

concentrations

methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is

recommended.

Chemotherapeutic agents

In clinical studies, EMEND (125 mg/80 mg regimen) was administered with the following

chemotherapeutic

agents

metabolised

primarily

part

CYP3A4:

etoposide,

vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel. The doses

of these agents were not adjusted to account for potential medicine interactions. Caution and

careful monitoring are advised in patients receiving these agents or other chemotherapy

agents

metabolised

primarily

3A4.

Post-marketing

events

neurotoxicity,

potential adverse event of ifosfamide, have been reported after aprepitant and ifosfamide

coadministration (see Section 4.4).

Docetaxel: In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not

influence the pharmacokinetics of docetaxel.

Vinorelbine: In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not

influence the pharmacokinetics of vinorelbine.

Warfarin

A single 125 mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and

3 to healthy subjects who were stabilised on chronic warfarin therapy. Although there was no

effect of EMEND on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there

decrease

S(-)

warfarin

CYP2C9

substrate)

trough

concentration

accompanied

decrease

prothrombin

time

(reported

International

Normalised Ratio or INR) 5 days after completion of dosing with EMEND. In patients on

chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2

week period, particularly at 7 to 10 days following initiation of the 3-day regimen (125 mg/80

mg) or administration of a single 165 mg dose of EMEND with each chemotherapy cycle, or

following administration of a single 40 mg dose of EMEND for the prevention of PONV.

Tolbutamide

EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the

AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on

Page 7 of 19

Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the

administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.

EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of

tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10%

on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the

administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered

clinically important.

Oral contraceptives

Aprepitant,

when

given

once

daily

days

capsule

with

oral

contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased

the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a single dose of an oral contraceptive containing ethinyl estradiol and

norethindrone was administered on Days 1 through 21 with EMEND, given as a regimen of

125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and

oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10 and 11. In the

study the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a

64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While

there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much

as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.

In another study, a single dose of an oral contraceptive containing ethinyl estradiol and

norgestimate (which is converted to norelgestromin) was administered on Days 1 through

21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol

decreased

respectively,

while

norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition,

the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were

generally lower following co-administration of the oral contraceptive with EMEND 40 mg on

Day 8 compared to the trough levels following administration of the oral contraceptive alone.

The efficacy of hormonal contraceptives during and for 28 days after administration of

EMEND may be reduced. Alternative or back-up methods of contraception should be used

during treatment with EMEND and for one month following the last dose of EMEND.

Midazolam

EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 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

Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2

through 5. A single dose of aprepitant 200 mg in the fed state (standard light breakfast) co-

administered orally with 2 mg midazolam increased the AUC of midazolam by 3.2-fold on

Day 1. No clinically important effect resulted on Day 4 (midazolam AUC 1.2-fold increase)

and a slight change in midazolam AUC was observed on Day 8 (35% decrease). The

potential effects of increased plasma concentrations of midazolam or other benzodiazepines

metabolised

CYP3A4

(alprazolam,

triazolam)

should

considered

when

administering these agents with EMEND (125 mg/80 mg or 165 mg).

A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1,

when a single oral dose of midazolam 2 mg was co-administered on Day 1 with EMEND 40

mg; this effect was not considered clinically important.

In another study with intravenous administration of midazolam, EMEND was given as 125

mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the

administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased

Page 8 of 19

the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on

Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not

considered clinically important. The AUC of midazolam on Day 15 was similar to that

observed at baseline.

An additional study was completed with intravenous administration of midazolam and

EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single

dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This

effect was not considered clinically important.

EFFECTS

OF

OTHER

AGENTS

ON

THE

PHARMACOKINETICS

OF

APREPITANT

Aprepitant is a substrate for CYP3A4; therefore, co-administration of EMEND with medicines

that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant.

Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g.,

ketoconazole) should be approached cautiously; but concomitant administration of EMEND

with moderate CYP3A4 inhibitors (e.g., diltiazem) does not result in clinically meaningful

changes in plasma concentrations of aprepitant.

Aprepitant is a substrate for CYP3A4; therefore, co-administration of EMEND with medicines

that

strongly

induce

CYP3A4

activity

(e.g.,

rifampicin)

result

reduced

plasma

concentrations of aprepitant that may result in decreased efficacy of EMEND.

Ketoconazole

When a single 125 mg dose of EMEND 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.

Concomitant

administration

EMEND

with strong CYP3A4 inhibitors

should be

approached cautiously.

Rifampicin

When a single 375 mg dose of EMEND 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

approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Co-

administration of EMEND with medicines that induce CYP3A4 activity may result in reduced

plasma concentrations and decreased efficacy of EMEND.

ADDITIONAL INTERACTIONS

Diltiazem

In patients with mild to moderate hypertension, administration of aprepitant once daily, as a

tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3

times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous

1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically

meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced

by diltiazem alone.

Paroxetine

Page 9 of 19

Co-administration of once daily doses of aprepitant, as a tablet formulation comparable to 85

mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a

decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant

and paroxetine.

4.6

Fertility, pregnancy and lactation

Effects on Fertility

Reproductive studies have been performed in rats and rabbits at doses up to 1.5 times the

systemic exposure at the adult human dose following oral aprepitant 125 mg and have

revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are,

however, no adequate and well-controlled studies in pregnant women. Because animal

reproduction studies are not always predictive of human response, this drug should be used

during pregnancy only if clearly needed.

Use in Pregnancy

There are no adequate and well-controlled studies in pregnant women. EMEND should be

used during pregnancy only if the potential benefit justifies the potential risk to the mother

and the foetus.

Use in Lactation

Aprepitant is excreted in the milk of lactating rats. It is not known whether this medicine is

excreted in human milk. Because many medicines are excreted in human milk and because

of the possible adverse effects of EMEND on nursing infants, a decision should be made

whether to discontinue nursing or to discontinue the medicine, taking into account the

importance of the medicine to the mother.

4.7

Effects on ability to drive and use machines

No studies of the effects of EMEND on the ability to drive and use of machines have been

performed. However, certain side effects that have been reported with EMEND may affect

some patients' ability to drive or operate machinery. Individual responses to EMEND may

vary (See Section 4.8).

4.8

Undesirable effects

Summary of the safety profile

The overall safety of aprepitant was evaluated in approximately 6500 individuals.

PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV)

Highly Emetogenic Chemotherapy (HEC)

well-controlled

clinical

trials

patients

receiving

highly

emetogenic

cancer

chemotherapy

(HEC),

patients

were

treated

with

aprepitant

during

Cycle

chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up

to 6 cycles of chemotherapy. The 3-day oral EMEND regimen was given in combination with

ondansetron

dexamethasone

generally

well

tolerated.

Most

adverse

experiences reported in these clinical studies were described as mild to moderate in

intensity.

Page 10 of 19

In Cycle 1, medicine-related clinical adverse experiences were reported in approximately

19% of patients treated with the 3-day oral aprepitant regimen compared with approximately

14% of patients treated with standard therapy. Treatment was discontinued due to medicine-

related clinical adverse experiences in 0.6% of patients treated with the 3-day oral aprepitant

regimen compared with 0.4% of patients treated with standard therapy.

The most common medicine-related adverse experiences reported in patients treated with

the 3-day oral aprepitant regimen and greater than standard therapy were: hiccups (4.6%),

increased

(2.8%),

dyspepsia

(2.6%),

constipation

(2.4%),

headache

(2.0%),

decreased appetite (2.0%).

In an additional active-controlled clinical study in 1169 patients receiving the 3-day oral

aprepitant regimen and HEC, the adverse experience profile was generally similar to that

seen in the other HEC studies with the 3-day oral aprepitant regimen.

Moderately Emetogenic Chemotherapy (MEC)

well-controlled

clinical

trials

patients

receiving

moderately

emetogenic

cancer

chemotherapy (MEC), 868 patients were treated with the 3-day oral aprepitant regimen

during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up

to 4 cycles of chemotherapy. In both studies, the 3-day oral EMEND regimen was given in

combination with ondansetron and dexamethasone (aprepitant regimen) and was generally

well tolerated. Most adverse experiences reported in these clinical studies were described as

mild to moderate in intensity.

In the combined analysis of Cycle 1 data for these 2 studies, medicine-related adverse

experiences were reported in approximately 14% of patients treated with the 3-day oral

aprepitant regimen compared with approximately 15% of patients treated with standard

therapy. Treatment was discontinued due to medicine-related adverse experiences in 0.7%

of patients treated with the 3-day oral aprepitant regimen compared with 0.2% of patients

treated with standard therapy.

The most common medicine-related adverse experience reported at a greater incidence in

patients treated with the 3-day oral aprepitant regimen than with standard therapy was

fatigue (1.4%).

PREVENTION OF POSTOPERATIVE NAUSEA AND VOMITING (PONV)

In well-controlled clinical studies in patients receiving general balanced anaesthesia, 564

patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg

ondansetron IV. EMEND was generally well tolerated. Most adverse experiences reported

in these clinical studies were described as mild to moderate in intensity.

Medicine-related clinical adverse experiences were reported in approximately 4% of patients

treated with 40 mg aprepitant compared with approximately 6% of patients treated with 4 mg

ondansetron IV.

The most common medicine-related adverse experience reported in patients treated with

aprepitant and at a greater incidence than ondansetron was ALT increased (1.1%).

Tabulated list of adverse reactions

Highly and Moderately Emetogenic Chemotherapy

In a pooled analysis of the HEC and MEC studies the following drug-related adverse

experiences were reported in patients treated with the 3-day oral aprepitant regimen and at a

greater incidence than standard therapy or in postmarketing use:

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