Emend IV

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Fosaprepitant dimeglumine 197.5 mg ((free acid) (120.8 mg))
Available from:
Merck Sharp & Dohme (New Zealand) Limited
INN (International Name):
Fosaprepitant dimeglumine 197.5 mg ((free acid) (120.8 mg))
Dosage:
115 mg
Pharmaceutical form:
Powder for injection
Composition:
Active: Fosaprepitant dimeglumine 197.5 mg ((free acid) (120.8 mg)) Excipient: Disodium edetate Hydrochloric acid Lactose Polysorbate 80 Sodium hydroxide Water for injection
Units in package:
Vial, glass, Borosilicate Type I with 13 mm latex free rubber stoper, 1 dose unit
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Laboratoires Merck Sharp & Dohme - Chibret
Product summary:
Package - Contents - Shelf Life: Vial, glass, Borosilicate Type I with 13 mm latex free rubber stoper - 1 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) 24 hours reconstituted stored at or below 25°C - Vial, glass, Borosilicate Type I with 13 mm latex free rubber stoper - 10 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) 24 hours reconstituted stored at or below 25°C
Authorization number:
TT50-7673
Authorization date:
2006-05-26

EMEND IV™

fosaprepitant dimeglumine

Intravenous

What is in this leaflet

This leaflet answers some common questions about EMEND IV. It does not contain all the

available information. It does not takethe place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you being

given EMEND IV against the benefitsthey expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor.

Keep this leaflet with the medicine. You may need to read it again.

What EMEND IV is used for

Your doctor has prescribed EMEND IVfor the prevention of nausea and vomiting

associated with your cancerchemotherapy treatment.

How EMEND IV works

EMEND IV is a member of a class of medicines called neurokinin 1 (NK

) receptor

antagonists that is used ALONG WITH OTHER MEDICINES to prevent and control

nausea (sick feeling in the back of throat andstomach) and vomiting (throwing up) caused

by your cancer chemotherapy treatment.

Before you are given EMEND IV

When you must not be given it

Do not have EMEND IV if:

you have an allergy to EMEND IV or any ofthe ingredients listed at the end of this

leaflet

the packaging is torn or shows signs of tampering

the expiry date on the pack has passed.

If you receive this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start EMEND IV, talk to your doctor.

EMEND IV has not been adequately studied in children. Therefore, EMEND IV should not

be given to children.

EMEND IV works equally well in and is equally well-tolerated by older and younger adult

patients. No dosage adjustment isnecessary for older patients.

Before EMEND IV is started

Tell your doctor if:

you are pregnant or intend to become pregnant

you are breast-feeding or plan to breast-feed

you have any past or present medical problems

you have any allergies.

If you have not told your doctor about any ofthe above, tell them before you take any

EMEND IV.

Taking other medicines

Tell your doctor if you are taking any othermedicines, including medicines that you buy

without a prescription from your pharmacy, supermarket or health food shop.

Do not take EMEND IV with pimozide, terfenadine, astemizole, or cisapride. Taking

EMEND IV with these medications could result inserious or life-threatening problems.

Your doctor may check that your medicines are working properly together if you are taking

other medicines such as:

anti-anxiety drugs (such as alprazolam)

birth control medicines (which may not work as well)

warfarin (a blood thinner)

ketoconazole (an antifungal)

rifampin (an antibiotic)

paroxetine (a medicine used to treat a certain type of depression)

diltiazem (a medicine used to treat high blood pressure)

tolbutamide (a medicine used to treat diabetes)

phenytoin (a medicine used to treat seizures)

Your doctor has more information on medicinesto be careful with or avoid while taking

EMEND IV.

How EMEND IV is given

EMEND IV is given intravenously onDay 1 only of a 3-day regimen.

EMEND IV 115 mg given along with capsules of EMEND ®

.

Day1 (Dayof chemotherapy): EMEND IV 115 mg will be given to you intravenously

approximately 30 minutes before you start your chemotherapy treatment.

Day2 and Day3 (the two daysafter chemotherapy): Take one 80 mg capsule of

EMEND ®

(aprepitant) each morning for the 2 daysfollowing your chemotherapy treatment.

If you take too much (overdose)

If you receive more than the prescribed dosage, contact your doctor immediately. Do this

even if there are no signs ofdiscomfort or poisoning.

While you are using EMEND IV

Things you must do

If you become pregnant while taking EMEND IV, 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 IV.

Things to be careful of

There have been side effects reported with EMEND IVthat may affect your ability to drive

or operate machinery. Individual responsesto EMEND IV may vary. (See Adverse

Effects.)

Things that would be helpful to manage your nausea and vomiting

While good nutrition is important for everyone,it is especially important for people on

chemotherapy. Small, frequent meals oreating a snack before your chemotherapy

treatment may also help you tolerate it better. Talk to your healthcare professional for

further information.

Adverse Effects

Tell your doctor as soon as possible if you donot feel well while you are taking EMEND IV.

EMEND IV helps most people with nausea and vomiting associated with cancer

chemotherapy treatment, but it may have unwanted adverse effects in a few people.

Adverse effects seen with capsules of EMEND may also be seen with EMEND IV. All

medicines can have adverse effects. Sometimes they are serious, most of the time they

are not. You may need medical treatment ifyou get some of the adverse effects.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice or have anyof the following and theyworryyou:

infusion site pain

hardening of the infusion site

redness and/or itching at the infusion site

hiccups

fatigue

constipation

headache

loss of appetite

These are usually the mild adverse effects of EMEND IV.

Also, tell your doctor if you notice:

dizziness

diarrhoea

indigestion

belching

Your doctor may find an increase in some of your blood tests (eg ALT & AST liver

enzymes).

These are other adverse effects that have been reported with EMEND IV.

Other adverse effects not listed above may also occur in some patients. Tell your doctor if

you notice any other effects.

The following side effects have been reported in general use:

Allergic reactions, which may be sudden and/or serious, and may include hives, rash,

itching, redness of the face/skin, and cause difficulty in breathing or swallowing.

Do not be alarmed by this list of possible adverse effects. You may not experience any of

them.

Product description

What it looks like

EMEND IV comes as a solid white to off white cake in a 10 mL vial. It is reconstituted with

a diluent to make a solution suitable for injection.

Ingredients

Active ingredient:

EMEND IV for CINV intravenous administration contains 115 mg of fosaprepitant.

Inactive ingredients:

edetate disodium

polysorbate 80 (57.5 mg)

lactose anhydrous

sodium hydroxide and/or hydrochloric acid (for pH adjustment)

Manufacturer/Supplier

EMEND IV is marketed in New Zealand by:

Merck Sharp & Dohme (New Zealand) Limited

P O Box 99 851

Newmarket

Auckland

NEW ZEALAND

Tel: 0800 500 673

This leaflet was prepared in April 2010

CP-EMV-0410(120410)

™ Trademark of Merck Sharp & Dohme Corp., a subsidiaryof Merck & Co., Inc., Whitehouse Station, NJ, USA

Copyright ©2007, 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station,

NJ, USA All Rights Reserved

Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station,

NJ, USA

Copyright ©2007 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ,

USA All Rights Reserved

Document Outline

Name of Medicine

EMEND IV™

fosaprepitant dimeglumine

Intravenous

Presentation

EMEND IV 115 mg is for intravenous use and comes in a 10 mL vial with a grey butyl

stopper and aluminium seal with a light blue plastic flip off lid.

EMEND IV 150 mg is for intravenous use and comes in a 10 mL vial with a grey butyl

stopper and aluminium seal with a dark grey plastic flip off lid.

Each 10 mL vial contains either 115 mg or 150mg of fosaprepitant free acid as a white to

off white lyophilised solid.

The reconstitution liquid is clear.

Therapeutic Class

EMEND IV (fosaprepitant dimeglumine, MSD), is a prodrug of aprepitant, a substance

P/neurokinin (NK

) receptor antagonist.

Indications

EMEND IV, 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 Dosage and Administration)

moderately emetogenic cancer chemotherapy (see Dosage and Administration).

Dosage andAdministration

EMEND IV for intravenous administration isa lyophilised prodrug of aprepitant (EMEND ® )

containing polysorbate 80 (PS80). EMEND IV is available as a 150 mg and 115 mg IV for

infusion.

EMEND IV 150 mg

EMEND IV 150 mg is administered on Day 1 only as an infusionover 20 – 30 minutes

initiated approximately 30 minutes prior tochemotherapy. No capsules of EMEND are

administered on Days 2 and 3. EMEND IV should be administered in conjunction with a

corticosteroid and a 5-HT

antagonist as specified in the tables below. The recommended

dosage of dexamethasone with EMEND IV 150mg differs from the recommended dosage

of dexamethasone with EMEND IV 115 mg on Days 3 and 4.

Recommended dosing for the prevention ofnausea and vomiting associated with highly

emetogenic cancer chemotherapy:

Day 1 Day 2 Day 3 Day 4

EMEND IV 150 mg IV none none none

Dexamethasone** 12 mg orally 8 mg orally 8 mg orallybid 8 mg orallybid

Ondansetron † 32 mg IV 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 shouldalso be administered in the evenings on Days 3

and 4. The dose of dexamethasone accounts for medicine interactions.

† Ondansetron should be administered 30 minutes prior to chemotherapy treatment on Day 1.

Recommended dosing for the preventionof nausea and vomiting associated with

moderately emetogenic cancer chemotherapy:

Day 1

EMEND IV 150 mg IV

Dexamethasone** 12 mg orally

Ondansetron † 32 mg IV

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

of dexamethasone accounts for drug interactions.

† Ondansetron 8-mg capsule should be administered 30to 60 minutes prior to chemotherapy treatment

and one 8-mg capsule should be administered8 hours after the first dose on Day 1.

Preparation of EMEND IV for Injection 150 mg

1.Inject 5 mL saline into the vial. Assure that saline is added to the vial along the vial wall

in order to prevent foaming. Swirl the vialgently. Avoid shaking and jetting saline into

the vial.

2.Prepare an infusion bag filled with 145 mL of saline.

3.Withdraw the entire volume from the vialand transfer it into an infusion bag containing

145 mL of saline to yield a total volume of150 mL. Gently invert the bag 2-3 times.

The reconstituted final medicine solutionis stable for 24 hours at ambient room

temperature (at or below 25°C).

Parenteral medicine products should be inspected visually for particulate matter and

discolouration before administrationwhenever solution and container permit.

EMEND IV 115 mg

EMEND IV 115 mg is administered on Day 1 only as an infusionover 15 minutesinitiated

approximately 30 minutes prior to chemotherapy. Capsules of EMEND 80 mg should be

administered on Days 2 and 3. EMEND IV 115 mg should be administered in conjunction

with a corticosteroid and a 5-HT

antagonist as specified in the tables below. The

recommended dosage of dexamethasone with EMEND IV 115 mg differs from the

recommended dosage of dexamethasone with EMEND IV 150 mg on Days 3 and 4.

Capsules of EMEND 125 mg may be substituted for EMEND IV 115 mg on Day 1.

Recommended dosing for the prevention ofnausea and vomiting associated with highly

emetogenic cancer chemotherapy:

Day 1 Day 2 Day 3 Day 4

EMEND IV/EMEND 115 mg IV 80 mg orally 80 mg orally none

Dexamethasone** 12 mg orally 8 mg orally

8 mg orally 8 mg orally

Ondansetron † 32 mg IV 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

accounts for medicine interactions.

† Ondansetron should be administered 30 minutesprior to chemotherapy treatment on

Day 1.

Recommended dosing for the preventionof nausea and vomiting associated with

moderately emetogenic cancer chemotherapy:

Day 1 Day 2 Day 3

EMEND IV/EMEND 115 IV 80 mg orally 80 mg orally

Dexamethasone** 12 mg orally none none

Ondansetron† 2 x 8 mg orally none none

**Dexamethasone should be administered 30 minutes prior to chemotherapy treatment

on Day 1. The dose of dexamethasone accounts for medicine interactions.

Ondansetron 8 mg capsule should be administered 30 to 60 minutes prior to

chemotherapy treatment and one 8 mg capsule should be administered 8 hours after

the first dose on Day 1.

Preparation of EMEND IV for Injection 115 mg

1.Inject 5 mL saline into the vial. Assurethat saline is added to the vial along the vial wall

in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into

the vial.

2.Prepare an infusion bag filled with110 mLof saline.

3.Withdraw the entire volume from the vialand transfer it into an infusion bag containing

110 mL of saline toyield a total volume of 115 mL. Gently invert the bag 2-3 times.

The reconstituted final medicine solutionis stable for 24 hours at ambient room

temperature (at or below 25°C).

Parenteral medicine products should be inspected visually for particulate matter and

discolouration before administrationwhenever solution and container permit.

EMEND IV is incompatible with any solutionscontaining divalent cations (e.g., Ca2+,

Mg2+), including Hartman’s and Lactated Ringer’s Solution. EMEND IV must not be

reconstituted or mixed with solutions for which physical and chemical compatibility have

not been established.

General Information

See Interactions for additional informationon the administration of EMEND IV with

corticosteroids.

Refer to the full prescribing informationfor co-administered antiemetic agents.

No dosage adjustment is necessary for the elderly.

No dosage adjustment is necessary based on gender or race.

No dosage adjustment is necessary for patientswith severe renal insufficiency (creatinine

clearance <30 mL/min) or for patients with end stage renal disease undergoing

haemodialysis.

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).

Contraindications

EMEND IV is contraindicated in patients who are hypersensitive to EMEND IV, aprepitant,

polysorbate 80 or any othercomponents of the product.

EMEND IV should not be used concurrentlywith pimozide, terfenadine, astemizole, or

cisapride. Inhibition of cytochrome P450isoenzyme 3A4 (CYP3A4) by aprepitant could

result in elevated plasma concentrations ofthese medicines, potentially causing serious or

life-threatening reactions (see Interactions).

Warnings and Precautions

Since fosaprepitant is rapidly converted to aprepitant (a weak to moderate inhibitor of

CYP3A4), fosaprepitant should be used with caution in patients receiving concomitant

orally administered medicinal products thatare primarily metabolised through CYP3A4;

some chemotherapy agents are metabolised byCYP3A4 (see Interactions). Moderate

inhibition of CYP3A4 by aprepitant and weakinhibition of CYP3A4 by fosaprepitant 150

mg could result in elevated plasma concentrations of these concomitant medicinal

products administered orally (see Interactions). The effect of oral aprepitant on the

pharmacokinetics of orally administered CYP3A4substrates is greater than the effect of

oral aprepitant on the pharmacokinetics of intravenously administered CYP3A4 substrates

(see Interactions).

Isolated reports of immediate hypersensitivity reactions including flushing, erythema, and

dyspnoea have occurred during infusion of fosaprepitant. These hypersensitivity reactions

have generally responded to discontinuationof the infusion and administration of

appropriate therapy. It is not recommended toreinitiate the infusion in patients who

experience hypersensitivity reactions.

Co-administration of oral aprepitant with warfarin may resultin a clinically significant

decrease in International Normalised Ratio (INR) of prothrombin time. In patients on

chronic warfarin therapy, the INR should beclosely monitored in the 2-week period,

particularly at 7 to 10 days, following initiation of fosaprepitantwith each chemotherapy

cycle (see Interactions).

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

fosaprepitant or oral aprepitant may be reduced. Alternative or back-up methods of

contraception should be used during treatment with fosaprepitantor oral aprepitant and for

one month following the last dose (see Interactions).

Pregnancy

There are no adequate and well-controlled studiesin pregnant women. EMEND IV should

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

mother and the foetus.

Nursing Mothers

EMEND IV, when administered intravenously,is rapidly converted to aprepitant.

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

excreted in human milk. Because manymedicines are excreted in human milk and

because of the possible adverse effects of aprepitant on nursing infants, a decision should

be made whether to discontinue nursing or todiscontinue the medicine, taking into

account the importance of the medicine to the mother.

Paediatric Use

Safety and effectiveness of EMEND IV inpaediatric patients have not been established.

Use In The Elderly

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

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

necessary in elderly patients.

Animal Toxicology

Acute Toxicity

The approximate oral LD

of aprepitant was >2000 mg/kg in female mice and rats. The

approximate LD

of fosaprepitant following intravenousadministration was >500 mg/kg in

female mice and >200 mg/kg in female rats.

Chronic Toxicity

Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant.

The toxicity potential of aprepitant was evaluated in a series of repeated-dose oral toxicity

studies in rats and in dogs for up to 1 year.

In rats, oral administration of aprepitant for6 months at doses up to the maximum feasible

dose of 1000 mg/kg twice daily (approximately equivalent to [females] or lower than

[males] the adult human dose based on systemicexposure following oral aprepitant 125

mg) produced increased hepatic weights thatcorrelated with hepatocellular hypertrophy,

increased thyroidal weights that correlated with thyroid follicular cell hypertrophy and/or

hyperplasia, and pituitary cell vacuolation.These findings are a species-specific

consequence of hepatic CYP enzyme induction inthe rat, and are consistent with changes

observed in rats with other structurally andpharmacologically dissimilar compounds that

have been shown to induce hepatic CYP enzymes.

In dogs administered aprepitant orally for 9 months at doses≥5 mg/kg twice daily (greater

than or equal to 13 times the adult human dose based on systemic exposure following oral

aprepitant 125 mg), toxicity was characterised by slight increases in serum alkaline

phosphatase activity and decreases in the albumin/globulin ratio. Significantly decreased

body weight gain, testicular degeneration, andprostatic atrophy were observed at doses

≥25 mg/kg twice daily (greater than orequal to 31 times the adult human dose based on

systemic exposure following oral aprepitant 125 mg). A slight increase in hepatic weights

with no histologic correlate was seen at 500 mg/kg twice daily (70 times the adult human

dose based on systemic exposure following oralaprepitant 125 mg). No toxicity was

observed in dogs administered 32 mg/kg/day(6 times the adult human dose based on

systemic exposure following oral aprepitant 125 mg) for 1 year.

Carcinogenesis

Carcinogenicity studies were conducted in miceand rats for 2 years with oral aprepitant.

Mice developed hepatocellular adenomas and/or carcinomas at doses of 500 to 2000

mg/kg/day (females) and hepatocellular carcinomas at doses of 1000 and 2000 mg/kg/day

(males). Systemic exposures at these dosesin mice were approximately 2.5 to 3.6 times

the exposure in humans at the recommended dose. Rats developed hepatocellular

adenomas at doses of 5 to 1000 mg/kg twicedaily (females) and 125 mg/kg twice daily

(males), hepatocellular carcinomas at dosesof 125 to 1000 mg/kg twice daily (females),

thyroid follicular cell adenomas at doses of125 to 1000 mg/kg twice daily (females and

males), and thyroid follicular cell carcinomas at doses of 125 to 1000 mg/kg twice daily

(males). Systemic exposures at these doses in rats were lower than or up to

approximately 2 times the exposure in humans at the recommended dose. Liver and

thyroid tumours of these types are a species-specific consequence of hepatic CYP

enzyme induction in rodents, and are consistent with changes observed in rodents with

other structurally and pharmacologically dissimilar compounds that have been shown to

induce hepatic CYP enzymes. Carcinogenicity studies were not conducted with

fosaprepitant.

Mutagenesis

Fosaprepitant and aprepitant were neithermutagenic nor genotoxic in assays conducted

to detect mutagenicity, DNA strand breaks, andchromosomal aberrations. Aprepitant was

negative in thein vitromicrobial and TK6 human lymphoblastoid cell mutagenesis assays,

thein vitroalkaline elution/rat hepatocyte DNA strand break test, thein vitrochromosomal

aberration assay in Chinese hamster ovary cells, and thein vivomouse micronucleus

assay in bone marrow.

Reproduction

Fosaprepitant, when administered intravenously, israpidly converted to aprepitant. In the

fertility studies conducted with fosaprepitant and aprepitant, the highest systemic

exposures to aprepitant were obtained following oral administration of aprepitant.

Aprepitant administered to female rats atdoses up to the maximum feasible dose of 1000

mg/kg twice daily (approximately equivalentto the adult human dose based on systemic

exposure following oral aprepitant 125 mg) hadno effects on mating performance, fertility,

or embryonic/foetal survival.

Administration of aprepitant to male rats atdoses up to the maximum feasible dose of

1000 mg/kg twice daily (lower than theadult human dose based on systemic exposure

following oral aprepitant 125 mg) produced no effects on mating performance, fertility,

embryonic/foetal survival, sperm count and motility, testicular weights, or the microscopic

appearance of the testes and epididymides.

Development

Fosaprepitant, when administered intravenously, israpidly converted to aprepitant. In the

teratology studies conducted with fosaprepitant and aprepitant, the highest systemic

exposures to aprepitant were obtained following oral administration of aprepitant.

In rats and rabbits administered oral dosesof aprepitant up to 1000 mg/kg twice daily and

25 mg/kg/day, respectively (up to 1.5 times the systemic exposure at the adult human

dose following oral aprepitant 125 mg), there was no evidence of developmental toxicity as

assessed by embryonic/foetal survival, foetalbody weight, and foetal external, visceral,

and skeletal morphology. Placental transfer ofaprepitant occurred in rats and rabbits at

these doses. Concentrations of aprepitant infoetal plasma were approximately 27% and

56% of maternal plasma concentrationsin rats and rabbits, respectively.

Significant concentrations of aprepitant wereobserved in the milk of lactating rats

administered 1000 mg/kg twice daily. At thisdose, the mean milk medicine concentration

was 90% of the mean maternal plasma concentration.

Effects on the Abilityto Drive and Use Machinery

No studies of the effects of EMEND IV onthe ability to drive and use of machines have

been performed. However, certain adverseeffects that have been reported with EMEND

IV may affect some patients' ability to driveor operate machinery. Individual responses to

EMEND IV may vary. (See Adverse Effects.)

Adverse Effects

Since fosaprepitant is converted to aprepitant, those adverse experiences associated with

aprepitant might also be expected to occur with EMEND IV.

The overall safety of fosaprepitant wasevaluated in approximately 1100 individuals, and

the overall safety of aprepitant wasevaluated in approximately 6500 individuals.

Prevention of ChemotherapyInduced Nausea and Vomiting (CINV)

Oral Aprepitant

Highly Emetogenic Chemotherapy (HEC)

In 2 well-controlled clinical trials inpatients receiving highly emetogenic cancer

chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy

and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of

chemotherapy. Oral aprepitant 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 Cycle 1, medicine-related clinical adverseexperiences were reported in approximately

17% of patients treated with the aprepitant regimen compared with approximately 13% of

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

related clinical adverse experiences in 0.6%of patients treated withthe aprepitant regimen

compared with 0.4% of patients treated with standard therapy.

The most common medicine-related adverse experiences reported inpatients treated with

the aprepitant regimen andgreater than standard therapy were: hiccups (4.6%),

asthenia/fatigue (2.9%), ALT increased (2.8%), constipation (2.2%), headache (2.2%), and

anorexia (2.0%).

In an additional active-controlled clinical study in 1169 patients receiving aprepitant and

highly emetogenic chemotherapy, the adverse experience profile was generally similar to

that seen in the other HEC studies with aprepitant.

Moderately Emetogenic Chemotherapy (MEC)

In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer

chemotherapy, 868 patients were treated with aprepitant during Cycle 1 of chemotherapy

and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In

both studies, oral aprepitant 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 forthese 2 studies, medicine-related adverse

experiences were reported in approximately14% of patients treated with the 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 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 aprepitant regimen than with standard therapy was fatigue (1.4%).

Highly and Moderately Emetogenic Chemotherapy

The following medicine-related adverse experiences were observed in either HEC or MEC

studies in patients treated with the aprepitant regimen and ata greater incidence than

standard therapy:

[Common (1/100, <1/10) Uncommon (>1/1000, <1/100)]

Infection and infestations:

Uncommon : candidiasis, staphylococcal infection.

Blood and the lymphatic system disorders:

Uncommon : anaemia, febrile neutropenia.

Metabolism and nutrition disorders:

Common : anorexia

Uncommon : weight gain, polydipsia.

Psychiatric disorders:

Uncommon : disorientation, euphoria, anxiety.

Nervous system disorders:

Common : headache, dizziness

Uncommon : dream abnormality, cognitive disorder, lethargy, somnolence.

Eye disorders:

Uncommon : conjunctivitis.

Ear and labyrinth disorders:

Uncommon : tinnitus.

Cardiac disorders:

Uncommon : bradycardia, palpitations.

Vascular disorders:

Uncommon : hot flush.

Respiratory, thoracic andmediastinal disorders:

Common : hiccups

Uncommon : pharyngitis, sneezing, cough, post nasal drip, throat irritation.

Gastrointestinal disorders:

Common : constipation, diarrhoea, dyspepsia, eructation

Uncommon : nausea, acid reflux, dysgeusia,epigastric discomfort, obstipation,

gastroesophageal reflux disease, perforating duodenalulcer, vomiting, abdominal pain, dry

mouth, enterocolitis, flatulence, stomatitis.

Skin and subcutaneous tissue disorders:

Uncommon : rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion.

Musculoskeletal and connective tissue disorders:

Uncommon : muscle cramp, myalgia.

Renal and urinary disorders:

Uncommon : polyuria, dysuria, pollakiuria.

General disorders and administration site conditions:

Common : asthenia/fatigue

Uncommon : oedema, flushing, sneezing, chest discomfort, malaise, thirst.

Investigations:

Common : ALT increased, AST increased

Uncommon : alkaline phosphatase increased, hyperglycaemia, microscopic haematuria,

hyponatraemia, weight decreased.

The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies

for up to 6 cycles of chemotherapy were generally similar to those observed in Cycle 1.

In another chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson

syndrome was reported as a serious adverse experience in a patient receiving aprepitant

with cancer chemotherapy.

Fosaprepitant

In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy,

safety was evaluated for 1143 patients receiving the 1-day regimen of EMEND IV 150 mg

compared to 1169 patients receiving the 3-dayregimen of EMEND (aprepitant). The

safety profile was generally similar to thatseen in prior HEC studies with aprepitant.

The following additional clinically important medicine related adverse experiences occurred

with fosaprepitant 150 mg and have not been reported in earlier clinical studies with oral

aprepitant (3-day regimen) as described above.

[Common (1/100, <1/10) Uncommon (>1/1000, <1/100)]

General disorders and administration site conditions:

Uncommon : infusion site erythema, infusion site pruritus, infusion site induration, infusion

site pain

Investigations:

Uncommon : blood pressure increased

Skin and subcutaneous tissue disorders:

Uncommon : erythema

Vascular disorders:

Uncommon : flushing, thrombophlebitis (predominantly, infusion-site thrombophlebitis)

Clinically significant laboratory analyses duringthe follow-up time period (Day 6 to 29)

indicated a higher incidence of serum alanine aminotransferase >5X ULN in patients

treated with the fosaprepitant regimen (1.8%) compared to patients treated with the

aprepitant regimen (0.5%). Monitoring of liverfunction tests may be considered, especially

in patients who have a known underlying hepatic condition.

Prevention of Postoperative Nausea and Vomiting (PONV)

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

patients were administered 40 mg aprepitantorally and 538 patients were administered 4

mg ondansetron IV. Aprepitant 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 adverseexperience reported inpatients treated with

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

The following medicine-related adverse experiences were observed in patients treated with

aprepitant and at a greaterincidence than ondansetron:

[Common (>1/100, <1/10) Uncommon (>1/1000, <1/100)]

Psychiatric disorders:

Uncommon : insomnia.

Nervous system disorders:

Uncommon : dysarthria, hypoaesthesia, sensory disturbance.

Eye disorders:

Uncommon : miosis, visual acuity reduced.

Cardiac disorders:

Uncommon : bradycardia.

Respiratory, thoracic andmediastinal disorders:

Uncommon : dyspnoea, wheezing.

Gastrointestinal disorders:

Uncommon : abdominal pain upper, bowel sounds abnormal, dry mouth, nausea, stomach

discomfort.

Investigations:

Common : ALT increased.

In addition, two serious adverse experiences were reported in postoperative nausea and

vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of

constipation and one case of sub-ileus.

Other Studies

Angioedema and urticaria were reported in apatient receiving aprepitant in a non-

CINV/non-PONV study.

Post-Marketing Experience

The following adverse reactions have been identified during post-marketing use. Because

these reactions are reported voluntarily from a population of uncertain size, it is generally

not possible to reliably estimate their frequencyor establish a causal relationship to the

medicine.

Skin and subcutaneous tissue disorders : pruritus, rash, urticaria, rarely Stevens-Johnson

syndrome/toxic epidermal necrolysis

Immune systemdisorders : hypersensitivity reactions including anaphylactic reactions

Immediate hypersensitivity reactionshave been observed during the infusion of

fosaprepitant which may include the following: flushing, erythema, dyspnoea (see

Warnings and Precautions).

Interactions

Medicine interactions following administrationof fosaprepitant are likely to occur with

medicines that interact with oral aprepitant. The following information was derived from

studies conducted with oral aprepitant andstudies conducted with fosaprepitant co-

administered with dexamethasone,midazolam or diltiazem.

Aprepitant is a substrate, a weak to moderate inhibitor, and an inducer of CYP3A4.

Aprepitant is also an inducer of CYP2C9.

EMEND IV 150 mg, given as a single dose, is a weak inhibitor of CYP3A4, and does not

induce CYP3A4. It is anticipated that EMENDI V 150 mg would cause less or no greater

induction of CYP2C9 than that caused bythe administration of oral aprepitant.

Effect of Fosaprepitant/Aprepitant onthe Pharmacokinetics of Other Agents

Aprepitant, as a weak to moderate inhibitor of CYP3A4, and EMEND IV 150 mg, as a

weak inhibitor of CYP3A4, can increase plasmaconcentrations of orally co-administered

medicinal products that are metabolised through CYP3A4.

Fosaprepitant should not be used concurrentlywith pimozide, terfenadine, astemizole, or

cisapride. Dose-dependent inhibition of CYP3A4by aprepitant could result in elevated

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

reactions (see Contraindications).

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

which are metabolised through CYP2C9. Co-administration of fosaprepitant with these

medicines or other medicines that are known to be metabolised by CYP2C9, such as

phenytoin, may result in lower plasma concentrations of these medicines.

Fosaprepitant or aprepitant are unlikely to interact with medicines that are substrates for

the P-glycoprotein transporter, asdemonstrated by the lack of interaction of oral aprepitant

with digoxin in a clinical medicine interaction study.

5-HT

3 antagonists

In clinical medicine interaction studies, aprepitant did not have clinically important effects

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

metabolite of dolasetron).

Corticosteroids

Dexamethasone : Fosaprepitant 150 mg administered as a single intravenous dose on

Day 1 increased the AUC

0-24hr of dexamethasone, a CYP3A4substrate, by approximately

2.0-fold on Days 1 and 2 when dexamethasone wasco-administered as a single 8 mg oral

dose on Days 1, 2, and 3. The oral dexamethasone dose on Days 1 and 2 should be

reduced by approximately 50% when co-administered with fosaprepitant 150 mg IV on

Day 1 to achieve exposures of dexamethasone similar to those obtained when given

without fosaprepitant 150 mg.

Oral aprepitant, when given as a regimen of125 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 8mg 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 a regimen of fosaprepitant 115 mg followed by aprepitant to achieve exposures of

dexamethasone similar to those obtained when itis given without aprepitant. The daily

dose of dexamethasone administered inclinical chemotherapy induced nausea and

vomiting studies with oral aprepitant reflectsan approximate 50% reduction of the dose of

dexamethasone (see Dosage and Administration).

Methylprednisolone : 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 ofmethylprednisolone, 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 shouldbe reduced by approximately 50% when co-

administered with a regimen offosaprepitant 115 mg followed by aprepitant to achieve

exposures of methylprednisolone similar tothose obtained when it is given without

aprepitant.

Chemotherapeutic agents

In clinical studies, the oral aprepitantregimen was administered with the following

chemotherapeutic agents metabolised primarily or in part by CYP3A4: etoposide,

vinorelbine, docetaxel, and paclitaxel. The doses of these agents were not adjusted to

account for potential medicine interactions.

Docetaxel : In a separate pharmacokinetic study, oral aprepitant (CINV regimen) did not

influence the pharmacokinetics of docetaxel.

Vinorelbine : In a separate pharmacokinetic study, oral aprepitant (CINV regimen) did not

influence the pharmacokinetics of vinorelbine.

Warfarin

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.

Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin

(a CYP2C9 substrate) determined on Day 3,there was a 34% decrease in S(-) warfarin

trough concentration accompanied by a 14% decrease in the prothrombin time (reported

as International Normalised Ratio or INR)5 days after completion of dosing with oral

aprepitant. In patients on chronic warfarintherapy, the prothrombin time (INR) should be

closely monitored in the 2 week period, particularly at 7 to 10 days following initiation of

fosaprepitant with each chemotherapy cycle.

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 CYP2C9substrate) 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.

Oral contraceptives

Aprepitant, when given once daily for 14 days as a 100 mg capsule with an 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 oral aprepitant, given as a

regimen of 125 mg on Day 8 and 80 mg/dayon 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 oralaprepitant 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.

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

fosaprepitant or aprepitant may be reduced. Alternative or back-up methods of

contraception should be used during treatmentwith fosaprepitant or aprepitant and for 1

month following the last dose.

Midazolam

Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the

0-∞ of midazolam by approximately 1.8-fold on Day 1 and had no effect (1.0 fold) on

Day 4 when midazolam was co-administered as a single oral dose of 2 mg on Days 1 and

4. Fosaprepitant 150 mg IV is a weak CYP3A4 inhibitor as a single dose on Day 1 with no

evidence of inhibition or induction of CYP3A4 observed on Day 4.

In addition, when fosaprepitant was administered as a dose of 100 mg over 15 minutes

along with a single dose of midazolam 2 mg, the plasma AUC of midazolam was increased

by 1.6-fold. This effect was not considered clinically important.

Oral aprepitant 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 regimenof oral aprepitant 125 mg on Day 1 and 80

mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of

midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam)

should be considered when co-administering these agents with fosaprepitant or aprepitant.

In another study with intravenous administrationof midazolam, oral aprepitant 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 oral aprepitant and on Days 4, 8, and

15. Oral aprepitant increased the AUC ofmidazolam by 25% on Day 4 and decreased the

AUC of midazolam by 19% on Day 8 relativeto the dosing of oral aprepitant on Days 1

through 3. These effects were not consideredclinically 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 oral

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

single dose of oral aprepitant 125 mg. Theplasma AUC of midazolam was increased by

1.5-fold. This effect was not considered clinically important.

Effect of other agents on the pharmacokinetics of aprepitant

Aprepitant is a substrate for CYP3A4; therefore, co-administrationof fosaprepitant or

aprepitant with medicines that inhibit CYP3A4activity may result in increased plasma

concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or

aprepitant with strong CYP3A4 inhibitors(e.g., ketoconazole) should be approached

cautiously; but concomitant administration ofaprepitant with moderate CYP3A4 inhibitors

(e.g., diltiazem) does not result in clinicallymeaningful changes in plasma concentrations

of aprepitant.

Aprepitant is a substrate for CYP3A4; therefore, co-administrationof fosaprepitant or

aprepitant with medicines that strongly induce CYP3A4 activity (eg., rifampin) may result in

reduced plasma concentrations and decreased efficacy.

Ketoconazole

When a single 125 mg dose of oral aprepitantwas 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 meanterminal half-life of aprepitant increased

approximately 3-fold. Concomitantadministration of fosaprepitant or aprepitant with strong

CYP3A4 inhibitors should be approached cautiously.

Rifampin

When a single 375 mg dose of oral aprepitantwas administered on Day 9 of a 14-day

regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant

decreased approximately 11-fold and the meanterminal half-life decreased approximately

3-fold. Co-administration of fosaprepitantor aprepitant with medicines that induce

CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

Additional interactions

Diltiazem

In patients with mild to moderate hypertension, infusion of100 mg fosaprepitant over 15

minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant

AUC and a 1.4 fold increase in diltiazem AUC. The pharmacokinetic effects resulted in a

small but clinically meaningful decrease indiastolic blood pressure (decrease of 16.8 mm

Hg with fosaprepitant versus 10.5 mm Hg withoutfosaprepitant) and may result in a small

but clinically meaningful decrease in systolicblood pressure (decrease of 24.4 mm Hg with

fosaprepitant versus 18.8 mm Hg without fosaprepitant), but did not result in a clinically

meaningful change in heart rate, or PR interval, beyond those changes induced by

diltiazem alone.

In the same study, 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

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 C

max by approximately 20% of both

aprepitant and paroxetine.

Overdosage

No specific information is available on the treatment of overdosage with EMEND IV.

Single doses up to 200 mg of fosaprepitantand 600 mg of aprepitant were generally well

tolerated in healthy subjects. Three out of33 subjects receiving 200 mg of fosaprepitant

experienced mild injection site thrombosis. Aprepitant was generally well tolerated when

administered as 375 mg once daily for up to 42 days to patients in non-CINV studies. In

33 cancer patients, administration of a single 375 mg dose of aprepitant on Day 1 and 250

mg once daily on Days 2 to 5 was generally well tolerated.

Drowsiness and headache were reported inone patient who ingested 1440 mg of

aprepitant.

In the event of overdose, EMEND IVshould be discontinued and general supportive

treatment and monitoring should be provided. Because of the antiemetic activity of

aprepitant, medicine-induced emesis may not be effective.

Aprepitant cannot be removed by haemodialysis.

Actions

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly

converted to aprepitant, a substance P/neurokinin 1 (NK

) receptor antagonist. Plasma

concentrations of fosaprepitant are below thelimits of quantification(10 ng/mL) within 30

minutes of the completion of infusion.

Fosaprepitant is a prodrug ofaprepitant and accordingly, its antiemetic effects are

attributable to aprepitant.

Aprepitant has a unique mode of action; it isa selective high affinity antagonist at human

substance P neurokinin 1 (NK

) receptors. Counter-screening assays showed that

aprepitant was at least 3,000-fold selective for the NK

receptor over other enzyme,

transporter, ion channel and receptor sitesincluding the dopamine and serotonin receptors

that are targets for existing CINV therapy.

-receptor antagonists have been shown pre-clinically to inhibit emesis induced by

cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Preclinical and

human Positron Emission Tomography (PET) studieswith aprepitant have shown that it is

brain penetrant and occupies brain NK

1 receptors. Preclinical studies show that aprepitant

has a long duration of central activity, inhibits both the acute and delayed phases of

cisplatin-induced emesis, and augments the antiemetic activity of the 5-HT

-receptor

antagonist ondansetron and the corticosteroiddexamethasone against cisplatin-induced

emesis.

Pharmacodynamics - Cardiac Electrophysiology

In a randomised, double-blind, positive controlled, thorough QTc study, a single 200 mg

dose of fosaprepitant had no effect on the QTc interval.

Pharmacokinetics

Absorption

Following a single intravenous 115 mg dose of fosaprepitant administered as a 15-minute

infusion to healthy volunteers the mean AUC

0-24hr of aprepitant was 19.8 mcg hr/mL and

the mean maximal aprepitant concentration was 3.26 mcg/mL.

The AUC of aprepitant which is formed following administration of 115 mg of the IV

prodrug fosaprepitant was equivalent to the AUC of 125 mg of orally administered

aprepitant. Mean plasma concentrations following single doses are depicted in Figure 1.

Figure 1: Mean Plasma Concentration of Aprepitant

Following 125 mg Oral Aprepitant and 115 mg IV Fosaprepitant

Time(hr) 0 12 24 36 48 60 72 M ean P las m a C onc ent ra tion of A pr p itant ( ng/ m L)

1000 1500 2000 2500 3000 3500

125-mg Oral Aprepitant

115-mg IVFosaprepitant

Following a single intravenous 150 mg dose of fosaprepitant administered as a 20-minute

infusion to healthy volunteers the mean AUC

0-∞ of aprepitant was 35.0 mcghr/mL and the

mean maximal aprepitant concentration was 4.01 mcg/mL.

Distribution

Fosaprepitant is rapidly converted to aprepitant.

Aprepitant is greater than 95% bound to plasma proteins. The geometric mean apparent

volume of distribution at steady state (Vd

) is approximately 66 L in humans.

Aprepitant crosses the placenta in rats, and crosses the blood brain barrier in rats and

ferrets. PET studies in humans indicate that aprepitant crosses the blood brain barrier

(see Actions).

Metabolism

Fosaprepitant was rapidly converted to aprepitant inin vitroincubations with liver

preparations from non-clinical species (rat and dog) and humans. Furthermore,

fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9

preparations from multiple other human tissues including kidney, lung and ileum. Thus, it

appears that the conversion of fosaprepitantto aprepitant can occur in multiple

extrahepatic tissues in addition to the liver. 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 24% of the radioactivity inplasma over 72 hours following a single oral

300 mg dose of [ 14 C]-aprepitant, indicating a substantial presence of metabolites in the

plasma. Seven metabolites of aprepitant, which are only weakly active, have been

identified in human plasma. The metabolism ofaprepitant occurs largely via oxidation at

the morpholine ring and its side chains. In vitrostudies using human liver microsomes

indicate that aprepitant is metabolised primarily by CYP3A4 with minor metabolism by

CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1.

All metabolites observed in urine, faeces and plasma following an intravenous 100 mg

C]-fosaprepitant dose were also observed following an oral dose of [ 14 C]-aprepitant.

Upon conversion of 188 mg of fosaprepitant dimeglumine (equivalent to 115 mg

fosaprepitant free acid) to aprepitant, 18.3 mgof phosphoric acid and 73 mg of meglumine

are liberated. Upon conversion of 245.3 mg offosaprepitant dimeglumine (equivalent to

150 mg fosaprepitant free acid) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of

meglumine are liberated.

Elimination

Following administration of a single IV 100 mg dose of [ 14 C]-fosaprepitant to healthy

subjects, 57% of the radioactivity was recovered in urine and 45% in faeces.

Aprepitant is eliminated primarily by metabolism; aprepitantis not renally excreted.

Following administration of a single oral 300 mg dose of [ 14 C]-aprepitant to healthy

subjects, 5% of the radioactivity was recovered in urine and 86% in faeces.

The apparent plasma clearance of aprepitant ranged from approximately 60 to 84 mL/min.

The apparent terminal half-life ranged from approximately 9 to 13 hours.

Characteristics In Patients

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly

converted to aprepitant.

Gender

Following oral administration of a single 125 mg dose of aprepitant, the C

max for aprepitant

is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower

in females as compared with males and its T

occurs at approximately the same time.

These differences are not considered clinically meaningful. No dosage adjustment is

necessary based on gender.

Elderly

Following oral administration of a single 125mg dose of aprepitant on Day 1 and 80 mg

once daily on Days 2 through 5, the AUC

0-24hr of aprepitant was 21% higher on Day 1 and

36% higher on Day 5 in elderly (≥65 years) relative to younger adults. The C

was 10%

higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These

differences are not considered clinically meaningful. No dosage adjustment is necessary

in elderly patients.

Paediatric

Fosaprepitant has not been evaluated inpatients below 18 years of age.

Race

Following oral administration of a single 125 mg dose of aprepitant, the AUC

0-24hr is

approximately 25% and 29% higher in Hispanics as compared with Caucasians and

Blacks, respectively. The C

is 22% and 31% higher in Hispanics as compared with

Caucasians and Blacks, respectively. These differences are not considered clinically

meaningful. No dosage adjustment is necessary based on race.

Hepatic Insufficiency

Fosaprepitant is metabolised in variousextrahepatic tissues; therefore hepatic

insufficiency is not expected to alter theconversion of fosaprepitant to aprepitant.

Oral aprepitant was well tolerated in patientswith mild to moderate hepatic insufficiency.

Following administration of a single 125 mg dose of oral aprepitant on Day 1 and 80 mg

once daily on Days 2 and 3 to patients with mild hepatic insufficiency (Child-Pugh score 5

to 6), the AUC

0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as

compared with healthy subjects given the same regimen. In patients with moderate

hepatic insufficiency (Child-Pugh score 7 to 9), the AUC

0-24hr of aprepitant was 10% higher

on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same

regimen. These differences in AUC

0-24hr are not considered clinically meaningful;

therefore, no dosage adjustment is necessaryin patients with mild to moderate hepatic

insufficiency.

There are no clinical or pharmacokinetic datain patients with severe hepatic insufficiency

(Child-Pugh score >9).

Renal Insufficiency

A single 240 mg dose of oral aprepitant wasadministered to patients with severe renal

insufficiency (CrCl<30 mL/min) and to patients with end stage renal disease (ESRD)

requiring haemodialysis.

In patients with severe renal insufficiency, the AUC

of total aprepitant (unbound and

protein bound) decreased by 21% and C

decreased by 32%, relative to healthy

subjects. In patients with ESRD undergoing haemodialysis, the AUC

of total aprepitant

decreased by 42% and C

decreased by 32%. Due to modest decreases in protein

binding of aprepitant in patients with renal disease, the AUC of pharmacologically active

unbound medicine was not significantly affected in patients with renal insufficiency

compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had

no significant effect on the pharmacokinetics ofaprepitant; less than 0.2% of the dose was

recovered in the dialysate.

No dosage adjustment is necessary for patients with severe renal insufficiency or for

patients with ESRD undergoing haemodialysis.

Pharmaceutical Precautions

Vials: Store at 2-8°C (36-46°F).

Medicine Classification

Prescription Medicine

Package Quantities

10 mL single dose vial containing either 115 mgor 150 mg fosaprepitant as the free acid.

Further Information

Chemistry

Fosaprepitant dimeglumine isa prodrug of aprepitant and ischemically described as 1-

Deoxy-1-(methylamino)-D-glucitol [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)

phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-

triazol-1-yl]phosphonate (2:1) (salt).

Its empirical formula is C

P ⋅2(C

) and its structural formula is:

Fosaprepitant dimeglumine is a white tooff-white amorphous powder with a molecular

weight of 1004.83. It is freely soluble in water.

Aprepitant is a structurally novel substance P neurokinin 1 (NK

) receptor antagonist,

chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-

fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its empirical formula is C

, and its structural formula is:

Aprepitant is a white to off-white crystallinesolid, with a molecular weight of 534.43. It is

practically insoluble in water. Aprepitantis sparingly soluble in ethanol and isopropyl

acetate and slightly soluble in acetonitrile.

Active Ingredients

EMEND IV is available as a 150 mg and 115 mg IVfor infusion. Each vial of EMEND IV

115 mg for CINV intravenous administration contains 188 mg of fosaprepitant dimeglumine

equivalent to 115 mg of fosaprepitant free acid.Each vial of EMEND IV 150 mg for CINV

intravenous administration contains 245.3 mg offosaprepitant dimeglumine equivalent to

150 mg of fosaprepitant free acid.

Inactive Ingredients

Each vial of EMEND IV 115 mg for CINV contains the following inactive ingredients:

edetate disodium, polysorbate 80 (57.5 mg),lactose anhydrous, sodium hydroxide and/or

hydrochloric acid (for pH adjustment). Eachvial of EMEND IV 150 mg for CINV contains

the following inactive ingredients: edetatedisodium, polysorbate 80 (75 mg), lactose

anhydrous, sodium hydroxide and/or hydrochloric acid (for pH adjustment).

Name andAddress

Merck Sharp & Dohme (NZ) Ltd

P O Box 99 851

Newmarket

Auckland

NEW ZEALAND

Tel: 0800 500 673

Date of Preparation

13 July 2011

WPC-MK0517-IV-032011

Copyright ©2007 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ,

USA All Rights Reserved

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