Aprepitant 125mg capsules

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Aprepitant
Available from:
Sandoz Ltd
ATC code:
A04AD12
INN (International Name):
Aprepitant
Dosage:
125mg
Pharmaceutical form:
Capsule
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: ; GTIN: 07613421026493

Page 1 of 3

1065019079_BOX_APREPITANT_80_125MG_CD_WAL1X1+2_GB.ai

aprepitant

1 x 125 mg hard capsule

2 x 80mg hard capsules

Aprepitant Zentiva 125mg/80mg hard capsules

Aprepitant Zentiva 125mg/80mg hard capsules

Aprepitant Zentiva 125mg/80mg hard capsules

Aprepitant Zentiva 125mg/80mg hard capsules

1 x 125 mg hard capsule and 2 x 80 mg hard capsule

Aprepitant 125mg/80 mg hard capsules

Each 80 mg capsule contains 80 mg of aprepitant.

Each 125 mg capsule contains 125 mg of aprepitant.

Contains sucrose and sodium

Read the package leaflet before use.

Oral use.

Store in the original package

in order to protect

from moisture.

KEEP OUT OF

THE SIGHT

AND REACH

OF CHILDREN.

PL 17780/0824

Zentiva Pharma UK Limited

12 New Fetter Lane

London EC4A 1JP

United Kingdom

1065019079

*will be implemented

not later than 2/2019

Data matrix code

printed on the right

of the variable data

Tamper evidence sol.

Orders with

serialization

Batch No:

EXP:

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EXP:

aprepitant

#125 mg/#80 mg

1065019079_BOX_APREPITANT_80_125MG_CD_WAL1X1+2_GB.pdf 1 6/2/2020 1:37:37 PM

Page 3 of 3

1065019079_BOX_APREPITANT_80_125MG_CD_WAL1X1+2_GB.ai

PMS 287 C PMS 7528 C PMS 568 C PMS 339 C PMS 2727 C

KEYLINE BRAILLE VARNISH FREE

Correction to the Braille text.

Space is required bewteen the number and the units 'mg' in the braille text.

This needs to be implemented in the next production run.

Correction to the Braille text.

Space is required bewteen the number and the units 'mg' in the braille text.

This needs to be implemented in the next production run.

aprepitant

#125 mg/#80 mg

aprepitant

#125 mg/#80 mg

Helvetica Neue LT Std 7 pt

100 x 24 x 145 mm

Pharmaten

02.06.2020

718149

APREPITANT 80;125MG; CD WAL1X1+2

1065019079

REEL POSITION

REEL POSITION

TECHNICAL COLOURS

TECHNICAL COLOURS

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TECHNICAL INFO

TECHNICAL INFO

GENERAL INFO

GENERAL INFO

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Aprepitant Zentiva 125mg/80mg hard capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 125 mg capsule contains 125mg of aprepitant.

Each 80 mg capsule contains 80 mg of aprepitant.

Excipient with known effect

Each 125mg capsule contains 125 mg of sucrose and 0.00026 mmol (0.006

mg) of sodium.

Each 80 mg capsule contains 80 mg of sucrose and 0.00022 mmol (0.005 mg)

of sodium.

For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Hard capsule (capsule)

The 125mg hard capsules are presented as opaque hard gelatin capsules of size No 1,

with a pink cap and white body, imprinted in black ink with “125mg” on the body.

The 80 mg hard capsules are presented as opaque hard gelatin capsules of size No 2,

with a white cap and white body, imprinted in black ink with “80mg” on the body.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Prevention of nausea and vomiting associated with highly and moderately emetogenic

cancer chemotherapy in adults and adolescents from the age of 12.

Aprepitant 125mg/80 mg is given as part of combination therapy (see section 4.2).

4.2

Posology and method of administration

Posology

Adults

Aprepitant is given for 3 days as part of a regimen that includes a corticosteroid and a

5-HT3 antagonist.

The recommended dose is 125mg orally once daily one hour before start of

chemotherapy on Day 1 and 80 mg orally once daily on Days 2 and 3 in the morning.

The following regimens are recommended in adults for the prevention of nausea and

vomiting associated with emetogenic cancer chemotherapy:

Highly Emetogenic Chemotherapy Regimen

Day 1

Day 2

Day 3

Day 4

Aprepitant

125mg

orally

80mg

orally

80mg

orally

none

Dexamethasone

12mg orally

8mg orally

8mg orally

8mg orally

5-HT

antagonists

Standard

dose of

5-HT

antagonists.

See the

product

information

for selected

5-HT

antagonist

appropriate

dosing

information

None

None

None

Dexamethasone should be administered 30 minutes prior to chemotherapy treatment

on Day 1 and in the morning on Day 2 to 4. The dose of dexamethasone accounts for

active substance interactions.

Moderately Emetogenic Chemotherapy Regimen

Day 1

Day 2

Day 3

Aprepitant

125mg orally

80mg orally

80mg orally

Dexamethasone

12mg orally

None

None

5-HT

antagonists

Standard dose of

5-HT

antagonists. See

the product

information for

selected

5-HT

antagonist

for appropriate

None

None

dosing

information

Dexamethasone should be administered 30 minutes prior to chemotherapy treatment

on Day 1. The dose of dexamethasone accounts for active substance interactions.

Paediatric population

Adolescents (aged 12 through 17 years)

Aprepitant is given for 3 days as part of a regimen that includes a 5-HT3 antagonist.

The recommended dose of capsules of aprepitant is 125mg orally on Days 1 and 80

mg orally on Days 2 and 3. Aprepitant is administered orally 1 hours prior to

chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3,

aprepitant should be administered in the morning. See the Summary of Product

Characteristics (SmPC) for the selected 5-HT3 antagonist for appropriate dosing

information. If a corticosteroid, such as dexamethasone, is co-administered with

aprepitant, the dose of the corticosteroid should be administered at 50% of the usual

dose (see sections 4.5 and 5.1).

The safety and efficacy of the 80 mg and 125mg capsules have not been demonstrated

in children less than 12 years of age. No data are available.

General

Efficacy data in combination with other corticosteroids and 5-HT3 antagonists are

limited. For additional information on the co-administration with corticosteroids, see

section 4.5. Please refer to the SmPC of co-administered 5-HT3 antagonist medicinal

products.

Special populations

Elderly (

65 years)

No dose adjustment is necessary for the elderly (see section 5.2).

Gender

No dose adjustment is necessary based on gender (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment or for patients

with end stage renal disease undergoing haemodialysis (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment. There are

limited data in patients with moderate hepatic impairment and no data in patients with

severe hepatic impairment.

Aprepitant should be used with caution in these patients (see sections 4.4 and 5.2).

Method of administration

For oral use. The hard capsule should be swallowed whole. Aprepitant may be taken

with or without food.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section

6.1. Co-administration with pimozide, terfenadine, astemizole or cisapride (see

section 4.5).

4.4

Special warnings and precautions for use

Patients with moderate to severe hepatic impairment

There are limited data in patients with moderate hepatic impairment and no data in

patients with severe hepatic impairment. Aprepitant should be used with caution in

these patients (see section 5.2).

CYP3A4 interactions

Aprepitant should be used with caution in patients receiving concomitant orally

administered active substances that are metabolised primarily through CYP3A4 and

with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus,

everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section

4.5). Additionally, concomitant administration with irinotecan should be approached

with particular caution as the combination might result in increased toxicity.

Co-administration with warfarin (a CYP2C9 substrate)

In patients on chronic warfarin therapy, the International Normalised Ratio (INR)

should be monitored closely during treatment with Aprepitant and for 14 days

following each 3-day course of Aprepitant (see section 4.5).

Co-administration with hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after

administration of aprepitant. Alternative non-hormonal back-up methods of

contraception should be used during treatment with aprepitant and for 2 months

following the last dose of aprepitant (see section 4.5).

Excipients

Aprepitant capsules contain sucrose. Patients with rare hereditary problems of

fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase

insufficiency should not take this medicinal product.

Aprepitant capsules contain sodium. This medicinal product contains less than 1

mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Aprepitant (125mg/80mg) is a substrate, a moderate inhibitor and an inducer of

CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with aprepitant,

CYP3A4 is inhibited. After the end of treatment, aprepitant causes a transient mild

induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant does not seem to

interact with the P-glycoprotein transporter, as suggested by the lack of interaction of

aprepitant with digoxin.

Effect of Aprepitant on the pharmacokinetics of other active substances

CYP3A4 inhibition

As a moderate inhibitor of CYP3A4, aprepitant (125mg/80mg) can increase plasma

concentrations of co-administered active substances that are metabolised through

CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase

up to approximately 3-fold during the 3-day treatment with aprepitant; the effect of

aprepitant on the plasma concentrations of intravenously administered CYP3A4

substrates is expected to be smaller. Aprepitant must not be used concurrently with

pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of

CYP3A4 by aprepitant could result in elevated plasma concentrations of these active

substances, potentially causing serious or life-threatening reactions. Caution is

advised during concomitant administration of aprepitant and orally administered

active substances that are metabolised primarily through CYP3A4 and with a narrow

therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil,

diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4).

Corticosteroids

Dexamethasone: The usual oral dexamethasone dose should be reduced by

approximately 50 % when co-administered with aprepitant 125mg/80mg regimen.

The dose of dexamethasone in chemotherapy-induced nausea and vomiting clinical

trials was chosen to account for active substance interactions (see section 4.2).

Aprepitant, when given as a regimen of 125mg with dexamethasone co-administered

orally as 20mg on Days 1, and aprepitant, when given as 80mg/day with

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

of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5.

Methylprednisolone: The usual intravenously administered methylprednisolone dose

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

should be reduced approximately 50 % when co-administered with aprepitant 125

mg/80 mg regimen. Aprepitant, when given as a regimen of 125mg 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 80 mg on Days

2 and 3.

During continuous treatment with methylprednisolone, the AUC of

methylprednisolone may decrease at later time points within 2 weeks following

initiation of the aprepitant dose, due to the inducing effect of aprepitant on CYP3A4.

This effect may be expected to be more pronounced for orally administered

methylprednisolone.

Chemotherapeutic medicinal products

In pharmacokinetic studies, aprepitant, when given as a regimen of 125mg on Day 1

and 80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel

administered intravenously on Day 1 or vinorelbine administered intravenously on

Day 1 or Day 8. Because the effect of aprepitant on the pharmacokinetics of orally

administered CYP3A4 substrates is greater than the effect of aprepitant on the

pharmacokinetics of intravenously administered CYP3A4 substrates, an interaction

with orally administered chemotherapeutic medicinal products metabolised primarily

or partly by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is

advised and additional monitoring may be appropriate in patients receiving medicinal

products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-

marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have

been reported after aprepitant and ifosfamide co-administration.

Immunosuppressants

During the 3-day CINV regimen, a transient moderate increase followed by a mild

decrease in

exposure of immunosuppressants metabolised by CYP3A4 (e.g. cyclosporine,

tacrolimus, everolimus and sirolimus) is expected. Given the short duration of the 3-

day regimen and the time-dependent limited changes in exposure, dose reduction of

the immunosuppressant is not recommended during the 3 days of co-administration

with aprepitant.

Midazolam

The potential effects of increased plasma concentrations of midazolam or other

benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be

considered when co-administering these medicinal products with aprepitant

(125mg/80mg).

Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold

on Day 1 and 3.3-fold on Day 5, when a single oral dose of 2 mg midazolam was co-

administered on Days 1 and 5 of a regimen of aprepitant 125mg on Day 1 and 80

mg/day on Days 2 to 5.

In another study with intravenous administration of midazolam, aprepitant was given

as 125mg on Day 1 and 80 mg/day on Days 2 and 3, and 2 mg midazolam was given

intravenously prior to the administration of the 3-day regimen of aprepitant and on

Days 4, 8, and 15. Aprepitant increased the AUC of midazolam 25 % on Day 4 and

decreased the AUC of midazolam 19 % on Day 8 and 4 % on Day 15. These effects

were not considered clinically important.

In a third study with intravenous and oral administration of midazolam, aprepitant

was given as 125mg on Day 1 and 80mg/day on Days 2 and 3, together with

ondansetron 32 mg Day 1, dexamethasone 12 mg Day 1 and 8 mg Days 2-4. This

combination (i.e. aprepitant, ondansetron and dexamethasone) decreased the AUC of

oral midazolam 16 % on Day 6, 9 % on Day 8, 7 % on Day 15 and 17 % on Day 22.

These effects were not considered clinically important.

An additional study was completed with intravenous administration of midazolam

and aprepitant. Intravenous 2 mg midazolam was given 1 hour after oral

administration of a single dose of aprepitant 125 mg. The plasma AUC of midazolam

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

Induction

As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease

plasma concentrations of substrates eliminated by these routes within two weeks

following initiation of treatment. This effect may become apparent only after the end

of a 3-day treatment with aprepitant. For CYP2C9 and CYP3A4 substrates the

induction is transient with a maximum effect reached after 3-5 days after the end of

the aprepitant 3-day treatment. The effect is maintained for a few days, thereafter

slowly declines and is clinically insignificant by two weeks after the end of aprepitant

treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant

given for 7 days. Data are lacking regarding effects on CYP2C8 and CYP2C19.

Caution is advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other

active substances that are known to be metabolised by CYP2C9 are administered

during this time period.

Warfarin

In patients on chronic warfarin therapy, the prothrombin time (INR) should be

monitored closely during treatment with aprepitant and for 2 weeks following each 3-

day course of aprepitant for chemotherapy-induced nausea and vomiting (see section

4.4). When a single 125 mg dose of aprepitant was administered on Day 1 and 80

mg/day on Days 2 and 3 to healthy subjects who were stabilised on chronic warfarin

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

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

CYP2C9 substrate) trough concentration accompanied by a 14 % decrease in INR 5

days after completion of treatment with aprepitant.

Tolbutamide

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

decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23 % on Day 4, 28 % on

Day 8, and 15 % on Day 15, when a single dose of tolbutamide 500 mg was

administered orally prior to the administration of the 3-day regimen of aprepitant and

on Days 4, 8, and 15.

Hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after

administration of aprepitant. Alternative non-hormonal back-up methods of

contraception should be used during treatment with aprepitant and for 2 months

following the last dose of aprepitant.

In a clinical study, single doses of an oral contraceptive containing ethinyl estradiol

and norethindrone were administered on Days 1 through 21 with aprepitant, given as

a regimen of 125mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32

mg intravenously on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8

mg/day on Days 9, 10, and 11. During days 9 through 21 in this study, there was as

much as a 64 % decrease in ethinyl estradiol trough concentrations and as much as a

60 % decrease in norethindrone trough concentrations.

5-HT3 antagonists

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

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

metabolite of dolasetron).

Effect of other medicinal products on the pharmacokinetics of Aprepitant

Concomitant administration of aprepitant with active substances that inhibit CYP3A4

activity (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin,

telithromycin, nefazodone and protease inhibitors) should be approached cautiously,

as the combination is expected to result in several-fold increased plasma

concentrations of aprepitant (see section 4.4).

Concomitant administration of aprepitant with active substances that strongly induce

CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should

be avoided as the combination results in reductions of the plasma concentrations of

aprepitant that may result in decreased efficacy of aprepitant.

Concomitant administration of aprepitant with herbal preparations containing St.

John’s Wort (Hypericum perforatum) is not recommended.

Ketoconazole

When a single 125 mg dose of aprepitant was administered on Day 5 of a 10-day

regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of

aprepitant increased approximately 5-fold and the mean terminal half-life of

aprepitant increased approximately 3-fold.

Rifampicin

When a single 375 mg dose of aprepitant was administered on Day 9 of a 14-day

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

aprepitant decreased 91 % and the mean terminal half-life decreased 68 %.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Contraception in males and females

The efficacy of hormonal contraceptives may be reduced during and for 28 days after

administration of aprepitant. Alternative non-hormonal back-up methods of

contraception should be used during treatment with aprepitant and for 2 months

following the last dose of aprepitant (see sections 4.4 and 4.5).

Pregnancy

For aprepitant no clinical data on exposed pregnancies are available. The potential for

reproductive toxicity of aprepitant has not been fully characterised, since exposure

levels above the therapeutic exposure in humans at the 125 mg/80 mg dose could not

be attained in animal studies. These studies did not indicate direct or indirect harmful

effects with respect to pregnancy, embryonal/foetal development, parturition or

postnatal development (see section 5.3). The potential effects on reproduction of

alterations in neurokinin regulation are unknown. Aprepitant should not be used

during pregnancy unless clearly necessary.

Breast-feeding

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

is excreted in human milk; therefore, breast-feeding is not recommended during

treatment with aprepitant.

Fertility

The potential for effects of aprepitant on fertility has not been fully characterised

because exposure levels above the therapeutic exposure in humans could not be

attained in animal studies. These fertility studies did not indicate direct or indirect

harmful effects with respect to mating performance, fertility, embryonic/foetal

development, or sperm count and motility (see section 5.3).

4.7

Effects on ability to drive and use machines

Aprepitant may have minor influence on the ability to drive, cycle and use machines.

Dizziness and fatigue may occur following administration of aprepitant (see section

4.8).

4.8

Undesirable effects

Summary of the safety profile

The safety profile of aprepitant was evaluated in approximately 6,500 adults in more

than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials.

The most common adverse reactions reported at a greater incidence in adults treated

with the aprepitant regimen than with standard therapy in patients receiving Highly

Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine

aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0

%), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased

appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a

greater incidence in patients treated with the aprepitant regimen than with standard

therapy in patients receiving Moderately Emetogenic Chemotherapy (MEC) was

fatigue (1.4 % versus 0.9 %).

The most common adverse reactions reported at a greater incidence in paediatric

patients treated with the aprepitant regimen than with the control regimen while

receiving emetogenic cancer chemotherapy were hiccups (3.3 % versus 0.0 %) and

flushing (1.1 % versus 0.0 %).

Tabulated list of adverse reactions

The following adverse reactions were observed in a pooled analysis of the HEC and

MEC studies at a greater incidence with aprepitant than with standard therapy in

adults or paediatric patients or in post-marketing use. The frequency categories given

in the table are based on the studies in adults; the observed frequencies in the

paediatric studies were similar or lower, unless shown in the table. Some less

common ADRs in the adult population were not observed in the paediatric studies.

Frequencies are defined as: very common (

1/10); common (

1/100 to < 1/10);

uncommon (

1/ 1,000 to < 1/100); rare (

1/10,000 to < 1/1,000) and very rare (<

1/10,000), not known (cannot be estimated from the available data).

System organ class

Adverse reaction

Frequency

Infection and

infestations

Candidiasis, staphylococcal infection

Rare

Blood and lymphatic

system disorders

Febrile neutropenia, anaemia

Uncommon

Immune system

disorders

Hypersensitivity reactions including

anaphylactic reactions

Not known

Decreased appetite

Common

Metabolism and

nutrition disorders

Polydipsia

Rare

Anxiety

Uncommon

Psychiatric disorders

Disorientation, euphoric mood

Rare

Headache

Common

Nervous system

disorders

Dizziness, somnolence

Uncommon

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