Capecitabine 150 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Capecitabine
Available from:
Fresenius Kabi Oncology Plc
ATC code:
L01BC; L01BC06
INN (International Name):
Capecitabine
Dosage:
150 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Pyrimidine analogues; capecitabine
Authorization status:
Not marketed
Authorization number:
PA1422/011/001
Authorization date:
2012-11-09

Capecitabine - Pack Insert - IRL+GBR

(Travesh Sharma) D:\Europe\Capecitabine\Ireland + UK\28 Nov 2013\Capecitabine - Pack Insert - IRL+GBR.indd

Size:

450 x 210 mm

4 August 2014 10:27 AM

Ver. 09

Times New Roman 8 pts.

Black

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Capecitabine

film-coated tablets

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TEMP

Capecitabine

film-coated tablets

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TEMP

Package leaflet: Information for the user

Capecitabine 150 mg film-coated tablets

Capecitabine 500 mg film-coated tablets

Read all of this leaflet carefully before you start taking this medicine because it

contains important information for you.

Keep-this-leaflet.-You-may-need-to-read-it-again.

If-you-have-any-further-questions,-ask-your-doctor-or-pharmacist.

This-medicine-has-been-prescribed-for-you-only.-Do-not-pass-it-on-to-others.-It-

may-harm-them,-even-if-their-signs-of-illness-are-the-same-as-yours.

If-you-get-any-side-effects,-talk-to-your-doctor-or-pharmacist.-This-includes-any-

possible-side-effects-not-listed-in-this-leaflet.

In this leaflet:

1.-- What-Capecitabine-is-and-what-it-is-used-for

2.-- What-you-need-to-know-before-you-take-Capecitabine

3.-- How-to-take-Capecitabine

4.-- Possible-side-effects

5.-- How-to-store-Capecitabine

6.-- Contents-of-the-pack-and-other-information

1.

What Capecitabine is and what it is used for

Capecitabine-belongs-to-the-group-of-medicines-called-“cytostatic-medicine”,-which-

stop-the-growth-of-cancer-cells.--Capecitabine-film-coated-tablets-contains-150-mg-

or-500-mg-capecitabine,-which-itself-is-not-a-cytostatic-medicine.-Only-after-being-

absorbed-by-the-body-is-it-changed-into-an-active-anti-cancer-agent-(more-in-tumour-

tissue-than-in-normal-tissue).

Capecitabine--is-used-in-the-treatment-of-colon,-rectal,-gastric,-or-breast-cancers.-

Furthermore,-capecitabine-is-used-to-prevent-new-occurrence-of-colon-cancer-after-

complete-removal-of-the-tumour-by-surgery.

Capecitabine-may-be-used-either-alone-or-in-combination-with-other-agents.

2.

What you need to know before you take Capecitabine

Do not use Capecitabine:

if-you-are-allergic-to-capecitabine-or-any-of-the-other-ingredients-of-this-medicine-

(listed-in-section-6).-You-must-inform-your-doctor-if-you-know-that-you-have-an-

allergy-or-over-reaction-to-this-medicine,

if-you-previously-have-had-severe-reactions-to-fluoropyrimidine-therapy-(a-group-

of-anticancer-medicines-such-as-fluorouracil),

if-you-are-pregnant-or-nursing,

if-you-have-severely-low-levels-of-white-cells-or-platelets-in-the-blood-(leukopenia,-

neutropenia-or-thrombocytopenia),

if-you-have-severe-liver-or-kidney-problems,

if-you-have-a-known-deficiency-for-the-enzyme-dihydropyrimidine-dehydrogenase-

(DPD)-involved-in-the-metabolism-of-uracil-and-thymine,-or

if- you- are- being- treated- now- or- have- been- treated- in- the- last- 4- weeks- with-

brivudine,- sorivudine- or- similar- classes- of- substance- as- part- of-

herpes zoster

(chickenpox-or-shingles)-therapy.

Warnings and precautions

Talk-to-your-doctor-or-pharmacist-before-taking-capecitabine.

if-you-have-liver-or-kidney-diseases

if-you-have-or-had--heart-problems-(for-example-an-irregular-heartbeat-or-pains-

to-the-chest-jaw-and-back-brought-on-by-physical-effort-and-due-to-problems-with-

the-blood-flow-to-the-heart)

if-you-have-brain-diseases-(for-example.-cancer-that-has-spread-to-the-brain,-or-

nerve-damage-(neuropathy)

if-you-have-calcium-imbalances-(seen-in-blood-tests)

if-you-have-diabetes

if- you- cannot- keep- food- or- water- in- your- body- because- of- severe- nausea- and-

vomiting

if-you-have-diarrhoea

if-you-are-or-become-dehydrated

if-you-have-imbalances-of-ions-in-your-blood-(electrolyte-imbalances,-seen-in-tests)

if-you-have-a-history-of-eye-problems-as-you-may-need-extra-monitoring-of-your-

eyes

if-you-have-a-severe-skin-reaction.

DPD deficiency

:-DPD-deficiency-is-a-rare-condition-present-at-birth-that-is-not-usually-

associated-with-health-problems-unless-you-receive-certain-medicines.-If-you-have-

an-unrecognised-DPD-deficiency-and-take-capecitabine,-you-may-experience-severe-

forms- of- the- side- effects- listed- under- section- 4- Possible- side- effects.- Contact- your-

doctor-immediately-if-you-are-concerned-about-any-of-the-side-effects-or-if-you-notice-

any-additional-side-effects-not-listed-in-the-leaflet-(see-section-4-Possible-side-effects).

Children and adolescents

Capecitabine-is-not-indicated-in-children-and-adolescents.-Do-not-give-capecitabine-

to-children-and-adolescents.

Other medicines and Capecitabine

Before- starting- treatment,- tell- your- doctor- or- pharmacist- if- you- are- taking,- have-

recently- taken- or- might- take- any- other- medicines.-This- is- extremely- important,- as-

taking-more-than-one-medicine-at-the-same-time-can-strengthen-or-weaken-the-effect-

of- the- medicines.-You- need- to- be- particularly- careful- if- you- are- taking- any- of- the-

following:

gout-medicines-(allopurinol),

blood-thinning-medicines-(coumarin,-warfarin),

certain-anti-viral-medicines-(sorivudine-and-brivudine),

medicines-for-seizures-or-tremors-(phenytoin),

interferon-alpha,

radiotherapy-and-certain-medicines-used-to-treat-cancer-(folinic-acid,-oxaliplatin,-

bevacizumab,-cisplatin,-irinotecan),

medicines-used-to-treat-folic-acid-deficiency.

Capecitabine with food and drink

You-should-take-capecitabine-no-later-than-30-minutes-after-meals-.

Pregnancy and breast-feeding

Before-starting-treatment,-you-must-tell-your-doctor-if-you-are-pregnant,-if-you-think-

you-are-pregnant-or-if-you-intend-to-become-pregnant.-You-must-not-take-capecitabine-

if-you-are-pregnant-or-think-you-might-be.-You-must-not-breast-feed-if-you-are-taking-

capecitabine.-Ask-your-doctor-or-pharmacist-for-advice-before-taking-this-medicine.

Driving and using machines

Capecitabine-may-make-you-feel-dizzy,-nauseous-or-tired.-It-is-therefore-possible-that-

capecitabine-could-affect-your-ability-to-drive-a-car-or-operate-machinery.

Capecitabine contains lactose

If-you-have-been-told-by-your-doctor-that-you-have-an-intolerance-to-some-sugars,-

contact-your-doctor-before-taking-this-medicine.

3.

How to take Capecitabine

Always-take-this-medicine-exactly-as-your-doctor-or-pharmacist-has-told-you.-Check-

with-your-doctor-or-pharmacist-if-you-are-not-sure.

Capecitabine- should- only- be- prescribed- by- a- doctor- experienced- in- the- use- of-

anticancer-medicines.

Capecitabine-tablets-should-be-

swallowed whole with water and within 30 minutes

of a meal.

Your- doctor- will- prescribe- a- dose- and- treatment-regimen- that- is- right- for-

you

.-The-

dose-of-capecitabine-is-based-on-your-body-surface-area.-This-is-calculated-from-your-

height- and- weight.- The- usual- dose- for- adults- is- 1250- mg/m

of- body- surface- area-

taken-two-times-daily-(morning-and-evening).-Two-examples-are-provided-here:-A-

person-whose-body-weight-is-64-kg-and-height-is-1.64-m-has-a-body-surface-area-of-

1.7-m

-and-should-take-4-tablets-of-500-mg-and-1-tablet-of-150-mg-two-times-daily.-A-

person-whose-body-weight-is-80-kg-and-height-is-1.80-m-has-a-body-surface-area-of-

2.00-m

-and-should-take-5-tablets-of-500-mg-two-times-daily.

Capecitabine-tablets-are-usually-taken-for-14-days-followed-by-a-7-day-rest-period-

(when-no-tablets-are-taken).-This-21-day-period-is-one-treatment-cycle.

In- combination- with- other- medicine- the- usual- dose- for- adults- may- be- less- than-

1250- mg/- m

- of- body- surface- area,- and- you- may- need- to- take- the- tablets- over- a-

different-time-period-(e.g.-every-day,-with-no-rest-period).

Your-doctor-will-tell-you-what-dose-you-need-to-take,-when-to-take-it-and-for-how-

long-you-need-to-take-it.

Your-doctor-may-want-you-to-take-a-combination-of-

150 mg

and-

500 mg

tablets-for-

each-dose.

-

Take-the-tablets-

morning and evening

as-prescribed-by-your-doctor.

-

Take-the-tablets-within-

30 minutes after the end of a meal

(breakfast-and-dinner).

-

It-is-important-that-you-take-all-your-medicine-as-prescribed-by-your-doctor.

If you take more Capecitabine than you should

If- you- take- more- capecitabine- than- you- should,- contact- your- doctor- as- soon- as-

possible-before-taking-the-next-dose.

You- might- get- the- following- side- effects- if- you- take- a- lot- more- capecitabine- than-

you-should:-feeling-or-being-sick,-diarrhoea,-inflammation-or-ulceration-of-the-gut-or-

mouth,-pain-or-bleeding-from-the-intestine-or-stomach,-or-bone-marrow-depression-

(reduction- in- certain- kinds- of- blood- cells).- Tell- your- doctor- immediately- if- you-

experience-any-of-these-symptoms.

If you forget to take Capecitabine

Do-not-take-the-missed-dose-at-all-and-do-not-double-the-next-one.-Instead,-continue-

your-regular-dosing-schedule-and-check-with-your-doctor.

If you stop taking Capecitabine

There- are- no- side- effects- caused- by- stopping- treatment- with- capecitabine.- In- case-

you-are-using-coumarin-anticoagulants-(containing-e.g.-phenprocoumon),-stopping-

capecitabine-might-require-that-your-doctor-adjusts-your-anticoagulant-dose.

If- you- have- any- further- questions- on- the- use- of- this- medicine,- ask- your- doctor- or-

pharmacist.

4.

POSSIBLE SIDE EFFECTS

Like- all- medicines,- this- medicine- can- cause- side- effects,- although- not- everybody-

gets-them.-

STOP

taking- capecitabine- immediately- and- contact- your- doctor- if- any- of- these-

symptoms-occur:

-

Diarrhoea

:-if-you-have-an-increase-of-4-or-more-bowel-movements-compared-to-

your-normal-bowel-movements-each-day-or-any-diarrhoea-at-night.

-

Vomiting

:-if-you-vomit-more-than-once-in-a-24-hour-time-period.

-

Nausea:

if-you-lose-your-appetite,-and-the-amount-of-food-you-eat-each-day-is-

much-less-than-usual.

-

Stomatitis

:- if- you- have- pain,- redness,- swelling- or- sores- in- your- mouth- and/or-

throat.

-

Hand-and-foot skin-reaction:

if-you-have-pain,-swelling,-redness-or-tingling-of-

hands-and/or-feet.

-

Fever:

if-you-have-a-temperature-of-38°C-or-greater.

-

Infection:

- if- you- experience- signs- of- infection- caused- by- bacteria- or- virus,- or-

other-organisms.

-

Chest pain:

if-you-experience-pain-localised-to-the-centre-of-the-chest,-especially-

if-it-occurs-during-exercise

.

-

Steven-Johnson syndrome:

- if- you- experience- painful- red- or- purplish- rash- that-

spreads-and-blisters-and/or-other-lesions-begin-to-appear-in-the-mucous-membrane-

(e.g.-mouth-and-lips),-in-particular-if-you-had-before-light-sensitivity,-infections-of-

the-respiratory-system-(e.g.-bronchitis)-and/or-fever.

If-caught-early,-these-side-effects-usually-improve-within-2-to-3-days-after-treatment-

discontinuation.-

these-

side-

effects-

continue,-

however,-

contact-

your-

doctor-

immediately.-Your-doctor-may-instruct-you-to-restart-treatment-at-a-lower-dose.

In-addition-to-the-above,-when-capecitabine-is-used-alone,-very-common-side-effects,-

which-may-affect-more-than-1-person-in-10-are:

-

abdominal-pain

-

rash,-dry-or-itchy-skin

-

tiredness

-

loss-of-appetite-(anorexia)

These- side- effects- can- become- severe;- therefore,- it- is- important- that- you-

always

contact your doctor immediately

- when- you- start- to- experience- a- side- effect.-

Your- doctor- may- instruct- you- to- decrease- the- dose- and/or- temporarily- discontinue-

treatment-with-capecitabine.-This-will-help-reduce-the-likelihood-that-the-side-effect-

continues-or-becomes-severe.

Other-side-effects-are:

Common-side-effects-(may-affect-up-to-1-in-10-people)-include:

-

decreases-in-the-number-of-white-blood-cells-or-red-blood-cells-(seen-in-tests),

-

dehydration,-weight-loss,

-

sleeplessness-(insomnia),-depression,

-

headache,- sleepiness,- dizziness,- abnormal- sensation- in- the- skin- (numbness- or-

tingling-sensation),-taste-changes,

-

eye-irritation,-increased-tears,-eye-redness-(conjunctivitis),

-

inflammation-of-the-veins-(thrombophlebitis),

-

shortness-of-breath,-nose-bleeds,-cough,-runny-nose,

-

cold-sores-or-other-herpes-infections,

-

infections-of-the-lungs-or-respiratory-system-(e.g.-pneumonia-or-bronchitis),

-

bleeding-from-the-gut,-constipation,-pain-in-upper-abdomen,-indigestion,-excess-

wind,-dry-mouth,

-

skin-rash,-hair-loss-(alopecia),-skin-reddening,-dry-skin,-itching-(pruritus),-skin-

discolouration,-skin-loss,-skin-inflammation,-nail-disorder,

-

pain-in-the-joints,-or-in-the-limbs-(extremities),-chest-or-back,

-

fever,-swelling-in-the-limbs,-feeling-ill,

-

problems-with-liver-function-(seen-in-blood-tests)-and-increased-blood-bilirubin-

(excreted-by-the-liver),

Circulation No. 1

Reason for the Artwork* :

Change in Text

Dimension

:

Artwork No.

:

Supersedes No. :

7220131854 / KM39A

Prepared By

PDD

Checked By

PDD

PDD

Production

QA

I&D RA

QM

Country RA

NA

NA

Approved By

Form-No.:-SOP/PDD/003-03--Rev.-05

CONFIDENTIAL

*Attached separate sheet if required

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Online

Capecitabine - Pack Insert - IRL+GBR

(Travesh Sharma) D:\Europe\Capecitabine\Ireland + UK\28 Nov 2013\Capecitabine - Pack Insert - IRL+GBR.indd

Size:

450 x 210 mm

4 August 2014 10:27 AM

Ver. 09

Times New Roman 8 pts.

Black

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V004

Uncommon-side-effects-(may-affect-up-to-1-in-100-people)-include:

-

blood- infection,- urinary- tract- infection,- infection- of- the- skin,- infections- in- the-

nose- and- throat,- fungal- infections- (including- those- of- the- mouth),- influenza,-

gastroenteritis,-tooth-abscess,

-

lumps-under-the-skin-(lipoma),

-

decreases-in-blood-cells-including-platelets,-thinning-of-blood-(seen-in-tests)

-

allergy

-

diabetes,-decrease-in-blood-potassium,-malnutrition,-increased-blood-triglycerides,

-

confusional-state,-panic-attacks,-depressed-mood,-decreased-libido,

-

difficulty-speaking,-impaired-memory,-loss-of-movement-coordination,-balance-

disorder,-fainting,-nerve-damage-(neuropathy)-and-problems-with-sensation

-

blurred-or-double-vision,

-

vertigo,-ear-pain.

-

irregular- heartbeat- and- palpitations- (arrhythmias),- chest- pain- and- heart- attack-

(infarction),

-

blood-clots-in-the-deep-veins,-high-or-low-blood-pressure,-hot-flushes,-cold-limbs-

(extremities),-purple-spots-on-the-skin

-

blood- clots- in- the- veins- in- the- lung- (pulmonary- embolism),- collapsed- lung,-

coughing-up-blood,-asthma,-shortness-of-breath-on-exertion,

-

bowel-obstruction,-collection-of-fluid-in-the-abdomen,-inflammation-of-the-small-

or- large- intestine,- the- stomach- or- the- oesophagus,- pain- in- the- lower- abdomen,-

abdominal- discomfort,- heartburn- (reflux- of- food- from- the- stomach),- blood- in-

the-stool,

-

jaundice-(yellowing-of-skin-and-eyes)

-

skin- ulcer- and- blister,- reaction- of- the- skin- with- sunlight,- reddening- of- palms,-

swelling-or-pain-of-the-face

-

joint-swelling-or-stiffness,-bone-pain,-muscle-weakness-or-stiffness,

-

fluid-collection-in-the-kidneys,-increased-frequency-of-urination-during-the-night,-

incontinence,- blood- in- the- urine,- increase- in- blood- creatinine- (sign- of- kidney-

dysfunction)

-

unusual-bleeding-from-the-vagina

-

swelling-(oedema),-chills-and-rigors

Some-of-these-side-effects-are-more-common-when-capecitabine-is-used-with-other-

medicines-for-the-treatment-of-cancer.-Other-side-effects-seen-in-this-setting-are-the-

following:

Common-side-effects-(may-affect-up-to-1-in-10-people)-include:

-

decrease-in-blood-sodium,-magnesium-or-calcium,-increase-in-blood-sugar,

-

nerve-pain,

-

ringing-or-buzzing-in-the-ears-(tinnitus),-loss-of-hearing,

-

vein-inflammation,

-

hiccups,-change-in-voice,

-

pain-or-altered/abnormal-sensation-in-the-mouth,-pain-in-the-jaw,

-

sweating,-night-sweats,

-

muscle-spasm,

-

difficulty-in-urination,-blood-or-protein-in-the-urine,

-

bruising-or-reaction-at-the-injection-site-(caused-by-medicines-given-by-injection-

at-the-same-time)

Rare-side-effects-(may-affect-up-to-1-in-1,000-people)-include:

-

narrowing-or-blockage-of-tear-duct-(lacrimal-duct-stenosis),

-

liver-failure,

-

inflammation-leading-to-dysfunction-or-obstruction-in-bile-secretion-(cholestatic-

hepatitis),

-

specific-changes-in-the-electrocardiogram-(QT-prolongation),

-

certain-types-of-arrhythmia-(including-ventricular-fibrillation,-torsade-de-pointes,-

and-bradycardia).

-

eye-inflammation-causing-eye-pain-and-possibly-eyesight-problems

-

inflammation- of- the- skin- causing- red- scaly- patches- due- to- an- immune- system-

illness

Very-rare-side-effects-(may-affect-up-to-1-in-10,000-people)-include:

-

severe- skin- reaction- such- as- skin- rash,- ulceration- and- blistering- which- may-

involve- ulcers- of- the- mouth,- nose,- genitalia,- hands,- feet- and- eyes- (red- and-

swollen-eyes).

Reporting of side effects

If-you-get-any-side-effects,-talk-to-your-doctor,-pharmacist-or-nurse.-This-includes-any-

possible-side-effects-not-listed-in-this-leaflet.

For UK

---You-can-also-report-side-effects-directly-via-the-Yellow-Card-Scheme-at:-

www.mhra.gov.uk/yellowcard

For Ireland

---Via;

HPRA-Pharmacovigilance

Earlsfort-Terrace

IRL---Dublin-2

Tel:-+353-1-6764971

Fax:-+353-1-6762517

Website:-www.hpra.ie

e-mail:-medsafety@hpra.ie

By- reporting- side- effects- you- can- help- provide- more- information- on- the- safety- of-

this-medicine.

5.

How to store Capecitabine

Keep-this-medicine-out-of-the-sight-and-reach-of-children.

Do-not-use-this-medicine-after-the-expiry-date-which-is-stated-on-the-outer-pack-and-

labels-after-EXP.-The-expiry-date-refers-to-the-last-day-of-that-month.

This-medicinal-product-does-not-require-any-special-storage-conditions.

Do-not-use-this-medicine-if-you-notice-any-visible-signs-of-deterioration.

Do- not- throw- away- any- medicines- via- wastewater- or- household- waste.-Ask- your-

pharmacist-how-to-throw-away-medicines-you-no-longer-use.-These-measures-will-

help-protect-the-environment.

6.

Contents of the pack and other information

What Capecitabine contains

The-active-substance-is-capecitabine.

Each-film-coated-tablet-contains-150-mg-capecitabine.

Each-film-coated-tablet-contains-500-mg-capecitabine.

The-other-ingredients-are:

Tablet-

core:-

Lactose-

monohydrate-

Microcrystalline-

cellulose-

(E460),-

Hypromellose-(E464),-Crosscarmellose-sodium,-Magnesium-stearate-(E572)

Tablet-coating:-Hypromellose-(E464),-Titanium-dioxide-(E171),--Macrogol,-

Iron-oxide-red-(E172)

What Capecitabine looks like and contents of the pack

Capecitabine 150 mg film-coated tablets

Pink-coloured,-capsule-shaped,-biconvex,-film-coated-tablets,-debossed-with-“150”on-

one-side-and-plain-on-other-side.

The-pack-contains-60-film-coated-tablets-(6-blisters-of-10-tablets).

Capecitabine 500 mg film-coated tablets

Pink-coloured,-capsule-shaped,-biconvex,-film-coated-tablets,-debossed-with-“500”-

on-one-side-and-plain-on-other-side.

The-pack-contains-120-film-coated-tablets-(12-blisters-of-10-tablets).

Marketing Authorisation Holder

Fresenius-Kabi-Oncology-Plc.

Lion-Court,-Farnham-Road,-Bordon

Hampshire,-GU35-0NF

United-Kingdom

Manufacturer

Fresenius-Kabi-Oncology-Plc.

Lion-Court,-Farnham-Road,-Bordon

Hampshire,-GU35-0NF

United-Kingdom

Pharmadox-Healthcare-Ltd.

KW20A-Kordin-Industrial-Park

Paola-PLA3000

MALTA.

This medicinal product is authorised in the Member States of the EEA under

the following names:

Austria

Capecitabin-Fresenius-Kabi-150-mg-Filmtabletten

Capecitabin-Fresenius-Kabi-500-mg-Filmtabletten

Belgium

Capecitabine-Fresenius-Kabi-150--mg-filmomhulde-tabletten

Capecitabine-Fresenius-Kabi-500--mg-filmomhulde-tabletten

Cyprus

Capecitabine-Fresenius-Kabi-150--mg-επικαλυμένα-με-λεπτό-

υμένιο-δισκία

Capecitabine-Fresenius-Kabi-500--mg-επικαλυμένα-με-λεπτό-

υμένιο-δισκία

Czech-

Republic

Capecitabine-Fresenius-Kabi-150--mg-potahované-tablety

Capecitabine-Fresenius-Kabi-500--mg-potahované-tablety

Denmark

Capecitabin-Fresenius-Kabi

Estonia

Capecitabine-Fresenius-Kabi-150--mg

Capecitabine-Fresenius-Kabi-500--mg

Greece

Capecitabine-Fresenius-Kabi-150-mg-επικαλυμμένα-με-λεπτό-

υμένιο-δισκία

Capecitabine-Fresenius-Kabi-500-mg-επικαλυμμένα-με-λεπτό-

υμένιο-δισκία

Spain

Capecitabina-Fresenius-Kabi-150-mg-comprimidos-recubiertos-con-

película-EFG

Capecitabina-Fresenius-Kabi-500-mg-comprimidos-recubiertos-con-

película-EFG

France

Capecitabine-Fresenius-Kabi-150-mg-comprimé-pelliculé

Capecitabine-Fresenius-Kabi-500-mg-comprimé-pelliculé

Hungary

Capecitabine-Fresenius-Kabi-150-mg-filmtabletta

Capecitabine-Fresenius-Kabi-500-mg-filmtabletta

Ireland

Capecitabine-150-mg-film-coated-tablet

Capecitabine-500-mg-film-coated-tablet

Iceland

Capecitabin-Fresenius-Kabi-150-mg-filmuhúðuð-tafla

Capecitabin-Fresenius-Kabi-500-mg-filmuhúðuð-tafla

Italy

Capecitabina-Fresenius-Kabi

Latvia

Capecitabine-Fresenius-Kabi-150--mg-apvalkotās-tabletes

Capecitabine-Fresenius-Kabi-500--mg-apvalkotās-tabletes

Lithuania

Capecitabine-Fresenius-Kabi-150-mg-plėvele-dengtos-tabletės

Capecitabine-Fresenius-Kabi-500-mg-plėvele-dengtos-tabletės

Malta

Capecitabine-150--mg-film-coated-tablet

Capecitabine-500--mg-film-coated-tablet

The-

Netherlands

Capecitabine-Fresenius-Kabi150-mg-filmomhulde-tabletten

Capecitabine-Fresenius-Kabi500-mg-filmomhulde-tabletten

Norway

Capecitabin-Fresenius-Kabi-150-mg-filmdrasjerte-tabletter

Capecitabin-Fresenius-Kabi-500-mg-filmdrasjerte-tabletter

Poland

Capecitabine-Fresenius-Kabi-

Portugal

Capecitabina-Fresenius-Kabi-150-mg-

Capecitabina-Fresenius-Kabi-500-mg

Romania

Capecitabina-Fresenius-Kabi-150-mg-comprimate-filmate

Capecitabina-Fresenius-Kabi500-mg-comprimate-filmate

Sweden

Capecitabin-Fresenius-Kabi-150-mg,-filmdragerade-tabletter

Capecitabin-Fresenius-Kabi-500-mg,-filmdragerade-tabletter

Slovenia

Kapecitabin-Fresenius-Kabi-150-mg-filmskoobloženetablete

Kapecitabin-Fresenius-Kabi-500-mg-filmskoobloženetablete

Slovak-

Republic

Capecitabine-Fresenius-Kabi-150-mg-filmom-obalené-tablety

Capecitabine-Fresenius-Kabi500-mg-filmom-obalené-tablety

United-

Kingdom

Capecitabine-150--mg-film-coated-tablet

Capecitabine-500--mg-film-coated-tablet

This leaflet was last revised in Jul 2014.

Circulation No. 1

Reason for the Artwork* :

Change in Text

Dimension

:

Artwork No.

:

Supersedes No. :

7220131854 / KM39A

Prepared By

PDD

Checked By

PDD

PDD

Production

QA

I&D RA

QM

Country RA

NA

NA

Approved By

Form-No.:-SOP/PDD/003-03--Rev.-05

CONFIDENTIAL

*Attached separate sheet if required

450 x 210 mm

xxxxxxxxxx

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Approved

Online

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Capecitabine 150 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg capecitabine.

Excipient (s) with known effect:

12 mg lactose monohydrate (150 mg tablet).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Pink coloured, capsule shaped, biconvex, film coated tablets, debossed with “150”on one side and plain on other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Capecitabine is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes'

stage C) colon

cancer (see section 5.1).

Capecitabine is indicated for the treatment of metastatic colorectal cancer (see section 5.1).

Capecitabine is indicated for first-line treatment of advanced gastric cancer in combination with a platinum-based

regimen (see section 5.1).

Capecitabine in combination with docetaxel (see section 5.1) is indicated for the treatment of patients with locally

advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an

anthracycline. Capecitabine is also indicated as monotherapy for the treatment of patients with locally advanced or

metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom

further anthracycline therapy is not indicated.

4.2 Posology and method of administration

Capecitabine should only be prescribed by a qualified physician experienced in the utilisation of anti-

neoplasticmedicinal products. Careful monitoring during the first cycle of treatment is recommended for all patients.

Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard and reduced dose

calculations according to body surface area for starting doses of capecitabine of 1250 mg/m

and 1000 mg/m

provided in tables 1 and 2, respectively.

Posology

Recommended posology (see section 5.1)

Monotherapy

Colon, colorectal and breast cancer

Given as single monotherapy, the recommended starting dose for capecitabine in the adjuvant treatment of colon

cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is

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1250 mg/m

administered twice daily (morning and evening; equivalent to 2500 mg/m

total daily dose) for 14 days

followed by a 7

day rest period. Adjuvant treatment in patients with stage III colon cancer is recommended for a total

of 6 months.

Combination therapy

Colon, colorectal and gastric cancer

In combination treatment, the recommended starting dose of capecitabine should be reduced to 800

1000 mg/m

when administered twice daily for 14 days followed by a 7

day rest period, or to 625 mg/m

twice daily when

administered continuously (see section 5.1). For combination with irinotecan, the recommended starting dose is 800

mg/m

when administered twice daily for 14 days followed by a 7-day rest period combined with irinotecan 200

mg/m

on day 1. The inclusion of bevacizumabin a combination regimen has no effect on the starting dose of

capecitabine. Premedication to maintain adequate hydration and anti

emesis according to the cisplatin summary of

product characteristics should be started prior to cisplatin administration for patients receiving the capecitabine plus

cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics

is recommended for patients receiving the capecitabine plus oxaliplatin combination. Adjuvant treatment in patients

with stage III colon cancer is recommended for a duration of 6 months.

Breast cancer

In combination with docetaxel, the recommended starting dose of capecitabine in the treatment of metastatic breast

cancer is 1250 mg/m

twice daily for 14 days followed by a 7

day rest period, combined with docetaxel at 75 mg/m

as a 1 hour intravenous infusion every 3 weeks. Premedication with an oral corticosteroid such as dexamethasone

according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for

patients receiving the capecitabine plus docetaxel combination.

Capecitabine Dose Calculations

Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of capecitabine of

1250 mg/m

Dose level 1250 mg/m

(twice daily)

Full dose

1250 mg/m

Number of 150 mg

tablets and/or

500 mg tablets per

administration

(each

administration to

be given morning

and evening)

Reduced dose

(75%)

950 mg/m

Reduced dose

(50%)

625 mg/m

Body Surface

Area (m

Dose per

administration

(mg)

150 mg

500 mg

Dose per

administration

(mg)

Dose per

administration

(mg)

1.26

1500

1150

1.27 - 1.38

1650

1300

1.39 - 1.52

1800

1450

1.53 - 1.66

2000

1500

1000

1.67 - 1.78

2150

1650

1000

1.79 - 1.92

2300

1800

1150

1.93 - 2.06

2500

1950

1300

2.07 - 2.18

2650

2000

1300

2.19

2800

2150

1450

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Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of capecitabine of

1000 mg/m

Posology adjustments during treatment:

General

Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or modification of the dose

(treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time.

For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g.

alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption.

Patients taking capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe

toxicity occurs. Doses of capecitabine omitted for toxicity are not replaced. The following are the recommended dose

modifications for toxicity:

Table 3 Capecitabine Dose Reduction Schedule (3-weekly Cycle or Continuous Treatment)

Dose level 1000 mg/m

(twice daily)

Full dose

1000 mg/m

Number of 150 mg

tablets and/or

500 mg tablets per

administration

(each

administration to

be given morning

and evening)

Reduced dose

(75%)

750 mg/m

Reduced dose

(50%)

500 mg/m

Body

Surface Area

Dose per

administration

(mg)

150 mg

500 mg

Dose per

administration

(mg)

Dose per

administration

(mg)

1.26

1150

1.27 - 1.38

1300

1000

1.39 - 1.52

1450

1100

1.53 - 1.66

1600

1200

1.67 - 1.78

1750

1300

1.79 - 1.92

1800

1400

1.93 - 2.06

2000

1500

1000

2.07 - 2.18

2150

1600

1050

2.19

2300

1750

1100

Toxicity grades*

Dose changes within a

treatment cycle

Dose adjustment for next

cycle/dose

(% of starting dose)

Grade 1

Maintain dose level

Maintain dose level

Grade 2

appearance

Interrupt until resolved to grade

100%

appearance

appearance

appearance

Discontinue treatment

permanently

Not applicable

Grade 3

-1st appearance

Interrupt until resolved to grade

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*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria

(version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation

Program, US National Cancer Institute, version 4.0. For hand-foot syndrome and hyperbilirubinaemia, see section 4.4.

Haematology

Patients with baseline neutrophil counts of <1.5 x 10

/L and/or thrombocyte counts of <100 x 10

/L should not be

treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil

count drops below 1.0 x 10

/L or that the platelet count drops below 75 x 10

/L, treatment with capecitabine should be

interrupted.

Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with other medicinal

products

Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with other medicinal

products should be made according to table 3 above for capecitabine and according to the appropriate summary of

product characteristics for the other medicinal product (s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the other

medicinal

product(s), then administration of all therapy should be delayed until the requirements for restarting all medicinal

products are met.

During a treatment cycle for those toxicities considered by the treating physician not to be related to capecitabine,

capecitabine should be continued and the dose of the other medicinal products should be adjusted according to the

appropriate Prescribing Information.

If the other medicinal product(s) have to be discontinued permanently, capecitabine treatment can be resumed when the

requirements for restarting capecitabine are met.

This advice is applicable to all indications and to all special populations.

Dose modifications for toxicity when capecitabine is used continuously in combination with other agents

Dose modifications for toxicity when capecitabine is used continuously in combination with other medicinal products

should be made according to table 3 above for capecitabine and according to the appropriate summary of product

characteristics for the other medicinal product(s).

Posology adjustments for special populations:

Hepatic impairment

Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment

recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.

Renal impairment

Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min

[Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal

appearance

appearance

Discontinue treatment

permanently

Not applicable

Grade 4

appearance

Discontinue permanently

or

If physician deems it to be in the

patient’s best interest to continue,

interrupt until resolved to grade

-2nd appearance

Discontinue permanently

Not applicable

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impairment (creatinine clearance 30

50 ml/min at baseline) is increased compared to the overall population. In patients

with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m

recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose

of 1000 mg/m

. In patients with mild renal impairment (creatinine clearance 51

80 ml/min at baseline) no adjustment

of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the

patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose adjustment as outlined in table 3

above. If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, capecitabine

should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and

combination use (see also section “Elderly” below).

Elderly

During capecitabine monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-

related adverse reactions were more frequent in patients

60 years of age compared to younger patients.

When capecitabine was used in combination with othermedicinal product, elderly patients (

65 years) experienced

more grade 3 and grade 4 adverse drug reactions, including those leading to discontinuation, compared to younger

patients. Careful monitoring of patients

60 years of age is advisable.

In combination with docetaxel: an increased incidence of grade 3 or 4 treatment

related adverse reactions and

treatment-related serious adverse reactions were observed in patients 60 years of age or more (see section 5.1). For

patients 60 years of age or more, a starting dose reduction of capecitabine to 75% (950 mg/m

twice daily) is

recommended. If no toxicity is observed in patients

60 years of age treated with a reduced capecitabine starting

dose in combination with docetaxel, the dose of capecitabine may be cautiously escalated to 1250 mg/m

twice

daily.

Paediatric population

There is no relevant use of capecitabine in the paediatric population in the indications colon, colorectal, gastric and

breast cancer.

Method of administration

Capecitabine tablets should be swallowed with water within 30 minutes after a meal.

4.3 Contraindications

Hypersensitivity to the capecitabine or to any of the excipients listed in section 6.1 or fluorouracil,

History of severe and unexpected reactions to fluoropyrimidine therapy,

In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4),

During pregnancy and lactation,

In patients with severe leukopaenia, neutropaenia, or thrombocytopaenia,

In patients with severe hepatic impairment,

In patients with severe renal impairment (creatinine clearance below 30 ml/min),

Treatment with sorivudine or its chemically related analogues, such as brivudine (see section 4.5),

If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product

should not be used.

4.4 Special warnings and precautions for use

Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin

reaction,

palmar

plantar

erythrodysaesthesia).

Most

adverse reactions are reversible and do not

require permanent

discontinuation of therapy, although doses may need to be withheld or reduced.

Diarrhoea. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if

they become dehydrated.

Standard antidiarrhoeal

treatments (e.g.

loperamide)

may be used.

NCIC CTC grade 2

diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools,

grade 3 diarrhoea as an increase of 7 to 9

stools/day or incontinence and malabsorption.

Grade 4 diarrhoea is an increase of

10 stools/day or grossly bloody

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diarrhoea or the need for parenteral support. Dose reduction should be applied as necessary (see section 4.2).

Dehydration.

Dehydration should be prevented or

corrected at

the onset.

Patients with anorexia,

asthenia,

nausea,

vomiting or

diarrhoea may rapidly become dehydrated.

Dehydration may cause acute renal

failure,

especially in

patients with pre-existing compromised renal

function or

when capecitabine is given concomitantly with known

nephrotoxic drugs.

Acute renal

failure secondary to dehydration might

be potentially fatal.

Grade 2 (or higher)

dehydration occurs, capecitabine treatment should be immediately interrupted and the dehydration corrected. Treatment

should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.

Dose modifications applied should be applied for the precipitating adverse event as necessary (see section 4.2).

Hand

foot syndrome (also known as hand-foot skin reaction or palmar

plantar erythrodysaesthesia or chemotherapy

induced acral

erythema).

Grade 1 hand- foot

syndrome is defined as numbness,

dysaesthesia/paraesthesia,

tingling,

painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patient’s normal

activities.

Grade 2 hand- foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the

patient’s activities of daily living.

Grade 3 hand- foot

syndrome is moist

desquamation,

ulceration,

blistering and severe pain of the hands and/or feet

and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or

3 hand- foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases

in intensity to grade 1. Following grade 3 hand- foot syndrome, subsequent doses of capecitabine should be decreased.

When capecitabine and cisplatin are used in combination,

the use of

vitamin B6 (pyridoxine)

is not

advised for

symptomatic or secondary prophylactic treatment

of hand–foot

syndrome,

because of published reports that

decrease the efficacy of

cisplatin.

There is some evidence that

dexpanthenol

is effective for

hand-foot

syndrome

prophylaxis in patients treated with capecitabine

Cardiotoxicity.

Cardiotoxicity has been associated with fluoropyrimidine therapy,

including myocardial

infarction,

angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of

QT prolongation).

These adverse reactions may be more common in patients with a prior history of coronary artery

disease.

Cardiac arrhythmias (including ventricular fibrillation,

torsade de pointes,

and bradycardia),

angina pectoris,

myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine. Caution

must be exercised in patients with history of significant cardiac disease,

arrhythmias and angina pectoris (see section

4.8).

Hypo- or hypercalcaemia. Hypo- or hypercalcaemia has been reported during capecitabine treatment. Caution must be

exercised in patients with pre-existing hypo

or hypercalcaemia (see section 4.8).

Central or peripheral nervous system disease. Caution must be exercised in patients with central or peripheral nervous

system disease, e.g. brain metastasis or neuropathy (see section 4.8).

Diabetes mellitus or electrolyte disturbances. Caution must be exercised in patients with diabetes mellitus or electrolyte

disturbances, as these may be aggravated during capecitabine treatment.

Coumarin

derivative anticoagulation. In a drug interaction study with single

dose warfarin administration, there was a

significant increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, probably due to an

inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients receiving concomitant capecitabine

and oral

coumarin

derivative anticoagulant

therapy should have their anticoagulant

response (INR or prothrombin

time) monitored closely and the anticoagulant dose adjusted accordingly (see section 4.5).

Hepatic impairment.

In the absence of safety and efficacy data in patients with hepatic impairment,

capecitabine use

should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence

of liver metastasis.

Administration of capecitabine should be interrupted if treatment-related elevations in bilirubin of

>3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment

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with capecitabine monotherapy may be resumed when bilirubin decreases to

3.0 x ULN or hepatic aminotransferases

decrease to

2.5 x ULN.

Renal

impairment.

The incidence of

grade 3 or

4 adverse reactions in patients with moderate renal

impairment

(creatinine clearance 30

50 ml/min) is increased compared to the overall population (see section 4.2 and 4.3).

DPD deficiency:

Rarely,

unexpected,

severe

toxicity (e.g.

stomatitis,

diarrhoea,

neutropenia

and neurotoxicity)

associated with 5-FU has been attributed to a deficiency of DPD activity. A link between decreased levels of DPD and

increased, potentially fatal toxic effects of 5-FU therefore

cannot be excluded.

Patients with known DPD deficiency should not

be treated with capecitabine (see section 4.3).

In patients with

unrecognised DPD deficiency treated with capecitabine,

life-threatening toxicities manifesting as acute overdose may

occur (see section 4.9). In the event of grade 2-4 acute toxicity,

treatment

must

be discontinued immediately until

observed toxicity resolves.

Permanent

discontinuation should be

considered based on clinical assessment of the onset, duration and severity of the observed toxicities.

Ophthalmologic complications: Patients should be carefully monitored for ophthalmological

complications such as

keratitis and corneal

disorders,

especially if they have a prior history of eye disorders.

Treatment

of eye disorders

should be initiated as clinically appropriate.

Severe skin reactions:

Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic

Epidermal

Necrolysis.

Capecitabine should be permanently discontinued in patients who experience a

severe skin

reaction during treatment.

As this medicinal

product

contains lactose monohydrate as an excipient,

patients with rare hereditary problems of

galactose intolerance, the Lapp lactase deficiency or glucose

galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Interaction with other medicinal products

Cytochrome P-450 2C9 substrates: Other than warfarin, no formal drug-drug interaction studies between capecitabine

and other CYP2C9 substrates have been conducted. Care should be exercised when capecitabine is co-administered

with 2C9 substrates (e.g., phenytoin). See also interaction with

coumarin-derivative anticoagulants below, and section 4.4.

Coumarin-derivative anticoagulants: altered coagulation parameters and/or bleeding have been reported in patients

taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.

These reactions occurred within several days and up to several months after initiating capecitabine therapy and, in a

few cases, within one month after stopping capecitabine. In a clinical pharmacokinetic interaction study, after a single

20 mg dose of warfarin, capecitabine treatment increased the AUC of S

warfarin by 57% with a 91% increase in INR

value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down

regulates

isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants

concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or

INR) and the anticoagulant dose adjusted accordingly.

Phenytoin: increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases

have been reported during concomitant use of capecitabine with phenytoin. Patients taking phenytoin concomitantly

with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.

Folinic acid/ folic acid: a combination study with capecitabine and folinic acid indicated that folinic acid has no major

effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid has an effect on the

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pharmacodynamics of capecitabine and its toxicity may be enhanced by folinic acid: the maximum tolerated dose

(MTD) of capecitabine alone using the intermittent regimen is 3000 mg/m

per day whereas it is only 2000 mg/m

day when capecitabine was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when

switching from 5-FU/LV to a capecitabine regimen. This may also be relevant with folic acid supplementation for

folate deficiency due to the similarity between folinic acid and folic acid.

Sorivudine and analogues: a clinically significant drug-drug interaction between sorivudine and 5

FU, resulting from

the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described. This interaction, which leads to

increased fluoropyrimidine toxicity, is potentially fatal. Therefore, capecitabine must not be administered

concomitantly with sorivudine or its chemically related analogues, such as brivudine (see section 4.3). There must be at

least a 4

week waiting period between end of treatment with sorivudine or its chemically related analogues such as

brivudine and start of capecitabine therapy.

Antacid: the effect of an aluminum hydroxide and magnesium hydroxide containing antacid on the pharmacokinetics of

capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite

DFCR); there was no effect on the 3 major metabolites (5'

DFUR, 5

FU and FBAL).

Allopurinol: interactions with allopurinol have been observed for 5

FU; with possible decreased efficacy of 5

Concomitant use of allopurinol with capecitabine should be avoided.

Interferon alpha: the MTD of capecitabine was 2000 mg/m

per day when combined with interferon alpha-2a

(3 MIU/m

per day) compared to 3000 mg/m

per day when capecitabine was used alone.

Radiotherapy: the MTD of capecitabine alone using the intermittent regimen is 3000 mg/m

per day, whereas, when

combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2000 mg/m

per day using either a

continuous schedule or given daily Monday through Friday during a 6

week course of radiotherapy.

Oxaliplatin: no clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total

platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with

oxaliplatin and bevacizumab.

Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of

capecitabine or its metabolites in the presence of oxaliplatin.

Food interaction

In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. Since current

safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered

with food. Administration with food decreases the rate of capecitabine absorption (see section 5.2).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential /Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with

capecitabine. If the patient becomes pregnant while receiving capecitabine, the potential hazard to the foetus must be

explained.

An effective method of contraception should be used during treatment.

Pregnancy

There are no studies in pregnant women using capecitabine; however, it should be assumed that capecitabine may cause

foetal harm if administered to pregnant women. In reproductive toxicity studies in animals, capecitabine administration

caused embryolethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives.

Capecitabine is contraindicated during pregnancy.

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Breastfeeding

It is not known whether capecitabine is excreted in human breast milk. In lactating mice, considerable amounts of

capecitabine and its metabolites were found in milk. Breast-feeding must be discontinued while receiving treatment

with capecitabine.

Fertility

There is no data on capecitabine and impact on fertility. The capecitabine pivotal studies included females of

childbearing potential and males only if they agreed to use an acceptable method of birth control to avoid pregnancy for

the duration of the study and for a reasonable period thereafter.

In animal studies effects on fertility were observed (see section 5.3)

4.7 Effects on ability to drive and use machines

Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause

dizziness, fatigue and nausea.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of capecitabine is based on data from over 3000 patients treated with capecitabine as

monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications. The safety

profiles of capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon

cancer populations are comparable. See section 5.1 for details of major studies, including study designs and major

efficacy results.

The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were

gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome

(palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those

with preexisting compromised renal function, and thrombosis/embolism.

Tabulated summary of adverse reactions

ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine

are listed in table 4 for capecitabine given as monotherapy and in table 5 for capecitabine given in combination with

different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by

frequency: 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), very rare (<1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing

seriousness.

Capecitabine Monotherapy:

Table 4 lists ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of safety data from

three major studies including over 1900 patients (studies M66001, SO14695, and SO14796). ADRs are added to the

appropriate frequency grouping according to the overall incidence from the pooled analysis.

Table 4 Summary of related ADRs reported in patients treated with capecitabine monotherapy

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Body System

Very Common

All grades

Common

All grades

Uncommon

Severe and/or

Life

threatening

(grade 3

4) or

considered medically

relevant

Infections and

infestations

Herpes viral infection,

Nasopharyngitis,

Lower respiratory tract

infection

Sepsis, Urinary tract

infection, Cellulitis,

Tonsillitis,

Pharyngitis, Oral

candidiasis,

Influenza,

Gastroenteritis,

Fungal infection,

Infection, Tooth

abscess

Neoplasms benign,

malignant and

unspecified (incl cysts

and polyps)

Lipoma

Blood and lymphatic

system disorders

Neutropenia, Anaemia

Febrile neutropenia,

Pancytopenia,

Granulocytopenia,

Thrombocytopenia,

Leukopenia,

Haemolytic anaemia,

International

Normalised Ratio

(INR)

increased/Prothrombin

time prolonged

Immune system

disorders

Hypersensitivity

Metabolism and

nutrition disorders

Anorexia

Dehydration,

Weight decreased

Diabetes,

Hypokalaemia,

Appetite disorder,

Malnutrition,

Hypertriglyceridaemia,

Psychiatric disorders

Insomnia, Depression

Confusional state,

Panic attack,

Depressed mood,

Libido decreased

Nervous system

disorders

Headache, Lethargy

Dizziness, Parasthesia

Dysgeusia

Aphasia, Memory

impairment, Ataxia,

Syncope, Balance

disorder, Sensory

disorder, Neuropathy

peripheral

Eye disorders

Lacrimation increased,

Conjunctivitis, Eye

irritation

Visual acuity

reduced, Diplopia

Ear and labyrinth

disorders

Vertigo, Ear pain

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0

Cardiac disorders

Angina unstable,

Angina pectoris,

Myocardial

ischaemia, Atrial

fibrillation,

Arrhythmia,

Tachycardia, Sinus

tachycardia,

Palpitations

Vascular disorders

Thrombophlebitis

Deep vein

thrombosis,

Hypertension,

Petechiae,

Hypotension, Hot

flush, Peripheral

coldness

Respiratory, thoracic

and mediastinal

disorders

Dyspnoea, Epistaxis,

Cough, Rhinorrhoea

Pulmonary

embolism,

Pneumothorax,

Haemoptysis,

Asthma, Dyspnoea

exertional

Gastrointestinal

disorders

Diarrhoea, Vomiting,

Nausea, Stomatitis,

Abdominal pain

Gastrointestinal

haemorrhage,

Constipation, Upper

abdominal pain,

Dyspepsia, Flatulence,

Dry mouth

Intestinal

obstruction, Ascites,

Enteritis, Gastritis,

Dysphagia,

Abdominal pain

lower, Oesophagitis,

Abdominal

discomfort,

Gastrooesophageal

reflux disease,

Colitis, Blood in

stool

Hepatobiliary

Disorders

Hyperbilirubinaemia ,

Liver function test

abnormalities

Jaundice

Skin and subcutaneous

tissue disorders

Palmar

plantar

erythrodysaesthesia

syndrome

Rash, Alopecia,

Erythema, Dry skin,

Pruritus, Skin hyper-

pigmentation, Rash

macular, Skin

desquamation,

Dermatitis,

Pigmentation disorder,

Nail disorder

Blister, Skin ulcer,

Rash, Urticaria,

Photosensitivity

reaction, Palmar

erythema, Swelling

face, Purpura,

Radiation recall

syndrome

Muskuloskeletal and

connective tissue

disorders

Pain in extremity,

Back pain, Arthralgia

Joint swelling, Bone

pain, Facial pain,

Musculoskeletal

stiffness, Muscular

weakness

Renal and urinary

disorders

Hydronephrosis,

Urinary

incontinence,

Haematuria,

Nocturia, Blood

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Capecitabine in combination therapy:

Table 5 lists ADRs associated with the use of capecitabine in combination with different chemotherapy regimens in

multiple indications based on safety data from over 3000 patients. ADRs are added to the appropriate frequency

grouping (Very common or Common) according to the highest incidence seen in any of the major clinical trials and are

only added when they were seen in addition to those seen with capecitabine monotherapy or seen at a higher

frequency grouping compared to capecitabine monotherapy (see table 4). Uncommon ADRs reported for capecitabine

in combination therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for

monotherapy with the combination medicinal product (in literature and/or respective summary of product

characteristics).

Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. peripheral sensory

neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however an exacerbation by

capecitabine therapy can not be excluded.

Table 5 Summary of related ADRs reported in patients treated with capecitabine in combination treatment in addition

to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine

monotherapy

creatinine increased

Reproductive system

and breast disorders

Vaginal haemorrhage

General disorders and

administration site

conditions

Fatigue, Asthenia

Pyrexia,

Lethargy,

Oedema peripheral,

Malaise, Chest pain

Oedema, Chills,

Influenza like illness,

Rigors, Body

temperature

increased

Body System

Very common

All grades

Common

All grades

Infections and

infestations

Herpes zoster, Urinary tract

infection, Oral candidiasis,

Upper respiratory tract

infection , Rhinitis, Influenza,

Infection, Oral herpes

Blood and lymphatic

system disorders

Neutropenia,

Leucopenia,

Anaemia,

Neutropenic

fever, Thrombocytopenia

Bone marrow depression,

Febrile Neutropenia

Immune system

disorders

Hypersensitivity

Metabolism and

nutrition disorders

Appetite decreased

Hypokalaemia,

Hyponatraemia,

Hypomagnesaemia,

Hypocalcaemia,

Hyperglycaemia

Psychiatric disorders

Sleep disorder, Anxiety

Nervous system

disorders

Paraesthesia,

dysaesthesia,

Peripheral neuropathy,

Peripheral sensory

neuropathy, Dysgeusia,

Headache

Neurotoxicity, Tremor,

Neuralgia, Hypersensitivity

reaction, Hypoaesthesia

Eye disorders

Lacrimation increased

Visual disorders, Dry eye, Eye

pain, Visual impairment,

Vision blurred

Ear and labyrinth

disorders

Tinnitus, Hypoacusis

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For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”, the frequency

count was based on grade 3-4 ADRs. ADRs are added according to the highest incidence seen in any of the major

combination trials.

Post-Marketing Experience:

The following additional serious adverse reactions have been identified during post-marketing exposure:

Table 6 Summary of events reported with capecitabine in the post-marketing setting

Cardiac disorders

Atrial fibrillation, Cardiac

ischemia/infarction

Vascular disorders

Lower limb oedema,

Hypertension,

Embolism

and thrombosis

Flushing, Hypotension,

Hypertensive crisis, Hot flush,

Phlebitis

Respiratory, thoracic

and mediastinal system

disorders

Sore throat, Dysaesthesia

pharynx

Hiccups, Pharyngolaryngeal

pain, Dysphonia

Gastrointestinal

disorders

Constipation, Dyspepsia

Upper gastrointestinal

haemorrhage, Mouth

ulceration, Gastritis,

Abdominal distension,

Gastroesophageal reflux

disease, Oral pain, Dysphagia,

Rectal haemorrhage,

Abdominal pain lower, Oral

dysaesthesia, Paraesthesia

oral, Hypoaesthesia oral,

Abdominal discomfort

Hepatobiliary

disorders

Hepatic function abnormal

Skin and subcutaneous

tissue disorders

Alopecia, Nail disorder

Hyperhidrosis, Rash

erythematous, Urticaria, Night

sweats

Musculoskeletal and

connective tissue

disorders

Myalgia, Arthralgia, Pain in

extremity

Pain in jaw , Muscle spasms,

Trismus, Muscular weakness

Renal and urinary

disorder

Haematuria, Proteinuria,

Creatinine renal clearance

decreased, Dysuria

General disorders and

administration site

conditions

Pyrexia, Weakness,

Lethargy, Temperature

intolerance

Mucosal inflammation, Pain

in limb, Pain, Chills, Chest

pain, Influenza-like illness,

Fever, Infusion related

reaction, Injection site

reaction, Infusion site pain,

Injection site pain

Injury, poisoning and

procedural

complications

Contusion

Body System

Rare

Very rare

Eye disorders

Lacrimal duct stenosis, corneal

disorders, keratitis, punctate keratitis

Cardiac disorders

Ventricular fibrillation, QT

prolongation, Torsade de pointes,

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Description of selected adverse reactions

Hand-foot syndrome (see section 4.4):

For the capecitabine dose of 1250 mg/m

twice daily on days 1 to 14 every 3 weeks, a frequency of 53% to 60% of all-

grades HFS (hand-foot syndrome) was observed in capecitabine monotherapy trials (comprising studies in adjuvant

therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast cancer) and a frequency of

63% was observed in the capecitabine/docetaxel arm for the treatment of metastatic breast cancer. For the capecitabine

dose of 1000 mg/m

twice daily on days 1 to 14 every 3 weeks, a frequency of 22% to 30% of all-grade HFS was

observed in capecitabine combination therapy.

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or

capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric

and breast cancer) showed that HFS (all grades) occurred in 2066 (43%) patients after a median time of 239 [95% CI

201, 288] days after starting treatment with capecitabine. In all studies combined, the following covariates were

statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose

(gram), decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six weeks,

increasing duration of study treatment (weeks), increasing age (by 10 year increments), female gender, and good

ECOG performance status at baseline (0 versus

Diarrhoea (see section 4.4):

Capecitabine can induce the occurrence of diarrhoea, which has been observed in up to 50% of patients.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed

that in all studies combined, the following covariates were statistically significantly associated with an increased risk of

developing diarrhoea: increasing capecitabine starting dose (gram), increasing duration of study treatment (weeks),

increasing age (by 10 year increments), and female gender. The following covariates were statistically significantly

associated with a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) and

increasing relative dose intensity in the first six weeks.

Cardiotoxicity (see section 4.4):

In addition to the ADRs described in tables 4 and 5, the following ADRs with an incidence of less than 0.1% were

associated with the use of capecitabine monotherapy based on a pooled analysis from clinical safety data from 7

clinical trials including 949 patients (2 phase III and 5 phase II clinical trials in metastatic colorectal cancer and

metastatic breast cancer): cardiomyopathy, cardiac failure, sudden death, and ventricular extrasystoles.

Encephalopathy:

In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis from clinical safety data

from 7 clinical trials, encephalopathy was also associated with the use of capecitabine monotherapy with an incidence

of less than 0.1%.

Special populations

Elderly patients (see section 4.2):

An analysis of safety data in patients

60 years of age treated with capecitabine monotherapy and an analysis of

patients treated with capecitabine plus docetaxel combination therapy showed an increase in the incidence of

Bradycardia, Vasospasm

Hepatobiliary disorders

Hepatic failure, cholestatic hepatitis

Skin and subcutaneous disorders

Cutaneous lupus erythematosus

Severe skin reactions

such as Stevens-

Johnson Syndrome

and Toxic Epidermal

Necrolysis (see

section 4.4)

Renal and urinary disorders

Acute renal failure secondary to

dehydration

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treatment

related grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared to patients

< 60 years of age. Patients

60 years of age treated with capecitabine plus docetaxel also had more early withdrawals

from treatment due to adverse reactions compared to patients < 60 years of age.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed

that in all studies combined, increasing age (by 10 year increments) was statistically significantly associated with an

increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Gender

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed

that in all studies combined, female gender was statistically significantly associated with an increased risk of

developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Patients with renal impairment (see section 4.2, 4.4, and 5.2):

An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) with baseline renal

impairment showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions compared to

patients with normal renal function (36% in patients without renal impairment n=268, vs. 41% in mild n=257 and 54%

in moderate n=59, respectively) (see section 5.2). Patients with moderately impaired renal function show an increased

rate of dose reduction (44%) vs. 33% and 32% in patients with no or mild renal impairment and an increase in early

withdrawals from treatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mild

renal impairment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via;

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: http://www.hpra.ie/

e-mail: medsafety@hpra.ie

4.9 Overdose

The manifestations of acute overdose include nausea, vomiting, diarrhoea, mucositis, gastrointestinal irritation and

bleeding, and bone marrow depression.

Medical management of overdose should include customary therapeutic and supportive medical interventions aimed at

correcting the presenting clinical manifestations and preventing their possible complications.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: cytostatic (antimetabolite), ATC code: L01BC06

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the

cytotoxic moiety 5

fluorouracil (5

FU). Capecitabine is activated via several enzymatic steps (see section 5.2). The

enzyme involved in the final conversion to 5

FU, thymidine phosphorylase (ThyPase), is found in tumour tissues, but

also in normal tissues, albeit usually at lower levels. In human cancer xenograft models capecitabine demonstrated a

synergistic effect in combination with docetaxel, which may be related to the upregulation of thymidine phosphorylase

by docetaxel.

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There is evidence that the metabolism of 5

FU in the anabolic pathway blocks the methylation reaction of

deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA). The

incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell

division and growth, the effect of 5

FU may be to create a thymidine deficiency that provokes unbalanced growth and

death of a cell. The effects of DNA and RNA deprivation are most marked on those cells which proliferate more

rapidly and which metabolise 5

FU at a more rapid rate.

Colon and colorectal cancer:

Monotherapy with capecitabine in adjuvant colon cancer

Data from one multicentre, randomised, controlled phase III clinical trial in patients with stage III (Dukes'

C) colon

cancer supports the use of capecitabine for the adjuvant treatment of patients with colon cancer (XACT Study;

M66001). In this trial, 1987 patients were randomised to treatment with capecitabine (1250 mg/m

twice daily for 2

weeks followed by a 1-week rest period and given as 3

week cycles for 24 weeks) or 5

FU and leucovorin (Mayo

Clinic regimen: 20 mg/m

leucovorin IV followed by 425 mg/m

IV bolus 5

FU, on days 1 to 5, every 28 days for 24

weeks). Capecitabine was at least equivalent to IV 5

FU/LV in disease-free survival in per protocol population (hazard

ratio 0.92; 95% CI 0.80

1.06). In the all-randomised population, tests for difference of capecitabine vs 5

FU/LV in

disease-free and overall survival showed hazard ratios of 0.88 (95% CI 0.77

1.01; p = 0.068) and 0.86 (95% CI

0.74

1.01; p = 0.060), respectively. The median follow up at the time of the analysis was 6.9 years. In a preplanned

multivariate Cox analysis, superiority of capecitabine compared with bolus 5

FU/LV was demonstrated. The following

factors were pre-specified in the statistical analysis plan for inclusion in the model: age, time from surgery to

randomization, gender, CEA levels at baseline, lymph nodes at baseline, and country. In the all-randomised population,

capecitabine was shown to be superior to 5

FU/LV for disease-free survival (hazard ratio 0.849; 95% CI

0.739

0.976; p = 0.0212), as well as for overall survival (hazard ratio 0.828; 95% CI 0.705 - 0.971; p = 0.0203).

Combination therapy in adjuvant colon cancer

Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III (Dukes'

C) colon

cancer supports the use of capecitabine in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients

with colon cancer (NO16968 study). In this trial, 944 patients were randomised to 3-week cycles for 24 weeks with

capecitabine (1000 mg/m

twice daily for 2 weeks followed by a 1

week rest period) in combination with oxaliplatin

(130 mg/m

intravenous infusion over 2

hours on day 1 every 3 weeks); 942 patients were randomized to bolus 5

and leucovorin. In the primary analysis for DFS in the ITT population, XELOX was shown to be significantly superior

to 5

FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-

FU/LV. The analysis for the secondary endpoint of RFS supports these results with a HR of 0.78 (95% CI=[0.67; 0.92];

p=0.0024) for XELOX vs. 5

FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72;

1.05]; p=0.1486) which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX

versus 74% for 5

FU/LV. The efficacy data is based on a median observation time of 59 months for OS and 57 months

for DFS. The rate of withdrawal due to adverse events was higher in the XELOX combination therapy arm (21 %) as

compared with that of the 5-FU/LV monotherapy arm (9 %) in the ITT population.

Monotherapy with capecitabine in metastatic colorectal cancer

Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials (SO14695; SO14796)

support the use of capecitabine for first line treatment of metastatic colorectal cancer. In these trials, 603 patients were

randomised to treatment with capecitabine (1250 mg/m

twice daily for 2 weeks followed by a 1

week rest period and

given as 3-week cycles). 604 patients were randomised to treatment with 5

FU and leucovorin (Mayo regimen:

20 mg/m

leucovorin IV followed by 425 mg/m

IV bolus 5

FU, on days 1 to 5, every 28 days). The overall objective

response rates in the all

randomised population (investigator assessment) were 25.7% (capecitabine) vs. 16.7% (Mayo

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regimen); p < 0.0002. The median time to progression was 140 days (capecitabine) vs. 144 days (Mayo regimen).

Median survival was 392 days (capecitabine) vs. 391 days (Mayo regimen). Currently, no comparative data are

available on capecitabine monotherapy in colorectal cancer in comparison with first line combination regimens.

Combination therapy in first-line treatment of metastatic colorectal cancer

Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use of capecitabine in

combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for the first-line treatment of

metastatic colorectal cancer. The study contained two parts: an initial 2-arm part in which 634 patients were

randomised to two different treatment groups, including XELOX or FOLFOX

4, and a subsequent 2x2 factorial part in

which 1401 patients were randomised to four different treatment groups, including XELOX plus placebo, FOLFOX

plus placebo, XELOX plus bevacizumab, and FOLFOX-4 plus bevacizumab. See Table 7 for treatment regimens.

Table 7 Treatment Regimens in Study NO16966 (mCRC)

Non-inferiority of the XELOX

containing arms compared with the FOLFOX

containing arms in the overall

comparison was demonstrated in terms of progression-free survival in the eligible patient population and the

intent

treat population (see table 8). The results indicate that XELOX is equivalent to FOLFOX

4 in terms of

overall survival (see table 8). A comparison of XELOX plus bevacizumab versus FOLFOX

4 plus bevacizumab was a

pre-specified exploratory analysis. In this treatment subgroup comparison, XELOX plus bevacizumab was similar

compared to FOLFOX

4 plus bevacizumab in terms of progression-free survival (hazard ratio 1.01; 97.5% CI

0.84

1.22). The median follow up at the time of the primary analyses in the intent

treat population was 1.5 years;

data from analyses following an additional 1 year of follow up are also included in table 8. However, the on-treatment

PFS analysis did not confirm the results of the general PFS and OS analysis: the hazard ratio of XELOX versus

FOLFOX

4 was 1.24 with 97.5% CI 1.07

1.44. Although sensitivity analyses show that differences in regimen

schedules and timing of tumor assessments impact the on-treatment PFS analysis, a full explanation for this result has

not been found.

Table 8 Key efficacy results for the non-inferiority analysis of Study NO16966

Treatment

Starting Dose

Schedule

FOLFOX

FOLFOX

Bevacizumab

Oxaliplatin

85 mg/m

IV 2hr

Oxaliplatin on Day 1, every 2

weeks

Leucovorin on Days 1 and 2,

every 2 weeks

fluorouracil IV

bolus/infusion, each on Days 1

and 2, every 2 weeks

Leucovorin

200 mg/m

IV 2 hr

5-Fluorouracil

400 mg/m

bolus, followed by

600 mg/ m

22 hr

Placebo or

Bevacizumab

5 mg/kg IV 30

mins

Day 1, prior to FOLFOX-4,

every 2 weeks

XELOX

XELOX+

Bevacizumab

Oxaliplatin

130 mg/m

IV 2 hr

Oxaliplatin on Day 1, every 3

weeks

Capecitabine oral twice daily for

2 weeks (followed by 1 week

off- treatment)

Capecitabine

1000 mg/m

oral

twice daily

Placebo or

Bevacizumab

7.5 mg/kg IV

90 mins

Day 1, prior to XELOX, every 3

weeks

Fluorouracil: IV bolus injection immediately after leucovorin

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*EPP=eligible patient population; **ITT=intent-to-treat population

In a randomised, controlled phase III study (CAIRO), the effect of usingcapecitabine at a starting dose of 1000 mg/m

for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic

colorectal cancer. 820 Patients were randomized to receive either sequential treatment (n=410) or combination

treatment (n=410). Sequential treatment consisted of first-line capecitabine (1250 mg/m

twice daily for 14 days),

second

line irinotecan (350 mg/m

on day 1), and third-line combination of capecitabine (1000 mg/m

twice daily for

14 days) with oxaliplatin (130 mg/m

on day 1). Combination treatment consisted of first-line capecitabine

(1000mg/m

twice daily for 14 days) combined with irinotecan (250 mg /m

on day 1) (XELIRI) and second

line

capecitabine (1000 mg/m

twice daily for 14 days) plus oxaliplatin (130 mg/m

on day 1). All treatment cycles were

administered at intervals of 3 weeks. In first-line treatment the median progression-free survival in the intent-to-treat

population was 5.8 months (95%CI 5.1

6.2 months) for capecitabine monotherapy and 7.8 months (95% CI 7.0

months; p=0.0002) for XELIRI. However this was associated with an increased incidence of gastrointestinal toxicity

and neutropenia during first-line treatment with XELIRI (26% and 11% for XELIRI and first line capecitabine

respectively). The XELIRI has been compared with 5-FU + irinotecan (FOLFIRI) in three randomised studies in

patients with metastatic colorectal cancer. The XELIRI regimens included capecitabine 1000 mg/m

twice daily on

days 1 to 14 of a three-week cycle combined with irinotecan 250 mg/m

on day1. In the largest study (BICC-C),

patients were randomised to receive either open label FOLFIRI (n=144), bolus 5-FU (mIFL) (n=145) or XELIRI

(n=141) and were additionally randomised to receive either double-blind treatment with celecoxib or placebo. Median

PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (p=0.004) for the comparison with FOLFIRI), and 5.8 months

for XELIRI (p=0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p=0.09), and 18.9 months

for XELIRI (p=0.27). Patients treated with XELIRI experienced excessive gastrointestinal toxicity compared with

FOLFIRI (diarrhoea 48% and 14% for XELIRI and FOLFIRI respectively).

In the EORTC study patients were randomised to receive either open label FOLFIRI (n=41) or XELIRI (n=44) with

additional randomisation to either double-blind treatment with celecoxib or placebo. Median PFS and overall survival

(OS) times were shorter for XELIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months), in

addition to which excessive rates of diarrhoea were reported in patients receiving the XELIRI regimen (41% XELIRI,

5.1% FOLFIRI).

In the study published by Skof et al, patients were randomised to receive either FOLFIRI or XELIRI . Overall response

rate was 49% in the XELIRI and 48% in the FOLFIRI arm (p=0.76). At the end of treatment, 37% of patients in the

PRIMARY ANALYSIS

XELOX/XELOX+P/

XELOX+BV

(EPP*: N=967; ITT**: N=1017)

FOLFOX-4/FOLFOX 4+P/

FOLFOX-4+BV

(EPP*: N = 937; ITT**: N= 1017)

Population

Median Time to Event (Days)

HR (97.5% CI)

Parameter: Progression-free Survival

1.05 (0.94; 1.18)

1.04 (0.93; 1.16)

Parameter: Overall Survival

0.97 (0.84; 1.14)

0.96 (0.83; 1.12)

ADDITIONAL 1 YEAR OF FOLLOW UP

Population

Median Time to Event (Days)

HR (97.5% CI)

Parameter: Progression-free Survival

1.02 (0.92; 1.14)

1.01 (0.91; 1.12)

Parameter: Overall Survival

1.00 (0.88; 1.13)

0.99 (0.88; 1.12)

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XELIRI and 26% of patients in the FOLFIRI arm were without evidence of the disease (p=0.56). Toxcity was similar

between treatments with the exception of neutropenia reported more commonly in patients treated with FOLFIRI.

Montagnani et al used the results from the above three studies to provide an overall analysis of randomised studies

comparing FOLFIRI and XELIRI treatment regimens in the treatment of mCRC. A significant reduction in the risk of

progression was associated with FOLFIRI (HR, 0.76; 95%CI, 0.62-0.95; P <0.01), a result partly due to poor tolerance

to the XELIRI regimens used.

Data from a randomised clinical study (Souglakos et al, 2012) comparing FOLFIRI + bevacizumab with XELIRI +

bevacizumab showed no significant differences in PFS or OS between treatments. Patients were randomised to receive

either FOLFIRI plus bevacizumab (Arm-A, n=167) or XELIRI plus bevacizumab (Arm-B, n-166). For Arm B, the

XELIRI regimen used capecitabine 1000 mg/m

twice daily for 14 days +irinotecan 250 mg/m

on day 1. Median

progression-free survival (PFS) was 10.0 and 8.9 months; p=0.64, overall survival 25.7 and 27.5 months; p=0.55 and

response rates 45.5 and 39.8%; p=0.32 for FOLFIRI-Bev and XELIRI-Bev, respectively. Patients treated with XELIRI

+ bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-foot skin reactions

than patients treated with FOLFIRI + bevacizumab with significantly increased treatment delays, dose reductions and

treatment discontinuations.

Data from a multicentre, randomised, controlled phase II study (AIO KRK 0604) supports the use of capecitabine at a

starting dose of 800 mg/m

for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for the first-

line treatment of patients with metastatic colorectal cancer. 120 Patients were randomised to a modified XELIRI

regimen with capecitabine 800 mg/m

twice daily for two weeks followed by a 7-day rest period), irinotecan (200

mg/m

as a 30 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on

day 1 every 3 weeks) ; 127 patients were randomised to treatment with capecitabine (1000 mg/m

twice daily for two

weeks followed by a 7-day rest period), oxaliplatin (130 mg/m

as a 2 hour infusion on day 1 every 3 weeks), and

bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Following a mean duration of follow-

up for the study population of 26.2 months, treatment responses were as shown below:

Table 9 Key efficacy results for AIO KRK study

Combination therapy in second-line treatment of metastatic colorectal cancer

Data from a multicentre, randomised, controlled phase III clinical study (NO16967) support the use of capecitabine in

combination with oxaliplatin for the second

line treatment of metastastic colorectal cancer. In this trial, 627 patients

with metastatic colorectal carcinoma who have received prior treatment with irinotecan in combination with a

XELOX + bevacizumab

(ITT: N=127)

Modified XELIRI+ bevacizumab

(ITT: N= 120)

Hazard

ratio

95% CI

P value

Progression-free Survival after 6 months

95% CI

69 - 84%

77 - 90%

Median progression free survival

95% CI

10.4 months

9.0 - 12.0

12.1 months

10.8 - 13.2

0.93

0.82 - 1.07

P=0.30

Median overall survival

95% CI

24.4 months

19.3 - 30.7

25.5 months

21.0 - 31.0

0.90

0.68 - 1.19

P=0.45

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fluoropyrimidine regimen as first line therapy were randomised to treatment with XELOX or FOLFOX

4. For the

dosing schedule of XELOX and FOLFOX-4 (without addition of placebo or bevacizumab), refer to table 7. XELOX

was demonstrated to be non-inferior to FOLFOX

4 in terms of progression

free survival in the per-protocol

population and intent

treat population (see table10). The results indicate that XELOX is equivalent to FOLFOX

in terms of overall survival (see table 10). The median follow up at the time of the primary analyses in the

intent

treat population was 2.1 years; data from analyses following an additional 6 months of follow up are also

included in table 10.

Table 10 Key efficacy results for the non-inferiority analysis of Study NO16967

*PPP=per-protocol population; **ITT=intent-to-treat population

Advanced gastric cancer:

Data from a multicentre, randomised, controlled phase III clinical trial in patients with advanced gastric cancer supports

the use of capecitabine for the first

line treatment of advanced gastric cancer (ML17032). In this trial, 160 patients

were randomised to treatment with capecitabine (1000 mg/m

twice daily for 2 weeks followed by a 7

day rest period)

and cisplatin (80 mg/m

as a 2-hour infusion every 3 weeks). A total of 156 patients were randomised to treatment with

FU (800 mg/m

per day, continuous infusion on days 1 to 5 every 3 weeks) and cisplatin (80 mg/m

as a 2

hour

infusion on day 1, every 3 weeks). Capecitabine in combination with cisplatin was non-inferior to 5

FU in combination

with cisplatin in terms of progression-free survival in the per protocol analysis (hazard ratio 0.81; 95% CI 0.63

1.04).

The median progression-free survival was 5.6 months (capecitabine + cisplatin) versus 5.0 months (5

FU + cisplatin).

The hazard ratio for duration of survival (overall survival) was similar to the hazard ratio for progression-free survival

(hazard ratio 0.85; 95% CI 0.64 - 1.13). The median duration of survival was 10.5 months (Capecitabine + cisplatin)

versus 9.3 months (5

FU + cisplatin).

Data from a randomised multicentre, phase III study comparing capecitabine to 5

FU and oxaliplatin to cisplatin in

patients with advanced gastric cancer supports the use of capecitabine for the first-line treatment of advanced gastric

cancer (REAL-2). In this trial, 1002 patients were randomised in a 2x2 factorial design to one of the following 4 arms:

ECF: epirubicin (50 mg/ m

as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m

as a two hour infusion on day

PRIMARY ANALYSIS

XELOX

(PPP*: N=251; ITT**: N=313)

FOLFOX-4

(PPP*: N = 252; ITT**: N= 314)

Population

Median Time to Event (Days)

HR (95% CI)

Parameter: Progression-free Survival

1.03 (0.87; 1.24)

0.97 (0.83; 1.14)

Parameter: Overall Survival

1.07 (0.88; 1.31)

1.03 (0.87; 1.23)

ADDITIONAL 6 MONTHS OF FOLLOW UP

Population

Median Time to Event (Days)

HR (95% CI)

Parameter: Progression-free Survival

1.04 (0.87; 1.24)

0.97 (0.83; 1.14)

Parameter: Overall Survival

1.05 (0.88; 1.27)

1.02 (0.86; 1.21)

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1 every 3 weeks) and 5

FU (200 mg/m

daily given by continuous infusion via a central line).

ECX: epirubicin (50 mg/m

as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m

as a two hour infusion on day

1 every 3 weeks), and capecitabine (625 mg/m

twice daily continuously).

EOF: epirubicin (50 mg/m

as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m

given as a 2 hour infusion

on day 1 every three weeks), and 5

FU (200 mg/m

daily given by continuous infusion via a central line).

EOX: epirubicin (50 mg/m

as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m

given as a 2 hour infusion

on day 1 every three weeks), and capecitabine (625 mg/m

twice daily continuously).

The primary efficacy analyses in the per protocol population demonstrated non

inferiority in overall survival for

capecitabine- vs 5

based regimens (hazard ratio 0.86; 95% CI 0.8 - 0.99) and for oxaliplatin- vs cisplatin-based

regimens (hazard ratio 0.92; 95% CI 0.80 - 1.1). The median overall survival was 10.9 months in capecitabine-based

regimens and 9.6 months in 5

FU based regimens. The median overall survival was 10.0 months in cisplatin-based

regimens and 10.4 months in oxaliplatin-based regimens.

Capecitabine has also been used in combination with oxaliplatin for the treatment of advanced gastric cancer. Studies

with capecitabine monotherapy indicate that capecitabine has activity in advanced gastric cancer.

Colon, colorectal and advanced gastric cancer: meta-analysis

A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, M17032) supports

capecitabine replacing 5

FU in mono

and combination treatment in gastrointestinal cancer. The pooled analysis

includes 3097 patients treated with capecitabine

containing regimens and 3074 patients treated with 5

containing

regimens. Median overall survival time was 703 days (95% CI: 671; 745) in patients treated with

capecitabine

containing regimens and 683 days (95% CI: 646; 715) in patients treated with 5

containing

regimens. The hazard ratio for overall survival was 0.94 (95% CI: 0.89; 1.00, p=0.0489) indicating that

capecitabine

containing regimens are superior to 5

containing regimens.

Breast cancer:

Combination therapy with capecitabine and docetaxel in locally advanced or metastatic breast cancer

Data from one multicentre, randomised, controlled phase III clinical trial support the use of capecitabine in

combination with docetaxel for treatment of patients with locally advanced or metastatic breast cancer after failure of

cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were randomised to treatment with

capecitabine (1250 mg/m

twice daily for 2 weeks followed by 1-week rest period and docetaxel 75 mg/m

as a 1 hour

intravenous infusion every 3 weeks). 256 patients were randomised to treatment with docetaxel alone (100 mg/m

as a

1 hour intravenous infusion every 3 weeks). Survival was superior in the capecitabine + docetaxel combination arm

(p=0.0126). Median survival was 442 days (capecitabine + docetaxel) vs. 352 days (docetaxel alone). The overall

objective response rates in the all

randomised population (investigator assessment) were 41.6% (capecitabine +

docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the capecitabine +

docetaxel combination arm (p<0.0001). The median time to progression was 186 days (capecitabine + docetaxel) vs.

128 days (docetaxel alone).

Monotherapy with capecitabine after failure of taxanes, anthracycline containing chemotherapy, and for whom

anthracycline therapy is not indicated

Data from two multicentre phase II clinical trials support the use of capecitabine monotherapy for treatment of patients

after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline

therapy is not indicated. In these trials, a total of 236 patients were treated with capecitabine (1250 mg/m

twice daily

for 2 weeks followed by 1-week rest period). The overall objective response rates (investigator assessment) were 20%

(first trial) and 25% (second trial). The median time to progression was 93 and 98 days. Median survival was 384 and

373 days.

All indications:

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A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or

capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric

and breast cancer) showed that patients on capecitabine who developed hand-foot syndrome (HFS) had a longer overall

survival compared to patients who did not develop HFS: median overall survival 1100 days (95% CI 1007;1200) vs

691 days (95% CI 638;754) with a hazard ratio of 0.61 (95% CI 0.56; 0.66).

5.2 Pharmacokinetic properties

The pharmacokinetics of capecitabine have been evaluated over a dose range of 502 - 3514 mg/m

/day. The parameters

of capecitabine, 5'

deoxy 5 fluorocytidine

DFCR) and 5'

deoxy 5 fluorouridine (5'

DFUR) measured on days 1 and 14 were similar. The AUC of 5 FU was

30% 35% higher on day 14. Capecitabine dose reduction decreases systemic exposure to 5 FU more than dose-

proportionally, due to non-linear pharmacokinetics for the active metabolite.

Absorption

After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the

metabolites, 5'

DFCR and 5'

DFUR. Administration with food decreases the rate of capecitabine absorption, but only

results in a minor effect on the AUC of 5'

DFUR, and on the AUC of the subsequent metabolite 5 FU. At the dose of

1250 mg/m

on day 14 with administration after food intake, the peak plasma concentrations (Cmax in µg/ml) for

capecitabine, 5'

DFCR, 5'

DFUR, 5 FU and FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 respectively. The time to peak

plasma concentrations (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-

values in µgh/ml were 7.75,

7.24, 24.6, 2.03 and 36.3.

Distribution

In vitro human plasma studies have determined that capecitabine, 5'

DFCR, 5'

DFUR and 5 FU are 54%, 10%, 62% and

10% protein bound, mainly to albumin.

Biotransformation

Capecitabine is first metabolised by hepatic carboxylesterase to 5'

DFCR, which is then converted to 5'

DFUR by

cytidine deaminase, principally located in the liver and tumour tissues. Further catalytic activation of 5'

DFUR then

occurs by thymidine phosphorylase (ThyPase). The enzymes involved in the catalytic activation are found in tumour

tissues but also in normal tissues, albeit usually at lower levels. The sequential enzymatic biotransformation of

capecitabine to 5 FU leads to higher concentrations within tumour tissues. In the case of colorectal tumours, 5 FU

generation appears to be in large part localised in tumour stromal cells. Following oral administration of capecitabine to

patients with colorectal cancer, the ratio of 5 FU concentration in colorectal tumours to adjacent tissues was 3.2 (ranged

from 0.9 to 8.0). The ratio of 5-FU concentration in tumour to plasma was 21.4 (ranged from 3.9 to 59.9, n=8) whereas

the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 to 25.8, n=8). Thymidine phosphorylase activity was

measured and found to be 4 times greater in primary colorectal tumour than in adjacent normal tissue. According to

immunohistochemical studies, thymidine phosphorylase appears to be in large part localised in tumour stromal cells.

5 FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro 5

fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5 fluoro ureidopropionic acid (FUPA).

Finally,

ureido propionase cleaves FUPA to

fluoro

alanine (FBAL) which is cleared in the urine.

Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step. Deficiency of DPD may lead to increased

toxicity of capecitabine (see section 4.3 and 4.4).

Elimination

The elimination half-life (t1/2 in hours) of capecitabine, 5'

DFCR, 5'

DFUR, 5 FU and FBAL were 0.85, 1.11, 0.66,

0.76 and 3.23 respectively. Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of

administered capecitabine dose is recovered in urine. Faecal excretion is minimal (2.6%). The major metabolite

excreted in urine is FBAL, which represents 57% of the administered dose. About 3% of the administered dose is

excreted in urine as unchanged drug.

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Combination therapy

Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice

versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (C

and AUC) and no

effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR.

Pharmacokinetics in special populations

A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients with colorectal

cancer dosed at 1250 mg/m

twice daily. Gender, presence or absence of liver metastasis at baseline, Karnofsky

Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the

pharmacokinetics of 5'

DFUR, 5 FU and FBAL.

Patients with hepatic impairment due to liver metastases: According to a pharmacokinetic study in cancer patients with

mild to moderate liver impairment due to liver metastases, the bioavailability of capecitabine and exposure to 5 FU

may increase compared to patients with no liver impairment. There are no pharmacokinetic data on patients with severe

hepatic impairment.

Patients with renal impairment: Based on a pharmacokinetic study in cancer patients with mild to severe renal

impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5 FU.

Creatinine clearance was found to influence the systemic exposure to 5'

DFUR (35% increase in AUC when creatinine

clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%).

FBAL is a metabolite without anti-proliferative activity.

Elderly: Based on the population pharmacokinetic analysis, which included patients with a wide range of ages (27 to 86

years) and included 234 (46%) patients greater or equal to 65, age has no influence on the pharmacokinetics of 5'

DFUR and 5 FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of

FBAL). This increase is likely due to a change in renal function.

Ethnic factors: Following oral administration of 825 mg/m

capecitabine twice daily for 14 days, Japanese patients

(n=18) had about 36% lower C

and 24% lower AUC for capecitabine than Caucasian patients (n=22). Japanese

patients had also about 25% lower Cmax and 34% lower AUC for FBAL than Caucasian patients. The clinical

relevance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'

DFCR, 5'

DFUR, and 5 FU).

5.3 Preclinical safety data

In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced

toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines. These toxicities

were reversible. Skin toxicity, characterised by degenerative/regressive changes, was observed with capecitabine.

Capecitabine was devoid of hepatic and CNS (central nervous system) toxicities. Cardiovascular toxicity (e.g. PR

interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but

not after repeated oral dosing (1379 mg/m

/day).

A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.

During standard fertility studies, impairment of fertility was observed in female mice receiving capecitabine; however,

this effect was reversible after a drug-free period. In addition, during a 13

week study, atrophic and degenerative

changes occurred in reproductive organs of male mice; however these effects were reversible after a drug-free period.

In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were

observed. In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of

teratogenicity.

Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene

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mutation assay). However, similar to other nucleoside analogues (ie, 5

FU), capecitabine was clastogenic in human

lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose (E460)

Hypromellose (E464)

Crosscarmellose sodium

Magnesium stearate (E572)

Tablet coating:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Nature: PVC/PVDC-AL blisters

Content:

Blister of 10 tablets (with/without cross perforation) composed of white opaque 0.25 mm PVC / PVDC film and 0.025

mm Soft aluminium blister foil.

The pack size is 60 (6 x10) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements

7 MARKETING AUTHORISATION HOLDER

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Fresenius Kabi Oncology Plc

Lion Court, Farnham Road,

Bordon, Hampshire, GU35 0NF

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA1422/011/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9

November 2012

10 DATE OF REVISION OF THE TEXT

January 2015

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