CAPECITABINE ACTAVIS 150 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
CAPECITABINE
Available from:
Actavis Group PTC ehf
ATC code:
L01BC06
INN (International Name):
CAPECITABINE
Dosage:
150 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Pyrimidine analogues
Authorization status:
Authorised
Authorization number:
PA1380/115/001
Authorization date:
2012-09-07

Capecitabine Actavis 150 mg film-coated tablets

Capecitabine Actavis 500 mg film-coated tablets

Package leaflet: Information for the user

capecitabine

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. See section 4.

What is in this leaflet:

1

What Capecitabine Actavis is and what

it is used for

2

What you need to know before you

take Capecitabine Actavis

3

How to take Capecitabine Actavis

4

Possible side effects

5

How to store Capecitabine Actavis

6

Contents of the pack and other

information

1

What Capecitabine Actavis is and what

it is used for

Capecitabine Actavis belongs to the group of

medicines called “cytostatic medicines”, which stop

the growth of cancer cells. Capecitabine Actavis

contains capecitabine, which itself is not a cytostatic

medicine. Only after being absorbed by the body is

it changed into an active anti‑cancer medicine (more

in tumour tissue than in normal tissue).

Capecitabine Actavis is used in the treatment of

colon, rectal, gastric, or breast cancers. Furthermore,

Capecitabine Actavis is used to prevent new

occurrence of colon cancer after complete removal

of the tumour by surgery.

Capecitabine Actavis may be used either alone or in

combination with other medicines.

2

What you need to know before you

take Capecitabine Actavis

Do not take Capecitabine Actavis:

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 breast‑feeding

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 know that you do not have any activity of

the enzyme dihydropyrimidine dehydrogenase

(DPD)

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 Actavis if you

know that you have a partial deficiency in

the activity of the enzyme dihydropyrimidine

dehydrogenase (DPD)

have liver or kidney diseases

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)

have brain diseases (for example. cancer that has

spread to the brain, or nerve damage (neuropathy))

have calcium imbalances (seen in blood tests)

have diabetes

cannot keep food or water in your body because of

severe nausea and vomiting

have diarrhoea

are or become dehydrated

have imbalances of ions in your blood (electrolyte

imbalances, seen in tests)

have a history of eye problems as you may need

extra monitoring of your eyes

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 Actavis, you are at

an increased risk of acute early onset of 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 Actavis is not indicated in children and

adolescents. Do not give Capecitabine Actavis to

children and adolescents.

Other medicines and Capecitabine Actavis

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 Actavis with food and drink

You should take Capecitabine Actavis no later than

30 minutes after meals.

Pregnancy and breast-feeding

If you are pregnant or breast‑feeding, think you may

be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this

medicine. You must not take Capecitabine Actavis

if you are pregnant or think you might be. You

must not breast‑feed if you are taking Capecitabine

Actavis. An effective method of contraception

should be used if you are taking Capecitabine

Actavis.

Driving and using machines

Capecitabine Actavis may make you feel dizzy,

nauseous or tired. It is therefore possible that

Capecitabine Actavis could affect your ability to drive

a car or operate machines.

Capecitabine Actavis contains lactose

monohydrate

If you have been told by your doctor that you have

an intolerance to some sugars, contact your doctor

before taking this medicinal product.

3

How to take Capecitabine Actavis

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 Actavis should only be prescribed

by a doctor experienced in the use of anticancer

medicines.

Your doctor will prescribe a dose and treatment

regimen that is right for you. The dose of

Capecitabine Actavis is based on your body surface

area. This is calculated from your height and weight.

The recommended dose for adults is 1250 mg/m

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.

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) and swallow

whole with water.

It is important that you take all your medicine as

prescribed by your doctor.

Capecitabine Actavis 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 medicines the

recommended 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).

If you take more Capecitabine Actavis than

you should

If you take more Capecitabine Actavis 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 Actavis

Do not take the missed dose at all. Do not take a

double dose to make up for a forgotten dose.

Instead, continue your regular dosing schedule and

check with your doctor.

If you stop taking Capecitabine Actavis

There are no side‑effects caused by stopping

treatment with Capecitabine Actavis. In case you

are using coumarin anticoagulants (containing

e.g. phenprocoumon), stopping Capecitabine

Actavis 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 Actavis 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.

Acute renal failure: low urine output or no urine

output as a consequence of dehydration.

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.

Capecitabine 150mg & 500mg Film-coated Tablets PIL - Ireland

item no: BBBA0009

print proof no: 4

origination date: 07.09.16

originated by: S.Anson

revision date: 09.02.17

revised by: S.Anson

dimensions: 150 x 500

pharmacode:

colours/plates:

approved for print/date

Non Printing Colours

1. Black

date sent: 07.09.16

supplier: Cipla Ltd

approved: 08.09.16

min pt size: 8

Technical Approval

BBBA0009

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.

DPD Deficiency: if you have a known DPD

deficiency, you are at an increased risk of acute

early‑onset of toxicity and severe, life‑threatening,

or fatal adverse reactions caused by Capecitabine

Actavis (e.g. stomatitis, mucosal inflammation,

diarrhoea, neutropenia, and neutrotoxicity).

If caught early, these side effects usually improve

within 2 to 3 days after treatment discontinuation.

If these side effects continue, however, contact your

doctor immediately. Your doctor may instruct you to

restart treatment at a lower dose.

Hand and foot skin‑reaction can led to loss of

fingerprint, which could impact your identification

by fingerprint scan.

In addition to the above, when Capecitabine Actavis

is used alone, very common side effects, which may

affect more than 1 in 10 people 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 Actavis. 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).

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

difficulty in swallowing, 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, hives, reaction of the skin with

sunlight, reddening of palms, swelling or pain of

the face

joint swelling or stiffness, bone pain, facial 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

kidney failure due to dehydration.

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).

toxic leukoencephalopathy.

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. You can also report

side effects directly 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 Actavis

Keep this medicine out of the sight and reach of

children.

This medicinal product does not require any special

storage conditions.

Do not use this medicine after the expiry date which

is stated on the outer carton, label and blister, after

EXP.

The expiry date refers to the last day of that month.

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 Actavis contains

The active substance is capecitabine (150 mg or

500 mg per film‑coated tablet).

The other ingredients are:

Tablet core: lactose monohydrate, microcrystalline

cellulose, hypromellose, croscarmellose sodium,

magnesium stearate.

Tablet coating: hypromellose, titanium dioxide

(E171), macrogol 6000, red iron oxide (E172).

What Capecitabine Actavis looks like and

contents of the pack

Pink coloured, capsule shaped, biconvex, film‑coated

tablets, debossed with “150” or “500” on one side and

plain on other side.

Capecitabine Actavis 150 mg film‑coated tablet pack

contains 60 film‑coated tablets.

Capecitabine Actavis 500 mg film‑coated tablet pack

contains 120 film‑coated tablets.

Marketing Authorisation Holder

Actavis Group PTC ehf,

Reykjavikurvegi 76‑78,

220 Hafnarfjordur,

Iceland

Manufacturer

Actavis Nordic A/S,

Ørnegårdsvej 16,

2820 Gentofte,

Denmark

Actavis Group PTC ehf,

Reykjavikurvegur 76‑78,

220 Hafnarfjordur,

Iceland

This medicinal product is authorised in the

Member States of the EEA under the following

names:

Austria

Capecitabin Actavis 150 / 500 mg

Filmtabletten

Capecitabin Actavis 150 / 500 mg

Filmtabletten

Belgium

Capécitabine Actavis 150 / 500 mg

comprimés pelliculés /

filmomhulde tabletten /

filmtabletten

Bulgaria

Capecitabine Actavis 150 / 500 mg

film‑coated tablets

Czech Republic

Capecitabin Actavis 150 / 500 mg

Denmark

Capecitabin Actavis

Estonia

Capecitabine Actavis

Finland

Capecitabin Actavis 150 / 500 mg

tabletti, kalvopäällysteinen

France

CAPECITABINE ARROW 150 /

500 mg, comprimé pelliculé

Hungary

Capecitabin Actavis 150 / 500 mg

filmtabletta

Iceland

Capecitabin Actavis

Ireland

Capecitabine Actavis 150 / 500 mg

film‑coated tablets

Italy

Capecitabina Aurobindo

Latvia

Capecitabine Actavis 150 / 500 mg

apvalkotās tabletes

Luxembourg

Capecitabine Actavis 150 / 500 mg

comprimés pelliculés

Netherlands

Capecitabine Aurobindo 150 /

500 mg filmomhulde tabletten

Norway

Capecitabin Actavis 150 / 500 mg

tabletter, filmdrasjerte

Portugal

Capecitabina Aurovitas

Romania

Capecitabina Actavis 150 / 500 mg

comprimate filmate

Slovakia

Capecitabine Actavis 150 / 500 mg

Spain

Capecitabina Aurovitas Spain 150

/ 500 mg comprimidos recubiertos

con película EFG

Sweden

Capecitabin Actavis

United Kingdom

Capecitabine Actavis 150 / 500 mg

Film‑coated Tablets

This leaflet was last revised in February 2017.

Capecitabine 150mg & 500mg Film-coated Tablets PIL - Ireland

item no: BBBA0009

print proof no: 4

origination date: 07.09.16

originated by: S.Anson

revision date: 09.02.17

revised by: S.Anson

dimensions: 150 x 500

pharmacode:

colours/plates:

approved for print/date

Non Printing Colours

1. Black

date sent: 07.09.16

supplier: Cipla Ltd

approved: 08.09.16

min pt size: 8

Technical Approval

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Capecitabine Actavis 150 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg capecitabine.

Excipient with known effect: 12.3 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Pink coloured, capsule shaped, biconvex, film coated tablets (approx. 11.1 mm x 5.6 mm), debossed with “150”on one

side and plain on other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Capecitabine is indicated for the treatment of:

for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon cancer (see section

5.1).

metastatic colorectal cancer (see section 5.1).

first

line treatment of advanced gastric cancer in combination with a platinumbased regimen (see section 5.1).

in combination with docetaxel (see section 5.1) for the treatment of patients with locally advanced or metastatic

breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.

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-neoplastic

medicinal 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.

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1

Posology

Recommended posology (see section 5.1):

Monotherapy

Colon, colorectal and breast cancer

Given as 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 1250 mg/m

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

total daily dose) for 14 days followed by a

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/m² when

administered twice daily for 14 days followed by a 7-day rest period combined with irinotecan 200 mg/m² on day 1.

The inclusion of bevacizumab in 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 anti-emetics 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.

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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

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

1000 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

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 (m

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

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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)

*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 hyperbilirubinemia, see section 4.4.

Haematology: Patients with baseline neutrophil counts of < 1.5 x 10

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

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.

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

-1st appearance

Interrupt until resolved to grade 0-1

100%

-2nd appearance

-3rd appearance

-4th appearance

Discontinue treatment permanently

Not applicable

Grade 3

-1st appearance

Interrupt until resolved to grade 0-1

-2nd appearance

-3rd appearance

Discontinue treatment permanently

Not applicable

Grade 4

-1st appearance

Discontinue permanently

or

If physician deems it to be in the

patient’s best interest to continue,

interrupt until resolved to grade 0-1

-2nd appearance

Discontinue permanently

Not applicable

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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 product 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 medicinal products:

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

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 other medicinal products, 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.

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4.3 Contraindications

History of severe and unexpected reactions to fluoropyrimidine therapy

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

In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) deficiency (see section

4.4)

During pregnancy and lactation

In patients with severe leukopenia, neutropenia, or thrombocytopenia

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

Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand

foot syndrome (hand

foot skin

reaction, palmar

plantar erythrodysesthesia). 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 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 medicinal

products. Acute renal failure secondary to dehydration might be potentially fatal. If 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 should be applied for the precipitating adverse event as necessary (see section 4.2).

Hand

foot syndrome

Hand-foot syndrome also known as hand

foot skin reaction or palmar

plantar erythrodysesthesia or chemotherapy

induced acral erythema. Grade 1 hand

foot syndrome is defined as numbness, dysesthesia/paresthesia, 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. Persistent or severe hand-foot syndrome (Grade 2 and above) can eventually lead

to loss of fingerprints which could impact patient identification. 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 it may decrease the efficacy of

cisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated

with capecitabine.

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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 an 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 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

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

Dihydropyrimidine dehydrogenase (DPD) deficiency

Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation neutropenia and neurotoxicity)

associated with 5-FU has been attributed to a deficiency of DPD activity.

Patients with low or absent DPD activity, an enzyme involved in fluorouracil degradation, are at increased risk for

severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely

defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD

gene locus, which can cause complete or near complete absence of DPD enzymatic activity (as determined from

laboratory assays), have the highest risk of life-threatening or fatal toxicity and should not be treated with capecitabine

(see section 4.3). No dose has been proven safe for patients with complete absence of DPD activity.

For patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the

benefits of capecitabine are considered to outweigh the risks (taking into account the suitability of an alternative non-

fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution and frequent

monitoring with dose adjusment according to toxicity. There is insufficient data to recommend a specific dose in

patients with partial DPD activity as measured by specific test.

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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. 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 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

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 anti

coagulant 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 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

per 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.

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Sorivudine and analogues

A clinically significant 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 aluminium 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

(5’

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

FU. 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 is 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 should 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 list 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.

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

Body System

Very Common

All grades

Common

All grades

Uncommon

Severe and/or Life-

threatening

(grade 3-4) or

considered medically

relevant

Rare/Very Rare

(Post-Marketing

Experience)

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

Neoplasm

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

Toxic

leukoencephalopathy

(very rare)

Eye disorders

Lacrimation

increased,

Conjunctivitis,

Eyeirritation

Visual acuity reduced,

Diplopia

Lacrimal duct stenosis

(rare), Corneal

disorders(rare),

keratitis (rare),

punctate keratitis

(rare)

Ear and

labyrinth

disorders

Vertigo, Ear pain

Cardiac

Angina unstable, Angina

Ventricular fibrillation

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1

** Based on the post-marketing experience,

persistent

severe palmar-plantar

erythrodysaesthesia syndrome can

eventually lead to loss of fingerprints (see section 4.4).

disorders

pectoris, Myocardial

ischaemia, Atrial

fibrillation,

Arrhythmia, Tachycardia,

Sinus tachycardia,

Palpitations

(rare), QT

prolongation (rare),

Torsade de pointes

(rare), Bradycardia

(rare), Vasospasm

(rare)

Vascular

disorders

Thrombophlebitis

Deep vein thrombosis,

Hypertension, Petechiae,

Hypotension, Hot flush,

Peripheral coldness

Respiratory,

thoracic

and mediastinal

disorders

Dyspnoea,

Epistaxis,

Cough, Rhinorrhea

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

Hyperbilirubinemia,

Liver function test

abnormalities

Jaundice

Hepatic failure (rare),

Cholestatic hepatitis

(rare)

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

Cutaneous lupus

erythematosus (rare),

Severe skin reactions

such as Stevens-

Johnson Syndrome

and Toxic Epidermal

Necrolysis (very rare)

(see section 4.4.)

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

creatinine increased

Reproductive

system

and breast

disorders

Vaginal haemorrhage

General

disorders

and

administration

site conditions

Fatigue, Asthenia

Pyrexia, Oedema

peripheral,Malaise,

Chest pain

Oedema, Chills, Influenza

like illness, Rigors, Body

temperature increased

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2

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 cannot 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

Body System

Very common

All grades

Common

All grades

Rare/Very Rare

(Post-Marketing

Experience)

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,

Leukopenia,

Anaemia,

Neutropenic fever,

Thrombocyto-penia

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

Cardiac disorders

Atrial fibrillation, Cardiac

ischemia/infarction

Vascular disorders

Lower limb

oedema,

Flushing, Hypotension,

Hypertensive crisis, Hot flush,

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3

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.

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

grades HFS 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

Hypertension,

Embolism and

thrombosis

Phlebitis

Respiratory, thoracic and

mediastinal 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

Acute renal failure

secondary to

dehydration (rare)

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

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(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 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

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suspected adverse reactions 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.

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.

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/m2 leucovorin intravenous followed by 425 mg/m

intravenous bolus 5

FU, on days 1 to 5,

every 28 days for 24 weeks). Capecitabine was at least equivalent to intravenous 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

randomised population, capecitabine was shown to be superior to 5FU/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).

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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 randomised 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 intravenous followed by 425 mg/m

intravenous 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 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 6 for treatment regimens.

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Table 6 Treatment regimens in study NO16966 (mCRC)

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 7). The results indicate that XELOX is equivalent to FOLFOX

4 in terms of

overall survival (see table 7). 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 7. 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.

Treatment

Starting Dose

Schedule

FOLFOX-4

FOLFOX-4 +

Bevacizumab

Oxaliplatin

Leucovorin

5-Fluorouracil

85 mg/m

intravenous 2

200 mg/m

intravenous

2 hr

400 mg/m

intravenous

bolus,

followed by 600 mg/m

intravenous 22 hr

Oxaliplatin on Day 1, every 2 weeks

Leucovorin on Days 1 and 2, every 2 weeks

5-fluorouracil intravenous bolus/infusion,

each on Days 1 and 2, every 2 weeks

Placebo or

Bevacizumab

5 mg/kg intravenous 30-

mins

Day 1, prior to FOLFOX-4, every

2 weeks

XELOX

XELOX+

Bevacizumab

Oxaliplatin

Capecitabine

130 mg/m

intravenous

2 hr

1000 mg/m

oral

twice daily

Oxaliplatin on Day 1, every 3 weeks

Capecitabine oral twice daily for 2

weeks (followed by 1 week off-treatment)

Placebo or

Bevacizumab

7.5 mg/kg intravenous

30-90

mins

Day 1, prior to XELOX, every

3 weeks

5-Fluorouracil: intravenous bolus injection immediately after leucovorin

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Table 7 Key efficacy results for the non

inferiority analysis of Study NO16966

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

In a randomised, controlled phase III study (CAIRO), the effect of using capecitabine 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 was studied.

820 patients were randomised to receive either

(1000 mg/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/m2 on da y 1). All treatment cycles were

administered at intervals of 3 weeks. In first-line treatment the media n 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 - 8.3

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 color ectal 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 da y1. 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).

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)

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 day1), 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

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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 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 mor e commonly in patients

treated with FOLFIRI.

Montagna ni 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 da y 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 tha n 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 8 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

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 6. XELOX

was demonstrated to be non

inferior to FOLFOX

4 in terms of progression

free survival in the per

protocol

XELOX + bevacizumab

(ITT: N=127)

Modified XELIRI+

bevacizumab

(ITT: N= 120)

Hazard ratio

95% CI

P value

Progression-free Survival after 6 months

ITT

95% CI

76%

69 - 84%

84%

77 - 90%

-

Median progression free survival

ITT

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

ITT

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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population and intent

treat population (see table 9). The results indicate that XELOX is equivalent to FOLFOX

in terms of overall survival (see table 9). 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 9.

Table 9 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 5

FU (800 mg/m

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

as a

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

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 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

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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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

FU-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

FU-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 non-inferior to 5

FU-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.

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All indications:

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).

Paediatric population:

The European Medicines Agency has waived the obligation to conduct studies with capecitabine in all subsets of the

paediatric population in adenocarcinoma of the colon and rectum, gastric adenocarcinoma and breast carcinoma (see

section 4.2 for information on paediatric use).

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

fluorocytidine (5'

DFCR) and 5'

deoxy

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 (C

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 (T

in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC

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

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.

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

dihydro

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 unchanged.

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 (Cmax 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

antiproliferative 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

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).

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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 toxicities. Cardiovascular toxicity (e.g. PR- and QT

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

(see section 4.6).

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 hamsterV79/HPRT gene

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),

croscarmellose sodium,

magnesium stearate (E572).

Tablet coating:

hypromellose (E464),

titanium dioxide (E171),

macrogol 6000,

red iron oxide (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.

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6.5 Nature and contents of container

Nature: PVC/PVDC-Aluminium - blisters

Content: 60 film-coated tablets

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf

Reykjavikurvegi 76 – 78

220 Hafnarfjordur

Iceland

8 MARKETING AUTHORISATION NUMBER

PA1380/115/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 7

September 2012

Date of Last Authorisation: 28

June 2017

10 DATE OF REVISION OF THE TEXT

February 2018

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