Capecitabine Accord: detailed information

Package leaflet: Information for the user

Capecitabina Accord 150 mg film-coated tablets, 300 mg film-coated tablets, 500 mg film-coated tablets

capecitabine
Please 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 questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist (see section 4).

Contents of this leaflet:

What Capecitabina Accord is and what it is used for
What you need to know before taking Capecitabina Accord
How to take Capecitabina Accord
Possible side effects
How to store Capecitabina Accord
Contents of the pack and other information

1. What Capecitabina Accord is and what it is used for

Capecitabina Accord belongs to a group of medicines called "cytostatic agents", which block the growth of tumour cells. Capecitabina Accord contains the active substance capecitabine, which in itself is not a cytostatic medicine. Only after being absorbed by the body is it converted into an active anticancer medicine (with conversion occurring to a greater extent in tumour tissues than in normal tissues).
Capecitabina Accord is used to treat cancers of the colon, rectum, stomach, or breast.
Additionally, Capecitabina Accord is prescribed to prevent the recurrence of colon cancer following complete surgical removal of the tumour.
Capecitabina Accord may be used alone or in combination with other medicines.

2. What you should know before taking Capecitabine Accord

Do not take Capecitabine Accord:

if you are allergic to capecitabine or to any of the other ingredients of this medicine (listed in section 6). You must inform your doctor if you know you are allergic or have excessive reactions to this medicine,
if you have previously had severe reactions to treatment with fluoropyrimidines (a group of anticancer medicines such as fluorouracil),
if you are pregnant or breastfeeding,
if you have severely low levels of white blood cells or platelets in your blood (leucopenia, neutropenia or thrombocytopenia),
if you have severe liver or kidney problems,
if you know you have no activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete absence of DPD activity),
if you are currently being treated or have been treated within the last 4 weeks with brivudine, used for the treatment of herpes zoster (shingles or chickenpox).

Warnings and precautions
Talk to your doctor or pharmacist before taking Capecitabine Accord:

if you know you have a partial deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD),
if you have a family history of partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD),
if you have liver or kidney disease,
if you have or have had heart problems (e.g. irregular heartbeat) or chest, jaw, or back pain caused by physical exertion due to impaired blood flow to the heart,
if you have brain disorders (e.g. cancer that has spread to the brain) or nerve damage (neuropathy),
if you have imbalances in calcium levels (detectable in blood tests),
if you have diabetes,
if you are unable to retain food or fluids due to severe nausea and vomiting,
if you have diarrhoea,
if you are or may become dehydrated,
if you have imbalances in blood ions (electrolyte imbalance, detected by blood tests),
if you have had eye problems, as you may require additional eye monitoring,
if you develop a severe skin reaction.

Dihydropyrimidine dehydrogenase (DPD) deficiency:
DPD deficiency is a genetic condition that is generally not associated with health problems unless certain medicines are taken. If you have DPD deficiency and take Capecitabine Accord, you are at higher risk of developing severe adverse effects (listed in section 4 Possible side effects). Testing for DPD deficiency is recommended before starting treatment. Do not take Capecitabine Accord if you have no enzyme activity. If you have reduced enzyme activity (partial deficiency), your doctor may prescribe a lower dose. Even if DPD deficiency tests are negative, severe or potentially life-threatening adverse effects may still occur.

Children and adolescents
Capecitabine Accord is not indicated for use in children and adolescents. Do not administer Capecitabine Accord to children and adolescents.

Other medicines and Capecitabine Accord
Before starting treatment, inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is extremely important, as taking multiple medicines together may increase or reduce their effects.

Do not take brivudine (an antiviral medicine used to treat shingles or chickenpox) concurrently with capecitabine treatment (including during treatment breaks when no capecitabine tablets are taken).
If you have taken brivudine, you must wait at least 4 weeks after stopping it before starting capecitabine therapy. See also section “Do not take Capecitabine Accord”.

Additionally, particular caution is required when taking the following medicines concomitantly:

medicines for gout (allopurinol),
medicines that thin the blood (coumarin, warfarin),
medicines for seizures or tremors (phenytoin),
a medicine used to treat tumours (interferon alfa),
radiotherapy and certain medicines used to treat cancer (folinic acid, oxaliplatin, bevacizumab, cisplatin, irinotecan),
medicines used to treat folic acid deficiency.

Capecitabine Accord with food and drink
You should take Capecitabine Accord within 30 minutes after meals.

Pregnancy, breastfeeding and fertility
If you are pregnant or breastfeeding, if you suspect you may be pregnant or are planning pregnancy, consult your doctor or pharmacist before taking this medicine. You must not take Capecitabine Accord if you are pregnant or suspect you are pregnant.
You must not breastfeed during treatment with Capecitabine Accord and for 2 weeks after the last dose.
If you are a woman of childbearing potential, you must use effective contraception during treatment with Capecitabine Accord and for 6 months after the last dose.
If you are a male patient and your partner is a woman of childbearing potential, you must use effective contraception during treatment with Capecitabine Accord and for 3 months after the last dose.

Driving and using machines
Capecitabine Accord may cause dizziness, nausea or fatigue. Therefore, your ability to drive or operate machinery may be impaired. Do not drive if you experience dizziness, nausea or fatigue after taking this medicine.

Capecitabine Accord contains lactose
This medicine contains lactose. If your doctor has diagnosed you with an intolerance to certain sugars, contact your doctor before taking this medicine.

Capecitabine Accord contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. essentially 'sodium-free'.

3. How to take Capecitabine Accord

Always take this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
Capecitabine Accord must be prescribed only by a doctor experienced in the use of anticancer medicines.
Your doctor will determine the dose and treatment schedule appropriate for you. The dose of Capecitabine Accord is based on body surface area, which is calculated according to your height and weight. The usual dose for adults is 1250 mg/m² of body surface area twice daily (morning and evening).
Two examples are provided: a person weighing 64 kg and 1.64 m tall has a body surface area of 1.7 m² and should take 4 tablets of 500 mg and 1 tablet of 150 mg twice daily. A person weighing 80 kg and 1.80 m tall has a body surface area of 2.00 m² and should take 5 tablets of 500 mg twice daily.
Your doctor will tell you which dose to take, when to take it, and for how long.
Your doctor may prescribe a combination of 150 mg and 500 mg tablets for each dose.

Take the tablets in the morning and in the evening, as prescribed by your doctor.
Take the tablets within 30 minutes after finishing a meal (breakfast and dinner) and swallow them whole with water. Do not crush or cut the tablets. If you are unable to swallow the Capecitabine Accord tablets whole, inform your healthcare provider.
It is important to take all medicines exactly as prescribed by your doctor.

Capecitabine Accord tablets are generally taken for 14 days, followed by a 7-day rest period (during which the tablets are not taken). These 21 days constitute one treatment cycle.
When used in combination with other medicines, the usual adult dose may be lower than 1250 mg/m² body surface area, and it may be necessary to take the tablets for a different duration (e.g., daily, without any rest period).

If you take more Capecitabine Accord than you should
If you take more Capecitabine Accord than prescribed, contact your doctor as soon as possible before taking the next dose.
If you take a significantly higher amount of capecitabine than recommended, you may experience the following adverse effects: nausea or vomiting, diarrhoea, inflammation or ulceration of the intestine or mouth, abdominal pain or gastrointestinal bleeding, or bone marrow suppression (reduction in certain types of blood cells). Contact your doctor immediately if you experience any of these symptoms.

If you forget to take Capecitabine Accord
Do not take the missed dose. Do not take a double dose to make up for the forgotten dose. Instead, continue with your regular dosing schedule and contact your doctor.

If you stop taking Capecitabine Accord
Stopping treatment with capecitabine does not cause adverse effects. However, if you are taking coumarin anticoagulants (e.g., containing fenprocoumon), stopping capecitabine may require your doctor to adjust your anticoagulant dose.

If you have any questions about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
STOP taking Capecitabine Accord immediately and contact your doctor if you experience any of the following symptoms:

Diarrhoea: if you have 4 or more additional bowel movements per day than your usual bowel movements, or nocturnal diarrhoea.
Vomiting: if you vomit more than once within 24 hours.
Nausea: if you lose your appetite and the amount of food you eat in a day is much lower than normal.
Stomatitis: if you have pain, redness, swelling, or ulcers in your mouth and/or throat.
Hand-foot reaction: if you have pain, swelling, redness, or tingling in your hands and/or feet.
Fever: if your body temperature is 38°C or higher.
Infection: if you develop signs of infection caused by bacteria, viruses, or other organisms.
Chest pain: if you experience pain located in the centre of your chest, especially if it occurs during physical activity.
Stevens-Johnson syndrome: if you develop a painful red or purplish rash that spreads and forms blisters and/or other lesions starting in the mucous membranes (e.g. mouth and lips), particularly if you previously experienced light sensitivity, respiratory tract infections (e.g. bronchitis), and/or fever.
Angioedema: If you notice any of the following symptoms, seek immediate medical help as urgent medical treatment may be required: swelling mainly affecting the face, lips, tongue, or throat causing difficulty in swallowing or breathing, sensation of itching, and skin rashes. This could be a sign of angioedema.
If detected early, these side effects usually improve within 2–3 days after stopping the medicine. However, if the side effects persist, contact your doctor immediately. Your doctor may advise you to restart the medicine at a lower dose.
If severe stomatitis (ulcers in the mouth and/or throat), mucosal inflammation, diarrhoea, neutropenia (increased risk of infections), or neurotoxicity occur during the first treatment cycle, this may be due to DPD deficiency (see Section 2: Warnings and precautions).
The hand-foot syndrome may lead to loss of fingerprints, which could affect your identification using fingerprint readers.

In addition to those listed above, other very common side effects reported with capecitabine monotherapy, which may affect more than 1 in 10 people, are:

abdominal pain
skin rash, dry or itchy skin
fatigue
loss of appetite (anorexia)

These side effects can become severe. Therefore, contact your doctor immediately if you experience any side effect. Your doctor may instruct you to reduce the dose and/or temporarily stop treatment with Capecitabine Accord. This will help reduce the likelihood of the side effect persisting or becoming severe.

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

decrease in white or red blood cell count (detected by blood tests)
dehydration, weight loss
insomnia, depression
headache, drowsiness, dizziness, abnormal sensation in the skin (numbness or tingling), taste alterations
eye irritation, increased tearing, eye redness (conjunctivitis)
inflammation of veins (thrombophlebitis)
shortness of breath, nosebleeds, cough, runny nose
cold sores or other herpes infections
lung or respiratory tract infections (e.g. pneumonia or bronchitis)
intestinal bleeding, constipation, upper abdominal pain, indigestion, excessive flatulence, dry mouth
skin rash, hair loss (alopecia), skin redness, dry skin, itching, skin discoloration, skin peeling, skin inflammation, nail disorders
joint or limb (extremity) pain, chest or back pain
fever, swelling in limbs, feeling unwell
liver function problems (detected by 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, skin infection, nose and throat infections, fungal infections (including in the mouth), influenza, gastroenteritis, dental abscess
fatty lumps under the skin (lipoma)
reduction in blood cells, including platelets, blood thinning (detected by blood tests)
allergy
diabetes, low blood potassium, malnutrition, increased blood triglycerides
confusion, panic attacks, depressed mood, reduced libido
difficulty speaking, memory impairment, loss of motor coordination, balance disorders, fainting, nerve damage (neuropathy), and sensory perception problems
blurred or double vision
vertigo, ear pain
irregular heartbeat and palpitations (arrhythmias), chest pain, heart attack (infarction)
blood clots in deep veins, high or low blood pressure, hot flushes, cold extremities, purple spots on the skin
blood clots in the lung veins (pulmonary embolism), collapsed lung, presence of blood in sputum, asthma, shortness of breath on exertion
intestinal obstruction, fluid accumulation in the abdomen, inflammation of the small or large intestine, stomach or oesophagus, lower abdominal pain, abdominal discomfort, heartburn (stomach contents reflux), blood in stools
jaundice (yellowing of the skin and eyes)
skin ulcers and blisters, skin reaction to sunlight, redness of the palms of the hands, facial swelling or pain
joint swelling or stiffness, bone pain, muscle weakness or stiffness
fluid accumulation in the kidneys, increased frequency of urination at night, incontinence, blood in urine, increased blood creatinine (a sign of kidney dysfunction)
unusual vaginal bleeding
swelling (oedema), chills, and stiffness.

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

narrowing or blockage of the tear duct (lacrimal duct stenosis)
liver failure
inflammation leading to impaired or blocked bile secretion (cholestatic hepatitis)
specific changes in the electrocardiogram (ECG) (prolongation of the QT interval)
certain types of arrhythmias (including ventricular fibrillation, torsades de pointes, and bradycardia)
eye inflammation causing eye pain and potential vision problems
skin inflammation leading to red patches and skin peeling due to an immune system disorder
swelling mainly affecting the face, lips, tongue, or throat, sensation of itching, and skin rashes (angioedema)

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

severe skin reactions, such as rash, ulceration, and blistering, which may lead to ulcers in the mouth, nose, genitals, hands, feet, and eyes (eye redness and swelling).

Some of these side effects are more common when capecitabine is used in combination with other anticancer medicines. Other side effects in this setting include:
Common side effects (may affect up to 1 in 10 people) include:

decreased blood sodium, magnesium, or calcium levels, increased blood sugar
nerve pain
ringing or buzzing in the ears (tinnitus), hearing loss
inflammation of veins
hiccups, voice changes
pain or altered/abnormal sensation in the mouth, jaw pain
sweating, night sweats
muscle spasms
difficulty urinating, blood or protein in urine
bruising or injection site reaction (caused by concomitantly administered injectable medicines)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Capecitabine Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and blister after
Exp.
For aluminium/aluminium blisters
This medicine does not require any special storage conditions.
For PVC/PVdC-aluminium blisters (perforated for single dose)
Do not store above 30°C.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Capecitabina Accord contains
The active substance is capecitabine.
Each film-coated tablet contains 150 mg of capecitabine.
Each film-coated tablet contains 300 mg of capecitabine.
Each film-coated tablet contains 500 mg of capecitabine.
The other components are:
Tablet core: anhydrous lactose, sodium croscarmellose, hypromellose, microcrystalline cellulose,
magnesium stearate.
Tablet coating (for 150 mg): hypromellose, titanium dioxide (E171), yellow iron oxide, red iron oxide (E172), talc.
Tablet coating (for 300 mg): hypromellose, titanium dioxide (E171), talc.
Tablet coating (for 500 mg): hypromellose, titanium dioxide (E171), yellow iron oxide, red iron oxide (E172), talc.

Description of the appearance of Capecitabina Accord and contents of the pack
Capecitabina Accord 150 mg film-coated tablets are light peach-coloured, biconvex, oblong film-coated tablets, 11.4 mm in length and 5.3 mm in width, with "150" printed on one side and smooth on the other side.
Capecitabina Accord 300 mg film-coated tablets are white to off-white, biconvex, oblong film-coated tablets, 14.6 mm in length and 6.7 mm in width, with "300" printed on one side and smooth on the other side.
Capecitabina Accord 500 mg film-coated tablets are peach-coloured, biconvex, oblong film-coated tablets, 15.9 mm in length and 8.4 mm in width, with "500" printed on one side and smooth on the other side.
Capecitabina Accord is available in packs of 30, 60 or 120 film-coated tablets in blisters or in packs of 30 x 1, 60 x 1 or 120 x 1 film-coated tablets in perforated blister packs for unit dose.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Accord Healthcare S.L.U.
World Trade Center, Moll de Barcelona, s/n,
Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer
Accord Healthcare Polska Sp.z o.o.,
ul. Lutomierska 50, 95-200 Pabianice, Poland
Accord Healthcare B.V.,
Winthontlaan 200,
3526 KV Utrecht,
The Netherlands
Accord Healthcare Single Member S.A.
64th Km National Road Athens,
Lamia, 32009,
Greece

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:
AT / BE / BG / CY / CZ / DE / DK / EE / FI / FR / HR / HU / IE / IS / IT / LT / LV / LX / MT / NL /
NO / PT / PL / RO / SE / SI / SK / ES
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64
EL
Win Medica Pharmaceutical S.A.
Tel: +30 210 7488 821

More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION TO THE TERMS
OF THE MARKETING AUTHORISATIONS

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for capecitabine, the scientific conclusions are as follows:
In light of available data from the literature demonstrating that impaired renal function is associated with increased levels of uracil in blood, which could lead to a false diagnosis of dihydropyrimidine dehydrogenase (DPD) deficiency and subsequently to underdosing of capecitabine, the PRAC concluded that the product information for medicinal products containing capecitabine should be amended accordingly.
Having reviewed the PRAC recommendation, the Committee for Medicinal Products for Human Use (CHMP) agrees with the overall conclusions and the rationale of the recommendation.

Reasons for the variation to the terms of the marketing authorisations
Based on the scientific conclusions for capecitabine, the CHMP considers that the benefit-risk balance of medicinal products containing capecitabine as listed in the EURD remains favourable, subject to the proposed changes to the product information.
The CHMP recommends that the terms of the marketing authorisations should be varied.