Xeloda

Package Leaflet: Information for the User

Xeloda 150 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. Never give it to others, even if they have the same symptoms as yours, because it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist (see section 4). Contents of this leaflet:
  1. What Xeloda is and what it is used for
  2. What you need to know before taking Xeloda
  3. How to take Xeloda
  4. Possible side effects
  5. How to store Xeloda
  6. Contents of the pack and other information

1. What Xeloda is and what it is used for

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

2. What you should know before taking Xeloda

Do not take Xeloda:

• 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 had excessive reactions to this medicine,
• if you have previously experienced severe reactions to fluoropyrimidine therapy (a group of anticancer medicines such as fluorouracil),
• if you are pregnant or breastfeeding,
• if you have very low levels of white blood cells and platelets in your blood (leukopenia, neutropenia or thrombocytopenia),
• if you have severe liver or kidney problems,
• if you have no activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete DPD deficiency),
• if you are currently being treated or have been treated within the last 4 weeks with brivudine for herpes zoster (shingles or chickenpox).

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

• if you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD),
• if you have a family member with partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD),
• if you have kidney or liver disease,
• if you have had or currently have heart problems (e.g. irregular heartbeat or chest pain radiating to the jaw and vice versa, caused by physical exertion and due to impaired blood flow to the heart),
• if you have brain disorders (e.g. a tumor 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 water due to severe nausea and vomiting,
• if you have diarrhea,
• if you are or may become dehydrated,
• if you have imbalances in blood ions (electrolyte imbalances, detectable in blood tests),
• if you have had eye problems, as you may need additional eye monitoring,
• if you experience a severe skin reaction.

Dihydropyrimidine dehydrogenase (DPD) deficiency
DPD deficiency is a genetic condition present from birth, which generally does not cause health problems unless certain medicines are taken. If you have DPD deficiency and take Xeloda, you are at higher risk of serious adverse effects (listed in section 4 “Possible side effects”).
It is recommended to test for DPD deficiency before starting treatment. If there is no enzyme activity, you must not take Xeloda. If enzyme activity is reduced (partial deficiency), your doctor may prescribe a lower dose. Even with negative test results for DPD deficiency, serious and potentially life-threatening adverse effects may still occur.

Children and adolescents
Xeloda is not indicated for the treatment of children and adolescents. Do not administer Xeloda to children and adolescents.

Other medicines and Xeloda
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 several medicines together may strengthen or weaken their effects.

You must not take brivudine (an antiviral medicine used to treat shingles or chickenpox) concomitantly 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 Xeloda”.

Particular caution is also required when taking the following medicines concomitantly:

• medicines for gout (allopurinol),
• blood-thinning medicines (coumarin, warfarin),
• medicines used to treat seizures or tremors (phenytoin),
• interferon alfa,
• radiotherapy and certain anticancer medicines (folinic acid, oxaliplatin, bevacizumab, cisplatin, irinotecan),
• medicines used to treat folic acid deficiency.

Xeloda with food and drink
You should take Xeloda within 30 minutes after finishing a meal.

Pregnancy and breastfeeding
If you are pregnant or breastfeeding, if you suspect you may be pregnant or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine. You must not take Xeloda if you are definitely or possibly pregnant.
You must not breastfeed during treatment with XELODA and for 2 weeks after the last dose.
If you are a woman of childbearing potential, you must use effective contraception during treatment with XELODA 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 XELODA and for 3 months after the last dose.

Driving and using machines
Xeloda may cause dizziness, nausea or fatigue. Therefore, Xeloda may affect your ability to drive or use machinery.

Xeloda contains anhydrous lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.

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

3. How to take Xeloda

Take this medicine exactly as your doctor or pharmacist has told you. If
you have any doubts, consult your doctor or pharmacist.
Xeloda should only be prescribed by a doctor experienced in the use of anticancer medicines.
Your doctor will prescribe the dosage and treatment schedule appropriate for you. The dose of Xeloda is
based on body surface area, which is calculated from your height and weight. The usual adult dose is 1250 mg/m² of body surface area, taken twice daily (in the morning and evening). Below are two examples: 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 the dose you need 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 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 Xeloda tablets whole, inform your healthcare provider.
• It is important to take all medicines exactly as prescribed by your doctor.

Xeloda tablets are generally taken for 14 days, followed by a 7-day rest period (during which no tablets are 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 of body surface area, and the tablets may need to be taken for a different duration (for example, every day without a rest period).

If you take more Xeloda than you should
If you take more Xeloda than prescribed, contact your doctor as soon as possible before taking your next dose.
If you take a much higher dose of capecitabine than recommended, you may experience the following side effects: nausea or vomiting, diarrhoea, inflammation or ulceration of the bowel or mouth, pain or bleeding from the bowel or stomach, or bone marrow suppression (reduction in certain types of blood cells). If you experience any of these symptoms, contact your doctor immediately.

If you forget to take Xeloda:
Do not take the missed dose. Do not take a double dose to make up for the forgotten dose. Instead, continue with your next scheduled dose as usual and contact your doctor.

If you stop taking Xeloda:
Stopping treatment with capecitabine does not cause withdrawal effects. However, if you are taking coumarin anticoagulants (e.g. phenprocoumon), stopping capecitabine may require your doctor to adjust your anticoagulant dose.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
STOP taking Xeloda 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 normal, 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 less than normal.
• Stomatitis: if you have pain, redness, swelling or ulcers in your mouth or throat.
• Hand-and-foot reaction: if you have pain, swelling, redness or tingling in your hands and/or feet.
• Fever: if your body temperature is equal to or above 38°C.
• Infection: if you develop signs of infection caused by bacteria, viruses, or other organisms.
• Chest pain: if you feel pain in the centre of your chest, especially if it occurs during physical exertion.
• Stevens-Johnson syndrome: if you develop a painful red or purple skin 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 treatment may be needed: swelling mainly affecting the face, lips, tongue or throat causing difficulty in swallowing or breathing, itching sensation 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 side effects persist, contact your doctor immediately. Your doctor may advise you to restart the medicine at a lower dose.
If severe stomatitis (sores in the mouth and/or throat), mucosal inflammation, diarrhoea, neutropenia (increased risk of infections), or neurotoxicity occur during the first treatment cycle, a DPD deficiency may be present (see section 2: Warnings and precautions).
The hand-and-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 Xeloda 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, always contact your doctor immediately if you notice any side effect. Your doctor may instruct you to reduce the dose and/or temporarily stop treatment with Xeloda. 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:

• decreased number of white or red blood cells in the blood (observed in blood tests)
• dehydration, weight loss
• sleeplessness (insomnia), depression
• headache, drowsiness, dizziness, abnormal skin sensation (numbness or tingling), altered taste
• 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, flatulence, dry mouth
• skin rash, hair loss (alopecia), skin redness, dry skin, itching, skin colour changes, skin peeling, skin inflammation, nail changes
• joint or limb (extremities) pain, chest pain, back pain
• fever, swelling of limbs, feeling unwell
• liver function problems (seen in blood tests) and increased bilirubin in the blood (excreted via 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, abscess
• soft swellings under the skin (lipoma)
• decreased blood cells including platelets, blood thinning (observed in blood tests)
• allergy
• diabetes, low potassium in the blood, malnutrition, increased triglycerides in the blood
• confusion, panic attacks, low mood, reduced libido
• difficulty speaking, memory disturbance, loss of coordination, balance problems, fainting, nerve damage (neuropathy) and sensory perception problems
• blurred or double vision
• vertigo, ear pain
• irregular heartbeat and palpitations (arrhythmia), chest pain and heart attack (infarction)
• blood clots in deep veins, high or low blood pressure, hot flushes, coldness in limbs (extremities), purplish spots on the skin
• blood clots in the lung veins (pulmonary embolism), lung collapse, coughing up blood, 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 palms, 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 creatinine in blood (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, torsade de pointes, and bradycardia)
• eye inflammation causing eye pain and potential vision problems
• skin inflammation leading to red, scaly patches due to an immune system disorder
• swelling mainly affecting face, lips, tongue or throat, itching sensation 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 together with other anticancer medicines. Other side effects observed in this setting are:

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

• decreased sodium, magnesium and calcium in the blood, increased blood sugar
• nerve pain
• ringing 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 reactions (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 Xeloda

Keep out of the sight and reach of children.
Do not store above 30 °C. Keep in the original packaging to protect the medicine from moisture.
Do not use this medicine after the expiry date stated on the outer packaging and blister after Exp./EXP. The expiry date refers to the last day of that month.
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 Xeloda contains

• The active substance is capecitabine.
• Xeloda 150 mg film-coated tablets: Each tablet contains 150 mg of capecitabine.
• Xeloda 500 mg film-coated tablets: Each tablet contains 500 mg of capecitabine.
• The other components are:
• Tablet core: anhydrous lactose, sodium croscarmellose, hypromellose (3 mPa.s), microcrystalline cellulose, magnesium stearate (see section 2 “Xeloda contains anhydrous lactose and sodium”).
• Tablet coating: hypromellose, titanium dioxide, yellow iron oxide, red iron oxide, and talc.

Description of the appearance of Xeloda and pack contents

Xeloda 150 mg film-coated tablets
Light peach-coloured, biconvex, oval film-coated tablets, marked with “150” on one side and “Xeloda” on the other side.

Each pack contains 60 film-coated tablets (6 blisters containing 10 tablets each).

Xeloda 500 mg film-coated tablets
Peach-coloured, biconvex, oval film-coated tablets, marked with “500” on one side and “Xeloda” on the other side.

Each pack contains 120 film-coated tablets (12 blisters containing 10 tablets each).

Marketing Authorisation Holder:
CHEPLAPHARM Arzneimittel GmbH
Ziegelhof 24
17489 Greifswald
Germany

Manufacturer:
Excella GmbH & Co. KG
Nuernberger Str. 12
90537 Feucht
Germany

CHEPLAPHARM Arzneimittel GmbH
Ziegelhof 23-24
17489 Greifswald
Germany

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

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

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and 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 the 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's recommendation, the Committee for Medicinal Products for Human Use (CHMP) agrees with the overall conclusions and the rationale of the recommendation.

Grounds for the variation of the terms of the marketing authorisations
Based on the scientific conclusions on capecitabine, the CHMP considers that the benefit-risk balance of medicinal products containing capecitabine, as listed in the EURD, remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisations.