Consumer medicine information

Capecitabine APOTEX Tablets

Capecitabine

BRAND INFORMATION

Brand name

Capecitabine APOTEX

Active ingredient

Capecitabine

Schedule

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

The name of your medicine is Capecitabine APOTEX. It contains the active ingredient capecitabine.

It is used to treat cancer of the:

bowel and rectum (colorectal)
breast and stomach and food pipe (oesophagus).

Capecitabine belongs to a group of medicines called anti-neoplastic agents. Within this group, capecitabine belongs to a class of medicines called fluoropyrimidine analogues.

Capecitabine is converted by the liver and cancer cells to another medicine called 5-fluorouracil (also called 5-FU).

It is 5-FU that acts to kill or stop the growth of cancer cells.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

There is no evidence that this medicine is addictive.

This medicine is available only with a doctor's prescription.

Do not give capecitabine to children. Safety and effectiveness of this medicine in persons under 18 years of age have not been established.

Before you take this medicine

When you must not use it

Do not take this medicine if you have an allergy to:

capecitabine
5-fluorouracil (also called 5-FU)
other fluoropyrimidine medicines
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take this medicine if you have any of the following medical conditions:

severe kidney disease
dihydropyramidine dehydrogenase (DPD) deficiency

Do not take this medicine if you are taking a medicine containing sorivudine or related medicines such as brivudine. Taking these medicines at the same time as capecitabine is potentially fatal.

Do not take this medicine if you are pregnant. Capecitabine may be harmful to an unborn baby when taken by a pregnant woman. It is not recommended that you take capecitabine while you are pregnant. Additionally, if you are a woman, you should use effective contraception to avoid becoming pregnant while you are taking capecitabine.

Do not breastfeed if you are taking this medicine. It is not known whether capecitabine and 5-FU pass into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

heart disease
liver disease
kidney disease
dehydration

Some signs and symptoms of dehydration include:

dry skin
dark coloured urine
thirst
weakness or fatigue
loss of appetite

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and capecitabine may interfere with each other. These include:

medicines used to thin the blood such as warfarin and phenprocoumon
phenytoin, used to treat epilepsy and heart irregularities
leucovorin, also called folinic acid, used to treat folic acid deficient anaemias
antacids, used to treat heart burn or indigestion

These medicines may be affected by capecitabine or may affect the way it works. You may need different amounts of your medicines or may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow carefully all directions given to you by your doctor carefully. Their instructions may be different to the information in this leaflet.

If you are not sure how to take this medicine, ask your doctor or pharmacist for help.

How much to take

Take this medicine exactly as your doctor has prescribed.

Capecitabine may be given with or without chemotherapy.

Your doctor will tell you how much of capecitabine you should take. This will depend on your condition, whether you are taking any other medicines and your height and weight. Elderly patients may be prescribed a lower dose.

Your doctor may want you to take a combination of 150 mg (light peach colour) and 500 mg (peach colour) tablets for each dose.

If a combination of tablets is prescribed, it is very important that you correctly identify the tablets.

How to take it

Swallow the tablets whole with a glass of water.

Do not chew the tablets.

When to take it

Capecitabine tablets should be taken with food. You should take this medicine no later than 30 minutes after food.

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

When taken in combination with chemotherapy, your doctor will advise which days of your treatment cycle capecitabine should be taken.

If you are not sure when to take capecitabine, ask your doctor.

How long to take it

The duration of treatment with capecitabine varies, depending on the nature of your illness and your individual response to the treatment.

Capecitabine therapy is made up of a series of treatment cycles which usually lasts for 21 days.

Your doctor will advise you how many cycles of treatment you will have and whether there are any rest days in the cycle.

In most cases, your treatment cycle will consist of intermittent capecitabine therapy, where you will take capecitabine for 14 days, followed by a rest period of 7 days.

During the rest period, you will not take any capecitabine.

Alternatively, your treatment cycle may be continuous, which involves 21 days of capecitabine treatment and no rest period.

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

Skip the missed dose and take your next dose at the usual time.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Take this medicine exactly as your doctor has told you to.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Tell your doctor if you feel the tablets are not helping your condition.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting with a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how capecitabine affects you.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking this medicine or if you have any questions or concerns.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following:

diarrhoea
vomiting
nausea (feeling like you want to vomit)
fatigue (tiredness), weakness or weariness
skin rashes, discolouration, dry or itchy skin
abdominal (stomach) pain
fever, or increased temperature sensitivity
constipation
headache
dizziness
loss of appetite, weight loss
hair loss
increased eye watering or irritation, sensitivity to light, conjunctivitis (itchy eyes and crusty eyelids)
taste disturbance
indigestion, wind
dry mouth, thirst
sore mouth, mouth ulcers, cold sores
nail disorders
sore throat, cough, nose bleeds
shortness of breath, difficulty in breathing, or tightening of the chest
redness or swelling of your hands and/or feet
tingling or numbness of the hands or feet
back pain, muscle and joint pain
dark coloured urine
difficulty sleeping
infections
depression

Tell your doctor immediately if you notice any of the following:

severe diarrhoea with more than 4 bowel movements each day
nausea that has reduced your appetite significantly
vomiting more than once in a 24-hour period
pain, redness and/or swelling of your hands and/or feet that has affected your normal activities (hand-foot-syndrome)
pain, redness, swelling or ulcers in the mouth (stomatitis)
passing little or no urine (this could be kidney disease) – other symptoms include drowsiness, nausea, vomiting and breathlessness

You need to stop taking capecitabine if you experience the above side effects. Your doctor will treat your side effects before they start you on capecitabine again.

Tell your doctor immediately or go to your nearest Accident and Emergency if you notice any of the following:

chest pain
irregular heart beat
shortness of breath
confusion, disorientation or memory loss
poor balance or lack of coordination
decreased strength or progressive weakness in your body, numbness or weakness of arms or legs
blurred or loss of vision
signs of infection such as swelling, redness and increased temperature
signs of liver disease such as yellowing of the skin and eyes
blood in the faeces
severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
severe skin reaction which starts with painful red areas, then large blisters and ends with peeling of layers of skin – this is accompanied by fever and chills, aching muscles and generally feeling unwell
symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

These are serious side effects. You may need urgent medical attention.

These side effects may differ when taking capecitabine in combination with a chemotherapy medicine.

Please consult your doctor for possible side effects that may be caused by taking capecitabine with a chemotherapy medicine.

Other side effects not listed above may occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list. Some of these side effects, for example changes in triglycerides, can only be found when your doctor does tests from time to time to check your progress.

Storage and disposal

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack it will not keep well.

Keep your tablets in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Capecitabine APOTEX looks like

Capecitabine APOTEX 150 mg tablets: Light peach, oval, biconvex, film-coated tablet, engraved "APO" on one side, "C150" on the other side. AUST R 202726.

Blister packs of 60 tablets.

Capecitabine APOTEX 500 mg tablets: Peach, oval, biconvex, filmcoated tablet, engraved "APO" on one side, "C500" on the other side. AUST R 202738.

Blister packs of 120 tablets.

Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Capecitabine APOTEX tablets contain either 150 mg or 500 mg of capecitabine as the active ingredient.

They also contain the following inactive ingredients:

lactose
croscarmellose sodium
methylcellulose
magnesium stearate
colloidal anhydrous silica
hypromellose
hyprolose
macrogol 8000
titanium dioxide
iron oxide red
iron oxide yellow

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113
Australia

This leaflet was last updated in September 2019.

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Capecitabine APOTEX

Active ingredient

Capecitabine

Schedule

1 Name of Medicine

Capecitabine.

6.7 Physicochemical Properties

Capecitabine is an oral, antineoplastic agent belonging to the fluoropyrimidine carbamate class. It was rationally designed as an orally administered precursor of 5'-deoxy-5- fluorouridine (5'-DFUR), which is selectively activated to the cytotoxic moiety, fluorouracil, in tumours. Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.
Chemical Name: Capecitabine.
Molecular Formula: C₁₅H₂₂FN₃O₆.
Molecular Weight: 359.35.

Chemical structure.

CAS number.

154361-50-9.

2 Qualitative and Quantitative Composition

Each tablet contains either 150 mg or 500 mg capecitabine.

Excipients with known effect.

Lactose.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capecitabine 150 mg tablets.

Light peach, oval, biconvex, film-coated tablet, engraved "APO" on one side, "C150" on the other side.

Capecitabine 500 mg tablets.

Peach, oval, biconvex, film-coated tablet, engraved "APO" on one side, "C500" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Capecitabine itself is noncytotoxic; however, it is selectively activated to the cytotoxic moiety, fluorouracil (5-FU), by thymidine phosphorylase in tumours.

Bioactivation.

Capecitabine is a fluoropyrimidine carbamate derivative that was designed as an orally administered, tumour activated and tumour selective cytotoxic agent. Capecitabine is noncytotoxic in vitro.
Capecitabine is absorbed unchanged from the gastrointestinal tract, metabolised primarily in the liver by the 60 kDa carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-DFCR), which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissue. Further metabolism of 5'-DFUR to the pharmacologically active agent 5-FU occurs mainly at the site of the tumour by the tumour associated angiogenic factor thymidine phosphorylase (dThdPase), which has levels considerably higher in tumour tissues compared to normal tissues. Several human tumours such as breast, gastric, colorectal, cervical and ovarian cancers have a higher level of thymidine phosphorylase than normal tissues. This minimises the exposure of healthy tissues to systemic 5-FU. Catabolism of 5-FU by dihydropyrimidine dehydrogenase (DPD) leads to formation of dihydro-5-fluorouracil (FUH²), followed by ring cleavage with dihydropyrimidinase (DHP) to 5-fluoro-ureido-propionic acid (FUPA) and finally to α-fluoro-β-alanine (FBAL) by the enzyme β-ureido-propionase (BUP). See Figure 1.

Mechanism of action.

Both normal and tumour cells metabolise 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor N^5-10 methylenetetrahydrofolate bind covalently to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding prevents formation of thymidylate from uracil, the necessary precursor of thymidine triphosphate that is required for DNA synthesis. A deficiency of thymidine triphosphate can inhibit cell division. The second mechanism results from the incorporation of FUTP into RNA in place of UTP, thereby preventing the correct nuclear processing of ribosomal RNA and messenger RNA. These effects are most marked on rapidly proliferating cells, such as tumour cells, which utilise 5-FU at a higher rate.

Clinical trials.

Colon and colorectal cancer.

Monotherapy - adjuvant colon cancer.

Data from an open label, multicenter, randomised, phase III clinical trial investigated the efficacy and safety of capecitabine for the adjuvant treatment in patients who underwent surgery for Dukes' stage C colon cancer (XACT: study M66001). In this trial, 1987 patients were randomised to treatment with capecitabine (1250 mg/m² twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles for 24 weeks) or 5-FU and leucovorin (Mayo regimen: 20 mg/m² leucovorin intravenous (IV) followed by 425 mg/m² IV bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks).
The major efficacy parameters assessed were disease free survival (DFS, primary endpoint) and overall survival (OS). The median follow up at the time of the analysis was 6.9 years. Capecitabine was shown to be at least equivalent to 5-FU/ leucovorin in DFS and OS. See Table 9.

Study M66001 did not include patients with Dukes' stage B disease. However, the findings of the study are considered to support the use of capecitabine as adjuvant therapy in patients with high risk stage B disease, such as those with inadequately sampled nodes, T4 lesions, perforation or poorly differentiated histology.

Combination therapy - adjuvant colon cancer.

Data from a multicentre, randomised, controlled phase III 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 (N016968). In this trial, 944 patients were randomised to 3 week cycles for 24 weeks with capecitabine (1000 mg/m² twice daily for 2 weeks followed by a 7 day rest period) in combination with oxaliplatin (130 mg/m² intravenous infusion over 2 hours on day 1 every 3 weeks); 942 patients were randomised to bolus 5-FU and leucovorin. In the primary analysis (ITT population), median observation time was 57 months for DFS and 59 months for OS. Capecitabine 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 relapse free survival (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). The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV.

Monotherapy - metastatic colorectal cancer.

A phase II open label, multicentre, randomised clinical trial was conducted to explore the efficacy and safety of three different treatment regimens in patients with advanced and/or metastatic colorectal cancer. These were continuous therapy with capecitabine (1331 mg/m²/day, n = 39) over 12 weeks; intermittent therapy with capecitabine (1250 mg/m² twice daily, n = 34) 2 weeks treatment followed by a 1 week rest period, given as 3 week cycles over 12 weeks and intermittent therapy with capecitabine in combination with oral leucovorin (capecitabine 1657 mg/m²/day; leucovorin 60 mg/day, n = 35). The objective response rate was 22% in the continuous arm, 25% in the intermittent arm and 24% in the combination arm.
Data from two identically designed, multicenter, randomised, controlled phase III clinical trials (SO14695; SO14796) conducted in 120 centres internationally, compared capecitabine with 5-FU in combination with leucovorin (Mayo regimen) as first line chemotherapy in patients with advanced and/or metastatic colorectal cancer. In these trials, 603 patients were randomised to treatment with capecitabine at a daily dose of 1250 mg/m² twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles over 30 weeks. A total of 604 patients were randomised to treatment with 5-FU/ leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1 to 5, every 28 days). The mean duration of treatment was 139 days for capecitabine treated patients and 140 days for 5-FU/ leucovorin treated patients.
The major efficacy endpoints assessed were time to disease progression (primary endpoint), objective response rate and OS. The objective response rate included partial and complete responses. The results from the two phase III trials were similar; the pooled efficacy data from both trials are given in Table 10.

Capecitabine was equivalent to 5-FU/ leucovorin in time to disease progression, equivalent in overall survival and superior in objective response rate.

Combination therapy - first line treatment of metastatic colorectal cancer.

Data from a multicenter, randomised, controlled phase III clinical study (N016966) support the use of capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab (BV) for the first line treatment of metastatic colorectal cancer. The study contained two parts: an initial 2 arm part in which patients were randomised to two different treatment groups, capecitabine or FOLFOX-4, and a subsequent 2 x 2 factorial part with four different treatment groups, capecitabine + placebo (P), FOLFOX-4 + P, capecitabine + BV, and FOLFOX-4 + BV. The treatment regimens are summarised in Table 11.

Noninferiority of the capecitabine containing arms compared with the FOLFOX-4 containing arms in the overall comparison was demonstrated in terms of progression free survival (PFS) in the eligible per protocol population (EPP), with progression determined by the study investigators who were not blinded to treatment allocation (see Table 11). The criterion set for concluding noninferiority was that the upper limit of the 97.5% confidence interval for the hazard ratio for PFS was less than 1.23. The results for OS are similar to those reported for PFS. A comparison of capecitabine plus BV versus FOLFOX-4 plus BV was a prespecified exploratory analysis. In this treatment subgroup comparison, capecitabine plus BV was similar compared to FOLFOX-4 plus BV in terms of PFS (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 to treat population was 1.5 years; data from analyses following an additional 1 year of follow up are included in Table 12.

Study NO16966 also demonstrated superiority of the bevacizumab containing arms over placebo containing arms.

Combination therapy - second line treatment of metastatic colorectal cancer.

Data from a multicenter, randomised, controlled phase III clinical study (N016967) support the use of capecitabine in combination with oxaliplatin for the second line treatment of metastatic colorectal cancer. In this trial, 627 patients with metastatic colorectal cancer who have received prior treatment with irinotecan in combination with a fluoropyrimidine regimen as first line therapy were randomised to treatment with capecitabine or FOLFOX-4. The treatment regimens used in study N016967 are summarised in Table 13.

Capecitabine was demonstrated to be noninferior to FOLFOX-4 in terms of PFS in the per protocol population (see Table 14). The criterion set for concluding noninferiority was the upper limit of the 95% confidence interval for the hazard ratio for PFS was less than 1.30. The results for overall survival were similar to those for PFS. The median follow up at the time of primary analyses in the intent to treat population was 2.1 years; data from analyses following an additional 6 months of follow up are also included in Table 14.

A pooled analysis of the efficacy data from first line (study NO16966; initial 2 arm part) and second line treatment (study NO16967) further support the noninferiority results of capecitabine versus FOLFOX-4 as obtained in the individual studies: PFS in the per protocol population (hazard ratio 1.00 [95% CI: 0.88; 1.14]) with a median PFS of 193 days (capecitabine; 508 patients) versus 204 days (FOLFOX-4; 500 patients). The results also indicate that capecitabine is comparable to FOLFOX-4 in terms of OS (hazard ratio 1.01 [95% CI: 0.87; 1.17]) with a median OS of 468 days (capecitabine) versus 478 days (FOLFOX-4).

Combination therapy - oesophagogastric cancer.

Two multicentre, randomised, controlled phase III clinical trials were conducted to evaluate the safety and efficacy of capecitabine in patients with previously untreated advanced or metastatic oesophagogastric.
Data from a multicentre, open label, randomised, controlled phase III clinical trial (ML17032) supports the use of capecitabine in this setting. In this trial, 160 patients with previously untreated advanced or metastatic gastric cancer were randomised to treatment with capecitabine (1000 mg/m² twice daily for 2 weeks followed by a 1 week rest period) and cisplatin (80 mg/m² as a 2 hour IV infusion every 3 weeks). A total of 156 patients were randomised to treatment with 5-FU (800 mg/m² per day, continuous infusion on days 1 to 5 every 3 weeks) and cisplatin (80 mg/m² as a 2 hour IV infusion on day 1, every 3 weeks). Patients received treatment for at least 6 weeks (2 cycles) and were treated until disease progression or unacceptable toxicity.
The primary objective of the study was met, capecitabine in combination with cisplatin was at least equivalent to 5-FU in combination with cisplatin in terms of PFS in the per protocol analysis. Duration of survival (overall survival) with the combination of capecitabine and cisplatin was also at least equivalent to that of 5-FU and cisplatin. See Table 15.

Data from a randomised multicenter, phase III study comparing capecitabine to 5-FU and oxaliplatin to cisplatin in patients with previously untreated locally advanced or metastatic oesophagogastric cancer supports the use of capecitabine for the first line treatment of advanced oesophagogastric cancer (REAL-2). In this trial, 1002 patients were randomised in a 2 x 2 factorial design to one of the following 4 arms. See Table 16.

The primary efficacy analyses in the per protocol population demonstrated noninferiority in OS for capecitabine versus 5-FU-based regimens (hazard ratio 0.86, 95% CI: 0.80 to 0.99) and for oxaliplatin versus cisplatin based regimens (hazard ratio 0.92, 95% CI: 0.80 to 1.10). The median OS was 10.9 months in capecitabine based regimens and 9.6 months in 5-FU-based regimens. The median OS was 10.0 months in cisplatin based regimens and 10.4 months in oxaliplatin based regimens.

Colon, colorectal and advanced gastric cancer: meta-analysis.

A meta-analysis of six clinical trials (studies S014695, S014796, M66001, NO16966, NO16967, ML17032) 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. The hazard ratio for OS was 0.94 (95% CI: 0.89; 1.00, p = 0.0489) indicating that capecitabine containing regimens are comparable to 5-FU containing regimens.

Monotherapy - breast cancer.

Two phase II open label, multicenter trials were conducted to evaluate the efficacy and safety of capecitabine in patients with locally advanced and/or metastatic breast cancer who had been previously treated with taxanes. Capecitabine was administered at a dose of 1250 mg/m² twice daily for 2 weeks treatment followed by a 1 week rest period, given as 3 week cycles.
In the first trial, 162 female outpatients were selected from an investigator's current practice or from referred patients. This heavily pretreated patient population was refractory to previous paclitaxel therapy (77% resistant, 23% failed). Additionally, most patients were resistant (41%) or had failed (26%) previous anthracycline therapy and 82% had been exposed to 5-FU.
In the second trial, 74 patients were treated; all but three had received prior treatment with taxanes (paclitaxel and/or docetaxel). In addition, over 95% had previously been treated with an anthracycline based chemotherapy. See Table 17.

A prospectively defined clinical benefit response score (pain, analgesic consumption and Karnofsky performance status) was used to assess the effect of treatment on tumour associated morbidity. The overall clinical benefit response was positive in 29 patients (20%) in the first trial and 8 patients (15%) in the second trial, 45 patients (31%) and 22 patients (41%), respectively, remained stable.
Of the 51 patients with baseline pain ≥ 20 mm on the visual analogue scale in the first trial, 24 patients (47%) had a positive response in pain intensity (greater than or equal to 50% decrease lasting for at least 4 weeks), similar analysis in the second trial showed 7/27 patients (26%) had a positive pain response.

Combination therapy - breast cancer.

The dose of capecitabine used in the phase III clinical trial in combination with docetaxel was based on the results of a phase I trial, where a range of doses of docetaxel given every 3 weeks in combination with an intermittent regimen of capecitabine (2 weeks treatment followed by a 1 week rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of docetaxel 75 mg/m² as a 1 hour intravenous infusion every 3 weeks in combination with 1250 mg/m² twice daily for 2 weeks of capecitabine administered every 3 weeks for at least 6 weeks. The approved dose of 100 mg/m² of docetaxel administered every 3 weeks was the control arm of the phase III study.
Capecitabine in combination with docetaxel was assessed in an open label, multicenter, randomised trial. A total of 511 patients with locally advanced and/or metastatic breast cancer resistant to, or recurring after an anthracycline containing therapy, or relapsing during or recurring within two years of completing an anthracycline containing adjuvant therapy were enrolled. In this trial, 255 patients were randomised to receive capecitabine in combination with docetaxel and 256 patients received docetaxel alone.
Capecitabine in combination with docetaxel resulted in statistically significant improvements in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 18 and Figures 2 and 3. Health related quality of life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ; C30 version 2, including Breast Cancer Module BR23). HRQoL was similar in the two treatment groups.

5.2 Pharmacokinetic Properties

Pharmacokinetics in tumours and adjacent healthy tissue.

A pharmacokinetic study in 19 colorectal patients was conducted investigating the tumour selectivity of capecitabine comparing 5-FU concentrations in tumour, healthy tissue and plasma. Following oral administration of capecitabine (1250 mg/m² twice daily, 5 to 7 days before surgery), concentrations of 5-FU were significantly greater in primary tumour than in adjacent healthy tissue (geometric mean ratio 2.5; 95% CI: [1.5 to 4.11] and plasma (geometric mean ratio 14).
Thymidine phosphorylase activity was four times greater in primary tumour tissue (colon) than in normal tissue.

Human pharmacokinetics.

The pharmacokinetics of capecitabine and its metabolites have been evaluated in 11 studies in a total of 213 cancer patients at a dosage range of 502 to 3514 mg/m²/day. In the dose range of 250 to 1250 mg/m² as a single dose, the pharmacokinetics of capecitabine and its metabolites were dose proportional, except for 5-FU. Area under the curve (AUC) of 5-FU was 30% higher on day 14, but did not increase subsequently (day 22). A summary of key data for a dose of 1255 mg/m² twice daily is presented below.

Absorption.

After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Administration of food decreases the rate of capecitabine absorption but has only a minor effect on the AUC of 5'-DFUR and the subsequent metabolite 5-FU. The absorption of capecitabine is confirmed since 95.5% of an orally administered dose is recovered in urine.

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 respectively, mainly to albumin.

Metabolism.

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. Formation of 5-FU occurs preferentially at the tumour site by the tumour associated angiogenic factor dThdPase, thereby minimising the exposure of healthy body tissues to systemic 5-FU.
The plasma AUC of 5-FU is 6 to 22 times lower than that following an IV bolus of 5-FU (dose of 600 mg/m²). The metabolites of capecitabine become cytotoxic only after conversion to 5-FU and anabolites of 5-FU. 5-FU is further catabolised to the inactive metabolites dihydro-5-fluorouracil (FUH²), 5-fluoro-ureidopropionic acid (FUPA) and a-fluoro-p-alanine (FBAL) via dihydropyrimidine dehydrogenase (DPD), which is rate limiting.

Excretion.

After oral administration, capecitabine metabolites are primarily recovered in the urine. Most (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 the urine as unchanged drug.

Pharmacokinetic parameters.

Table 19 shows the time course of pharmacokinetic parameters for capecitabine and 5-FU in plasma at steady-state (day 14) following administration of the recommended dose (1250 mg/m² twice daily) in 8 cancer patients. The peak of plasma concentrations of intact drug and 5-FU are reached within 1.5 and 2 hours, respectively (median times), and the concentrations decline with half-lives of 0.85 and 0.76 hours, respectively.

Combination therapy.

Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (C_max and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR.

Pharmacokinetics in special populations.

Also see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration for recommendations regarding the use of capecitabine in (i) the elderly; (ii) patients with hepatic impairment and (iii) patients with renal impairment.
A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients with colorectal cancer dosed at 1250 mg/m² twice daily. Gender, presence or absence of liver metastasis at baseline, Karnofsky performance status, total bilirubin, serum albumin, AST/ALT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Elderly.

A 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 years of age, found age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal function.

Race.

Based on the population pharmacokinetic analysis of 455 white patients (90.1%), 22 black patients (4.4%) and 28 patients of other race or ethnicity (5.5%), the pharmacokinetics of black patients were not different compared to white patients. For the other minority groups the numbers were too small to draw a conclusion. Limited available data suggest that there are no clinically significant differences in capecitabine pharmacokinetics between Caucasians and Oriental subjects.

Hepatic impairment.

Capecitabine has been evaluated in patients with mild to moderate hepatic impairment due to liver metastases as defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase. C_max of capecitabine, 5'-DFUR and 5-FU were increased by 49%, 33% and 28%, respectively. AUC_0-∞ of capecitabine 5'-DFUR and 5-FU were increased by 48%, 20% and 15%, respectively. Conversely, C_max and AUC of 5'-DFCR decreased by 29% and 35%, respectively. Therefore, bioactivation of capecitabine is not affected.

Renal impairment.

A pharmacokinetic study in cancer patients with mild to severe renal impairment showed that renal impairment significantly increased systemic 5'-DFUR exposure. 5'-DFUR is the direct precursor of 5-FU and is considered an indicator of tissue exposure to 5-FU. A 50% reduction in creatinine clearance increased 5'-DFUR AUC by 35%, 95% CI: [12, 64], on the first day of capecitabine treatment. Exposure to another metabolite, FBAL increased 114%, 95% CI: [73, 165], when creatinine clearance was decreased by 50%. This was expected since most of the capecitabine dose is recovered as FBAL in urine. FBAL does not have antitumour activity.

5.3 Preclinical Safety Data

Genotoxicity.

Capecitabine was not mutagenic or clastogenic in the following models: in vitro Ames test (bacterial) and V79/HPRT (mammalian) gene mutation assays and in vivo mouse micronucleus test. However, consistent with the known chromosome damaging potential of nucleoside analogues, capecitabine was clastogenic in vitro in human peripheral blood lymphocytes in the absence of S9 metabolic activation.

Carcinogenicity.

In a two year carcinogenicity study in mice, there was no evidence for a carcinogenicity potential of capecitabine at dietary doses up to 90 mg/kg/day (270 mg/m²/day). In terms of plasma AUC values, systemic exposure to capecitabine and 5'-DFUR at the highest dose was at least 10 times lower than that in humans at the recommended dose.

4 Clinical Particulars

4.1 Therapeutic Indications

Colon cancer.

Capecitabine is indicated for the adjuvant treatment of patients with Dukes' stage C and high risk stage B, colon cancer, either as monotherapy or in combination with oxaliplatin.

Colorectal cancer.

Capecitabine is indicated for the treatment of patients with advanced or metastatic colorectal cancer.

Oesophagogastric cancer.

Capecitabine is indicated for the first line treatment of patients with advanced oesophagogastric cancer in combination with a platinum based regimen.

Breast cancer.

Capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline containing chemotherapy regimen unless therapy with these and other standard agents are clinically contraindicated.
Capecitabine in combination with docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.

4.3 Contraindications

Capecitabine is contraindicated in patients who have:
a known hypersensitivity to capecitabine or to any of the excipients contained in the tablets;
a history of severe and unexpected reactions to fluoropyrimidine therapy or with known hypersensitivity to fluorouracil;
severe renal impairment (creatinine clearance below 30 mL/min);
known dihydropyrimidine dehydrogenase (DPD) deficiency;
treatment with sorivudine or its chemically related analogues, such as brivudine.
If contraindications exist to any of the agents in combination regimen, that agent should not be used.

4.4 Special Warnings and Precautions for Use

General.

Patients receiving therapy with capecitabine should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Patients should be carefully monitored for toxicity. Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced (see Section 4.2 Dose and Method of Administration).

Information for patients.

Patients and patients' caregivers should be informed of the expected adverse effects of capecitabine, particularly of nausea, vomiting, diarrhoea and hand-foot syndrome. The frequent oral administration of capecitabine allows patient specific dose adaptations during therapy (see Section 4.2 Dose and Method of Administration). Patients should be encouraged to recognise the common toxicities associated with capecitabine treatment.

Diarrhoea.

Patients experiencing grade 2 diarrhoea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking capecitabine immediately. Standard antidiarrhoeal treatments (e.g. loperamide) are recommended.

Nausea.

Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.

Vomiting.

Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24 hour period) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.

Hand-foot syndrome.

Patients experiencing grade 2 hand-foot syndrome (painful erythema and swelling of the hands and/or feet that results in discomfort affecting the patient's activities of daily living) or greater should be instructed to stop taking capecitabine immediately.

Stomatitis.

Patients experiencing grade 2 stomatitis (painful erythema, oedema or ulcers, but able to eat) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.

Diarrhoea.

Capecitabine can induce diarrhoea, which can sometimes be severe. In patients receiving capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhoea was 31 days, and median duration of grade 3 or 4 diarrhoea was 4.5 days. Patients with severe diarrhoea should be carefully monitored and, if they become dehydrated, should be given fluid and electrolyte replacement. National Cancer Institute of Canada (NCIC) 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, and grade 4 diarrhoea as an increase of ≥ 10 stools/day or grossly bloody diarrhoea or the need for parenteral support. Standard antidiarrhoeal treatments (e.g. loperamide) should be initiated, as medically appropriate, as early as possible. Dose reduction should be applied as necessary.

Dehydration.

Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. If grade 2 (or higher) dehydration occurs, capecitabine treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be applied for the precipitating adverse event as necessary (see Section 4.2 Dose and Method of Administration).
Dehydration may cause acute renal failure, especially in patients with pre-existing compromised renal function or when capecitabine is given concomitantly with known nephrotoxic agents. Fatal outcome of renal failure has been reported in these situations (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

Hand-foot syndrome.

Capecitabine can induce hand-foot syndrome (palmar plantar erythrodysaesthesia or chemotherapy induced acral erythema), which is a cutaneous toxicity. Persistent or severe hand-foot syndrome (Grade 2 and above) can lead to loss of fingerprints. For patients receiving capecitabine monotherapy in the metastatic setting, the median time to onset was 79 days (range from 11 to 360 days), with a severity range of grades 1 to 3.
Grade 1 is defined by numbness, dysaesthesia/ paraesthesia, tingling, or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activity. Grade 2 hand-foot syndrome is defined as painful erythema and swelling of the hands and/or feet that results in discomfort affecting the patient's activities of daily living. Grade 3 hand-foot syndrome is defined as moist desquamation, ulceration, blistering and severe pain of the hands and/or feet that results in severe discomfort that causes the patient to be unable to work or perform activities of daily living.
If grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of capecitabine should be decreased (see Section 4.2 Dose and Method of Administration).
When capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyroxidine) 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.

Cardiac.

The spectrum of cardiotoxicity observed with capecitabine is similar to that of other fluorinated pyrimidines. This includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure and electrocardiograph changes. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

Use in hepatic impairment.

Patients with hepatic impairment should be carefully monitored when capecitabine is administered. The effect of hepatic impairment not due to liver metastases or of severe hepatic impairment on the disposition of capecitabine is not known (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in renal impairment.

In patients with moderate renal impairment (creatinine clearance 30-50 mL/min) at baseline, a dose reduction to 75% for starting doses is recommended for both monotherapy and combination use. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse reaction with subsequent dose adjustment as outlined (see Section 4.2 Dose and Method of Administration).
Physicians should exercise caution when capecitabine is administered to patients with impaired renal function. As seen with 5-FU, the incidence of treatment related grade 3 or 4 adverse reactions is higher in patients with moderate renal impairment (creatinine clearance 30-50 mL) (see Section 4.2 Dose and Method of Administration, Dose adjustment in special populations). Capecitabine is contraindicated in patients with creatinine clearance below 30 mL/min (see Section 4.3 Contraindications).

Haematologic.

In 949 patients with either advanced or metastatic colorectal cancer or breast cancer who received a dose of capecitabine 1250 mg/m² twice daily for 2 weeks followed by a 1 week rest period, 3.6, 2.0 and 3.1% of patients had grade 3 or 4 neutropenia, thrombocytopenia and decreases in haemoglobin respectively.
In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, abnormal laboratory values showed 68%, 2.8% and 9.6% of patients had grade 3 or 4 neutropenia/ granulocytopenia, thrombocytopenia and haemoglobin respectively. The majority of cases did not require medical intervention.

Dihydropyrimidine dehydrogenase.

Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased potentially fatal toxic effects of 5-FU therefore cannot be excluded.

Hyperbilirubinaemia.

Capecitabine can induce hyperbilirubinaemia. Administration of capecitabine should be interrupted if treatment related elevations in bilirubin of > 3.0 x the upper limit of normal (ULN) or treatment related elevations in hepatic aminotransferases (ALT, AST) of > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to ≤ 3.0 x ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN.
In 949 patients, grade 3 hyperbilirubinaemia occurred in 133 (14.0%) patients and grade 4 hyperbilirubinaemia occurred in 35 (3.7%) patients. These reactions were rarely associated with significant elevations in alkaline phosphatase or liver transaminases. The majority of these elevations occurred in patients with progressive hepatic metastases.
In 251 patients with metastatic breast cancer who received combination of capecitabine and docetaxel, grade 3 hyperbilirubinaemia occurred in 6.8% (n = 17) and grade 4 hyperbilirubinaemia occurred in 2% (n = 5).

Use in the elderly.

In 949 patients assessed for safety, patients were also assessed for the incidence of grade 3 and 4 reactions in terms of age groups as illustrated in Table 4.

Amongst patients with colorectal cancer aged 60-79 years receiving capecitabine monotherapy in the metastatic setting, the incidence of grade 3 and 4 toxicity was similar to that in the overall population. In patients aged 80 years or older, a larger percentage experienced reversible grade 3 or 4 adverse reactions. When capecitabine was used in combination with other agents, elderly patients (> 65 years of age) experienced more grade 3 and 4 adverse reactions (ADRs) and ADRs that led to discontinuation than younger patients. An analysis of safety data in patients equal to or greater than 60 years of age treated with capecitabine in combination with docetaxel showed an increase in the incidence of treatment related grade 3 or 4 adverse reactions, treatment related serious adverse reactions and early withdrawals from treatment due to adverse reactions compared to patients less than 60 years of age.

Paediatric use.

The safety and effectiveness of capecitabine in persons < 18 years of age has not been established.

Effects on laboratory tests.

No data available.

Skin reactions.

Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN). Capecitabine should be permanently discontinued in patients who experience a severe skin reaction possibly attributable to capecitabine treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Interaction with food.

The effect of food on the pharmacokinetics of capecitabine was investigated in 11 cancer patients. The rate and extent of absorption of capecitabine is decreased when administered with food. The effect on AUC_0-∞ of the 3 main metabolites in plasma (5'-DFUR, 5-FU, FBAL) is minor. In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Antacid.

The effect of an aluminium hydroxide (220 mg/5 mL) and magnesium hydroxide (195 mg/5 mL) containing antacid on the pharmacokinetics of capecitabine was investigated in 12 cancer patients. 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).

Leucovorin (folinic acid).

A phase I study evaluating the effect of leucovorin on the pharmacokinetics of capecitabine was conducted in 22 cancer patients. Leucovorin has no effect on the pharmacokinetics of capecitabine and its metabolites. However, leucovorin has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by leucovorin.

Coumarin 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 events 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 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. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites. Patients taking coumarin derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly.

Phenytoin.

Increase phenytoin plasma concentrations have been reported during concomitant use of capecitabine with phenytoin. Formal interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme system by capecitabine (see Coumarin anticoagulants). Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations and associated clinical symptoms.

Cytochrome P450 2C9.

No formal interaction studies with capecitabine and other medicines known to be metabolised by the cytochrome P450 2C9 isoenzyme have been conducted. Care should be exercised when capecitabine is coadministered with these medicines.

Sorivudine and analogues.

A clinically significant medicine interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described in the literature. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, capecitabine should not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine. There must be at least a 4 week waiting period between the end of treatment with sorivudine or its chemically related analogues such as brivudine, and the start of capecitabine therapy.

Oxaliplatin.

No clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occur when capecitabine and oxaliplatin were administered in combination, with or without bevacizumab.

Bevacizumab.

There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites.

Interaction with food.

See Section 4.4 Special Warnings and Precautions for Use.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Impairment of fertility was observed in female mice receiving capecitabine at 760 mg/kg/day (2292 mg/m²/day), a disruption in the oestrous cycle occurred with a subsequent failure of mating. A reduction in live litter size, decreased foetal weight and foetal abnormalities were observed in mice dosed at 380 mg/kg/day (1174 mg/m²/day) before implantation. At the no effect dose of 190 mg/kg/day (587 mg/m²/day), plasma C_max for 5'-DFUR was similar to that observed in humans at the recommended dose, while the AUC value was 4-fold lower than that in humans. The effect of capecitabine on female fertility was reversible after a drug free period.
In male mice, degenerative changes and a decrease in the number of spermatocytes and spermatids were noted at 760 mg/kg/day (2401 mg/m²/day). At the no effect dose of 380 mg/kg/day (1201 mg/m²/day), plasma C_max for 5-DFUR was slightly greater than that observed in humans at the recommended dose, while AUC was about half that in humans.
(Category D)
Capecitabine may cause foetal harm when administered to pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine.
There are no adequate and well controlled studies in pregnant women using capecitabine. If the medicine is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be advised of the potential hazard to the foetus.

Studies conducted in animals.

Mice.

Capecitabine and/or its metabolites have been shown to cross the placenta in mice. Capecitabine was shown to be teratogenic and embryolethal when administered orally to mice during organogenesis at a dose of 198 mg/kg/day (676 mg/m²/day). Teratogenic findings included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilatation of cerebral ventricles. The nonteratogenic dose level in mice was 50 mg/kg/day (approximately 170 mg/m²/day). Systemic exposure to 5'-DFUR at the 50 mg/kg/day dose level was not assessed in any studies; however, this dose level is estimated to be about 20 times lower than that in patients dosed at 2510 mg/m²/day, based on plasma AUC values.
Capecitabine administered to mice dams for the period following organogenesis through to weaning at doses up to 400 mg/kg/day (1428 mg/m²/day) was not associated with any adverse effects on the dams or offspring. In separate studies, this dose produced 5'-DFUR C_max and AUC values about 1.4 and 0.43 times, respectively, of the corresponding values in patients administered 2510 mg/m²/day.

Monkeys.

Capecitabine was embryolethal when administered to dams during organogenesis at a dose of 90 mg/kg/day equivalent to 1095 mg/m²/day. However, no teratogenic effects were observed in those foetuses that did survive at that dose level. The no effect dose was 45 mg/kg/day (560 mg/m²/day), which produced a plasma 5'-DFUR AUC value that was about one third of the corresponding value in patients at the recommended dose.
It is not known whether capecitabine and its metabolites are excreted in human milk. In a study of single oral administration of capecitabine in lactating mice, a significant amount of capecitabine metabolites was detected in the milk. No effects were observed on the offspring of lactating mice dosed orally with capecitabine at 400 mg/kg/day (1428 mg/m²/day). However, plasma AUC for 5'-DFUR at this dose was lower than that in patients receiving the recommended dose of the medicine. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving capecitabine therapy.