Capecitabine SUN

1 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine SUN 150 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 150 mg of capecitabine. 
 
Excipient(s) with known effect:  
Each film-coated tablet contains 20.69 mg anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Capecitabine SUN 150 mg film-coated tablets are light peach coloured, oval, biconvex, 11.5 mm x 
5.7 mm tablets with inscription ‘150’on one side and plain on other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Capecitabine is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ 
stage C) colon cancer (see section 5.1). 
 
Capecitabine is indicated for the treatment of metastatic colorectal cancer (see section 5.1). 
 
Capecitabine is indicated for first-line treatment of advanced gastric cancer in combination with a 
platinum-based regimen (see section 5.1). 
 
Capecitabine in combination with docetaxel (see section 5.1) is indicated for the treatment of patients 
with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous 
therapy should have included an anthracycline. Capecitabine is also indicated as monotherapy for the 
treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an 
anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not 
indicated. 
 
4.2 Posology and method of administration 
 
Capecitabine should only be prescribed by a qualified physician experienced in the utilisation of 
anti-neoplastic medicinal products. Careful monitoring during the first cycle of treatment is 
recommended for all patients.  
Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard 
and reduced dose calculations according to body surface area for starting doses of capecitabine of 
1250 mg/m2 and 1000 mg/m2 are provided in tables 1 and 2, respectively. 
 
Posology 
 
Recommended posology (see section 5.1): 
 
Monotherapy 

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Colon, colorectal and breast cancer 
Given as monotherapy, the recommended starting dose for capecitabine in the adjuvant treatment of 
colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic 
breast cancer is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 
2500 mg/m2 total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment in 
patients with stage III colon cancer is recommended for a total of 6 months. 
 
Combination therapy 
Colon, colorectal and gastric cancer 
In combination treatment, the recommended starting dose of capecitabine should be reduced to 
800 - 1000 mg/m2 when administered twice daily for 14 days followed by a 7-day rest period, or to 
625 mg/m2 twice daily when administered continuously (see section 5.1). For combination with 
irinotecan, the recommended starting dose is 800 mg/m2 when administered twice daily for 14 days 
followed by a 7-day rest period combined with irinotecan 200 mg/m2 on day 1. The inclusion of 
bevacizumab in a combination regimen has no effect on the starting dose of capecitabine. 
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of 
product characteristics should be started prior to cisplatin administration for patients receiving the 
capecitabine plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin 
summary of product characteristics is recommended for patients receiving the capecitabine plus 
oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended 
for a duration of 6 months. 
 
Breast cancer 
In combination with docetaxel, the recommended starting dose of capecitabine in the treatment of 
metastatic breast cancer is 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period, 
combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Pre-medication 
with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product 
characteristics should be started prior to docetaxel administration for patients receiving the 
capecitabine plus docetaxel combination. 
 
Capecitabine dose calculations 
 
Table 1 Standard and reduced dose calculations according to body surface area for a starting dose 

of capecitabine of 1250 mg/m2 
 Dose level 1250 mg/m2 (twice daily) 

 
 Full dose  

1250 mg/m2 

Number of 150 mg 
tablets and/or  

500 mg tablets per 
administration (each 
administration to be 
given morning and 

evening) 

Reduced dose 
(75%) 

 
950 mg/m2 

Reduced dose 
(50%) 

 
625 mg/m2 

Body Surface 
Area (m2) 

Dose per 
administration 

(mg) 

 
150 mg 

 

 
500 mg 

Dose per 
administration  

(mg) 

Dose per 
administration  

(mg) 
≤1.26 1500 - 3 1150 800 
1.27 - 1.38 1650 1 3 1300 800 
1.39 - 1.52 1800 2 3 1450 950 
1.53 - 1.66 2000 - 4 1500 1000 
1.67 - 1.78 2150 1 4 1650 1000 
1.79 - 1.92 2300 2 4 1800 1150 
1.93 - 2.06 2500 - 5 1950 1300 
2.07 - 2.18 2650 1 5 2000 1300 
≥2.19 2800 2 5 2150 1450 

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

of capecitabine of 1000 mg/m2 
 Dose level 1000 mg/m2 (twice daily) 

 
 Full dose  

 
 

1000 mg/m2 

Number of 150 mg 
tablets and/or 

500 mg tablets per 
administration (each 
administration to be 
given morning and 

evening) 

Reduced dose 
(75%) 

 
750 mg/m2 

Reduced dose 
(50%) 

 
500 mg/m2 

Body Surface 
Area (m2) 

Dose per 
administration  

(mg) 

 
150 mg 

 
500 mg 

Dose per 
administration  

(mg) 

Dose per 
administration  

(mg) 
≤1.26 1150 1 2 800 600 
1.27 - 1.38 1300 2 2 1000 600 
1.39 - 1.52 1450 3 2 1100 750 
1.53 - 1.66 1600 4 2 1200 800 
1.67 - 1.78 1750 5 2 1300 800 
1.79 - 1.92 1800 2 3 1400 900 
1.93 - 2.06 2000 - 4 1500 1000 
2.07 - 2.18 2150 1 4 1600 1050 
≥2.19 2300 2 4 1750 1100 
 
Posology adjustments during treatment 
 
General 
Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or 
modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it 
should not be increased at a later time. For those toxicities considered by the treating physician to be 
unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can 
be continued at the same dose without reduction or interruption. Patients taking capecitabine should be 
informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses 
of capecitabine omitted for toxicity are not replaced. The following are the recommended dose 
modifications for toxicity: 
 
Table 3 Capecitabine dose reduction schedule (3-weekly cycle or continuous treatment) 

Toxicity 
grades* 

Dose changes within a treatment 
cycle 

Dose adjustment for next 
cycle/dose (% of starting 

dose) 
•    Grade 1 Maintain dose level Maintain dose level 
•    Grade 2 
 
-1st appearance Interrupt until resolved to grade 0-1 100% 
-2nd appearance  75% 
-3rd appearance  50% 
-4th appearance Discontinue treatment permanently Not applicable 
•    Grade 3 
 
-1st appearance Interrupt until resolved to grade 0-1 75% 
-2nd appearance  50% 
-3rd appearance Discontinue treatment permanently Not applicable 

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Toxicity 
grades* 

Dose changes within a treatment 
cycle 

Dose adjustment for next 
cycle/dose (% of starting 

dose) 
•    Grade 4 
-1st appearance Discontinue permanently 

or 
If physician deems it to be in the 
patient’s best interest to continue, 

interrupt until resolved to grade 0-1 

50% 

-2nd appearance Discontinue permanently Not applicable 
*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 
1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US 
National Cancer Institute, version 4.0. For hand-foot syndrome and hyperbilirubinemia, see section 4.4. 
 
Haematology  
Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of  
<100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a 
treatment cycle show that the neutrophil count drops below 1.0 x 109/L or that the platelet count drops 
below 75 x 109/L, treatment with capecitabine should be interrupted. 
 
Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with 
other medicinal products 
Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with 
other medicinal products should be made according to table 3 above for capecitabine and according to 
the appropriate summary of product characteristics for the other medicinal product(s). 
 
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the 
other medicinal product(s), then administration of all therapy should be delayed until the requirements 
for restarting all medicinal products are met. 
 
During a treatment cycle for those toxicities considered by the treating physician not to be related to 
capecitabine, capecitabine should be continued and the dose of the other medicinal product should be 
adjusted according to the appropriate Prescribing Information. 
 
If the other medicinal product(s) have to be discontinued permanently, capecitabine treatment can be 
resumed when the requirements for restarting capecitabine are met. 
 
This advice is applicable to all indications and to all special populations. 
 
Dose modifications for toxicity when capecitabine is used continuously in combination with other 
medicinal products  
Dose modifications for toxicity when capecitabine is used continuously in combination with other 
medicinal products should be made according to table 3 above for capecitabine and according to the 
appropriate summary of product characteristics for the other medicinal product(s). 
 
Posology adjustments for special populations 
 
Hepatic impairment  
Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose 
adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or 
hepatitis. 
 
Renal impairment  
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 
30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in 
patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased 

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compared to the overall population. In patients with moderate renal impairment at baseline, a dose 
reduction to 75% for a starting dose of 1250 mg/m2 is recommended. In patients with moderate renal 
impairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m2. In patients 
with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the 
starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended 
if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose 
adjustment as outlined in table 3 above. If the calculated creatinine clearance decreases during 
treatment to a value below 30 ml/min, capecitabine should be discontinued. These dose adjustment 
recommendations for renal impairment apply both to monotherapy and combination use (see also 
section “Elderly” below). 
 
Elderly 
During capecitabine monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 
treatment-related adverse reactions were more frequent in patients ≥60 years of age compared to 
younger patients. 
When capecitabine was used in combination with other medicinal products, elderly patients 
(≥65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to 
discontinuation, compared to younger patients. Careful monitoring of patients ≥60 years of age is 
advisable. 
- In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse 

reactions and treatment-related serious adverse reactions were observed in patients 60 years of 
age or more (see section 5.1). For patients 60 years of age or more, a starting dose reduction of 
capecitabine to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in 
patients ≥60 years of age treated with a reduced capecitabine starting dose in combination with 
docetaxel, the dose of capecitabine may be cautiously escalated to 1250 mg/m2 twice daily. 

 
Paediatric population 
There is no relevant use of capecitabine in the paediatric population in the indications colon, 
colorectal, gastric and breast cancer. 
 
Method of administration 
Capecitabine SUN tablets should be swallowed with water within 30 minutes after a meal. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or 

fluorouracil. 
- History of severe and unexpected reactions to fluoropyrimidine therapy. 
- In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4). 
- During pregnancy and lactation. 
- In patients with severe leukopenia, neutropenia, or thrombocytopenia. 
- In patients with severe hepatic impairment. 
- In patients with severe renal impairment (creatinine clearance below 30 ml/min). 
- Treatment with sorivudine or its chemically related analogues, such as brivudine (see 

section 4.5). 
- If contraindications exist to any of the medicinal products in the combination regimen, that 

medicinal product should not be used. 
 
4.4 Special warnings and precautions for use 
 
Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome 
(hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and 
do not require permanent discontinuation of therapy, although doses may need to be withheld or 
reduced. 
 

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Diarrhoea. Patients with severe diarrhoea should be carefully monitored and given fluid and 
electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. 
loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day 
or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and 
malabsorption. Grade 4 diarrhoea is an increase of ≥10 stools/day or grossly bloody diarrhoea or the 
need for parenteral support. Dose reduction should be applied as necessary (see section 4.2). 
 
Dehydration. Dehydration should be prevented or corrected at the onset. Patients with anorexia, 
asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. Dehydration may cause acute 
renal failure, especially in patients with pre-existing compromised renal function or when capecitabine 
is given concomitantly with known nephrotoxic drugs. Acute renal failure secondary to dehydration 
might be potentially fatal. If grade 2 (or higher) dehydration occurs, capecitabine treatment should be 
immediately interrupted and the dehydration corrected. Treatment should not be restarted until the 
patient is rehydrated and any precipitating causes have been corrected or controlled. Dose 
modifications applied should be applied for the precipitating adverse event as necessary (see 
section 4.2). 
 
Hand-foot syndrome (also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or 
chemotherapy induced acral erythema). Grade 1 hand- foot syndrome is defined as numbness, 
dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or 
discomfort which does not disrupt the patient’s normal activities. 
Grade 2 hand- foot syndrome is painful erythema and swelling of the hands and/or feet and/or 
discomfort affecting the patient’s activities of daily living. 
Grade 3 hand- foot syndrome is moist desquamation, ulceration, blistering and severe pain of the 
hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform 
activities of daily living. If grade 2 or 3 hand- foot syndrome occurs, administration of capecitabine 
should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 
hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine and 
cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic 
or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may 
decrease the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot 
syndrome prophylaxis in patients treated with capecitabine. 
 
Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, including 
myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and 
electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions 
may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias 
(including ventricular fibrillation, torsade de pointes, and bradycardia), angina pectoris, myocardial 
infarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine. 
Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and 
angina pectoris (see section 4.8). 
 
Hypo- or hypercalcaemia. Hypo- or hypercalcaemia has been reported during capecitabine treatment. 
Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia (see section 4.8). 

Central or peripheral nervous system disease. Caution must be exercised in patients with central or 
peripheral nervous system disease, e.g. brain metastasis or neuropathy (see section 4.8). 
 
Diabetes mellitus or electrolyte disturbances. Caution must be exercised in patients with diabetes 
mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment. 
 
Coumarin-derivative anticoagulation. In a drug interaction study with single-dose warfarin 
administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results 
suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system 
by capecitabine. Patients receiving concomitant capecitabine and oral coumarin-derivative 
anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored 
closely and the anticoagulant dose adjusted accordingly (see section 4.5). 

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Hepatic impairment. In the absence of safety and efficacy data in patients with hepatic impairment, 
capecitabine use should be carefully monitored in patients with mild to moderate liver dysfunction, 
regardless of the presence or absence of liver metastasis. Administration of capecitabine should be 
interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in 
hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with capecitabine 
monotherapy may be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferases 
decrease to ≤ 2.5 x ULN. 
 
Renal impairment. The incidence of grade 3 or 4 adverse reactions in patients with moderate renal 
impairment (creatinine clearance 30-50 ml/min) is increased compared to the overall population (see 
sections 4.2 and 4.3). 
 
DPD deficiency. Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, neutropenia and 
neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity. A link 
between decreased levels of DPD and increased, potentially fatal toxic effects of 5-FU therefore 
cannot be excluded. 
Patients with known DPD deficiency should not be treated with capecitabine (see section 4.3). In 
patients with unrecognised DPD deficiency treated with capecitabine, life-threatening toxicities 
manifesting as acute overdose may occur (see section 4.9). In the event of grade 2-4 acute toxicity, 
treatment must be discontinued immediately until observed toxicity resolves. Permanent 
discontinuation should be considered based on clinical assessment of the onset, duration and severity 
of the observed toxicities. 
 
Ophthalmologic complications. Patients should be carefully monitored for ophthalmological 
complications such as keratitis and corneal disorders, especially if they have a prior history of eye 
disorders. Treatment of eye disorders should be initiated as clinically appropriate. 
 
Severe skin reactions. Capecitabine can induce severe skin reactions such as Stevens-Johnson 
syndrome and Toxic Epidermal Necrolysis. Capecitabine should be permanently discontinued in 
patients who experience a severe skin reaction during treatment. 
 
Excipients. As this medicinal product contains anhydrous lactose as an excipient, patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults.  
 
Interaction with other medicinal products 
 
Cytochrome P-450 2C9 substrates: Other than warfarin, no formal drug-drug interaction studies 
between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised 
when capecitabine is co-administered with 2C9 substrates (e.g., phenytoin). See also interaction with 
coumarin-derivative anticoagulants below, and section 4.4. 

Coumarin-derivative anticoagulants: altered coagulation parameters and/or bleeding have been 
reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such 
as warfarin and phenprocoumon. These reactions occurred within several days and up to several 
months after initiating capecitabine therapy and, in a few cases, within one month after stopping 
capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, 
capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. 
Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-
regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-
derivative anticoagulants concomitantly with capecitabine should be monitored regularly for 

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alterations in their coagulation parameters (PT or INR) and the anti-coagulant dose adjusted 
accordingly. 
 
Phenytoin: increased phenytoin plasma concentrations resulting in symptoms of phenytoin 
intoxication in single cases have been reported during concomitant use of capecitabine with phenytoin. 
Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased 
phenytoin plasma concentrations. 
 
Folinic acid/folic acid: a combination study with capecitabine and folinic acid indicated that folinic 
acid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic 
acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by 
folinic acid: the maximum tolerated dose (MTD) of capecitabine alone using the intermittent regimen 
is 3000 mg/m2 per day whereas it is only 2000 mg/m2 per day when capecitabine was combined with 
folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV 
to a capecitabine regimen. This may also be relevant with folic acid supplementation for folate 
deficiency due to the similarity between folinic acid and folic acid. 
 
Sorivudine and analogues: a clinically significant drug-drug interaction between sorivudine and 5-FU, 
resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described. 
This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, 
capecitabine must not be administered concomitantly with sorivudine or its chemically related 
analogues, such as brivudine (see section 4.3). There must be at least a 4-week waiting period between 
end of treatment with sorivudine or its chemically related analogues such as brivudine and start of 
capecitabine therapy. 
 
Antacid: the effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the 
pharmacokinetics of capecitabine was investigated. There was a small increase in plasma 
concentrations of capecitabine and one metabolite (5’-DFCR); there was no effect on the 3 major 
metabolites (5’-DFUR, 5-FU and FBAL). 
 
Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreased 
efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided. 
 
Interferon alpha: the MTD of capecitabine was 2000 mg/m2 per day when combined with interferon 
alpha-2a (3 MIU/m2 per day) compared to 3000 mg/m2 per day when capecitabine was used alone. 
 
Radiotherapy: the MTD of capecitabine alone using the intermittent regimen is 3000 mg/m2 per day, 
whereas, when combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2000 mg/m2 
per day using either a continuous schedule or given daily Monday through Friday during a 6-week 
course of radiotherapy. 
 
Oxaliplatin: no clinically significant differences in exposure to capecitabine or its metabolites, free 
platinum or total platinum occurred when capecitabine was administered in combination with 
oxaliplatin or in combination with oxaliplatin and bevacizumab. 
 
Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic 
parameters of capecitabine or its metabolites in the presence of oxaliplatin. 
 
Food interaction 
In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. 
Since current safety and efficacy data are based upon administration with food, it is recommended that 
capecitabine be administered with food. Administration with food decreases the rate of capecitabine 
absorption (see section 5.2). 
 

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4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females  
Women of childbearing potential should be advised to avoid becoming pregnant while receiving 
treatment with capecitabine. If the patient becomes pregnant while receiving capecitabine, the 
potential hazard to the foetus must be explained. An effective method of contraception should be used 
during treatment. 
 
Pregnancy 
There are no studies in pregnant women using capecitabine; however, it should be assumed that 
capecitabine may cause foetal harm if administered to pregnant women. In reproductive toxicity 
studies in animals, capecitabine administration caused embryolethality and teratogenicity. These 
findings are expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated during 
pregnancy. 
 
Breastfeeding 
It is not known whether capecitabine is excreted in human breast milk. In lactating mice, considerable 
amounts of capecitabine and its metabolites were found in milk. Breast-feeding should be discontinued 
while receiving treatment with capecitabine. 
 
Fertility 
There is no data on capecitabine and impact on fertility. The capecitabine pivotal studies included 
females of childbearing potential and males only if they agreed to use an acceptable method of birth 
control to avoid pregnancy for the duration of the study and for a reasonable period thereafter. 
In animal studies effects on fertility were observed (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine 
may cause dizziness, fatigue and nausea. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The overall safety profile of capecitabine is based on data from over 3000 patients treated with 
capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in 
multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, 
metastatic colorectal cancer and adjuvant colon cancer populations are comparable. See section 5.1 for 
details of major studies, including study designs and major efficacy results. 
 
The most commonly reported and/or clinically relevant treatment-related adverse drug reactions 
(ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, 
stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, 
cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and 
thrombosis/embolism. 

Tabulated summary of adverse reactions 
 
ADRs considered by the investigator to be possibly, probably, or remotely related to the 
administration of capecitabine are listed in table 4 for capecitabine given as a monotherapy and in 
table 5 for capecitabine given in combination with different chemotherapy regimens in multiple 
indications. The following headings are used to rank the ADRs by frequency: very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very 
rare (< 1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing 
seriousness. 
 

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Capecitabine monotherapy 
Table 4 lists ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of 
safety data from three major studies including over 1900 patients (studies M66001, SO14695, and 
SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence 
from the pooled analysis. 
 
Table 4 Summary of related ADRs reported in patients treated with capecitabine monotherapy 

Body System  Very Common 
 

All grades  

Common  
 

All grades  

Uncommon  
 

Severe and/or Life-

threatening (grade 3-

4) or considered 

medically relevant  

Rare/Very Rare 
(Post-Marketing 

Experience) 

Infections and 
infestations  

-  Herpes viral 
infection, 
Nasopharyngitis, 
Lower respiratory 
tract infection  

Sepsis, Urinary tract 
infection, Cellulitis, 
Tonsillitis, Pharyngitis, 
Oral candidiasis, 
Influenza, 
Gastroenteritis, Fungal 
infection, Infection, 
Tooth abscess  

 

Neoplasm 
benign, 
malignant and 
unspecified  

-  -  Lipoma   

Blood and 
lymphatic 
system 
disorders  

-  Neutropenia, 
Anaemia  

Febrile neutropenia, 
Pancytopenia, 
Granulocytopenia, 
Thrombocytopenia, 
Leukopenia, 
Haemolytic anaemia, 
International 
Normalised Ratio 
(INR) 
increased/Prothrombin 
time prolonged  

 

Immune system 
disorders  

-  -  Hypersensitivity   

Metabolism 
and nutrition 
disorders  

Anorexia  Dehydration, Weight 
decreased  

Diabetes, 
Hypokalaemia, 
Appetite disorder, 
Malnutrition, 
Hypertriglyceridaemia,  

 

Psychiatric 
disorders  

-  Insomnia, Depression  Confusional state, 
Panic attack, 
Depressed mood, 
Libido decreased  

 

Nervous 
system 
disorders  

-  Headache, Lethargy 
Dizziness, 
Parasthesia 
Dysgeusia  

Aphasia, Memory 
impairment, Ataxia, 
Syncope, Balance 
disorder, Sensory 
disorder, Neuropathy 
peripheral  

Toxic leukoence-
phalopathy (very 
rare) 

Eye disorders  -  Lacrimation 
increased, 
Conjunctivitis, Eye 
irritation  

Visual acuity reduced, 
Diplopia  

Lacrimal duct 
stenosis (rare), 
Corneal disorders 
(rare), keratitis 
(rare), punctate 

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Body System  Very Common 
 

All grades  

Common  
 

All grades  

Uncommon  
 

Severe and/or Life-

threatening (grade 3-

4) or considered 

medically relevant  

Rare/Very Rare 
(Post-Marketing 

Experience) 

keratitis (rare) 

Ear and 
labyrinth 
disorders  

-  -  Vertigo, Ear pain   

Cardiac 
disorders  

-  -  Angina unstable, 
Angina pectoris, 
Myocardial ischaemia, 
Atrial fibrillation, 
Arrhythmia, 
Tachycardia, Sinus 
tachycardia, 
Palpitations  

Ventricular 
fibrillation (rare), 
QT prolongation 
(rare), Torsade de 
pointes (rare), 
Bradycardia 
(rare), Vasospasm 
(rare) 

Vascular 
disorders  

-  Thrombophlebitis  Deep vein thrombosis, 
Hypertension, 
Petechiae, 
Hypotension, Hot 
flush, Peripheral 
coldness  

 

Respiratory, 
thoracic and 
mediastinal 
disorders  

-  Dyspnoea, Epistaxis, 
Cough, Rhinorrhoea  

Pulmonary embolism, 
Pneumothorax, 
Haemoptysis, Asthma, 
Dyspnoea exertional  

 

Gastroin-
testinal 
disorders  

Diarrhoea, 
Vomiting, 
Nausea, 
Stomatitis, 
Abdominal pain  

Gastrointestinal 
haemorrhage, 
Constipation, Upper 
abdominal pain, 
Dyspepsia, 
Flatulence, Dry 
mouth  

Intestinal obstruction, 
Ascites, Enteritis, 
Gastritis, Dysphagia, 
Abdominal pain lower, 
Oesophagitis, 
Abdominal discomfort, 
Gastrooesophageal 
reflux disease, Colitis, 
Blood in stool  

 

Hepatobiliary 
disorders  

-  Hyperbilirubinemia, 
Liver function test 
abnormalities  

Jaundice  Hepatic failure 
(rare), Cholestatic 
hepatitis (rare) 

Skin and 
subcutaneous 
tissue 
disorders  

Palmar-plantar 
erythro-
dysaesthesia 
syndrome  

Rash, Alopecia, 
Erythema, Dry skin, 
Pruritus, Skin hyper-
pigmentation, Rash 
macular, Skin 
desquamation, 
Dermatitis, 
Pigmentation 
disorder, Nail 
disorder  

Blister, Skin ulcer, 
Rash, Urticaria, 
Photosensitivity 
reaction, Palmar 
erythema, Swelling 
face, Purpura, 
Radiation recall 
syndrome  

Cutaneous lupus 
erythematosus 
(rare), Severe skin 
reactions such as 
Stevens-Johnson 
Syndrome and 
toxic Epidermal 
Necrolysis (vary 
rare) (see section 
4.4) 

Muskulo-
skeletal and 
connective 
tissue 
disorders  

-  Pain in extremity, 
Back pain, Arthralgia  

Joint swelling, Bone 
pain, Facial pain, 
Musculoskeletal 
stiffness, Muscular 
weakness 

 

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Body System  Very Common 
 

All grades  

Common  
 

All grades  

Uncommon  
 

Severe and/or Life-

threatening (grade 3-

4) or considered 

medically relevant  

Rare/Very Rare 
(Post-Marketing 

Experience) 

Renal and 
urinary 
disorders  

-  -  Hydronephrosis, 
Urinary incontinence, 
Haematuria, Nocturia, 
Blood creatinine 
increased  

 

Reproductive 
system and 
breast 
disorders  

-  -  Vaginal haemorrhage   

General 
disorders  
and 
administration 
site conditions  

Fatigue, 
Asthenia  

Pyrexia,  
Oedema peripheral, 
Malaise, Chest pain  

Oedema, Chills, 
Influenza like illness, 
Rigors, Body 
temperature increased  

 

 
Capecitabine in combination therapy  
Table 5 lists ADRs associated with the use of capecitabine in combination with different 
chemotherapy regimens in multiple indications based on safety data from over 3000 patients. ADRs 
are added to the appropriate frequency grouping (Very common or Common) according to the highest 
incidence seen in any of the major clinical trials and are only added when they were seen in addition 
to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to 
capecitabine monotherapy (see table 4). Uncommon ADRs reported for capecitabine in combination 
therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for 
monotherapy with the combination agent (in literature and/or respective summary of product 
characteristics). 
 
Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. 
peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); 
however an exacerbation by capecitabine therapy can not be excluded. 
 
Table 5 Summary of related ADRs reported in patients treated with capecitabine in combination 

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

Body System Very common 
 

All grades  

Common 
 

All grades  

Rare/Very 
Rare  
(Post-

Marketing 
Experience) 

Infections and 
infestations  

-  Herpes zoster, Urinary tract infection, 
Oral candidiasis, Upper respiratory tract 
infection, Rhinitis, Influenza, +Infection, 
Oral herpes  

 

Blood and 
lymphatic 
system 
disorders  

+Neutropenia, 
+Leucopenia, +Anaemia, 
+Neutropenic fever, 
Thrombocytopenia  

Bone marrow depression, +Febrile 
Neutropenia  

 

Immune system 
disorders  

-  Hypersensitivity   

Metabolism and 
nutrition 
disorders  

Appetite decreased  Hypokalaemia, Hyponatraemia, 
Hypomagnesaemia, Hypocalcaemia, 
Hyperglycaemia  

 

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Body System Very common 
 

All grades  

Common 
 

All grades  

Rare/Very 
Rare  
(Post-

Marketing 
Experience) 

Psychiatric 
disorders  

-  Sleep disorder, Anxiety   

Nervous system 
disorders  

Paraesthesia, 
Dysaesthesia, Peripheral 
neuropathy, Peripheral 
sensory neuropathy, 
Dysgeusia, Headache  

Neurotoxicity, Tremor, Neuralgia, 
Hypersensitivity reaction, 
Hypoaesthesia  

 

Eye disorders  Lacrimation increased  Visual disorders, Dry eye, Eye pain, 
Visual impairment, Vision blurred  

 

Ear and 
labyrinth 
disorders  

-  Tinnitus, Hypoacusis   

Cardiac 
disorders  

-  Atrial fibrillation, Cardiac 
ischaemia/infarction  

 

Vascular 
disorders  

Lower limb oedema, 
Hypertension, +Embolism 
and thrombosis  

Flushing, Hypotension, Hypertensive 
crisis, Hot flush, Phlebitis  

 

Respiratory, 
thoracic and 
mediastinal 
system 
disorders  

Sore throat, Dysaesthesia 
pharynx  

Hiccups, Pharyngolaryngeal pain, 
Dysphonia  

 

Gastrointestinal 
disorders  
 

Constipation, Dyspepsia  Upper gastrointestinal haemorrhage, 
Mouth ulceration, Gastritis, Abdominal 
distension, Gastroesophageal reflux 
disease, Oral pain, Dysphagia, Rectal 
haemorrhage, Abdominal pain lower, 
Oral dysaesthesia, Paraesthesia oral, 
Hypoaesthesia oral, Abdominal 
discomfort  

 

Hepatobiliary 
disorders  

-  Hepatic function abnormal   

Skin and 
subcutaneous 
tissue disorders  

Alopecia, Nail disorder  Hyperhidrosis, Rash erythematous, 
Urticaria, Night sweats  

 

Musculoskeletal 
and connective 
tissue disorders  

Myalgia, Arthralgia, Pain 
in extremity  

Pain in jaw , Muscle spasms, Trismus, 
Muscular weakness  

 

Renal and 
urinary 
disorder  

-  Haematuria, Proteinuria, Creatinine 
renal clearance decreased, Dysuria  

Acute renal 
failure 
secondary to 
dehydration 
(rare) 

General 
disorders and 
administration 
site conditions  

Pyrexia, Weakness, 
+Lethargy, Temperature 
intolerance  

Mucosal inflammation, Pain in limb, 
Pain, Chills, Chest pain, Influenza-like 
illness, +Fever, Infusion related reaction, 
Injection site reaction, Infusion site 
pain, Injection site pain  

 

Injury, 
poisoning and 
procedural 
complications  

-  Contusion   

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+ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”, 
the frequency count was based on grade 3-4 ADRs. ADRs are added according to the highest 
incidence seen in any of the major combination trials. 
 
Description of selected adverse reactions 
 
Hand-foot syndrome (see section 4.4) 
For the capecitabine dose of 1250 mg/m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 
53% to 60% of all-grades HFS was observed in capecitabine monotherapy trials (comprising studies in 
adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast 
cancer) and a frequency of 63% was observed in the capecitabine/docetaxel arm for the treatment of 
metastatic breast cancer. For the capecitabine dose of 1000 mg/m2 twice daily on days 1 to 14 every 
3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination 
therapy. 
 
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine 
monotherapy or capecitabine in combination with different chemotherapy regimens in multiple 
indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 
2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment with 
capecitabine. In all studies combined, the following covariates were statistically significantly 
associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), 
decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six 
weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female 
gender, and good ECOG performance status at baseline (0 versus ≥1). 
 
Diarrhoea (see section 4.4) 
Capecitabine can induce the occurrence of diarrhoea, which has been observed in up to 50% of 
patients. 
 
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with 
capecitabine showed that in all studies combined, the following covariates were statistically 
significantly associated with an increased risk of developing diarrhoea: increasing capecitabine 
starting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 year 
increments), and female gender. The following covariates were statistically significantly associated 
with a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) and 
increasing relative dose intensity in the first six weeks. 
 
Cardiotoxicity (see section 4.4) 
In addition to the ADRs described in tables 4 and 5, the following ADRs with an incidence of less than 
0.1% were associated with the use of capecitabine monotherapy based on a pooled analysis from 
clinical safety data from 7 clinical trials including 949 patients (2 phase III and 5 phase II clinical trials 
in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, cardiac failure, sudden 
death, and ventricular extrasystoles. 
 
Encephalopathy 
In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis from 
clinical safety data from 7 clinical trials, encephalopathy was also associated with the use of 
capecitabine monotherapy with an incidence of less than 0.1%. 
 
Special populations 
 
Elderly patients (see section 4.2) 
An analysis of safety data in patients ≥60 years of age treated with capecitabine monotherapy and an 
analysis of patients treated with capecitabine plus docetaxel combination therapy showed an increase 
in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious 
adverse reactions compared to patients <60 years of age. Patients ≥60 years of age treated with 

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capecitabine plus docetaxel also had more early withdrawals from treatment due to adverse reactions 
compared to patients <60 years of age. 
 
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with 
capecitabine showed that in all studies combined, increasing age (by 10 year increments) was 
statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a 
decreased risk of developing neutropenia. 
 
Gender  
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with 
capecitabine showed that in all studies combined, female gender was statistically significantly 
associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of 
developing neutropenia.  
 
Patients with renal impairment (see section 4.2, 4.4, and 5.2)  
An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) with 
baseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4 
adverse reactions compared to patients with normal renal function (36% in patients without renal 
impairment n=268, vs. 41% in mild n=257 and 54% in moderate n=59, respectively) (see section 5.2). 
Patients with moderately impaired renal function show an increased rate of dose reduction (44%) vs. 
33% and 32% in patients with no or mild renal impairment and an increase in early withdrawals from 
treatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mild 
renal impairment. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in the Appendix V*. 
 
4.9 Overdose 
 
The manifestations of acute overdose include nausea, vomiting, diarrhoea, mucositis, gastrointestinal 
irritation and bleeding, and bone marrow depression. Medical management of overdose should include 
customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical 
manifestations and preventing their possible complications. 
 
 
5. PHARMACOLOGICAL PROPERTIES  
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code: 
L01BC06 
 
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally 
administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via 
several enzymatic steps (see section 5.2). The enzyme involved in the final conversion to 5-FU, 
thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeit 
usually at lower levels. In human cancer xenograft models capecitabine demonstrated a synergistic 
effect in combination with docetaxel, which may be related to the upregulation of thymidine 
phosphorylase by docetaxel. 
 
There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation 
reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of 
deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein 

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synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be 
to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of 
DNA and RNA deprivation are most marked on those cells which proliferate more rapidly and which 
metabolise 5-FU at a more rapid rate. 
 
Colon and colorectal cancer  
 
Monotherapy with capecitabine in adjuvant colon cancer  
Data from one multicentre, randomised, controlled phase III clinical trial in patients with stage III 
(Dukes’ C) colon cancer supports the use of capecitabine for the adjuvant treatment of patients with 
colon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment with 
capecitabine (1250 mg/m2

 
twice daily for 2 weeks followed by a 1-week rest period and given as 

3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo Clinic regimen: 20 mg/m2
 
leucovorin IV 

followed by 425 mg/m2
 
IV bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks). Capecitabine was 

at least equivalent to IV 5-FU/LV in disease-free survival in per protocol population (hazard ratio 
0.92; 95% CI 0.80 - 1.06). In the all-randomised population, tests for difference of capecitabine vs. 
5-FU/LV in disease-free and overall survival showed hazard ratios of 0.88 (95% CI 0.77 - 1.01; p 
= 0.068) and 0.86 (95% CI 0.74 - 1.01; p = 0.060), respectively. The median follow up at the time of 
the analysis was 6.9 years. In a preplanned multivariate Cox analysis, superiority of capecitabine 
compared with bolus 5-FU/LV was demonstrated. The following factors were pre-specified in the 
statistical analysis plan for inclusion in the model: age, time from surgery to randomization, gender, 
CEA levels at baseline, lymph nodes at baseline, and country. In the all-randomised population, 
capecitabine was shown to be superior to 5FU/LV for disease-free survival (hazard ratio 0.849; 95% 
CI 0.739 - 0.976; p = 0.0212), as well as for overall survival (hazard ratio 0.828; 95% CI 
0.705 - 0.971; p = 0.0203). 
 
Combination therapy in adjuvant colon cancer  
Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III 
(Dukes’ C) colon cancer supports the use of capecitabine in combination with oxaliplatin (XELOX) 
for the adjuvant treatment of patients with colon cancer (NO16968 study). In this trial, 944 patients 
were randomised to 3-week cycles for 24 weeks with capecitabine (1000 mg/m2 twice daily for 
2 weeks followed by a 1-week 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 for DFS in the ITT population, XELOX was shown to be 
significantly superior to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate 
was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of RFS 
supports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5-FU/LV. 
XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486) 
which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus 
74% for 5-FU/LV. The efficacy data is based on a median observation time of 59 months for OS and 
57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOX 
combination therapy arm (21%) as compared with that of the 5-FU/LV monotherapy arm (9%) in the 
ITT population. 
 
Monotherapy with capecitabine in metastatic colorectal cancer 
Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials 
(SO14695; SO14796) support the use of capecitabine for first line treatment of metastatic colorectal 
cancer. In these trials, 603 patients were randomised to treatment with capecitabine (1250 mg/m2

 
twice 

daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles). 604 patients were 
randomised to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m2

 
leucovorin IV followed 

by 425 mg/m2
 
IV bolus 5-FU, on days 1 to 5, every 28 days). The overall objective response rates in 

the all-randomised population (investigator assessment) were 25.7% (capecitabine) vs. 16.7% (Mayo 
regimen); p <0.0002. The median time to progression was 140 days (capecitabine) vs. 144 days (Mayo 
regimen). Median survival was 392 days (capecitabine) vs. 391 days (Mayo regimen). Currently, no 
comparative data are available on capecitabine monotherapy in colorectal cancer in comparison with 
first line combination regimens. 

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Combination therapy in first-line treatment of metastatic colorectal cancer  
Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use of 
capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for 
the first-line treatment of metastatic colorectal cancer. The study contained two parts: an initial 2-arm 
part in which 634 patients were randomised to two different treatment groups, including XELOX or 
FOLFOX-4, and a subsequent 2x2 factorial part in which 1401 patients were randomised to four 
different treatment groups, including XELOX plus placebo, FOLFOX-4 plus placebo, XELOX plus 
bevacizumab, and FOLFOX-4 plus bevacizumab. See table 6 for treatment regimens. 
 
Table 6 Treatment regimens in study NO16966 (mCRC) 

 Treatment  Starting Dose  Schedule  
FOLFOX-4 

or 
FOLFOX-4 + 
Bevacizumab 

Oxaliplatin 
 
Leucovorin 
 
5-Fluorouracil 

85 mg/m2 IV 2 hr  
 
200 mg/m2 IV 2 hr 
 
400 mg/m2 IV bolus, 
followed by 600 mg/m2 
IV 22 hr 

Oxaliplatin on Day 1, every 2 weeks  
 
Leucovorin on Days 1 and 2, every 
2 weeks 
5-fluorouracil IV bolus/infusion, 
each on Days 1 and 2, every 2 weeks 

 Placebo or 
Bevacizumab 

5 mg/kg IV 30-90 mins Day 1, prior to FOLFOX-4, every 
2 weeks 

XELOX 
or 

XELOX+ 
Bevacizumab 

Oxaliplatin 
Capecitabine 

130 mg/m2 IV 2 hr 
1000 mg/m2 oral twice 
daily 

Oxaliplatin on Day 1, every 3 weeks 
Capecitabine oral twice daily for 
2 weeks (followed by 1 week off-
treatment) 

 
 

Placebo or 
Bevacizumab 

7.5 mg/kg IV 
30-90 mins 

Day 1, prior to XELOX, every 
3 weeks 

5-Fluorouracil:       IV bolus injection immediately after leucovorin 
 
Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the 
overall comparison was demonstrated in terms of progression-free survival in the eligible patient 
population and the intent-to-treat population (see table 7). The results indicate that XELOX is 
equivalent to FOLFOX-4 in terms of overall survival (see table 7). A comparison of XELOX plus 
bevacizumab versus FOLFOX-4 plus bevacizumab was a pre-specified exploratory analysis. In this 
treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus 
bevacizumab in terms of progression-free survival (hazard ratio 1.01; 97.5% CI 0.84 - 1.22). The 
median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; 
data from analyses following an additional 1 year of follow up are also included in table 7. However, 
the on-treatment PFS analysis did not confirm the results of the general PFS and OS analysis: the 
hazard ratio of XELOX versus FOLFOX-4 was 1.24 with 97.5% CI 1.07 - 1.44. Although sensitivity 
analyses show that differences in regimen schedules and timing of tumor assessments impact the on-
treatment PFS analysis, a full explanation for this result has not been found.  

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Table 7 Key efficacy results for the non-inferiority analysis of study NO16966 
PRIMARY ANALYSIS  

XELOX/XELOX+P/ XELOX+BV  
(EPP*: N=967; ITT**: N=1017)  

FOLFOX-4/FOLFOX-4+P/ FOLFOX-4+BV  
(EPP*: N = 937; ITT**: N= 1017)  

Population  Median Time to Event (Days)  HR  
(97.5% CI)  

Parameter: Progression-free Survival  
EPP  
ITT  

241  
244  

259  
259  

1.05 (0.94; 1.18)  
1.04 (0.93; 1.16)  

Parameter: Overall Survival  
EPP  
ITT  

577  
581  

549  
553  

0.97 (0.84; 1.14)  
0.96 (0.83; 1.12)  

ADDITIONAL 1 YEAR OF FOLLOW UP  
Population  Median Time to Event (Days)  HR  

(97.5% CI)  
Parameter: Progression-free Survival  

EPP  
ITT  

242  
244  

259  
259  

1.02 (0.92; 1.14)  
1.01 (0.91; 1.12)  

Parameter: Overall Survival  
EPP  
ITT  

600  
602  

594  
596  

1.00 (0.88; 1.13)  
0.99 (0.88; 1.12)  

*EPP=eligible patient population; **ITT=intent-to-treat population 
 
In a randomised, controlled phase III study (CAIRO), the effect of using capecitabine at a starting dose 
of 1000 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of 
patients with metastatic colorectal cancer was studied. 820 Patients were randomised to receive either 
sequential treatment (n=410) or combination treatment (n=410). Sequential treatment consisted of 
first-line capecitabine (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 
1), and third-line combination of capecitabine (1000 mg/m2 twice daily for 14 days) with oxaliplatin 
(130 mg/m2 on day 1). Combination treatment consisted of first-line capecitabine (1000 mg/m2 twice 
daily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-line 
capecitabine (1000 mg/m2 twice daily for 14 days) plus oxaliplatin (130 mg/m2 on day 1). All 
treatment cycles were administered at intervals of 3 weeks. In first-line treatment the median 
progression-free survival in the intent-to-treat population was 5.8 months (95%CI 5.1 - 6.2 months) 
for capecitabine monotherapy and 7.8 months (95%CI 7.0 - 8.3 months; p=0.0002) for XELIRI. 
However this was associated with an increased incidence of gastrointestinal toxicity and neutropenia 
during first-line treatment with XELIRI (26% and 11% for XELIRI and first line capecitabine 
respectively). 
 
The XELIRI has been compared with 5-FU + irinotecan (FOLFIRI) in three randomised studies in 
patients with metastatic colorectal cancer. The XELIRI regimens included capecitabine 1000 mg/m2 
twice daily on days 1 to 14 of a three-week cycle combined with irinotecan 250 mg/m2 on day 1. In the 
largest study (BICC-C), patients were randomised to receive either open label FOLFIRI (n=144), 
bolus 5-FU (mIFL) (n=145) or XELIRI (n=141) and were additionally randomised to receive either 
double-blind treatment with celecoxib or placebo. Median PFS was 7.6 months for FOLFIRI, 5.9 
months for mIFL (p=0.004) for the comparison with FOLFIRI), and 5.8 months for XELIRI 
(p=0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p=0.09), and 18.9 
months for XELIRI (p=0.27). Patients treated with XELIRI experienced excessive gastrointestinal 
toxicity compared with FOLFIRI (diarrhoea 48% and 14% for XELIRI and FOLFIRI respectively). 
 
In the EORTC study patients were randomised to receive either open label FOLFIRI (n=41) or 
XELIRI (n=44) with additional randomisation to either double-blind treatment with celecoxib or 
placebo. Median PFS and overall survival (OS) times were shorter for XELIRI versus FOLFIRI (PFS 
5.9 versus 9.6 months and OS 14.8 versus 19.9 months), in addition to which excessive rates of 
diarrhoea were reported in patients receiving the XELIRI regimen (41% XELIRI, 5.1% FOLFIRI). 
 
In the study published by Skof et al, patients were randomised to receive either FOLFIRI or XELIRI. 
Overall response rate was 49% in the XELIRI and 48% in the FOLFIRI arm (p=0.76). At the end of 
treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without 

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evidence of the disease (p=0.56). Toxcity was similar between treatments with the exception of 
neutropenia reported more commonly in patients treated with FOLFIRI. 
 
Montagnani et al used the results from the above three studies to provide an overall analysis of 
randomised studies comparing FOLFIRI and XELIRI treatment regimens in the treatment of mCRC. 
A significant reduction in the risk of progression was associated with FOLFIRI (HR, 0.76; 95%CI, 
0.62-0.95; P <0.01), a result partly due to poor tolerance to the XELIRI regimens used. 
 
Data from a randomised clinical study (Souglakos et al, 2012) comparing FOLFIRI + bevacizumab 
with XELIRI + bevacizumab showed no significant differences in PFS or OS between treatments. 
Patients were randomised to receive either FOLFIRI plus bevacizumab (Arm-A, n=167) or XELIRI 
plus bevacizumab (Arm-B, n-166). For Arm B, the XELIRI regimen used capecitabine 1000 mg/m2 
twice daily for 14 days + irinotecan 250 mg/m2 on day 1. Median progression-free survival (PFS) was 
10.0 and 8.9 months; p=0.64, overall survival 25.7 and 27.5 months; p=0.55 and response rates 45.5 
and 39.8%; p=0.32 for FOLFIRI-Bev and XELIRI-Bev, respectively. Patients treated with XELIRI + 
bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-foot 
skin reactions than patients treated with FOLFIRI + bevacizumab with significantly increased 
treatment delays, dose reductions and treatment discontinuations. 
 
Data from a multicentre, randomised, controlled phase II study (AIO KRK 0604) supports the use of 
capecitabine at a starting dose of 800 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan 
and bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. 120 Patients 
were randomised to a modified XELIRI regimen with capecitabine 800 mg/m2 twice daily for two 
weeks followed by a 7-day rest period), irinotecan (200 mg/m2 as a 30 minute infusion on day 1 every 
3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks); 127 
patients were randomised to treatment with capecitabine (1000 mg/m2 twice daily for two weeks 
followed by a 7-day rest period), oxaliplatin (130 mg/m2 as a 2 hour infusion on day 1 every 3 weeks), 
and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Following a mean 
duration of follow-up for the study population of 26.2 months, treatment responses were as shown 
below:  
 
Table 8  Key efficacy results for AIO KRK study 
 XELOX + bevacizumab 

 

(ITT: N=127) 

Modified XELIRI+ 

bevacizumab 

(ITT: N= 120) 

Hazard ratio 

95% CI 

P value 

Progression-free Survival after 6 months 
ITT 

95% CI 
76% 

69 - 84% 
84%  

77 - 90% 
- 

Median progression free survival 
ITT 

95% CI 
10.4 months 

9.0 - 12.0 
12.1 months 

10.8 - 13.2 
0.93 

0.82 - 1.07 

P=0.30 

Median overall survival 
ITT 

95% CI 

24.4 months 

19.3 - 30.7 

25.5 months 

21.0 - 31.0 

0.90 

0.68 - 1.19 

P=0.45 

 
Combination therapy in second-line treatment of metastatic colorectal cancer  
Data from a multicentre, randomised, controlled phase III clinical study (NO16967) support the use of 
capecitabine in combination with oxaliplatin for the second-line treatment of metastastic colorectal 
cancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received prior 
treatment with irinotecan in combination with a fluoropyrimidine regimen as first line therapy were 
randomised to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and 
FOLFOX-4 (without addition of placebo or bevacizumab), refer to table 6. XELOX was demonstrated 
to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population 
and intent-to-treat population (see table 9). The results indicate that XELOX is equivalent to 
FOLFOX-4 in terms of overall survival (see table 9). The median follow up at the time of the primary 

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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 9. 
 
Table 9 Key efficacy results for the non-inferiority analysis of study NO16967 

PRIMARY ANALYSIS  
XELOX  

(PPP*: N=251; ITT**: N=313)  
FOLFOX-4  

(PPP*: N = 252; ITT**: N= 314)  
Population  Median Time to Event (Days)  HR  

(95% CI)  
Parameter: Progression-free Survival  

PPP  
ITT  

154  
144  

168  
146  

1.03 (0.87; 1.24)  
0.97 (0.83; 1.14)  

Parameter: Overall Survival  
PPP  
ITT  

388  
363  

401  
382  

1.07 (0.88; 1.31)  
1.03 (0.87; 1.23)  

ADDITIONAL 6 MONTHS OF FOLLOW UP  
Population  Median Time to Event (Days)  HR  

(95% CI)  
Parameter: Progression-free Survival  

PPP  
ITT  

154  
143  

166  
146  

1.04 (0.87; 1.24)  
0.97 (0.83; 1.14)  

Parameter: Overall Survival  
PPP  
ITT  

393  
363  

402  
382  

1.05 (0.88; 1.27)  
1.02 (0.86; 1.21)  

*PPP=per-protocol population; **ITT=intent-to-treat population 
 
Advanced gastric cancer 
Data from a multicentre, randomised, controlled phase III clinical trial in patients with advanced 
gastric cancer supports the use of capecitabine for the first-line treatment of advanced gastric cancer 
(ML17032). In this trial, 160 patients were randomised to treatment with capecitabine (1000 mg/m2

 

twice daily for 2 weeks followed by a 7-day rest period) and cisplatin (80 mg/m2
 
as a 2-hour 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 infusion on day 

1, every 3 weeks). Capecitabine in combination with cisplatin was non-inferior to 5-FU in 
combination with cisplatin in terms of progression-free survival in the per protocol analysis (hazard 
ratio 0.81; 95% CI 0.63 - 1.04). The median progression-free survival was 5.6 months (capecitabine + 
cisplatin) versus 5.0 months (5-FU + cisplatin). The hazard ratio for duration of survival (overall 
survival) was similar to the hazard ratio for progression-free survival (hazard ratio 0.85; 95% CI 
0.64 - 1.13). The median duration of survival was 10.5 months (capecitabine + cisplatin) versus 
9.3 months (5-FU + cisplatin). 
 
Data from a randomised multicentre, phase III study comparing capecitabine to 5-FU and oxaliplatin 
to cisplatin in patients with advanced gastric cancer supports the use of capecitabine for the first-line 
treatment of advanced gastric cancer (REAL-2). In this trial, 1002 patients were randomised in a 2x2 
factorial design to one of the following 4 arms: 
 
- ECF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a two 

hour infusion on day 1 every 3 weeks) and 5-FU (200 mg/m2
 
daily given by continuous infusion 

via a central line). 
- ECX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a two 

hour infusion on day 1 every 3 weeks), and capecitabine (625 mg/m2
 
twice daily continuously).  

- EOF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given as 
a 2 hour infusion on day 1 every three weeks), and 5-FU (200 mg/m2

 
daily given by continuous 

infusion via a central line).  
- EOX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given as 

a 2 hour infusion on day 1 every three weeks), and capecitabine (625 mg/m2 twice daily 
continuously). 

 

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The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overall 
survival for capecitabine vs. 5-FU-based regimens (hazard ratio 0.86; 95% CI 0.8 - 0.99) and for 
oxaliplatin vs. cisplatin-based regimens (hazard ratio 0.92; 95% CI 0.80 - 1.1). The median overall 
survival was 10.9 months in capecitabine-based regimens and 9.6 months in 5-FU based regimens. 
The median overall survival was 10.0 months in cisplatin-based regimens and 10.4 months in 
oxaliplatin-based regimens. 
 
Capecitabine has also been used in combination with oxaliplatin for the treatment of advanced gastric 
cancer. Studies with capecitabine monotherapy indicate that capecitabine has activity in advanced 
gastric cancer. 
 
Colon, colorectal and advanced gastric cancer: meta-analysis 
A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, 
M17032) supports capecitabine replacing 5-FU in mono- and combination treatment in gastrointestinal 
cancer. The pooled analysis includes 3097 patients treated with capecitabine-containing regimens and 
3074 patients treated with 5-FU-containing regimens. Median overall survival time was 703 days 
(95% CI: 671; 745) in patients treated with capecitabine-containing regimens and 683 days (95% CI: 
646; 715) in patients treated with 5-FU-containing regimens. The hazard ratio for overall survival was 
0.94 (95% CI: 0.89; 1.00, p=0.0489) indicating that capecitabine-containing regimens are non-inferior 
to 5-FU-containing regimens. 
 
Breast cancer 
 
Combination therapy with capecitabine and docetaxel in locally advanced or metastatic breast cancer  
Data from one multicentre, randomised, controlled phase III clinical trial support the use of 
capecitabine in combination with docetaxel for treatment of patients with locally advanced or 
metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this 
trial, 255 patients were randomised to treatment with capecitabine (1250 mg/m2

 
twice daily for 

2 weeks followed by 1-week rest period and docetaxel 75 mg/m2
 
as a 1 hour intravenous infusion 

every 3 weeks). 256 patients were randomised to treatment with docetaxel alone (100 mg/m2
 
as a 

1 hour intravenous infusion every 3 weeks). Survival was superior in the capecitabine + docetaxel 
combination arm (p=0.0126). Median survival was 442 days (capecitabine + docetaxel) vs. 352 days 
(docetaxel alone). The overall objective response rates in the all-randomised population (investigator 
assessment) were 41.6% (capecitabine + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to 
progressive disease was superior in the capecitabine + docetaxel combination arm (p<0.0001). The 
median time to progression was 186 days (capecitabine + docetaxel) vs. 128 days (docetaxel alone). 
 
Monotherapy with capecitabine after failure of taxanes, anthracycline containing chemotherapy, and 
for whom anthracycline therapy is not indicated  
Data from two multicentre phase II clinical trials support the use of capecitabine monotherapy for 
treatment of patients after failure of taxanes and an anthracycline-containing chemotherapy regimen or 
for whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients were 
treated with capecitabine (1250 mg/m2

 
twice daily for 2 weeks followed by 1-week rest period). The 

overall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial). 
The median time to progression was 93 and 98 days. Median survival was 384 and 373 days. 
 
All indications 
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine 
monotherapy or capecitabine in combination with different chemotherapy regimens in multiple 
indications (colon, colorectal, gastric and breast cancer) showed that patients on capecitabine who 
developed hand-foot syndrome (HFS) had a longer overall survival compared to patients who did not 
develop HFS: median overall survival 1100 days (95% CI 1007;1200) vs. 691 days (95% CI 638;754) 
with a hazard ratio of 0.61 (95% CI 0.56; 0.66). 
 

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Paediatric population 
The European Medicines Agency has waived the obligation to conduct studies with the reference 
medicinal product containing capecitabine in all subsets of the paediatric population in 
adenocarcinoma of the colon and rectum, gastric adenocarcinoma and breast carcinoma (see section 
4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of capecitabine have been evaluated over a dose range of 502-3514 mg/m2/day. 
The parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine 
(5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30%-35% higher on day 
14. Capecitabine dose reduction decreases systemic exposure to 5-FU more than dose-proportionally, 
due to non-linear pharmacokinetics for the active metabolite. 
 
Absorption 
After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive 
conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of 
capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of 
the subsequent metabolite 5-FU. At the dose of 1250 mg/m2

 
on day 14 with administration after food 

intake, the peak plasma concentrations (Cmax in μg/ml) for capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and 
FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 respectively. The time to peak plasma concentrations (Tmax 
in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-∞ values in μg•h/ml were 7.75, 7.24, 24.6, 
2.03 and 36.3. 
 
Distribution  
In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 
54%, 10%, 62% and 10% protein bound, mainly to albumin. 
 
Biotransformation  
Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 
5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissues. Further catalytic 
activation of 5'-DFUR then occurs by thymidine phosphorylase (ThyPase). The enzymes involved in 
the catalytic activation are found in tumour tissues but also in normal tissues, albeit usually at lower 
levels. The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher 
concentrations within tumour tissues. In the case of colorectal tumours, 5-FU generation appears to be 
in large part localised in tumour stromal cells. Following oral administration of capecitabine to 
patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumours to adjacent 
tissues was 3.2 (ranged from 0.9 to 8.0). The ratio of 5-FU concentration in tumour to plasma was 21.4 
(ranged from 3.9 to 59.9, n=8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 
to 25.8, n=8). Thymidine phosphorylase activity was measured and found to be 4 times greater in 
primary colorectal tumour than in adjacent normal tissue. According to immunohistochemical studies, 
thymidine phosphorylase appears to be in large part localised in tumour stromal cells. 
 
5-FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less 
toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 
5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-
alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD) activity is the 
rate limiting step. Deficiency of DPD may lead to increased toxicity of capecitabine (see section 4.3 
and 4.4). 
 
Elimination 
The elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 
0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Capecitabine and its metabolites are predominantly 
excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Faecal excretion is 
minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the 
administered dose. About 3% of the administered dose is excreted in urine as unchanged capecitabine. 

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Combination therapy  
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or 
paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or 
paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 
5’-DFUR. 
 
Pharmacokinetics in special populations 
A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients 
with colorectal cancer dosed at 1250 mg/m2

 
twice daily. Gender, presence or absence of liver 

metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and 
ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. 
 
Patients with hepatic impairment due to liver metastases: According to a pharmacokinetic study in 
cancer patients with mild to moderate liver impairment due to liver metastases, the bioavailability of 
capecitabine and exposure to 5-FU may increase compared to patients with no liver impairment. There 
are no pharmacokinetic data on patients with severe hepatic impairment. 
 
Patients with renal impairment: Based on a pharmacokinetic study in cancer patients with mild to 
severe renal impairment, there is no evidence for an effect of creatinine clearance on the 
pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic 
exposure to 5’-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to 
FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite 
without antiproliferative activity. 
 
Elderly: Based on the population pharmacokinetic analysis, which included patients with a wide range 
of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence 
on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase 
in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal 
function. 
 
Ethnic factors: Following oral administration of 825 mg/m2

 
capecitabine twice daily for 14 days, 

Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than 
Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for 
FBAL than Caucasian patients. The clinical relevance of these differences is unknown. No significant 
differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU). 
 
5.3 Preclinical safety data 
 
In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and 
mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for 
fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised by 
degenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepatic 
and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in 
cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing 
(1379 mg/m2/day). 
 
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine. 
 
During standard fertility studies, impairment of fertility was observed in female mice receiving 
capecitabine; however, this effect was reversible after a drug-free period. In addition, during a 
13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; 
however these effects were reversible after a drug-free period (see section 4.6). 
 

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In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and 
teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, 
but there was no evidence of teratogenicity. 
 
Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster 
V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), 
capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse 
bone marrow micronucleus tests (in vivo). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core:  
talc (E553b) 
anhydrous lactose 
croscarmellose sodium (E468) 
hypromellose (E464) 
microcrystalline cellulose (E460) 
magnesium stearate (E572) 
 
Tablet coating:  
hypromellose (E464)  
titanium dioxide (E171) 
lactose monohydrate 
macrogol 
yellow iron oxide (E172) and red iron oxide (E172). 
 
6.2 Incompatibilities  
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage  
 
Do not store above 25°C. 
 
6.5 Nature and contents of container  
 
Alu/Alu blister containing 10 film-coated tablets. Each carton contains 60 film-coated tablets 
(6 blisters of 10 tablets). 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe BV 
Polarisavenue 87 
2132 JH Hoofddorp 

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The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/831/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 June 2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency: http://www.ema.europa.eu. 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine SUN 500 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 500 mg of capecitabine. 
 
Excipient(s) with known effect:  
Each film-coated tablet contains 68.95 mg anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
Capecitabine SUN 500 mg film-coated tablets are peach coloured, oval, biconvex, 17.5 mm x 8.7 mm 
tablets, with inscription ‘500’on one side and plain on other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Capecitabine is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ 
stage C) colon cancer (see section 5.1). 
 
Capecitabine is indicated for the treatment of metastatic colorectal cancer (see section 5.1). 
 
Capecitabine is indicated for first-line treatment of advanced gastric cancer in combination with a 
platinum-based regimen (see section 5.1). 
 
Capecitabine in combination with docetaxel (see section 5.1) is indicated for the treatment of patients 
with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous 
therapy should have included an anthracycline. Capecitabine is also indicated as monotherapy for the 
treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an 
anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not 
indicated. 
 
4.2 Posology and method of administration 
 
Capecitabine should only be prescribed by a qualified physician experienced in the utilisation of 
anti-neoplastic medicinal products. Careful monitoring during the first cycle of treatment is 
recommended for all patients.  
Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard 
and reduced dose calculations according to body surface area for starting doses of capecitabine of 
1250 mg/m2 and 1000 mg/m2 are provided in tables 1 and 2, respectively. 
 
Posology 
 
Recommended posology (see section 5.1): 
 
Monotherapy 

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Colon, colorectal and breast cancer 
Given as monotherapy, the recommended starting dose for capecitabine in the adjuvant treatment of 
colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic 
breast cancer is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 
2500 mg/m2 total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment in 
patients with stage III colon cancer is recommended for a total of 6 months. 
 
Combination therapy  
Colon, colorectal and gastric cancer 
In combination treatment, the recommended starting dose of capecitabine should be reduced to 
800 - 1000 mg/m2 when administered twice daily for 14 days followed by a 7-day rest period, or to 
625 mg/m2 twice daily when administered continuously (see section 5.1). For combination with 
irinotecan, the recommended starting dose is 800 mg/m2 when administered twice daily for 14 days 
followed by a 7-day rest period combined with irinotecan 200 mg/m2 on day 1. The inclusion of 
bevacizumab in a combination regimen has no effect on the starting dose of capecitabine. 
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of 
product characteristics should be started prior to cisplatin administration for patients receiving the 
capecitabine plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin 
summary of product characteristics is recommended for patients receiving the capecitabine plus 
oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended 
for a duration of 6 months. 
 
Breast cancer 
In combination with docetaxel, the recommended starting dose of capecitabine in the treatment of 
metastatic breast cancer is 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period, 
combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Pre-medication 
with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product 
characteristics should be started prior to docetaxel administration for patients receiving the 
capecitabine plus docetaxel combination. 
 
Capecitabine dose calculations 
 
Table 1 Standard and reduced dose calculations according to body surface area for a starting dose 

of capecitabine of 1250 mg/m2 
 Dose level 1250 mg/m2 (twice daily) 

 
 Full dose  

1250 mg/m2 

Number of 150 mg 
tablets and/or  

500 mg tablets per 
administration (each 
administration to be 
given morning and 

evening) 

Reduced dose 
(75%) 

 
950 mg/m2 

Reduced dose 
(50%) 

 
625 mg/m2 

Body Surface 
Area (m2) 

Dose per 
administration 

(mg) 

 
150 mg 

 

 
500 mg 

Dose per 
administration  

(mg) 

Dose per 
administration  

(mg) 
≤1.26 1500 - 3 1150 800 
1.27 - 1.38 1650 1 3 1300 800 
1.39 - 1.52 1800 2 3 1450 950 
1.53 - 1.66 2000 - 4 1500 1000 
1.67 - 1.78 2150 1 4 1650 1000 
1.79 - 1.92 2300 2 4 1800 1150 
1.93 - 2.06 2500 - 5 1950 1300 
2.07 - 2.18 2650 1 5 2000 1300 
≥2.19 2800 2 5 2150 1450 

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

of capecitabine of 1000 mg/m2 
 Dose level 1000 mg/m2 (twice daily) 

 
 Full dose  

 
 

1000 mg/m2 

Number of 150 mg 
tablets and/or 

500 mg tablets per 
administration (each 
administration to be 
given morning and 

evening) 

Reduced dose 
(75%) 

 
750 mg/m2 

Reduced dose 
(50%) 

 
500 mg/m2 

Body Surface 
Area (m2) 

Dose per 
administration  

(mg) 

 
150 mg 

 
500 mg 

Dose per 
administration  

(mg) 

Dose per 
administration  

(mg) 
≤1.26 1150 1 2 800 600 
1.27 - 1.38 1300 2 2 1000 600 
1.39 - 1.52 1450 3 2 1100 750 
1.53 - 1.66 1600 4 2 1200 800 
1.67 - 1.78 1750 5 2 1300 800 
1.79 - 1.92 1800 2 3 1400 900 
1.93 - 2.06 2000 - 4 1500 1000 
2.07 - 2.18 2150 1 4 1600 1050 
≥2.19 2300 2 4 1750 1100 
 
Posology adjustments during treatment 
General 
Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or 
modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it 
should not be increased at a later time. For those toxicities considered by the treating physician to be 
unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can 
be continued at the same dose without reduction or interruption. Patients taking capecitabine should be 
informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses 
of capecitabine omitted for toxicity are not replaced. The following are the recommended dose 
modifications for toxicity: 
 
Table 3 Capecitabine dose reduction schedule (3-weekly cycle or continuous treatment) 

Toxicity 
grades* 

Dose changes within a treatment 
cycle 

Dose adjustment for next 
cycle/dose (% of starting 

dose) 
•    Grade 1 Maintain dose level Maintain dose level 
•    Grade 2 
 
-1st appearance Interrupt until resolved to grade 0-1 100% 
-2nd appearance  

 
75% 

-3rd appearance  
 

50% 

-4th appearance Discontinue treatment permanently Not applicable 
•    Grade 3 
 
-1st appearance Interrupt until resolved to grade 0-1 75% 
-2nd appearance  

 
50% 

-3rd appearance Discontinue treatment permanently Not applicable 

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Toxicity 
grades* 

Dose changes within a treatment 
cycle 

Dose adjustment for next 
cycle/dose (% of starting 

dose) 
•    Grade 4 
-1st appearance Discontinue permanently 

or 
If physician deems it to be in the 
patient’s best interest to continue, 

interrupt until resolved to grade 0-1 

50% 

-2nd appearance Discontinue permanently Not applicable 
*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 
1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US 
National Cancer Institute, version 4.0. For hand-foot syndrome and hyperbilirubinemia, see section 4.4. 
 
Haematology  
Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of  
<100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a 
treatment cycle show that the neutrophil count drops below 1.0 x 109/L or that the platelet count drops 
below 75 x 109/L, treatment with capecitabine should be interrupted. 
 
Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with 
other medicinal products 
Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with 
other medicinal products should be made according to table 3 above for capecitabine and according to 
the appropriate summary of product characteristics for the other medicinal product(s). 
 
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the 
other medicinal product(s), then administration of all therapy should be delayed until the requirements 
for restarting all medicinal products are met. 
 
During a treatment cycle for those toxicities considered by the treating physician not to be related to 
capecitabine, capecitabine should be continued and the dose of the other medicinal product should be 
adjusted according to the appropriate Prescribing Information. 
 
If the other medicinal product(s) have to be discontinued permanently, capecitabine treatment can be 
resumed when the requirements for restarting capecitabine are met. 
 
This advice is applicable to all indications and to all special populations. 
 
Dose modifications for toxicity when capecitabine is used continuously in combination with other 
medicinal products  
Dose modifications for toxicity when capecitabine is used continuously in combination with other 
medicinal products should be made according to table 3 above for capecitabine and according to the 
appropriate summary of product characteristics for the other medicinal product(s). 
 
Posology adjustments for special populations 
 
Hepatic impairment  
Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose 
adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or 
hepatitis. 
 
Renal impairment  
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 
30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in 
patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased 

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compared to the overall population. In patients with moderate renal impairment at baseline, a dose 
reduction to 75% for a starting dose of 1250 mg/m2 is recommended. In patients with moderate renal 
impairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m2. In patients 
with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the 
starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended 
if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose 
adjustment as outlined in table 3 above. If the calculated creatinine clearance decreases during 
treatment to a value below 30 ml/min, capecitabine should be discontinued. These dose adjustment 
recommendations for renal impairment apply both to monotherapy and combination use (see also 
section “Elderly” below). 
 
Elderly 
During capecitabine monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 
treatment-related adverse reactions were more frequent in patients ≥60 years of age compared to 
younger patients. 
When capecitabine was used in combination with other medicinal products, elderly patients 
(≥65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to 
discontinuation, compared to younger patients. Careful monitoring of patients ≥60 years of age is 
advisable. 
- In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse 

reactions and treatment-related serious adverse reactions were observed in patients 60 years of 
age or more (see section 5.1). For patients 60 years of age or more, a starting dose reduction of 
capecitabine to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in 
patients ≥60 years of age treated with a reduced capecitabine starting dose in combination with 
docetaxel, the dose of capecitabine may be cautiously escalated to 1250 mg/m2 twice daily. 

 
Paediatric population 
There is no relevant use of capecitabine in the paediatric population in the indications colon, 
colorectal, gastric and breast cancer. 
 
Method of administration 
Capecitabine SUN tablets should be swallowed with water within 30 minutes after a meal. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or 

fluorouracil. 
- History of severe and unexpected reactions to fluoropyrimidine therapy. 
- In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4). 
- During pregnancy and lactation. 
- In patients with severe leukopenia, neutropenia, or thrombocytopenia. 
- In patients with severe hepatic impairment. 
- In patients with severe renal impairment (creatinine clearance below 30 ml/min). 
- Treatment with sorivudine or its chemically related analogues, such as brivudine (see 

section 4.5). 
- If contraindications exist to any of the medicinal products in the combination regimen, that 

medicinal product should not be used. 
 
4.4 Special warnings and precautions for use 
 
Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome 
(hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and 
do not require permanent discontinuation of therapy, although doses may need to be withheld or 
reduced. 
 

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Diarrhoea. Patients with severe diarrhoea should be carefully monitored and given fluid and 
electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. 
loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day 
or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and 
malabsorption. Grade 4 diarrhoea is an increase of ≥10 stools/day or grossly bloody diarrhoea or the 
need for parenteral support. Dose reduction should be applied as necessary (see section 4.2). 
 
Dehydration. Dehydration should be prevented or corrected at the onset. Patients with anorexia, 
asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. Dehydration may cause acute 
renal failure, especially in patients with pre-existing compromised renal function or when capecitabine 
is given concomitantly with known nephrotoxic drugs. Acute renal failure secondary to dehydration 
might be potentially fatal. If grade 2 (or higher) dehydration occurs, capecitabine treatment should be 
immediately interrupted and the dehydration corrected. Treatment should not be restarted until the 
patient is rehydrated and any precipitating causes have been corrected or controlled. Dose 
modifications applied should be applied for the precipitating adverse event as necessary (see 
section 4.2). 
 
Hand-foot syndrome (also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or 
chemotherapy induced acral erythema). Grade 1 hand- foot syndrome is defined as numbness, 
dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or 
discomfort which does not disrupt the patient’s normal activities. 
Grade 2 hand- foot syndrome is painful erythema and swelling of the hands and/or feet and/or 
discomfort affecting the patient’s activities of daily living. 
Grade 3 hand- foot syndrome is moist desquamation, ulceration, blistering and severe pain of the 
hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform 
activities of daily living. If grade 2 or 3 hand- foot syndrome occurs, administration of capecitabine 
should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 
hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine and 
cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic 
or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may 
decrease the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot 
syndrome prophylaxis in patients treated with capecitabine. 
 
Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, including 
myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and 
electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions 
may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias 
(including ventricular fibrillation, torsade de pointes, and bradycardia), angina pectoris, myocardial 
infarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine. 
Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and 
angina pectoris (see section 4.8).  
 
Hypo- or hypercalcaemia. Hypo- or hypercalcaemia has been reported during capecitabine treatment. 
Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia (see section 4.8). 
 
Central or peripheral nervous system disease. Caution must be exercised in patients with central or 
peripheral nervous system disease, e.g. brain metastasis or neuropathy (see section 4.8). 
 
Diabetes mellitus or electrolyte disturbances. Caution must be exercised in patients with diabetes 
mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment. 
 
Coumarin-derivative anticoagulation. In a drug interaction study with single-dose warfarin 
administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results 
suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system 
by capecitabine. Patients receiving concomitant capecitabine and oral coumarin-derivative 
anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored 
closely and the anticoagulant dose adjusted accordingly (see section 4.5). 

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Hepatic impairment. In the absence of safety and efficacy data in patients with hepatic impairment, 
capecitabine use should be carefully monitored in patients with mild to moderate liver dysfunction, 
regardless of the presence or absence of liver metastasis. Administration of capecitabine should be 
interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in 
hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with capecitabine 
monotherapy may be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferases 
decrease to ≤ 2.5 x ULN. 
 
Renal impairment. The incidence of grade 3 or 4 adverse reactions in patients with moderate renal 
impairment (creatinine clearance 30-50 ml/min) is increased compared to the overall population (see 
sections 4.2 and 4.3). 
 
DPD deficiency. Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, neutropenia and 
neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity. A link 
between decreased levels of DPD and increased, potentially fatal toxic effects of 5-FU therefore 
cannot be excluded. 
Patients with known DPD deficiency should not be treated with capecitabine (see section 4.3). In 
patients with unrecognised DPD deficiency treated with capecitabine, life-threatening toxicities 
manifesting as acute overdose may occur (see section 4.9). In the event of grade 2-4 acute toxicity, 
treatment must be discontinued immediately until observed toxicity resolves. Permanent 
discontinuation should be considered bases on clinical assessment of the onset, duration and severity 
of the observed toxicities. 
 
Ophthalmologic complications: Patients should be carefully monitored for ophthalmological 
complications such as keratitis and corneal disorders, especially if they have a prior history of eye 
disorders. Treatment of eye disorders should be initiated as clinically appropriate. 
 
Severe skin reactions: Capecitabine can induce severe skin reactions such as Stevens-Johnson 
syndrome and Toxic Epidermal Necrolysis. Capecitabine should be permanently discontinued in 
patients who experience a severe skin reaction during treatment. 
 
Excipients. As this medicinal product contains anhydrous lactose as an excipient, patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults.  
 
Interaction with other medicinal products 
 
Cytochrome P-450 2C9 substrates: Other than warfarin, no formal drug-drug interaction studies 
between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised 
when capecitabine is co-administered with 2C9 substrates (e.g., phenytoin). See also interaction with 
coumarin-derivative anticoagulants below, and section 4.4. 

Coumarin-derivative anticoagulants: altered coagulation parameters and/or bleeding have been 
reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such 
as warfarin and phenprocoumon. These reactions occurred within several days and up to several 
months after initiating capecitabine therapy and, in a few cases, within one month after stopping 
capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, 
capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. 
Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-
regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-
derivative anticoagulants concomitantly with capecitabine should be monitored regularly for 

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alterations in their coagulation parameters (PT or INR) and the anti-coagulant dose adjusted 
accordingly. 
 
Phenytoin: increased phenytoin plasma concentrations resulting in symptoms of phenytoin 
intoxication in single cases have been reported during concomitant use of capecitabine with phenytoin. 
Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased 
phenytoin plasma concentrations. 
 
Folinic acid/folic acid: a combination study with capecitabine and folinic acid indicated that folinic 
acid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic 
acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by 
folinic acid: the maximum tolerated dose (MTD) of capecitabine alone using the intermittent regimen 
is 3000 mg/m2 per day whereas it is only 2000 mg/m2 per day when capecitabine was combined with 
folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV 
to a capecitabine regimen. This may also be relevant with folic acid supplementation for folate 
deficiency due to the similarity between folinic acid and folic acid. 
 
Sorivudine and analogues: a clinically significant drug-drug interaction between sorivudine and 5-FU, 
resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described. 
This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, 
capecitabine must not be administered concomitantly with sorivudine or its chemically related 
analogues, such as brivudine (see section 4.3). There must be at least a 4-week waiting period between 
end of treatment with sorivudine or its chemically related analogues such as brivudine and start of 
capecitabine therapy. 
 
Antacid: the effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the 
pharmacokinetics of capecitabine was investigated. There was a small increase in plasma 
concentrations of capecitabine and one metabolite (5’-DFCR); there was no effect on the 3 major 
metabolites (5’-DFUR, 5-FU and FBAL). 
 
Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreased 
efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided. 
 
Interferon alpha: the MTD of capecitabine was 2000 mg/m2 per day when combined with interferon 
alpha-2a (3 MIU/m2 per day) compared to 3000 mg/m2 per day when capecitabine was used alone. 
 
Radiotherapy: the MTD of capecitabine alone using the intermittent regimen is 3000 mg/m2 per day, 
whereas, when combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2000 mg/m2 
per day using either a continuous schedule or given daily Monday through Friday during a 6-week 
course of radiotherapy. 
 
Oxaliplatin: no clinically significant differences in exposure to capecitabine or its metabolites, free 
platinum or total platinum occurred when capecitabine was administered in combination with 
oxaliplatin or in combination with oxaliplatin and bevacizumab. 
 
Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic 
parameters of capecitabine or its metabolites in the presence of oxaliplatin. 
 
Food interaction 
In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. 
Since current safety and efficacy data are based upon administration with food, it is recommended that 
capecitabine be administered with food. Administration with food decreases the rate of capecitabine 
absorption (see section 5.2). 
 

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4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females  
Women of childbearing potential should be advised to avoid becoming pregnant while receiving 
treatment with capecitabine. If the patient becomes pregnant while receiving capecitabine, the 
potential hazard to the foetus must be explained. An effective method of contraception should be used 
during treatment. 
 
Pregnancy 
There are no studies in pregnant women using capecitabine; however, it should be assumed that 
capecitabine may cause foetal harm if administered to pregnant women. In reproductive toxicity 
studies in animals, capecitabine administration caused embryolethality and teratogenicity. These 
findings are expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated during 
pregnancy. 
 
Breastfeeding 
It is not known whether capecitabine is excreted in human breast milk. In lactating mice, considerable 
amounts of capecitabine and its metabolites were found in milk. Breast-feeding should be discontinued 
while receiving treatment with capecitabine. 
 
Fertility 
There is no data on capecitabine and impact on fertility. The capecitabine pivotal studies included 
females of childbearing potential and males only if they agreed to use an acceptable method of birth 
control to avoid pregnancy for the duration of the study and for a reasonable period thereafter. 
In animal studies effects on fertility were observed (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine 
may cause dizziness, fatigue and nausea. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The overall safety profile of capecitabine is based on data from over 3000 patients treated with 
capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in 
multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, 
metastatic colorectal cancer and adjuvant colon cancer populations are comparable. See section 5.1 for 
details of major studies, including study designs and major efficacy results. 
 
The most commonly reported and/or clinically relevant treatment-related adverse drug reactions 
(ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, 
stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, 
cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and 
thrombosis/embolism. 

Tabulated summary of adverse reactions 
 
ADRs considered by the investigator to be possibly, probably, or remotely related to the 
administration of capecitabine are listed in table 4 for capecitabine given as a monotherapy and in 
table 5 for capecitabine given in combination with different chemotherapy regimens in multiple 
indications. The following headings are used to rank the ADRs by frequency: very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very 
rare (< 1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing 
seriousness. 
 

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Capecitabine monotherapy 
Table 4 lists ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of 
safety data from three major studies including over 1900 patients (studies M66001, SO14695, and 
SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence 
from the pooled analysis. 
 
Table 4 Summary of related ADRs reported in patients treated with capecitabine monotherapy 

Body System  Very Common 
 

All grades  

Common  
 

All grades  

Uncommon  
Severe and/or Life-

threatening (grade 3-4) 

or considered 

medically relevant  

Rare/Very Rare 
(Post-Marketing 

Experience) 

Infections and 
infestations  

-  Herpes viral 
infection, 
Nasopharyngitis, 
Lower respiratory 
tract infection  

Sepsis, Urinary tract 
infection, Cellulitis, 
Tonsillitis, Pharyngitis, 
Oral candidiasis, 
Influenza, 
Gastroenteritis, Fungal 
infection, Infection, 
Tooth abscess  

 

Neoplasm 
benign, 
malignant and 
unspecified  

-  -  Lipoma   

Blood and 
lymphatic 
system 
disorders  

-  Neutropenia, 
Anaemia  

Febrile neutropenia, 
Pancytopenia, 
Granulocytopenia, 
Thrombocytopenia, 
Leukopenia, 
Haemolytic anaemia, 
International 
Normalised Ratio (INR) 
increased/Prothrombin 
time prolonged  

 

Immune system 
disorders  

-  -  Hypersensitivity   

Metabolism 
and nutrition 
disorders  

Anorexia  Dehydration, 
Weight decreased  

Diabetes, 
Hypokalaemia, 
Appetite disorder, 
Malnutrition, 
Hypertriglyceridaemia,  

 

Psychiatric 
disorders  

-  Insomnia, 
Depression  

Confusional state, Panic 
attack, Depressed 
mood, Libido decreased  

 

Nervous 
system 
disorders  

-  Headache, Lethargy 
Dizziness, 
Parasthesia 
Dysgeusia  

Aphasia, Memory 
impairment, Ataxia, 
Syncope, Balance 
disorder, Sensory 
disorder, Neuropathy 
peripheral  

Toxic leukoence-
phalopathy (very 
rare) 

Eye disorders  -  Lacrimation 
increased, 
Conjunctivitis, Eye 
irritation  

Visual acuity reduced, 
Diplopia  

Lacrimal duct 
stenosis (rare), 
Corneal disorders 
(rare), keratitis 
(rare), punctate 
keratitis (rare) 

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Body System  Very Common 
 

All grades  

Common  
 

All grades  

Uncommon  
Severe and/or Life-

threatening (grade 3-4) 

or considered 

medically relevant  

Rare/Very Rare 
(Post-Marketing 

Experience) 

Ear and 
labyrinth 
disorders  

-  -  Vertigo, Ear pain   

Cardiac 
disorders  

-  -  Angina unstable, 
Angina pectoris, 
Myocardial ischaemia, 
Atrial fibrillation, 
Arrhythmia, 
Tachycardia, Sinus 
tachycardia, 
Palpitations  

Ventricular 
fibrillation (rare), 
QT prolongation 
(rare), Torsade de 
pointes (rare), 
Bradycardia 
(rare), Vasospasm 
(rare) 

Vascular 
disorders  

-  Thrombophlebitis  Deep vein thrombosis, 
Hypertension, 
Petechiae, Hypotension, 
Hot flush, Peripheral 
coldness  

 

Respiratory, 
thoracic and 
mediastinal 
disorders  

-  Dyspnoea, Epistaxis, 
Cough, Rhinorrhoea  

Pulmonary embolism, 
Pneumothorax, 
Haemoptysis, Asthma, 
Dyspnoea exertional  

 

Gastroin-
testinal 
disorders  

Diarrhoea, 
Vomiting, 
Nausea, 
Stomatitis, 
Abdominal pain  

Gastrointestinal 
haemorrhage, 
Constipation, Upper 
abdominal pain, 
Dyspepsia, 
Flatulence, Dry 
mouth  

Intestinal obstruction, 
Ascites, Enteritis, 
Gastritis, Dysphagia, 
Abdominal pain lower, 
Oesophagitis, 
Abdominal discomfort, 
Gastrooesophageal 
reflux disease, Colitis, 
Blood in stool  

 

Hepatobiliary 
disorders  

-  Hyperbilirubinemia, 
Liver function test 
abnormalities  

Jaundice  Hepatic failure 
(rare), Cholestatic 
hepatitis (rare) 

Skin and 
subcutaneous 
tissue 
disorders  

Palmar-plantar 
erythro-
dysaesthesia 
syndrome  

Rash, Alopecia, 
Erythema, Dry skin, 
Pruritus, Skin hyper-
pigmentation, Rash 
macular, Skin 
desquamation, 
Dermatitis, 
Pigmentation 
disorder, Nail 
disorder  

Blister, Skin ulcer, 
Rash, Urticaria, 
Photosensitivity 
reaction, Palmar 
erythema, Swelling 
face, Purpura, Radiation 
recall syndrome  

Cutaneous lupus 
erythematosus 
(rare), Severe skin 
reactions such as 
Steven-Johnson 
Syndrome and 
toxic Epidermal 
Necrolysis (very 
rare) (see section 
4.4) 

Muskulo-
skeletal and 
connective 
tissue 
disorders  

-  Pain in extremity, 
Back pain, 
Arthralgia  

Joint swelling, Bone 
pain, Facial pain, 
Musculoskeletal 
stiffness, Muscular 
weakness 

 

Renal and 
urinary 
disorders  

-  -  Hydronephrosis, 
Urinary incontinence, 
Haematuria, Nocturia, 
Blood creatinine 
increased  

 

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Body System  Very Common 
 

All grades  

Common  
 

All grades  

Uncommon  
Severe and/or Life-

threatening (grade 3-4) 

or considered 

medically relevant  

Rare/Very Rare 
(Post-Marketing 

Experience) 

Reproductive 
system and 
breast 
disorders  

-  -  Vaginal haemorrhage   

General 
disorders  
and 
administration 
site conditions  

Fatigue, 
Asthenia  

Pyrexia,  
Oedema peripheral, 
Malaise, Chest pain  

Oedema, Chills, 
Influenza like illness, 
Rigors, Body 
temperature increased  

 

 
Capecitabine in combination therapy  
Table 5 lists ADRs associated with the use of capecitabine in combination with different 
chemotherapy regimens in multiple indications based on safety data from over 3000 patients. ADRs 
are added to the appropriate frequency grouping (Very common or Common) according to the highest 
incidence seen in any of the major clinical trials and are only added when they were seen in addition 
to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to 
capecitabine monotherapy (see Table 4). Uncommon ADRs reported for capecitabine in combination 
therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for 
monotherapy with the combination medicinal product (in literature and/or respective summary of 
product characteristics). 
 
Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. 
peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); 
however an exacerbation by capecitabine therapy can not be excluded. 
 
Table 5 Summary of related ADRs reported in patients treated with capecitabine in combination 

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

Body System  Very common 
 

All grades  

Common 
 

All grades  

Rare/Very 
Rare 
(Post-

Marketing 
Experience) 

Infections and 
infestations  

-  Herpes zoster, Urinary tract infection, 
Oral candidiasis, Upper respiratory tract 
infection, Rhinitis, Influenza, +Infection, 
Oral herpes  

 

Blood and 
lymphatic 
system 
disorders  

+Neutropenia, 
+Leucopenia, +Anaemia, 
+Neutropenic fever, 
Thrombocytopenia  

Bone marrow depression, +Febrile 
Neutropenia  

 

Immune system 
disorders  

-  Hypersensitivity   

Metabolism and 
nutrition 
disorders  

Appetite decreased  Hypokalaemia, Hyponatraemia, 
Hypomagnesaemia, Hypocalcaemia, 
Hyperglycaemia  

 

Psychiatric 
disorders  

-  Sleep disorder, Anxiety   

Nervous system 
disorders  

Paraesthesia, 
Dysaesthesia, Peripheral 
neuropathy, Peripheral 
sensory neuropathy, 

Neurotoxicity, Tremor, Neuralgia, 
Hypersensitivity reaction, 
Hypoaesthesia  

 

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Body System  Very common 
 

All grades  

Common 
 

All grades  

Rare/Very 
Rare 
(Post-

Marketing 
Experience) 

Dysgeusia, Headache  

Eye disorders  Lacrimation increased  Visual disorders, Dry eye, Eye pain, 
Visual impairment, Vision blurred  

 

Ear and 
labyrinth 
disorders  

-  Tinnitus, Hypoacusis   

Cardiac 
disorders  

-  Atrial fibrillation, Cardiac 
ischaemia/infarction  

 

Vascular 
disorders  

Lower limb oedema, 
Hypertension, +Embolism 
and thrombosis  

Flushing, Hypotension, Hypertensive 
crisis, Hot flush, Phlebitis  

 

Respiratory, 
thoracic and 
mediastinal 
system 
disorders  

Sore throat, Dysaesthesia 
pharynx  

Hiccups, Pharyngolaryngeal pain, 
Dysphonia  

 

Gastrointestinal 
disorders  

Constipation, Dyspepsia  Upper gastrointestinal haemorrhage, 
Mouth ulceration, Gastritis, Abdominal 
distension, Gastroesophageal reflux 
disease, Oral pain, Dysphagia, Rectal 
haemorrhage, Abdominal pain lower, 
Oral dysaesthesia, Paraesthesia oral, 
Hypoaesthesia oral, Abdominal 
discomfort  

 

Hepatobiliary 
disorders  

-  Hepatic function abnormal   

Skin and 
subcutaneous 
tissue disorders  

Alopecia, Nail disorder  Hyperhidrosis, Rash erythematous, 
Urticaria, Night sweats  

 

Musculoskeletal 
and connective 
tissue disorders  

Myalgia, Arthralgia, Pain 
in extremity  

Pain in jaw , Muscle spasms, Trismus, 
Muscular weakness  

 

Renal and 
urinary 
disorder  

-  Haematuria, Proteinuria, Creatinine 
renal clearance decreased, Dysuria  

Acute renal 
failure 
secondary to 
dehydration 
(rare) 

General 
disorders and 
administration 
site conditions  

Pyrexia, Weakness, 
+Lethargy, Temperature 
intolerance  

Mucosal inflammation, Pain in limb, 
Pain, Chills, Chest pain, Influenza-like 
illness, +Fever, Infusion related reaction, 
Injection site reaction, Infusion site 
pain, Injection site pain  

 

Injury, 
poisoning and 
procedural 
complications  

-  Contusion   

+ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”, 
the frequency count was based on grade 3-4 ADRs. ADRs are added according to the highest 
incidence seen in any of the major combination trials. 
 

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Description of selected adverse reactions 
 
Hand-foot syndrome (see section 4.4) 
For the capecitabine dose of 1250 mg/m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 
53% to 60% of all-grades HFS was observed in capecitabine monotherapy trials (comprising studies in 
adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast 
cancer) and a frequency of 63% was observed in the capecitabine/docetaxel arm for the treatment of 
metastatic breast cancer. For the capecitabine dose of 1000 mg/m2 twice daily on days 1 to 14 every 
3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination 
therapy. 
 
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine 
monotherapy or capecitabine in combination with different chemotherapy regimens in multiple 
indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 
2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment with 
capecitabine. In all studies combined, the following covariates were statistically significantly 
associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), 
decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six 
weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female 
gender, and good ECOG performance status at baseline (0 versus ≥1). 
 
Diarrhoea (see section 4.4) 
Capecitabine can induce the occurrence of diarrhoea, which has been observed in up to 50% of 
patients. 
 
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with 
capecitabine showed that in all studies combined, the following covariates were statistically 
significantly associated with an increased risk of developing diarrhoea: increasing capecitabine 
starting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 year 
increments), and female gender. The following covariates were statistically significantly associated 
with a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) and 
increasing relative dose intensity in the first six weeks. 
 
Cardiotoxicity (see section 4.4) 
In addition to the ADRs described in tables 4 and 5, the following ADRs with an incidence of less than 
0.1% were associated with the use of capecitabine monotherapy based on a pooled analysis from 
clinical safety data from 7 clinical trials including 949 patients (2 phase III and 5 phase II clinical trials 
in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, cardiac failure, sudden 
death, and ventricular extrasystoles. 
 
Encephalopathy 
In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis from 
clinical safety data from 7 clinical trials, encephalopathy was also associated with the use of 
capecitabine monotherapy with an incidence of less than 0.1%. 
 
Special populations 
 
Elderly patients (see section 4.2) 
An analysis of safety data in patients ≥60 years of age treated with capecitabine monotherapy and an 
analysis of patients treated with capecitabine plus docetaxel combination therapy showed an increase 
in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious 
adverse reactions compared to patients <60 years of age. Patients ≥60 years of age treated with 
capecitabine plus docetaxel also had more early withdrawals from treatment due to adverse reactions 
compared to patients <60 years of age. 
 
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with 
capecitabine showed that in all studies combined, increasing age (by 10 year increments) was 

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statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a 
decreased risk of developing neutropenia. 
 
Gender  
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with 
capecitabine showed that in all studies combined, female gender was statistically significantly 
associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of 
developing neutropenia.  
 
Patients with renal impairment (see section 4.2, 4.4, and 5.2)  
An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) with 
baseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4 
adverse reactions compared to patients with normal renal function (36% in patients without renal 
impairment n=268, vs. 41% in mild n=257 and 54% in moderate n=59, respectively) (see section 5.2). 
Patients with moderately impaired renal function show an increased rate of dose reduction (44%) vs. 
33% and 32% in patients with no or mild renal impairment and an increase in early withdrawals from 
treatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mild 
renal impairment. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V*. 
 
4.9 Overdose 
 
The manifestations of acute overdose include nausea, vomiting, diarrhoea, mucositis, gastrointestinal 
irritation and bleeding, and bone marrow depression. Medical management of overdose should include 
customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical 
manifestations and preventing their possible complications. 
 
 
5. PHARMACOLOGICAL PROPERTIES  
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code: 
L01BC06 
 
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally 
administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via 
several enzymatic steps (see section 5.2). The enzyme involved in the final conversion to 5-FU, 
thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeit 
usually at lower levels. In human cancer xenograft models capecitabine demonstrated a synergistic 
effect in combination with docetaxel, which may be related to the upregulation of thymidine 
phosphorylase by docetaxel. 
 
There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation 
reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of 
deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein 
synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be 
to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of 
DNA and RNA deprivation are most marked on those cells which proliferate more rapidly and which 
metabolise 5-FU at a more rapid rate. 
 

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Colon and colorectal cancer  
 
Monotherapy with capecitabine in adjuvant colon cancer  
Data from one multicentre, randomised, controlled phase III clinical trial in patients with stage III 
(Dukes’ C) colon cancer supports the use of capecitabine for the adjuvant treatment of patients with 
colon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment with 
capecitabine (1250 mg/m2

 
twice daily for 2 weeks followed by a 1-week rest period and given as 3-

week cycles for 24 weeks) or 5-FU and leucovorin (Mayo Clinic regimen: 20 mg/m2
 
leucovorin IV 

followed by 425 mg/m2
 
IV bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks). Capecitabine was 

at least equivalent to IV 5-FU/LV in disease-free survival in per protocol population (hazard ratio 
0.92; 95% CI 0.80-1.06). In the all-randomised population, tests for difference of capecitabine vs. 
5-FU/LV in disease-free and overall survival showed hazard ratios of 0.88 (95% CI 0.77 - 1.01; p 
= 0.068) and 0.86 (95% CI 0.74 - 1.01; p = 0.060), respectively. The median follow up at the time of 
the analysis was 6.9 years. In a preplanned multivariate Cox analysis, superiority of capecitabine 
compared with bolus 5-FU/LV was demonstrated. The following factors were pre-specified in the 
statistical analysis plan for inclusion in the model: age, time from surgery to randomization, gender, 
CEA levels at baseline, lymph nodes at baseline, and country. In the all-randomised population, 
capecitabine was shown to be superior to 5FU/LV for disease-free survival (hazard ratio 0.849; 95% 
CI 0.739 - 0.976; p = 0.0212), as well as for overall survival (hazard ratio 0.828; 95% CI 
0.705 - 0.971; p = 0.0203). 
 
Combination therapy in adjuvant colon cancer  
Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III 
(Dukes’ C) colon cancer supports the use of capecitabine in combination with oxaliplatin (XELOX) 
for the adjuvant treatment of patients with colon cancer (NO16968 study). In this trial, 944 patients 
were randomised to 3-week cycles for 24 weeks with capecitabine (1000 mg/m2 twice daily for 
2 weeks followed by a 1-week 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 for DFS in the ITT population, XELOX was shown to be 
significantly superior to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate 
was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of RFS 
supports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5-FU/LV. 
XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486) 
which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus 
74% for 5-FU/LV. The efficacy data is based on a median observation time of 59 months for OS and 
57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOX 
combination therapy arm (21%) as compared with that of the 5-FU/LV monotherapy arm (9%) in the 
ITT population. 
 
Monotherapy with capecitabine in metastatic colorectal cancer 
Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials 
(SO14695; SO14796) support the use of capecitabine for first line treatment of metastatic colorectal 
cancer. In these trials, 603 patients were randomised to treatment with capecitabine (1250 mg/m2

 
twice 

daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles). 604 patients were 
randomised to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m2

 
leucovorin IV followed 

by 425 mg/m2
 
IV bolus 5-FU, on days 1 to 5, every 28 days). The overall objective response rates in 

the all-randomised population (investigator assessment) were 25.7% (capecitabine) vs. 16.7% (Mayo 
regimen); p <0.0002. The median time to progression was 140 days (capecitabine) vs. 144 days (Mayo 
regimen). Median survival was 392 days (capecitabine) vs. 391 days (Mayo regimen). Currently, no 
comparative data are available on capecitabine monotherapy in colorectal cancer in comparison with 
first line combination regimens. 
 
Combination therapy in first-line treatment of metastatic colorectal cancer  
Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use of 
capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for 
the first-line treatment of metastatic colorectal cancer. The study contained two parts: an initial 2-arm 

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part in which 634 patients were randomised to two different treatment groups, including XELOX or 
FOLFOX-4, and a subsequent 2x2 factorial part in which 1401 patients were randomised to four 
different treatment groups, including XELOX plus placebo, FOLFOX-4 plus placebo, XELOX plus 
bevacizumab, and FOLFOX-4 plus bevacizumab. See table 6 for treatment regimens. 
 
Table 6 Treatment regimens in study NO16966 (mCRC) 

 Treatment  Starting Dose  Schedule  
FOLFOX-4 

or 
FOLFOX-4 + 
Bevacizumab 

Oxaliplatin 
 
Leucovorin 
 
5-Fluorouracil 

85 mg/m2 IV 2 hr  
 
200 mg/m2 IV 2 hr 
 
400 mg/m2 IV bolus, 
followed by 600 mg/m2 
IV 22 hr 

Oxaliplatin on Day 1, every 2 weeks  
 
Leucovorin on Days 1 and 2, every 
2 weeks 
5-fluorouracil IV bolus/infusion, 
each on Days 1 and 2, every 2 weeks 

 Placebo or 
Bevacizumab 

5 mg/kg IV 30-90 mins Day 1, prior to FOLFOX-4, every 
2 weeks 

XELOX 
or 

XELOX+ 
Bevacizumab 

Oxaliplatin 
Capecitabine 

130 mg/m2 IV 2 hr 
1000 mg/m2 oral twice 
daily 

Oxaliplatin on Day 1, every 3 weeks 
Capecitabine oral twice daily for 
2 weeks (followed by 1 week off-
treatment) 

 
 

Placebo or 
Bevacizumab 

7.5 mg/kg IV 
30-90 mins 

Day 1, prior to XELOX, every 
3 weeks 

5-Fluorouracil:       IV bolus injection immediately after leucovorin 
 
Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the 
overall comparison was demonstrated in terms of progression-free survival in the eligible patient 
population and the intent-to-treat population (see table 7). The results indicate that XELOX is 
equivalent to FOLFOX-4 in terms of overall survival (see table 7). A comparison of XELOX plus 
bevacizumab versus FOLFOX-4 plus bevacizumab was a pre-specified exploratory analysis. In this 
treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus 
bevacizumab in terms of progression-free survival (hazard ratio 1.01; 97.5% CI 0.84 - 1.22). The 
median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; 
data from analyses following an additional 1 year of follow up are also included in table 7. However, 
the on-treatment PFS analysis did not confirm the results of the general PFS and OS analysis: the 
hazard ratio of XELOX versus FOLFOX-4 was 1.24 with 97.5% CI 1.07 - 1.44. Although sensitivity 
analyses show that differences in regimen schedules and timing of tumor assessments impact the on-
treatment PFS analysis, a full explanation for this result has not been found.  
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Table 7 Key efficacy results for the non-inferiority analysis of study NO16966 
PRIMARY ANALYSIS  

XELOX/XELOX+P/ XELOX+BV  
(EPP*: N=967; ITT**: N=1017)  

FOLFOX-4/FOLFOX-4+P/ FOLFOX-4+BV  
(EPP*: N = 937; ITT**: N= 1017)  

Population  Median Time to Event (Days)  HR  
(97.5% CI)  

Parameter: Progression-free Survival  
EPP  
ITT  

241  
244  

259  
259  

1.05 (0.94; 1.18)  
1.04 (0.93; 1.16)  

Parameter: Overall Survival  
EPP  
ITT  

577  
581  

549  
553  

0.97 (0.84; 1.14)  
0.96 (0.83; 1.12)  

ADDITIONAL 1 YEAR OF FOLLOW UP  
Population  Median Time to Event (Days)  HR  

(97.5% CI)  
Parameter: Progression-free Survival  

EPP  
ITT  

242  
244  

259  
259  

1.02 (0.92; 1.14)  
1.01 (0.91; 1.12)  

Parameter: Overall Survival  
EPP  
ITT  

600  
602  

594  
596  

1.00 (0.88; 1.13)  
0.99 (0.88; 1.12)  

*EPP=eligible patient population; **ITT=intent-to-treat population 
 
In a randomised, controlled phase III study (CAIRO), the effect of using capecitabine at a starting dose 
of 1000 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of 
patients with metastatic colorectal cancer was studied. 820 Patients were randomised to receive either 
sequential treatment (n=410) or combination treatment (n=410). Sequential treatment consisted of 
first-line capecitabine (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day 
1), and third-line combination of capecitabine (1000 mg/m2 twice daily for 14 days) with oxaliplatin 
(130 mg/m2 on day 1). Combination treatment consisted of first-line capecitabine (1000 mg/m2 twice 
daily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-line 
capecitabine (1000 mg/m2 twice daily for 14 days) plus oxaliplatin (130 mg/m2 on day 1). All 
treatment cycles were administered at intervals of 3 weeks. In first-line treatment the median 
progression-free survival in the intent-to-treat population was 5.8 months (95%CI 5.1 - 6.2 months) 
for capecitabine monotherapy and 7.8 months (95%CI 7.0 - 8.3 months; p=0.0002) for XELIRI. 
However this was associated with an increased incidence of gastrointestinal toxicity and neutropenia 
during first-line treatment with XELIRI (26% and 11% for XELIRI and first line capecitabine 
respectively). 
 
The XELIRI has been compared with 5-FU + irinotecan (FOLFIRI) in three randomised studies in 
patients with metastatic colorectal cancer. The XELIRI regimens included capecitabine 1000 mg/m2 
twice daily on days 1 to 14 of a three-week cycle combined with irinotecan 250 mg/m2 on day1. In the 
largest study (BICC-C), patients were randomised to receive either open label FOLFIRI (n=144), 
bolus 5-FU (mIFL) (n=145) or XELIRI (n=141) and were additionally randomised to receive either 
double-blind treatment with celecoxib or placebo. Median PFS was 7.6 months for FOLFIRI, 5.9 
months for mIFL (p=0.004) for the comparison with FOLFIRI), and 5.8 months for XELIRI 
(p=0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p=0.09), and 18.9 
months for XELIRI (p=0.27). Patients treated with XELIRI experienced excessive gastrointestinal 
toxicity compared with FOLFIRI (diarrhoea 48% and 14% for XELIRI and FLFIRI respectively). 
 
In the EORTC study patients were randomised to receive either open label FOLFIRI (n=41) or 
XELIRI (n=44) with additional randomisation to either double-blind treatment with celecoxib or 
placebo. Median PFS and overall survival (OS) times were shorter for XELIRI versus FOLFIRI (PFS 
5.9 versus 9.6 months and OS 14.8 versus 19.9 months), in addition to which excessive rates of 
diarrhoea were reported in patients receiving the XELIRI regimen (41% XELIRI, 5.1% FOFIRI).  
 
In the study published by Skof et al, patients were randomised to receive either FOLFIRI or XELIRI. 
Overall response rate was 49% in the XELIRI and 48% in the FOLFIRI arm (p=0.76). At the end of 
treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without 

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evidence of the disease (p=0.56). Toxcity was similar between treatments with the exception of 
neutropenia reported more commonly in patients treated with FOLFIRI. 
 
Montagnani et al used the results from the above three studies to provide an overall analysis of 
randomised studies comparing FOLFIRI and XELIRI treatment regimens in the treatment of mCRC. 
A significant reduction in the risk of progression was associated with FOLFIRI (HR, 0.76; 95%CI, 
0.62-0.95; P <0.01), a result partly due to poor tolerance to the XELIRI regimens used. 
 
Data from a randomised clinical study (Souglakos et al, 2012) comparing FOLFIRI + bevacizumab 
with XELIRI + bevacizumab showed no significant differences in PFS or OS between treatments. 
Patients were randomised to receive either FOLFIRI plus bevacizumab (Arm-A, n=167) or XELIRI 
plus bevacizumab (Arm-B, n-166). For Arm B, the XELIRI regimen used capecitabine 1000 mg/m2 
twice daily for 14 days +irinotecan 250 mg/m2 on day 1. Median progression-free survival (PFS) was 
10.0 and 8.9 months; p=0.64, overall survival 25.7 and 27.5 months; p=0.55 and response rates 45.5 
and 39.8%; p=0.32 for FOLFIRI-Bev and XELIRI-Bev, respectively. Patients treated with XELIRI + 
bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-foot 
skin reactions than patients treated with FOLFIRI + bevacizumab with significantly increased 
treatment delays, dose reductions and treatment discontinuations. 
 
Data from a multicentre, randomised, controlled phase II study (AIO KRK 0604) supports the use of 
capecitabine at a starting dose of 800 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan 
and bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. 120 Patients 
were randomised to a modified XELIRI regimen with capecitabine 800 mg/m2 twice daily for two 
weeks followed by a 7-day rest period), irinotecan (200 mg/m2 as a 30 minute infusion on day 1 every 
3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks); 127 
patients were randomised to treatment with capecitabine (1000 mg/m2 twice daily for two weeks 
followed by a 7-day rest period), oxaliplatin (130 mg/m2 as a 2 hour infusion on day 1 every 3 weeks), 
and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Following a mean 
duration of follow-up for the study population of 26.2 months, treatment responses were as shown 
below: 
 
Table 8  Key efficacy results for AIO KRK study 
 XELOX + bevacizumab 

 

(ITT: N=127) 

Modified XELIRI+ 

bevacizumab 

(ITT: N= 120) 

Hazard ratio 

95% CI 

P value 

Progression-free Survival after 6 months 
ITT 

95% CI 
76% 

69 - 84% 
84%  

77 - 90% 
- 

Median progression free survival 
ITT 

95% CI 
10.4 months 

9.0 - 12.0 
12.1 months 

10.8 - 13.2 
0.93 

0.82 - 1.07 

P=0.30 

Median overall survival 
ITT 

95% CI 

24.4 months 

19.3 - 30.7 

25.5 months 

21.0 - 31.0 

0.90 

0.68 - 1.19 

P=0.45 

 
Combination therapy in second-line treatment of metastatic colorectal cancer  
Data from a multicentre, randomised, controlled phase III clinical study (NO16967) support the use of 
capecitabine in combination with oxaliplatin for the second-line treatment of metastastic colorectal 
cancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received prior 
treatment with irinotecan in combination with a fluoropyrimidine regimen as first line therapy were 
randomised to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and 
FOLFOX-4 (without addition of placebo or bevacizumab), refer to table 6. XELOX was demonstrated 
to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population 
and intent-to-treat population (see table 9). The results indicate that XELOX is equivalent to 
FOLFOX-4 in terms of overall survival (see table 9). The median follow up at the time of the primary 

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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 9. 
 
Table 9 Key efficacy results for the non-inferiority analysis of study NO16967 

PRIMARY ANALYSIS  
XELOX  

(PPP*: N=251; ITT**: N=313)  
FOLFOX-4  

(PPP*: N = 252; ITT**: N= 314)  
Population  Median Time to Event (Days)  HR  

(95% CI)  
Parameter: Progression-free Survival  

PPP  
ITT  

154  
144  

168  
146  

1.03 (0.87; 1.24)  
0.97 (0.83; 1.14)  

Parameter: Overall Survival  
PPP  
ITT  

388  
363  

401  
382  

1.07 (0.88; 1.31)  
1.03 (0.87; 1.23)  

ADDITIONAL 6 MONTHS OF FOLLOW UP  
Population  Median Time to Event (Days)  HR  

(95% CI)  
Parameter: Progression-free Survival  

PPP  
ITT  

154  
143  

166  
146  

1.04 (0.87; 1.24)  
0.97 (0.83; 1.14)  

Parameter: Overall Survival  
PPP  
ITT  

393  
363  

402  
382  

1.05 (0.88; 1.27)  
1.02 (0.86; 1.21)  

*PPP=per-protocol population; **ITT=intent-to-treat population 
 
Advanced gastric cancer 
Data from a multicentre, randomised, controlled phase III clinical trial in patients with advanced 
gastric cancer supports the use of capecitabine for the first-line treatment of advanced gastric cancer 
(ML17032). In this trial, 160 patients were randomised to treatment with capecitabine (1000 mg/m2

 

twice daily for 2 weeks followed by a 7-day rest period) and cisplatin (80 mg/m2
 
as a 2-hour 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 infusion on day 

1, every 3 weeks). Capecitabine in combination with cisplatin was non-inferior to 5-FU in 
combination with cisplatin in terms of progression-free survival in the per protocol analysis (hazard 
ratio 0.81; 95% CI 0.63 - 1.04). The median progression-free survival was 5.6 months (capecitabine + 
cisplatin) versus 5.0 months (5-FU + cisplatin). The hazard ratio for duration of survival (overall 
survival) was similar to the hazard ratio for progression-free survival (hazard ratio 0.85; 95% CI 
0.64 - 1.13). The median duration of survival was 10.5 months (capecitabine + cisplatin) versus 
9.3 months (5-FU + cisplatin). 
 
Data from a randomised multicentre, phase III study comparing capecitabine to 5-FU and oxaliplatin 
to cisplatin in patients with advanced gastric cancer supports the use of capecitabine for the first-line 
treatment of advanced gastric cancer (REAL-2). In this trial, 1002 patients were randomised in a 2x2 
factorial design to one of the following 4 arms: 
 
- ECF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a two 

hour infusion on day 1 every 3 weeks) and 5-FU (200 mg/m2
 
daily given by continuous infusion 

via a central line). 
- ECX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a two 

hour infusion on day 1 every 3 weeks), and capecitabine (625 mg/m2
 
twice daily continuously).  

- EOF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given as 
a 2 hour infusion on day 1 every three weeks), and 5-FU (200 mg/m2

 
daily given by continuous 

infusion via a central line).  
- EOX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given as 

a 2 hour infusion on day 1 every three weeks), and capecitabine (625 mg/m2 twice daily 
continuously). 

 

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The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overall 
survival for capecitabine vs. 5-FU-based regimens (hazard ratio 0.86; 95% CI 0.8 - 0.99) and for 
oxaliplatin vs. cisplatin-based regimens (hazard ratio 0.92; 95% CI 0.80 - 1.1). The median overall 
survival was 10.9 months in capecitabine-based regimens and 9.6 months in 5-FU based regimens. 
The median overall survival was 10.0 months in cisplatin-based regimens and 10.4 months in 
oxaliplatin-based regimens. 
 
Capecitabine has also been used in combination with oxaliplatin for the treatment of advanced gastric 
cancer. Studies with capecitabine monotherapy indicate that capecitabine has activity in advanced 
gastric cancer. 
 
Colon, colorectal and advanced gastric cancer: meta-analysis 
A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, 
M17032) supports capecitabine replacing 5-FU in mono- and combination treatment in gastrointestinal 
cancer. The pooled analysis includes 3097 patients treated with capecitabine-containing regimens and 
3074 patients treated with 5-FU-containing regimens. Median overall survival time was 703 days 
(95% CI: 671; 745) in patients treated with capecitabine-containing regimens and 683 days (95% CI: 
646; 715) in patients treated with 5-FU-containing regimens. The hazard ratio for overall survival was 
0.94 (95% CI: 0.89; 1.00, p=0.0489) indicating that capecitabine-containing regimens are non-inferior 
to 5-FU-containing regimens. 
 
Breast cancer 
 
Combination therapy with capecitabine and docetaxel in locally advanced or metastatic breast cancer  
Data from one multicentre, randomised, controlled phase III clinical trial support the use of 
capecitabine in combination with docetaxel for treatment of patients with locally advanced or 
metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this 
trial, 255 patients were randomised to treatment with capecitabine (1250 mg/m2

 
twice daily for 

2 weeks followed by 1-week rest period and docetaxel 75 mg/m2
 
as a 1 hour intravenous infusion 

every 3 weeks). 256 patients were randomised to treatment with docetaxel alone (100 mg/m2
 
as a 

1 hour intravenous infusion every 3 weeks). Survival was superior in the capecitabine + docetaxel 
combination arm (p=0.0126). Median survival was 442 days (capecitabine + docetaxel) vs. 352 days 
(docetaxel alone). The overall objective response rates in the all-randomised population (investigator 
assessment) were 41.6% (capecitabine + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to 
progressive disease was superior in the capecitabine + docetaxel combination arm (p<0.0001). The 
median time to progression was 186 days (capecitabine + docetaxel) vs. 128 days (docetaxel alone). 
 
Monotherapy with capecitabine after failure of taxanes, anthracycline containing chemotherapy, and 
for whom anthracycline therapy is not indicated  
Data from two multicentre phase II clinical trials support the use of capecitabine monotherapy for 
treatment of patients after failure of taxanes and an anthracycline-containing chemotherapy regimen or 
for whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients were 
treated with capecitabine (1250 mg/m2

 
twice daily for 2 weeks followed by 1-week rest period). The 

overall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial). 
The median time to progression was 93 and 98 days. Median survival was 384 and 373 days. 
 
All indications 
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine 
monotherapy or capecitabine in combination with different chemotherapy regimens in multiple 
indications (colon, colorectal, gastric and breast cancer), showed that patients on capecitabine who 
developed hand-foot syndrome (HFS) had a longer overall survival compared to patients who did not 
develop HFS: median overall survival 1100 days (95% CI 1007; 1200) vs. 691 days (95% CI 638; 
754) with a hazard ratio of 0.61 (95% CI 0.56; 0.66). 
 

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Paediatric population 
The European Medicines Agency has waived the obligation to conduct studies with the reference 
medicinal product containing capecitabine in all subjects of the paediatric population in 
adenocarcinoma of the colon and rectum, gastric adenocarcinoma and breast carcinoma (see section 
4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of capecitabine have been evaluated over a dose range of 502-3514 mg/m2/day. 
The parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine 
(5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30%-35% higher on day 
14. Capecitabine dose reduction decreases systemic exposure to 5-FU more than dose-proportionally, 
due to non-linear pharmacokinetics for the active metabolite. 
 
Absorption  
After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive 
conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of 
capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of 
the subsequent metabolite 5-FU. At the dose of 1250 mg/m2

 
on day 14 with administration after food 

intake, the peak plasma concentrations (Cmax in μg/ml) for capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and 
FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 respectively. The time to peak plasma concentrations (Tmax 
in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-∞ values in μg•h/ml were 7.75, 7.24, 24.6, 
2.03 and 36.3. 
 
Distribution  
In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 
54%, 10%, 62% and 10% protein bound, mainly to albumin. 
 
Biotransformation  
Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 
5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissues. Further catalytic 
activation of 5'-DFUR then occurs by thymidine phosphorylase (ThyPase). The enzymes involved in 
the catalytic activation are found in tumour tissues but also in normal tissues, albeit usually at lower 
levels. The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher 
concentrations within tumour tissues. In the case of colorectal tumours, 5-FU generation appears to be 
in large part localised in tumour stromal cells. Following oral administration of capecitabine to 
patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumours to adjacent 
tissues was 3.2 (ranged from 0.9 to 8.0). The ratio of 5-FU concentration in tumour to plasma was 21.4 
(ranged from 3.9 to 59.9, n=8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 
to 25.8, n=8). Thymidine phosphorylase activity was measured and found to be 4 times greater in 
primary colorectal tumour than in adjacent normal tissue. According to immunohistochemical studies, 
thymidine phosphorylase appears to be in large part localised in tumour stromal cells. 
 
5-FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less 
toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 
5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-
alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD) activity is the 
rate limiting step. Deficiency of DPD may lead to increased toxicity of capecitabine (see section 4.3 
and 4.4). 
 
Elimination 
The elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 
0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Capecitabine and its metabolites are predominantly 
excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Faecal excretion is 
minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the 
administered dose. About 3% of the administered dose is excreted in urine as unchanged capecitabine. 

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Combination therapy 
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or 
paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or 
paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 
5’-DFUR. 
 
Pharmacokinetics in special populations  
A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients 
with colorectal cancer dosed at 1250 mg/m2

 
twice daily. Gender, presence or absence of liver 

metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and 
ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. 
 
Patients with hepatic impairment due to liver metastases: According to a pharmacokinetic study in 
cancer patients with mild to moderate liver impairment due to liver metastases, the bioavailability of 
capecitabine and exposure to 5-FU may increase compared to patients with no liver impairment. There 
are no pharmacokinetic data on patients with severe hepatic impairment. 
 
Patients with renal impairment: Based on a pharmacokinetic study in cancer patients with mild to 
severe renal impairment, there is no evidence for an effect of creatinine clearance on the 
pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic 
exposure to 5’-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to 
FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite 
without antiproliferative activity. 
 
Elderly: Based on the population pharmacokinetic analysis, which included patients with a wide range 
of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence 
on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase 
in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal 
function. 
 
Ethnic factors: Following oral administration of 825 mg/m2

 
capecitabine twice daily for 14 days, 

Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than 
Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for 
FBAL than Caucasian patients. The clinical relevance of these differences is unknown. No significant 
differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU). 
 
5.3 Preclinical safety data 
 
In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and 
mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for 
fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised by 
degenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepatic 
and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in 
cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing 
(1379 mg/m2/day). 
 
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine. 
 
During standard fertility studies, impairment of fertility was observed in female mice receiving 
capecitabine; however, this effect was reversible after a drug-free period. In addition, during a 
13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; 
however these effects were reversible after a drug-free period (see section 4.6). 
 

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In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and 
teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, 
but there was no evidence of teratogenicity. 
 
Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster 
V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), 
capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse 
bone marrow micronucleus tests (in vivo). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core:  
talc (E553b) 
anhydrous lactose 
croscarmellose sodium (E468) 
hypromellose (E464) 
microcrystalline cellulose (E460) 
magnesium stearate (E572) 
 
Tablet coating:  
hypromellose (E464)  
titanium dioxide (E171) 
lactose monohydrate 
macrogol 
Yellow iron oxide (E172) and red iron oxide (E172). 
 
6.2 Incompatibilities  
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage  
 
Do not store above 25°C. 
 
6.5 Nature and contents of container  
 
Alu/Alu blister containing 10 film-coated tablets. Each carton contains 120 film-coated tablets 
(12 blisters of 10 tablets). 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe BV 
Polarisavenue 87 
2132 JH Hoofddorp 

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51 

 

The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/831/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 June 2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency: http://www.ema.europa.eu. 

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52 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

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53 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2) . 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 

 Periodic safety update reports  
 

At the time of granting the marketing authorisation, the submission of periodic safety update reports 
is not required for this medicinal product.  However, the marketing authorisation holder shall 
submit periodic safety update reports for this medicinal product if the product is included in the list 
of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and published on the European medicines web-portal. 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

Not applicable. 

 

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54 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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55 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine SUN 150 mg film-coated tablets 
capecitabine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 150 mg capecitabine. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains anhydrous lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
 
 

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57 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe B.V.  
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/831/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Capecitabine SUN 150 mg film-coated tablets 

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58 

 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine SUN 150 mg film-coated tablets 
capecitabine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 

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59 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine SUN 500 mg film-coated tablets  
capecitabine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 500 mg capecitabine. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains anhydrous lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
120 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
 
 

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60 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe B.V.  
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/831/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Capecitabine SUN 500 mg film-coated tablets 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine SUN 500 mg film-coated tablets 
capecitabine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 

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B. PACKAGE LEAFLET  

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Package leaflet: Information for the user 
 

Capecitabine SUN 150 mg film-coated tablets 
capecitabine 

 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.  
 
 
What is in this leaflet 
 
1. What Capecitabine SUN is and what it is used for 
2. What you need to know before you take Capecitabine SUN 
3. How to take Capecitabine SUN 
4. Possible side effects 
5. How to store Capecitabine SUN 
6. Contents of the pack and other information 
 
 
1. What Capecitabine SUN is and what it is used for 
 
Capecitabine SUN belongs to the group of medicines called "cytostatic agents", which stop the growth 
of cancer cells. Capecitabine SUN contains capecitabine, which itself is not a cytostatic agent. Only 
after being absorbed by the body is it changed into an active anti-cancer agent (more in tumour tissue 
than in normal tissue). 
 
Capecitabine SUN is used in the treatment of colon, rectal, gastric, or breast cancers.  
Furthermore, Capecitabine SUN is used to prevent new occurrence of colon cancer after complete 
removal of the tumour by surgery. 
 
Capecitabine SUN may be used either alone or in combination with other medicines. 
 
 
2. What you need to know before you take Capecitabine SUN 
 
Do not take Capecitabine SUN 
- if you are allergic to capecitabine or any of the other ingredients of this medicine (listed in 

section 6). You must inform your doctor if you know that you have an allergy to capecitabine. 
- if you previously have had severe reactions to fluoropyrimidine therapy (a group of anticancer 

medicines such as fluorouracil)  
- if you are pregnant or breast-feeding 
- if you have severely low levels of white cells or platelets in the blood (leucopenia, neutropenia 

or thrombocytopenia) 
- if you have severe liver or kidney problems 
- if you have a known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD),  

involved in the metabolism of uracil and thymine, or 
- if you are being treated now or have been treated in the last 4 weeks with brivudine, sorivudine 

or similar classes of substance as part of herpes zoster (chickenpox or shingles) therapy. 
 

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64 

 

Warnings and precautions  
Talk to your doctor before taking Capecitabine SUN, if you 
- have liver or kidney diseases 
- have or had heart problems (for example an irregular heartbeat or pains to the chest jaw and 

back brought on by physical effort and due to problems with the blood flow to the heart)  
- have brain diseases (for example. cancer that has spread to the brain), or nerve damage 

(neuropathy)  
- have calcium imbalances (seen in blood tests) 
- have diabetes 
- cannot keep food or water in your body because of severe nausea and vomiting 
- have diarrhoea 
- are, or become dehydrated 
- have imbalances of ions in your blood (electrolyte imbalances, seen in tests) 
- have a history of eye problems as you may need extra monitoring of your eyes 
- have a severe skin reaction. 
 
DPD deficiency: DPD deficiency is a rare condition present at birth that is not usually associated with 
health problems unless you receive certain medicines. If you have an unrecognised DPD deficiency 
and take Capecitabine SUN, you may experience severe forms of the side effects listed under section 4 
Possible side effects. Contact your doctor immediately if you are concerned about any of the side 
effects or if you notice any additional side effects not listed in the leaflet (see section 4 Possible side 
effects). 
 
Children and adolescents 
Capecitabine SUN is not indicated in children and adolescents. Do not give Capecitabine SUN to 
children and adolescents. 
 
Other medicines and Capecitabine SUN 
Before starting treatment, tell your doctor or pharmacist if you are taking, have recently taken or might 
take any other medicines, including medicines obtained without a prescription. This is extremely 
important, as taking more than one medicine at the same time can strengthen or weaken the effect of 
the medicines. You need to be particularly careful if you are taking any of the following: 
- gout medicines (allopurinol) 
- blood-thinning medicines (coumarin, warfarin) 
- certain anti-viral medicines (sorivudine and brivudine)  
- medicines for seizures or tremors (phenytoin) 
- a medicine to treat cancer (interferon alpha)  
- radiotherapy and certain medicines used to treat cancer (folinic acid, oxaliplatin, bevacizumab, 

cisplatin, irinotecan) 
- medicines used to treat folic acid deficiency. 
 
Capecitabine SUN with food and drink 
You should take Capecitabine SUN no later than 30 minutes after meals. 
 
Pregnancy and breast-feeding 
Before starting treatment, you must tell your doctor if you are pregnant, if you think you may be 
pregnant or if you intend to become pregnant. You must not take Capecitabine SUN if you are 
pregnant or think you might be.  
Effective contraceptive precautions must be taken by patients who are taking Capecitabine SUN. 
You must not breast-feed if you are taking Capecitabine SUN.  
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Capecitabine SUN may make you feel dizzy, nauseous or tired. It is therefore possible that 
Capecitabine SUN could affect your ability to drive a car or operate machines. Do not drive if you feel 
dizzy, nauseous or tired after taking this medicine. 

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Capecitabine SUN contains anhydrous lactose 
This medicine contains anhydrous lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Capecitabine SUN 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Capecitabine should only be prescribed by a doctor experienced in the use of anticancer medicines. 
 
Capecitabine SUN tablets should be swallowed whole with water, and within 30 minutes of a meal. 
 
Your doctor will prescribe a dose and treatment regimen that is right for you. The dose of 
Capecitabine SUN is based on your body surface area. This is calculated from your height and weight. 
The usual dose for adults is 1250 mg/m2 of body surface area taken two times daily (morning and 
evening). Two examples are provided here: A person whose body weight is 64 kg and height is 1.64 m 
has a body surface area of 1.7 m2 and should take 4 tablets of 500 mg and 1 tablet of 150 mg two times 
daily. A person whose body weight is 80 kg and height is 1.80 m has a body surface area of 2.00 m2 
and should take 5 tablets of 500 mg two times daily. 
 
Capecitabine SUN tablets are usually taken for 14 days followed by a 7 day rest period (when no 
tablets are taken). This 21 day period is one treatment cycle. 
 
In combination with other medicines the usual dose for adults may be less than 1250 mg/m2 of body 
surface area, and you may need to take the tablets over a different time period (e.g. every day, with no 
rest period). 
 
Your doctor will tell you what dose you need to take, when to take it and for how long you need to 
take it. 
 
Your doctor may want you to take a combination of 150 mg and 500 mg tablets for each dose. 
- Take the tablets in the morning and evening as prescribed by your doctor. 
- Take the tablets within 30 minutes after the end of a meal (breakfast and dinner). 
- It is important that you take all your medicines as prescribed by your doctor. 
 
If you take more Capecitabine SUN than you should  
Contact your doctor as soon as possible before taking the next dose. 
You might get the following side effects if you take a lot more capecitabine than you should: feeling 
or being sick, diarrhoea, inflammation or ulceration of the gut or mouth, pain or bleeding from the 
intestine or stomach, or bone marrow depression (reduction in certain kinds of blood cells). Tell your 
doctor immediately if you experience any of these symptoms. 
 
If you forget to take Capecitabine SUN 
Do not take the missed dose at all and do not double the next one. Instead, continue your regular 
dosing schedule and check with your doctor. 
 
If you stop taking Capecitabine SUN 
There are no side-effects caused by stopping treatment with Capecitabine SUN. In case you are using 
coumarin anticoagulants (containing e.g. phenprocoumon), stopping Capecitabine SUN might require 
that your doctor adjusts your anticoagulant dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 

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4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
STOP taking Capecitabine SUN immediately and contact your doctor if any of these symptoms occur: 
- Diarrhoea: if you have an increase of 4 or more bowel movements compared to your normal 

bowel movements each day or any diarrhoea at night. 
- Vomiting: if you vomit more than once in a 24-hour time period. 
- Nausea: if you lose your appetite, and the amount of food you eat each day is much less than 

usual. 
- Stomatitis: if you have pain, redness, swelling or sores in your mouth and/or throat. 
- Hand-and-foot skin-reaction: if you have pain, swelling, redness or tingling of hands and/or 

feet. 
- Fever: if you have a temperature of 38°C or greater. 
- Infection: if you experience signs of infection caused by bacteria or virus, or other organisms. 
- Chest pain: if you experience pain localised to the centre of the chest, especially if it occurs 

during exercise. 
- Steven-Johnson syndrome: if you experience painful red or purplish rash that spreads and 

blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips), in 
particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) 
and/or fever. 

 
If caught early, these side effects usually improve within 2 to 3 days after stopping treatment. If these 
side effects continue, contact your doctor immediately. Your doctor may instruct you to restart 
treatment at a lower dose. 
 
In addition to the above, when Capecitabine SUN is used alone, very common side effects which may 
affect more than 1 person in 10 are: 
- abdominal pain 
- rash, dry or itchy skin 
- tiredness 
- loss of appetite (anorexia). 
 
These side effects can become severe; therefore, it is important that you always contact your doctor 
immediately when you start to experience a side effect. Your doctor may instruct you to decrease the 
dose and/or temporarily discontinue treatment with Capecitabine SUN. This will help reduce the 
likelihood that the side effect continues or becomes severe. 
 
Other side effects are:  
 
Common side effects (may affect up to 1 in 10 people) include: 
- decreases in the number of white blood cells or red blood cells (seen in tests) 
- dehydration, weight loss 
- sleeplessness (insomnia), depression 
- headache, sleepiness, dizziness, abnormal sensation in the skin (numbness or tingling 

sensation), taste changes 
- eye irritation, increased tears, eye redness (conjunctivitis)  
- inflammation of the veins (thrombophlebitis)  
- shortness of breath, nose bleeds, cough, runny nose  
- cold sores or other herpes infections 
- infections of the lungs or respiratory system (e.g. pneumonia or bronchitis)  
- bleeding from the gut, constipation, pain in upper abdomen, indigestion, excess wind, dry 

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

skin loss, skin inflammation, nail disorder  

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- pain in the joints, or in the limbs (extremities), chest or back 
- fever, swelling in the limbs, feeling ill  
- problems with liver function (seen in blood tests) and increased blood bilirubin (excreted by the 

liver).  
 
Uncommon side effects (may affect up to 1 in 100 people) include:  
- blood infection, urinary tract infection, infection of the skin, infections in the nose and throat, 

fungal infections (including those of the mouth), influenza, gastroenteritis, tooth abscess 
- lumps under the skin (lipoma)  
- decreases in blood cells including platelets, thinning of blood (seen in tests)  
- allergy  
- diabetes, decrease in blood potassium, malnutrition, increased blood triglycerides 
- confusional state, panic attacks, depressed mood, decreased libido 
- difficulty speaking, impaired memory, loss of movement coordination, balance disorder, 

fainting, nerve damage (neuropathy) and problems with sensation  
- blurred or double vision 
- vertigo, ear pain  
- irregular heartbeat and palpitations (arrhythmias), chest pain and heart attack (infarction)  
- blood clots in the deep veins, high or low blood pressure, hot flushes, cold limbs (extremities), 

purple spots on the skin  
- blood clots in the veins in the lung (pulmonary embolism), collapsed lung, coughing up blood, 

asthma, shortness of breath on exertion  
- bowel obstruction, collection of fluid in the abdomen, inflammation of the small or large 

intestine, the stomach or the oesophagus, pain in the lower abdomen, abdominal discomfort, 
heartburn (reflux of food from the stomach), blood in the stool  

- jaundice (yellowing of skin and eyes)  
- skin ulcer and blister, reaction of the skin with sunlight, reddening of palms, swelling or pain of 

the face  
- joint swelling or stiffness, bone pain, muscle weakness or stiffness  
- fluid collection in the kidneys, increased frequency of urination during the night, incontinence, 

blood in the urine, increase in blood creatinine (sign of kidney dysfunction)  
- unusual bleeding from the vagina  
- swelling (oedema), chills and rigors. 
 
Some of these side effects are more common when capecitabine is used with other medicines for the 
treatment of cancer. Other side effects seen in this setting are the following:  
 
Common side effects (may affect up to 1 in 10 people) include:  
- decrease in blood sodium, magnesium or calcium, increase in blood sugar  
- nerve pain  
- ringing or buzzing in the ears (tinnitus), loss of hearing  
- vein inflammation  
- hiccups, change in voice  
- pain or altered/abnormal sensation in the mouth, pain in the jaw  
- sweating, night sweats  
- muscle spasm  
- difficulty in urination, blood or protein in the urine  
- bruising or reaction at the injection site (caused by medicines given by injection at the same 

time).  
 
Rare side effects (may affect up to 1 in 1,000 people) include:   
- narrowing or blockage of tear duct (lacrimal duct stenosis) 
- liver failure 
- inflammation leading to dysfunction or obstruction in bile secretion (cholestatic hepatitis) 
- specific changes in the electrocardiogram (QT prolongation) 

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

- eye inflammation causing eye pain and possibly eyesight problems 
- inflammation of the skin causing red scaly patches due to an immune system illness. 

 
Very rare side effects (may affect up to 1 in 10,000 people) include:   
- severe skin reaction such as skin rash, ulceration and blistering which may involve ulcers of the 

mouth, nose, genitalia, hands, feet and eyes (red and swollen eyes). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V*. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Capecitabine SUN 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. 
 
Do not store above 25°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Capecitabine SUN contains 
- The active substance is capecitabine. Each film-coated tablet contains 150 mg of capecitabine. 
- The other ingredients are: 

- Tablet core: talc (E553b), anhydrous lactose, croscarmellose sodium (E468), 
hypromellose (E464), cellulose microcrystalline (E460), magnesium stearate (E572). 

- Tablet coating: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, 
macrogol and ferric oxide yellow and red (E172). 

 
What Capecitabine SUN looks like and contents of the pack 
Capecitabine SUN 150 mg are light peach coloured, oval, biconvex, film-coated tablet debossed with 
‘150’ on one side and plain on other side. 
 
Each pack contains 60 film-coated tablets (6 blisters of 10 tablets). 
 
Marketing Authorisation Holder and Manufacturer 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/Κύπρος/ 
Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 

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69 

 

Malta/Nederland/Norge/Österreich/Polska/Portugal/ 
România/Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/Ολλανδία/ 
Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Holandia/Países Baixos/ 
Olanda/Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Kandelstrasse 7 
79199 Kirchzarten 
Deutschland 
tel. +49 (0) 7661 90 91 58-0 
 
España 
Sun Pharmaceuticals Spain S.L.U. 
C/Bobinadora 1-5 Planta 1a Local 13 
Mataro, 08302 
Barcelona 
España 
tel. +34 93 798 02 85 
 
France 
Sun Pharmaceuticals France 
34, Rue Jean Mermoz 
78600 Maisons Laffitte 
France 
tel. +33 1 39 62 10 24 
 
Italia 
Sun Pharmaceuticals Italia S.R.L. 
Via Luigi Rizzo, 8 
I-20151 – Milano 
Italia 
tel. +39 02 33 49 07 93 
 
United Kingdom 
Sun Pharmaceuticals UK Limited 
4100 Park Approach 
Thorpe Park 
Leeds 
LS15 8GB 
United Kingdom 
tel. +44 (0) 113 397 08 70 
 
This leaflet was last revised in {MM/YYYY} 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

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70 

 

Package leaflet: Information for the user 
 

Capecitabine SUN 500 mg film-coated tablets 
capecitabine 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Capecitabine SUN is and what it is used for 
2. What you need to know before you take Capecitabine SUN 
3. How to take Capecitabine SUN 
4. Possible side effects 
5. How to store Capecitabine SUN 
6. Contents of the pack and other information 
 
 
1. What Capecitabine SUN is and what it is used for 
 
Capecitabine SUN belongs to the group of medicines called "cytostatic agents", which stop the growth 
of cancer cells. Capecitabine SUN contains capecitabine, which itself is not a cytostatic agent. Only 
after being absorbed by the body is it changed into an active anti-cancer agent (more in tumour tissue 
than in normal tissue). 
 
Capecitabine SUN is  used in the treatment of colon, rectal, gastric, or breast cancers.  
Furthermore, Capecitabine SUN is used to prevent new occurrence of colon cancer after complete 
removal of the tumour by surgery. 
 
Capecitabine SUN may be used either alone or in combination with other medicines. 
 
 
2. What you need to know before you take Capecitabine SUN 
 
Do not take Capecitabine SUN 
- if you are allergic to capecitabine or any of the other ingredients of this medicine (listed in 

section 6). You must inform your doctor if you know that you have an allergy to capecitabine. 
- if you previously have had severe reactions to fluoropyrimidine therapy (a group of anticancer 

medicines such as fluorouracil) 
- if you are pregnant or breast-feeding 
- if you have severely low levels of white cells or platelets in the blood (leucopenia, neutropenia 

or thrombocytopenia) 
- if you have severe liver or kidney problems 
- if you have a known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD),  

involved in the metabolism of uracil and thymine, or 
- if you are being treated now or have been treated in the last 4 weeks with brivudine, sorivudine 

or similar classes of substance as part of herpes zoster (chickenpox or shingles) therapy. 
 

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Warnings and precautions  
Talk to your doctor before taking Capecitabine SUN, if you 
- have liver or kidney diseases 
- have or had heart problems (for example an irregular heartbeat or pains to the chest jaw and 

back brought on by physical effort and due to problems with the blood flow to the heart)  
- have brain diseases (for example. cancer that has spread to the brain), or nerve damage 

(neuropathy)  
- have calcium imbalances (seen in blood tests) 
- have diabetes 
- cannot keep food or water in your body because of severe nausea and vomiting 
- have diarrhoea 
- are, or become dehydrated 
- have imbalances of ions in your blood (electrolyte imbalances, seen in tests) 
- have a history of eye problems as you may need extra monitoring of your eyes 
- have a severe skin reaction. 
 
DPD deficiency: DPD deficiency is a rare condition present at birth that is not usually associated with 
health problems unless you receive certain medicines. If you have an unrecognised DPD deficiency 
and take Capecitabine SUN, you may experience severe forms of the side effects listed under section 4 
Possible side effects. Contact your doctor immediately if you are concerned about any of the side 
effects or if you notice any additional side effects not listed in the leaflet (see section 4 Possible side 
effects). 
 
Children and adolescents 
Capecitabine SUN is not indicated in children and adolescents. Do not give Capecitabine SUN to 
children and adolescents. 
 
Other medicines and Capecitabine SUN 
Before starting treatment, tell your doctor or pharmacist if you are taking, have recently taken or might 
take any other medicines, including medicines obtained without a prescription. This is extremely 
important, as taking more than one medicine at the same time can strengthen or weaken the effect of 
the medicines. You need to be particularly careful if you are taking any of the following: 
- gout medicines (allopurinol) 
- blood-thinning medicines (coumarin, warfarin) 
- certain anti-viral medicines (sorivudine and brivudine)  
- medicines for seizures or tremors (phenytoin) 
- a medicine to treat cancer (interferon alpha)  
- radiotherapy and certain medicines used to treat cancer (folinic acid, oxaliplatin, bevacizumab, 

cisplatin, irinotecan) 
- medicines used to treat folic acid deficiency. 
 
Capecitabine SUN with food and drink  
You should take Capecitabine SUN no later than 30 minutes after meals. 
 
Pregnancy and breast-feeding 
Before starting treatment, you must tell your doctor if you are pregnant, if you think you may be 
pregnant or if you intend to become pregnant. You must not take Capecitabine SUN if you are 
pregnant or think you might be.  
Effective contraceptive precautions must be taken by patients who are taking Capecitabine SUN. 
You must not breast-feed if you are taking Capecitabine SUN.  
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Capecitabine SUN may make you feel dizzy, nauseous or tired. It is therefore possible that 
Capecitabine SUN could affect your ability to drive a car or operate machines. Do not drive if you feel 
dizzy, nauseous or tired after taking this medicine. 

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Capecitabine SUN contains anhydrous lactose 
This medicine contains anhydrous lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Capecitabine SUN 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Capecitabine should only be prescribed by a doctor experienced in the use of anticancer medicines. 
 
Capecitabine SUN tablets should be swallowed whole with water, and within 30 minutes of a meal. 
 
Your doctor will prescribe a dose and treatment regimen that is right for you. The dose of 
Capecitabine SUN is based on your body surface area. This is calculated from your height and weight. 
The usual dose for adults is 1250 mg/m2 of body surface area taken two times daily (morning and 
evening). Two examples are provided here: A person whose body weight is 64 kg and height is 1.64 m 
has a body surface area of 1.7 m2 and should take 4 tablets of 500 mg and 1 tablet of 150 mg two times 
daily. A person whose body weight is 80 kg and height is 1.80 m has a body surface area of 2.00 m2 
and should take 5 tablets of 500 mg two times daily. 
 
Capecitabine SUN tablets are usually taken for 14 days followed by a 7 day rest period (when no 
tablets are taken). This 21 day period is one treatment cycle. 
 
In combination with other medicines the usual dose for adults may be less than 1250 mg/m2 of body 
surface area, and you may need to take the tablets over a different time period (e.g. every day, with no 
rest period). 
 
Your doctor will tell you what dose you need to take, when to take it and for how long you need to 
take it. 
 
Your doctor may want you to take a combination of 150 mg and 500 mg tablets for each dose. 
- Take the tablets in the morning and evening as prescribed by your doctor. 
- Take the tablets within 30 minutes after the end of a meal (breakfast and dinner). 
- It is important that you take all your medicines as prescribed by your doctor. 
 
If you take more Capecitabine SUN than you should  
Contact your doctor as soon as possible before taking the next dose. 
You might get the following side effects if you take a lot more capecitabine than you should: feeling 
or being sick, diarrhoea, inflammation or ulceration of the gut or mouth, pain or bleeding from the 
intestine or stomach, or bone marrow depression (reduction in certain kinds of blood cells). Tell your 
doctor immediately if you experience any of these symptoms. 
 
If you forget to take Capecitabine SUN 
Do not take the missed dose at all and do not double the next one. Instead, continue your regular 
dosing schedule and check with your doctor. 
 
If you stop taking Capecitabine SUN 
There are no side-effects caused by stopping treatment with Capecitabine SUN. In case you are using 
coumarin anticoagulants (containing e.g. phenprocoumon), stopping Capecitabine SUN might require 
that your doctor adjusts your anticoagulant dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 

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4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
STOP taking Capecitabine SUN immediately and contact your doctor if any of these symptoms occur: 
- Diarrhoea: if you have an increase of 4 or more bowel movements compared to your normal 

bowel movements each day or any diarrhoea at night. 
- Vomiting: if you vomit more than once in a 24-hour time period. 
- Nausea: if you lose your appetite, and the amount of food you eat each day is much less than 

usual. 
- Stomatitis: if you have pain, redness, swelling or sores in your mouth and/or throat. 
- Hand-and-foot skin-reaction: if you have pain, swelling, redness or tingling of hands and/or 

feet. 
- Fever: if you have a temperature of 38°C or greater. 
- Infection: if you experience signs of infection caused by bacteria or virus, or other organisms. 
- Chest pain: if you experience pain localised to the centre of the chest, especially if it occurs 

during exercise. 
- Steven-Johnson syndrome: if you experience painful red or purplish rash that spreads and 

blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips), in 
particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) 
and/or fever. 

 
If caught early, these side effects usually improve within 2 to 3 days after stopping treatment. If these 
side effects continue, contact your doctor immediately. Your doctor may instruct you to restart 
treatment at a lower dose. 
 
In addition to the above, when Capecitabine SUN is used alone, very common side effects which may 
affect more than 1 person in 10 are: 
- abdominal pain 
- rash, dry or itchy skin 
- tiredness 
- loss of appetite (anorexia). 
 
These side effects can become severe; therefore, it is important that you always contact your doctor 
immediately when you start to experience a side effect. Your doctor may instruct you to decrease the 
dose and/or temporarily discontinue treatment with Capecitabine SUN. This will help reduce the 
likelihood that the side effect continues or becomes severe. 
 
Other side effects are:  
 
Common side effects (may affect up to 1 in 10 people) include: 
- decreases in the number of white blood cells or red blood cells (seen in tests) 
- dehydration, weight loss 
- sleeplessness (insomnia), depression 
- headache, sleepiness, dizziness, abnormal sensation in the skin (numbness or tingling 

sensation), taste changes 
- eye irritation, increased tears, eye redness (conjunctivitis)  
- inflammation of the veins (thrombophlebitis)  
- shortness of breath, nose bleeds, cough, runny nose  
- cold sores or other herpes infections 
- infections of the lungs or respiratory system (e.g. pneumonia or bronchitis)  
- bleeding from the gut, constipation, pain in upper abdomen, indigestion, excess wind, dry 

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

skin loss, skin inflammation, nail disorder  

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74 

 

- pain in the joints, or in the limbs (extremities), chest or back 
- fever, swelling in the limbs, feeling ill  
- problems with liver function (seen in blood tests) and increased blood bilirubin (excreted by the 

liver).  
 
Uncommon side effects (may affect up to 1 in 100 people) include:  
- blood infection, urinary tract infection, infection of the skin, infections in the nose and throat, 

fungal infections (including those of the mouth), influenza, gastroenteritis, tooth abscess 
- lumps under the skin (lipoma)  
- decreases in blood cells including platelets, thinning of blood (seen in tests)  
- allergy  
- diabetes, decrease in blood potassium, malnutrition, increased blood triglycerides 
- confusional state, panic attacks, depressed mood, decreased libido 
- difficulty speaking, impaired memory, loss of movement coordination, balance disorder, 

fainting, nerve damage (neuropathy) and problems with sensation  
- blurred or double vision 
- vertigo, ear pain  
- irregular heartbeat and palpitations (arrhythmias), chest pain and heart attack (infarction)  
- blood clots in the deep veins, high or low blood pressure, hot flushes, cold limbs (extremities), 

purple spots on the skin  
- blood clots in the veins in the lung (pulmonary embolism), collapsed lung, coughing up blood, 

asthma, shortness of breath on exertion  
- bowel obstruction, collection of fluid in the abdomen, inflammation of the small or large 

intestine, the stomach or the oesophagus, pain in the lower abdomen, abdominal discomfort, 
heartburn (reflux of food from the stomach), blood in the stool  

- jaundice (yellowing of skin and eyes)  
- skin ulcer and blister, reaction of the skin with sunlight, reddening of palms, swelling or pain of 

the face  
- joint swelling or stiffness, bone pain, muscle weakness or stiffness  
- fluid collection in the kidneys, increased frequency of urination during the night, incontinence, 

blood in the urine, increase in blood creatinine (sign of kidney dysfunction)  
- unusual bleeding from the vagina  
- swelling (oedema), chills and rigors. 
 
Some of these side effects are more common when capecitabine is used with other medicines for the 
treatment of cancer. Other side effects seen in this setting are the following:  
 
Common side effects (may affect up to 1 in 10 people) include:  
- decrease in blood sodium, magnesium or calcium, increase in blood sugar  
- nerve pain  
- ringing or buzzing in the ears (tinnitus), loss of hearing  
- vein inflammation  
- hiccups, change in voice  
- pain or altered/abnormal sensation in the mouth, pain in the jaw  
- sweating, night sweats  
- muscle spasm  
- difficulty in urination, blood or protein in the urine  
- bruising or reaction at the injection site (caused by medicines given by injection at the same 

time).  
 
Rare side effects (may affect up to 1 in 1,000 people) include:   
- narrowing or blockage of tear duct (lacrimal duct stenosis) 
- liver failure 
- inflammation leading to dysfunction or obstruction in bile secretion (cholestatic hepatitis) 
- specific changes in the electrocardiogram (QT prolongation) 

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75 

 

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

- eye inflammation causing eye pain and possibly eyesight problems 
- inflammation of the skin causing red scaly patches due to an immune system illness. 

 
Very rare side effects (may affect up to 1 in 10,000 people) include:   
- severe skin reaction  such as skin rash, ulceration and blistering which  may involve ulcers of 

the mouth, nose, genitalia, hands, feet and eyes (red and swollen eyes). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V*. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Capecitabine SUN 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. 
 
Do not store above 25°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Capecitabine SUN contains 
- The active substance is capecitabine. Each film-coated tablet contains 500 mg of capecitabine. 
- The other ingredients are: 

- Tablet core: talc (E553b), anhydrous lactose, croscarmellose sodium (E468), 
hypromellose (E464), cellulose microcrystalline (E460), magnesium stearate (E572). 

- Tablet coating: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, 
macrogol and ferric oxide yellow and red (E172). 

 
What Capecitabine SUN looks like and contents of the pack 
Capecitabine SUN 500 mg are peach coloured, oval, biconvex, film-coated tablet debossed with ’500’ 
on one side and plain on other side. 
 
Each pack contains 120 film-coated tablets (12 blisters of 10 tablets). 
 
Marketing Authorisation Holder and Manufacturer 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/Κύπρος/Latvija/Lietuva/Luxembourg/Luxemb
urg/Magyarország/ 

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76 

 

Malta/Nederland/Norge/Österreich/Polska/Portugal/ 
România/Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/Ολλανδία/ 
Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Holandia/Países Baixos/ 
Olanda/Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Kandelstrasse 7 
79199 Kirchzarten 
Deutschland 
tel. +49 (0) 7661 90 91 58-0 
 
España 
Sun Pharmaceuticals Spain S.L.U. 
C/Bobinadora 1-5 Planta 1a Local 13 
Mataro, 08302 
Barcelona 
España 
tel. +34 93 798 02 85 
 
France 
Sun Pharmaceuticals France 
34, Rue Jean Mermoz 
78600 Maisons Laffitte 
France 
tel. +33 1 39 62 10 24 
 
Italia 
Sun Pharmaceuticals Italia S.R.L. 
Via Luigi Rizzo, 8 
I-20151 – Milano 
Italia 
tel. +39 02 33 49 07 93 
 
United Kingdom 
Sun Pharmaceuticals UK Limited 
4100 Park Approach 
Thorpe Park 
Leeds 
LS15 8GB 
United Kingdom 
tel. +44 (0) 113 397 08 70 
 
This leaflet was last revised in {MM/YYYY} 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET