Capecitabine Medac

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 150 mg film-coated tablets 
Capecitabine medac 300 mg film-coated tablets 
Capecitabine medac 500 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Capecitabine medac 150 mg film-coated tablets 
Each film-coated tablet contains 150 mg capecitabine. 
 
Capecitabine medac 300 mg film-coated tablets 
Each film-coated tablet contains 300 mg capecitabine. 
 
Capecitabine medac 500 mg film-coated tablets 
Each film-coated tablet contains 500 mg capecitabine. 
 
 
Excipients with known effect 
 
Capecitabine medac 150 mg film-coated tablets 
Each film-coated tablet contains 7 mg anhydrous lactose. 
 
Capecitabine medac 300 mg film-coated tablets 
Each film-coated tablet contains 15 mg anhydrous lactose. 
 
Capecitabine medac 500 mg film-coated tablets 
Each film-coated tablet contains 25 mg anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Capecitabine medac 150 mg film-coated tablets 
The film-coated tablets are light peach coloured, oblong shaped, biconvex tablets of 11.4 mm in length 
and 5.3 mm in width, debossed with ‘150’ on one side and plain on other side. 
 
Capecitabine medac 300 mg film-coated tablets 
The film-coated tablets are white to off white, oblong shaped, biconvex tablets of 14.6 mm in length 
and 6.7 mm in width, debossed with ‘300’ on one side and plain on other side. 
 
Capecitabine medac 500 mg film-coated tablets 
The film-coated tablets are peach coloured, oblong shaped, biconvex tablets of 15.9 mm in length and 
8.4 mm in width, debossed with ‘500’ on one side and plain on other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Capecitabine medac is indicated:  



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• for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon 
cancer (see section 5.1). 

 
• for the treatment of metastatic colorectal cancer (see section 5.1). 
 
• for first-line treatment of advanced gastric cancer in combination with a platinum based regimen 

(see section 5.1). 
 
• in combination with docetaxel (see section 5.1) for the treatment of patients with locally 

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

 
• 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 medac 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 medac 
of 1,250 mg/m² and 1,000 mg/m² are provided in tables 1 and 2, respectively. 
 
Posology 
Recommended posology (see section 5.1): 
 
Monotherapy 
Colon, colorectal and breast cancer 
Given as monotherapy, the recommended starting dose for capecitabine in the adjuvant treatment of 
colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic 
breast cancer is 1,250 mg/m² administered twice daily (morning and evening; equivalent to 
2,500 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 
800-1,000 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 1,250 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 



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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 medac dose calculations 
 
Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of 

capecitabine of 1,250 mg/m². 
 Dose level 1,250 mg/m² (twice daily) 
 Full dose 

 
 

1,250 mg/m² 

Number of 150 mg tablets, 
300 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 300 mg 500 mg 

Dose per 
administration 

(mg) 

Dose per 
administration 

(mg) 
≤ 1.26 1,500 - - 3 1,150 800 
1.27 - 1.38 1,650 1 - 3 1,300 800 
1.39 - 1.52 1,800 - 1 3 1,450 950 
1.53 - 1.66 2,000 - - 4 1,500 1,000 
1.67 - 1.78 2,150 1 - 4 1,650 1,000 
1.79 - 1.92 2,300 - 1 4 1,800 1,150 
1.93 - 2.06 2,500 - - 5 1,950 1,300 
2.07 - 2.18 2,650 1 - 5 2,000 1,300 
≥ 2.19 2,800 - 1 5 2,150 1,450 
 
Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of 

capecitabine of 1,000 mg/m² 
 Dose level 1,000 mg/m² (twice daily) 
 Full dose 

 
 

1,000 mg/m² 

Number of 150 mg tablets, 
300 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 300 mg 500 mg 

Dose per 
administration 

(mg) 

Dose per 
administration 

(mg) 
≤1.26 1,150 1 - 2 800 600 
1.27 - 1.38 1,300 - 1 2 1,000 600 
1.39 - 1.52 1,450 1 1 2 1,100 750 
1.53 - 1.66 1,600 - 2 2 1,200 800 
1.67 - 1.78 1,750 1 2 2 1,300 800 
1.79 - 1.92 1,800 - 1 3 1,400 900 
1.93 - 2.06 2,000 - - 4 1,500 1,000 
2.07 - 2.18 2,150 1 - 4 1,600 1,050 
≥ 2.19 2,300 - 1 4 1,750 1,100 
 
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 



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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 
•  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 (HFS) and 
hyperbilirubinaemia, 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. 



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If the other medicinal product(s) have to be discontinued permanently, capecitabine treatment can be 
resumed when the requirements for restarting capecitabine are met. 
 
This advice is applicable to all indications and to all special populations. 
 
Dose modifications for toxicity when capecitabine is used continuously in combination with other 
medicinal products 
Dose modifications for toxicity when capecitabine is used continuously in combination with other 
medicinal products should be made according to table 3 above for capecitabine and according to the 
appropriate summary of product characteristics for the other medicinal product(s). 
 
Posology adjustments for special populations 
 
Hepatic impairment 
Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose 
adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or 
hepatitis. 
 
Renal impairment 
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 
30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in 
patients with moderate renal impairment (creatinine clearance 30 - 50 ml/min at baseline) is increased 
compared to the overall population. In patients with moderate renal impairment at baseline, a dose 
reduction to 75 % for a starting dose of 1,250 mg/m² is recommended. In patients with moderate renal 
impairment at baseline, no dose reduction is required for a starting dose of 1,000 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 medac 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 (ADRs), 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 1,250 mg/m² twice daily. 

 
Paediatric population 
There is no relevant use of Capecitabine medac in the paediatric population in the indications colon, 
colorectal, gastric and breast cancer. 
 
Method of administration 
Capecitabine medac tablets should be swallowed whole with water within 30 minutes after a meal. 



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Capecitabine medac tablets should not be crushed or cut. 
 
4.3 Contraindications 
 
• History of severe and unexpected reactions to fluoropyrimidine therapy, 
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or 

fluorouracil, 
• Known complete 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), 
• Recent or concomitant treatment with brivudine (see section 4.4 and 4.5 for drug drug 

interaction), 
• If contraindications exist to any of the medicinal products in the combination regimen, that 

medicinal product should not be used. 
 
4.4 Special warnings and precautions for use 
 
Dose limiting toxicities  
Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome 
(HFS, hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are 
reversible and do not require permanent discontinuation of therapy, although doses may need to be 
withheld or reduced. 
 
Diarrhoea  
Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte 
replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be 
used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools, 
grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 
diarrhoea is an increase of ≥ 10 stools/day or grossly bloody diarrhoea or the need for parenteral 
support. Dose reduction should be applied as necessary (see section 4.2). 
 
Dehydration  
Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, 
vomiting or diarrhoea may rapidly become dehydrated. Dehydration may cause acute renal failure, 
especially in patients with pre-existing compromised renal function or when capecitabine is given 
concomitantly with known nephrotoxic medicinal products. Acute renal failure secondary to 
dehydration might be potentially fatal. If grade 2 (or higher) dehydration occurs, capecitabine 
treatment should be immediately interrupted and the dehydration corrected. Treatment should not be 
restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. 
Dose modifications applied should be applied for the precipitating adverse event as necessary (see 
section 4.2). 
 
Hand--foot syndrome  
HFS also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or chemotherapy 
induced acral erythema. Grade 1 HFS 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 HFS is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the 
patient’s activities of daily living. 
Grade 3 HFS is moist desquamation, ulceration, blistering and severe pain of the hands and/or feet 
and/or severe discomfort that causes the patient to be unable to work or perform activities of daily 
living. Persistent or severe HFS (Grade 2 and above) can eventually lead to loss of fingerprints which 
could impact patient identification. If grade 2 or 3 HFS occurs, administration of capecitabine should 



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be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 HFS, 
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 HFS, because of published reports that it may decrease the efficacy of 
cisplatin. There is some evidence that dexpanthenol is effective for HFS 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 an interaction study with single-dose warfarin administration, there was a significant increase in the 
mean AUC (+57 %) of S-warfarin. These results suggest an interaction, probably due to an inhibition 
of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients receiving concomitant 
capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant 
response (International Normalised Ratio [INR] or prothrombin time) monitored closely and the 
anticoagulant dose adjusted accordingly (see section 4.5). 
 
Brivudine 
Brivudine must not be administered concomitantly with capecitabine. Fatal cases have been reported 
following this drug interaction. There must be at least a 4-week waiting period between end of 
treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started 
24 hours after the last dose of capecitabine (see section 4.3 and 4.5). 
In the event of accidental administration of brivudine to patients being treated with capecitabine, 
effective measures should be taken to reduce the toxicity of capecitabine. Immediate admission to 
hospital is recommended. All measures should be initiated to prevent systemic infections and 
dehydration. 
 
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  



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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). 
 
Dihydropyrimidine dehydrogenase (DPD) deficiency  
 
DPD activity is rate limiting in the catabolism of 5-fluorouracil (see section 5.2). Patients with DPD 
deficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for example 
stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.  
 
DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose 
increase.  
 
Complete DPD deficiency  
Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Patients with complete DPD deficiency 
are at high risk of life-threatening or fatal toxicity and must not be treated with Capecitabine medac 
(see section 4.3).  
 
Partial DPD deficiency  
Partial DPD deficiency is estimated to affect 3-9% of the Caucasian population. Patients with partial 
DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced 
starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a 
parameter to be taken into account in conjunction with other routine measures for dose reduction. 
Initial dose reduction may impact the efficacy of treatment. In the absence of serious toxicity, 
subsequent doses may be increased with careful monitoring.  
 
Testing for DPD deficiency  
Phenotype and/or genotype testing prior to the initiation of treatment with Capecitabine medac is 
recommended despite uncertainties regarding optimal pre-treatment testing methodologies. 
Consideration should be given to applicable clinical guidelines.  
 
Genotypic characterisation of DPD deficiency  
Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.  
 
The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], 
c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymatic 
activity. Other rare variants may also be associated with an increased risk of severe or life-threatening 
toxicity. 
 
Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g. 
combinations of the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known 
to cause complete or near complete absence of DPD enzymatic activity.  
 
Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T 
and c.1236G>A/HapB3) have increased risk of severe toxicity when treated with fluoropyrimidines.  
 
The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients is 
around 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for 
c.1679T>G.  
 
Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. At 
the present, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) 
are considered virtually absent in populations of African (-American) or Asian origin. 
 
Phenotypic characterisation of DPD deficiency  
For phenotypic characterisation of DPD deficiency, the measurement of pre-therapeutic blood levels 
of the endogenous DPD substrate uracil (U) in plasma is recommended.  



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Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite 
uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level 
≥ 16 ng/ml and < 150 ng/ml should be considered indicative of partial DPD deficiency and associated 
with an increased risk for fluoropyrimidine toxicity. A blood uracil level ≥ 150 ng/ml should be 
considered indicative of complete DPD deficiency and associated with a risk for life-threatening or 
fatal fluoropyrimidine toxicity. 
 
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. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say 
essentially ‘sodium-free’. 
 
Capecitabine medac tablets should not be crushed or cut. In case of exposure of either patient or 
caregiver to crushed or cut Capecitabine medac tablets adverse drug reactions could occur (see 
section 4.8). 
 
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 
 
Brivudine  
A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 
5-fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by 
brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is 
potentially fatal. Therefore, brivudine must not be administered concomitantly with capecitabine  (see 
section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with 
brivudine and start of capecitabine therapy. Treatment with brivudine can be started 24 hours after the 
last dose of capecitabine. 
 
Cytochrome P450 2C9 (CYP2C9) substrates  
Other than warfarin, no formal interaction studies between capecitabine and other CYP2C9 substrates 
have been conducted. Care should be exercised when capecitabine is co-administered with 2C9 
substrates (e.g. phenytoin). See also interaction with coumarin-derivative anticoagulants below, and 
section 4.4. 
 
Coumarin-derivative anticoagulants  
Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine 
concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These 
reactions occurred within several days and up to several months after initiating capecitabine therapy 
and, in a few cases, within one month after stopping capecitabine. 



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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 alterations in their 
coagulation parameters (PT or INR) and the anticoagulant 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 3,000 mg/m² per day 
whereas it is only 2,000 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. 
 
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’-deoxy-5-fluorocytidine (5’-DFCR); there was no 
effect on the 3 major metabolites: 5’-deoxy-5-fluorouridine (5’-DFUR), 5-FU and α-fluoro-β-alanine 
(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 2,000 mg/m² per day when combined with interferon alpha- 2a 
(3 MIU/m² per day) compared to 3,000 mg/m² per day when capecitabine was used alone. 
 
Radiotherapy  
The MTD of capecitabine alone using the intermittent regimen is 3,000 mg/m² per day, whereas, when 
combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2,000 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 



12 

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). 
 
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 and for 6 months after the last dose of capecitabine. 
Based on genetic toxicity findings, male patients with female partners of reproductive potential should 
use effective contraception during treatment and for 3 months following the last dose of capecitabine. 
 
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. 
 
Breast-feeding 
It is not known whether capecitabine is excreted in human breast milk. No studies have been 
conducted to assess the impact of capecitabine on milk production or its presence in human breast 
milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. 
As the potential for harm to the nursing infant is unknown, breast-feeding should be discontinued 
while receiving treatment with capecitabine and for 2 weeks after the final dose. 
 
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 3,000 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 ADRs were gastrointestinal 
disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), HFS (palmar-plantar 
erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those 
with pre-existing compromised renal function, and thrombosis/embolism. 
 



13 

Tabulated list of adverse reactions 
 
ADRs considered by the investigator to be possibly, probably, or remotely related to the 
administration of capecitabine are listed in table 4 for capecitabine given as monotherapy and in 
table 5 for capecitabine given in combination with different chemotherapy regimens in multiple 
indications. The following headings are used to rank the ADRs by frequency: very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very 
rare (< 1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing 
seriousness. 
 
Capecitabine monotherapy 
Table 4 lists ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of 
safety data from three major studies including over 1,900 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, 
INR 
increased/Prothrombin 
time prolonged 

 

Immune system 
disorders 

- - Hypersensitivity  

Metabolism and 
nutrition 
disorders 

Anorexia Dehydration, Weight 
decreased 

Diabetes, 
Hypokalaemia, 
Appetite disorder, 
Malnutrition, 
Hypertriglyceridaemia 

 

Psychiatric - Insomnia, Depression Confusional state,  



14 

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) 

disorders Panic attack, 
Depressed mood, 
Libido decreased 

Nervous system 
disorders 

- Headache, Lethargy, 
Dizziness, 
Paraesthesia, 
Dysgeusia 

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

Toxic 
leukoencephalopathy 
(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) 

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 

 

Gastrointestinal 
disorders 

Diarrhoea, 
Vomiting, Nausea, 
Stomatitis, 
Abdominal pain 

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

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

 



15 

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) 

Blood in stool 

Hepatobiliary 
disorders 

- Hyperbilirubinaemia, 
Liver function test 
abnormalities 

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

Skin and 
subcutaneous 
tissue disorders 

Palmar-plantar 
erythrodysaesthesia 
syndrome**  

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

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

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

Musculoskeletal 
and connective 
tissue disorders 

- Pain in extremity, 
Back pain, Arthralgia 

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

 

Renal and 
urinary 
disorders 

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

 

Reproductive 
system and 
breast disorders 

- - Vaginal haemorrhage  

General 
disorders and 
administration 
site conditions 

Fatigue, Asthenia Pyrexia, Oedema 
peripheral, Malaise, 
Chest pain 

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

 

** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia syndrome 
can eventually lead to loss of fingerprints (see section 4.4) 

 
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 3,000 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). 
 



16 

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, 
+Leukopenia, +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, 
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 

 



17 

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 
disorders 

- 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. 
 
Description of selected adverse reactions 
 
HFS (see section 4.4) 
For the capecitabine dose of 1,250 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 1,000 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 4,700 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 
2,066 (43 %) patients after a median time of 239 [95 % CI 201, 288] days after starting treatment with 



18 

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 Eastern Cooperative Oncology Group (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 4,700 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 %. 
 
Exposure to crushed or cut capecitabine tablets 
In the instance of exposure to crushed or cut capecitabine tablets, the following adverse drug reactions 
have been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, 
gastric irritation, and vomiting. 
 
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 4,700 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 4,700 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. 



19 

 
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: Pyrimidine analogues, antineoplastic agents, ATC code: L01BC06 
 
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally 
administered precursor of the cytotoxic moiety 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 ThyPase 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 ribonucleic acid 
(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. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


20 

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, 1,987 patients were randomised to treatment with 
capecitabine (1,250 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 
intravenous followed by 425 mg/m² intravenous bolus 5-FU, on days 1 to 5, every 28 days for 
24 weeks). Capecitabine was at least equivalent to intravenous 5-FU/LV in disease-free survival in per 
protocol population (hazard ratio 0.92; 95 % CI 0.80 - 1.06). In the all-randomised population, tests 
for difference of capecitabine vs 5-FU/LV in disease-free and overall survival showed hazard ratios of 
0.88 (95 % CI 0.77 - 1.01; p = 0.068) and 0.86 (95 % CI 0.74 - 1.01; p = 0.060), respectively. The 
median follow up at the time of the analysis was 6.9 years. In a pre-planned 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 
randomisation, gender, carcinoembryonic antigen (CEA) levels at baseline, lymph nodes at baseline, 
and country. In the all-randomised population, capecitabine was shown to be superior to 5-FU/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 (1,000 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, multi centre, 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 (1,250 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 
intravenous followed by 425 mg/m² intravenous bolus 5-FU, on days 1 to 5, every 28 days). The 
overall objective response rates in the all-randomised population (investigator assessment) were 
25.7 % (capecitabine) vs. 16.7 % (Mayo regimen); p < 0.0002. The median time to progression was 
140 days (capecitabine) vs. 144 days (Mayo regimen). Median survival was 392 days (capecitabine) 
vs. 391 days (Mayo regimen). Currently, no comparative data are available on capecitabine 
monotherapy in colorectal cancer in comparison with first line combination regimens. 
 
Combination therapy in first-line treatment of metastatic colorectal cancer 
Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use of 
capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for 
the first-line treatment of metastatic colorectal cancer. The study contained two parts: an initial 2-arm 



21 

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 1,401 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 85 mg/m² intravenous 
2 hr 

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

 Leucovorin  200 mg/m² intravenous 
2 hr 

5-Fluorouracil 400 mg/m² intravenous 
bolus, followed by 
600 mg/ m² intravenous 
22 hr 

Placebo or 
Bevacizumab 

5 mg/kg intravenous 
30 - 90 mins 

Day 1, prior to FOLFOX-4, every 2 weeks 

XELOX 
or 

XELOX+ 
Bevacizumab 

Oxaliplatin 130 mg/m² intravenous 
2 hr 

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

Capecitabine 1,000 mg/m² oral twice 
daily 

Placebo or 
Bevacizumab 

7.5 mg/kg intravenous 
30 - 90 mins 

Day 1, prior to XELOX, every 3 weeks 

5-Fluorouracil: intravenous bolus injection immediately after leucovorin 
 
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 (PFS) 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 PFS (hazard ratio 1.01; 97.5 % CI 0.84 – 1.22). The median follow up at the 
time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses 
following an additional 1 year of follow up are 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 tumour assessments impact the on-treatment PFS 
analysis, a full explanation for this result has not been found. 
 



22 

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 = 1,017) 

FOLFOX-4/FOLFOX-4+P 
/FOLFOX-4+BV 
(EPP*: N = 937; ITT**: 
N = 1,017) 

 

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 1,000 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 (1,250 mg/m² twice daily for 14 days), second-line irinotecan 
(350 mg/m² on day 1), and third-line combination of capecitabine (1,000 mg/m² twice daily for 
14 days) with oxaliplatin (130 mg/m² on day 1). Combination treatment consisted of first-line 
capecitabine (1,000 mg/m² twice daily for 14 days) combined with irinotecan (250 mg/m² on day 1) 
(XELIRI) and second-line capecitabine (1,000 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 PFS 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 1,000 mg/m² 
twice daily on days 1 to 14 of a 3-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 



23 

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 
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 1,000 mg/m² 
twice daily for 14 days + irinotecan 250 mg/m² on day 1. Median 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 1every 3 weeks); 
127 patients were randomised to treatment with capecitabine (1,000 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: 
 



24 

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 PFS 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 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. 
 



25 

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 (1,000 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 PFS in the per protocol analysis (hazard ratio 0.81; 95 % CI 
0.63 – 1.04). The median PFS 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 PFS (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, 1,002 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). 



26 

- 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). 

 
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 3,097 patients treated with capecitabine-containing regimens and 
3,074 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 (1,250 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 (1,250 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. 
 



27 

All indications 
 
A meta-analysis of 14 clinical trials with data from over 4,700 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 HFS had a longer overall survival compared to patients who did not develop HFS: median 
overall survival 1,100 days (95 % CI 1,007;1,200) vs 691 days (95 % CI 638;754) with a hazard ratio 
of 0.61 (95 % CI 0.56; 0.66). 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to conduct studies with capecitabine in all 
subsets of the paediatric population in adenocarcinoma of the colon and rectum, gastric 
adenocarcinoma and breast carcinoma (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of capecitabine have been evaluated over a dose range of 502 –
 3,514 mg/m²/day. The parameters of capecitabine, 5’-DFCR and 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 1,250 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 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). ThyPase 
activity was measured and found to be 4 times greater in primary colorectal tumour than in adjacent 
normal tissue. According to immunohistochemical studies, ThyPase appears to be in large part 
localised in tumour stromal cells. 
 
5-FU is further catabolised by the enzyme 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 FBAL which is cleared in the urine. DPD activity is the 
rate limiting step. Deficiency of DPD may lead to increased toxicity of capecitabine (see section 4.3 
and 4.4). 



28 

 
Elimination 
The elimination half-life (t1/2 in hours) of capecitabine, 5’-DFCR, 5’-DFUR, 5-FU and FBAL were 
0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Capecitabine and its metabolites are predominantly 
excreted in urine; 95.5 % of administered capecitabine dose is recovered in urine. Faecal excretion is 
minimal (2.6 %). The major metabolite excreted in urine is FBAL, which represents 57 % of the 
administered dose. About 3 % of the administered dose is excreted in urine unchanged. 
 
Combination therapy 
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or 
paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or 
paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 
5’-DFUR. 
 
Pharmacokinetics in special populations 
A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients 
with colorectal cancer dosed at 1,250 mg/m² twice daily. Gender, presence or absence of liver 
metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, 
aspartate-aminotransferase (ASAT) and alanine-aminotransferase (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 
(1,379 mg/m²/day). 



29 

 
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine. 
 
During standard fertility studies, impairment of fertility was observed in female mice receiving 
capecitabine; however, this effect was reversible after a drug-free period. In addition, during a 
13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; 
however these effects were reversible after a drug-free period (see section 4.6). 
 
In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and 
teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, 
but there was no evidence of teratogenicity. 
 
Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster 
V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (i.e., 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 
Anhydrous lactose 
Cellulose, microcrystalline (E460) 
Croscarmellose sodium (E468) 
Hypromellose (E464) 
Magnesium stearate (E572) 
 
Tablet coating 
 
Capecitabine medac 150 mg film-coated tablets 
Hypromellose (E464) 
Talc 
Titanium dioxide (E171) 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
 
Capecitabine medac 300 mg film-coated tablets 
Hypromellose (E464) 
Talc 
Titanium dioxide (E171) 
 
Capecitabine medac 500 mg film-coated tablets 
Hypromellose (E464) 
Talc 
Titanium dioxide (E171) 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 



30 

6.3 Shelf life 
 
Aluminium/aluminium blisters 
3 years 
 
PVC/PVdC/Aluminium blisters 
3 years 
 
6.4 Special precautions for storage 
 
Aluminium/aluminium blisters 
This medicinal product does not require any special storage conditions. 
 
PVC/PVdC/Aluminium blisters 
Do not store above 30 °C. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium or PVC/PVdC/Aluminium blisters. 
 
Pack sizes: 28, 30, 56, 60, 84, 112 or 120 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Procedures for safe handling of cytotoxic drugs should be followed.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
medac 
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/802/001-014 
EU/1/12/802/015-028 
EU/1/12/802/029-042 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2012 
Date of latest renewal: 16 June 2017 
 
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. 

http://www.ema.europa.eu/


31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) 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 
 
 



32 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 

 
Pharmacare Premium Ltd 
HHF 003, Hal Far Industrial Estate Birzebbugia,  
BBG 3000 
Malta 
 
LABORATORI FUNDACIÓ DAU  
C/ C, 12-14 Pol. Ind. Zona Franca, Barcelona 
08040 Barcelona 
Spain 

 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 

 
 
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 

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates 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. 

 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTER 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 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 the package leaflet for further information. 
 
 
4.  PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablets 
 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
84 film-coated tablets 
112 film-coated tablets 
120 film-coated tablets  
 
 
5.  METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral 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: 



36 

 
 
9.  SPECIAL STORAGE CONDITIONS 
 
For PVC/PVdC/Aluminium blisters: 
Do not store above 30 °C 
 
 
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 
 
medac  
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12.  MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/802/001-014 
 
 
13.  BATCH NUMBER 
 
Lot: 
 
 
14.  GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15.  INSTRUCTIONS ON USE 
 
 
16.  INFORMATION IN BRAILLE 
 
Capecitabine medac 150 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



37 

PC:  
SN:  
NN:  



38 

  
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 150 mg tablets 
capecitabine 
 
 
2.  NAME OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
 
 
3.  EXPIRY DATE 
 
EXP: 
 
 
4.  BATCH NUMBER 
 
Lot: 
 
 
5.  OTHER 



39 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTER 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 300 mg film-coated tablets 
capecitabine 
 
 
2.  STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 300 mg capecitabine. 
 
 
3.  LIST OF EXCIPIENTS 
 
Also contains anhydrous lactose, see the package leaflet for further information. 
 
 
4.  PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablets 
 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
84 film-coated tablets 
112 film-coated tablets 
120 film-coated tablets  
 
 
5.  METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral 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: 



40 

 
 
9.  SPECIAL STORAGE CONDITIONS 
 
For PVC/PVdC/Aluminium blisters: 
Do not store above 30 °C 
 
 
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 
 
medac  
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12.  MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/802/015-028 
 
 
13.  BATCH NUMBER 
 
Lot: 
 
 
14.  GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15.  INSTRUCTIONS ON USE 
 
 
16.  INFORMATION IN BRAILLE 
 
Capecitabine medac 300 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



41 

PC:  
SN:  
NN:  



42 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 300 mg tablets 
capecitabine 
 
 
2.  NAME OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
 
 
3.  EXPIRY DATE 
 
EXP: 
 
 
4.  BATCH NUMBER 
 
Lot: 
 
 
5.  OTHER 



43 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR BLISTER 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 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 the package leaflet for further information. 
 
 
4.  PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
84 film-coated tablets 
112 film-coated tablets 
120 film-coated tablets  
 
 
5.  METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral 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: 
 
 



44 

9.  SPECIAL STORAGE CONDITIONS 
 
For PVC/PVdC/Aluminium blisters: 
Do not store above 30 °C 
 
 
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 
 
medac  
Gesellschaft für klinische 
Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12.  MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/802/029-042 
 
 
13.  BATCH NUMBER 
 
Lot: 
 
 
14.  GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15.  INSTRUCTIONS ON USE 
 
 
16.  INFORMATION IN BRAILLE 
 
Capecitabine medac 500 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  



45 

NN:  
 



46 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Capecitabine medac 500 mg tablets 
capecitabine 
 
 
2.  NAME OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
 
 
3.  EXPIRY DATE 
 
EXP: 
 
 
4.  BATCH NUMBER 
 
Lot: 
 
 
5.  OTHER 
 



47 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



48 

Package leaflet: Information for the patient 
 

Capecitabine medac 150 mg film-coated tablets 
Capecitabine medac 300 mg film-coated tablets 
Capecitabine medac 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 medac is and what it is used for 
2. What you need to know before you take Capecitabine medac 
3. How to take Capecitabine medac 
4. Possible side effects 
5. How to store Capecitabine medac 
6. Contents of the pack and other information 
 
 
1. What Capecitabine medac is and what it is used for 
 
Capecitabine medac belongs to the group of medicines called "cytostatic medicines", which stop the 
growth of cancer cells. Capecitabine medac contains capecitabine, which itself is not a cytostatic 
medicine. Only after being absorbed by the body is it changed into an active anti-cancer medicine 
(more in tumour tissue than in normal tissue). 
 
Capecitabine medac is used in the treatment of colon, rectal, gastric, or breast cancers. 
Furthermore, Capecitabine medac is used to prevent new occurrence of colon cancer after complete 
removal of the tumour by surgery. 
 
Capecitabine medac may be used either alone or in combination with other medicines. 
 
 
2. What you need to know before you take Capecitabine medac 
 
Do not take Capecitabine medac 
• if you are allergic to capecitabine or any of the other ingredients of this medicine (listed in 

section 6). You must inform your doctor if you know that you have an allergy or over-reaction 
to this medicine, 

• if you previously have had severe reactions to fluoropyrimidine therapy (a group of anticancer 
medicines such as fluorouracil), 

• if you are pregnant or breast-feeding, 
• if you have severely low levels of white cells or platelets in the blood (leukopenia, neutropenia 

or thrombocytopenia), 
• if you have severe liver or kidney problems, 
• if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase 

(DPD) (complete DPD defiency), 



49 

• if you are being treated now or have been treated in the last 4 weeks with brivudine as part of 
herpes zoster (chickenpox or shingles) therapy. 

 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Capecitabine medac 
• if you know that you have a partial deficiency in the activity of the enzyme dihydropyrimidine 

dehydrogenase (DPD), 
• if you have a family member who has partial or complete deficiency of the enzyme 

dihydropyrimidine dehydrogenase (DPD), 
• if you have liver or kidney diseases, 
• if you have or had heart problems (for example an irregular heart beat or pains to the chest, jaw 

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

(neuropathy), 
• if you have calcium imbalances (seen in blood tests), 
• if you have diabetes, 
• if you cannot keep food or water in your body because of severe nausea and vomiting, 
• if you have diarrhoea, 
• if you are or become dehydrated, 
• if you have imbalances of ions in your blood (electrolyte imbalances, seen in tests), 
• if you have a history of eye problems as you may need extra monitoring of your eyes, 
• if you have a severe skin reaction. 
 
DPD deficiency  
DPD deficiency is a genetic condition that is not usually associated with health problems unless you 
receive certain medicines. If you have DPD deficiency and take Capecitabine medac, you are at an 
increased risk of severe side effects (listed under section 4 Possible side effects). It is recommended to 
test you for DPD deficiency before start of treatment. If you have no activity of the enzyme you 
should not take Capecitabine medac. If you have a reduced enzyme activity (partial deficiency) your 
doctor might prescribe a reduced dose. If you have negative test results for DPD deficiency, severe 
and life-threatening side effects may still occur. 
 
Children and adolescents 
Capecitabine medac is not indicated in children and adolescents. Do not give Capecitabine medac to 
children and adolescents. 
 
Other medicines and Capecitabine medac 
Before starting treatment, tell your doctor or pharmacist if you are taking, have recently taken or might 
take any other medicines. This is extremely important, as taking more than one medicine at the same 
time can strengthen or weaken the effect of the medicines.  
 
You must not take brivudine (an anti-viral medicine for the treatment of shingles or chickenpox) 
at the same time as capecitabine treatment (including during any rest periods when you are not 
taking any capecitabine tablets). 
If you have taken brivudine you must wait for at least 4 weeks after stopping brivudine before 
starting to take capecitabine. See also section “Do not take Capecitabine medac”. 
 
Also, you need to be particularly careful if you are taking any of the following: 
• gout medicines (allopurinol) 
• blood-thinning medicines (coumarin, warfarin) 
• medicines for seizures or tremors (phenytoin) 
• interferon alpha 
• radiotherapy and certain medicines used to treat cancer (folinic acid, oxaliplatin, bevacizumab, 

cisplatin, irinotecan) 
• medicines used to treat folic acid deficiency 



50 

 
Capecitabine medac with food and drink 
You should take Capecitabine medac no later than 30 minutes after meals. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.You must not take Capecitabine 
medac if you are pregnant or think you might be. 
You must not breast-feed if you are taking Capecitabine medac and for 2 weeks after the last dose. 
If you are a woman who could become pregnant you should use effective contraception during 
treatment with Capecitabine medac and for 6 months after the last dose. 
If you are a male patient and your female partner could become pregnant, you should use effective 
contraception during treatment with Capecitabine medac and for 3 months after the last dose. 
 
Driving and using machines 
Capecitabine medac may make you feel dizzy, nauseous or tired. It is therefore possible that 
Capecitabine medac could affect your ability to drive a car or operate machines.  
 
Capecitabine medac contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
Capecitabine medac contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say 
essentially ‘sodium-free’. 
 
 
3. How to take Capecitabine medac 
 
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 medac should only be prescribed by a doctor experienced in the use of anticancer 
medicines. 
 
Your doctor will prescribe a dose and treatment regimen that is right for you. The dose of Capecitabine 
medac is based on your body surface area. This is calculated from your height and weight. The usual 
dose for adults is 1,250 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. 
 
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, 300 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) and swallow 

whole with water. Do not crush or cut tablets. If you cannot swallow Capecitabine medac 
tablets whole, tell your healthcare provider. 

• It is important that you take all your medicine as prescribed by your doctor. 
 
Capecitabine medac 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. 
 



51 

In combination with other medicines the usual dose for adults may be less than 1,250 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). 
 
If you take more Capecitabine medac than you should 
If you take more Capecitabine medac 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 medac 
Do not take the missed dose at all. Do not take a double dose to make up for a forgotten dose. Instead, 
continue your regular dosing schedule and check with your doctor. 
 
If you stop taking Capecitabine medac 
There are no side effects caused by stopping treatment with capecitabine. In case you are using 
coumarin anticoagulants (containing e.g. phenprocoumon), stopping capecitabine might require that 
your doctor adjusts your anticoagulant dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
STOP taking Capecitabine medac 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. 
• Stevens-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 treatment discontinuation. If 
these side effects continue, however, contact your doctor immediately. Your doctor may instruct you 
to restart treatment at a lower dose. 
 
If severe stomatitis (sores in your mouth and/or throat), mucosal inflammation, diarrhoea, neutropenia 
(increased risk for infections), or neurotoxicity occurs during the first cycle of treatment a DPD 
deficiency may be involved (please see Section 2: Warning and precautions). 
 



52 

Hand and foot skin-reaction can lead to loss of fingerprint, which could impact your identification by 
fingerprint scan. 
 
In addition to the above, when Capecitabine medac is used alone, very common side effects which 
may affect more than 1 in 10 people are: 
• abdominal pain 
• rash, dry or itchy skin 
• tiredness 
• loss of appetite (anorexia) 
 
These side effects can become severe; therefore, it is important that you always contact your doctor 
immediately when you start to experience a side effect. Your doctor may instruct you to decrease the 
dose and/or temporarily discontinue treatment with Capecitabine medac. This will help reduce the 
likelihood that the side effect continues or becomes severe. 
 
Other side effects are: 
 
Common (may affect up to 1 in 10 people): 
• decreases in the number of white blood cells or red blood cells (seen in tests) 
• dehydration, weight loss 
• sleeplessness (insomnia), depression 
• headache, sleepiness, dizziness, abnormal sensation in the skin (numbness or tingling sensation), 

taste changes 
• eye irritation, increased tears, eye redness (conjunctivitis) 
• inflammation of the veins (thrombophlebitis) 
• shortness of breath, nose bleeds, cough, runny nose 
• cold sores or other herpes infections 
• infections of the lungs or respiratory system (e.g. pneumonia or bronchitis) 
• bleeding from the gut, constipation, pain in upper abdomen, indigestion, excess wind, dry mouth 
• skin rash, hair loss (alopecia), skin reddening, dry skin, itching (pruritus), skin discolouration, 

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

liver) 
 
Uncommon (may affect up to 1 in 100 people): 
• 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 



53 

• 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 (may affect up to 1 in 10 people): 
• 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 (may affect up to 1 in 1,000 people): 
• narrowing or blockage of tear duct (lacrimal duct stenosis) 
• liver failure 
• inflammation leading to dysfunction or obstruction in bile secretion (cholestatic hepatitis) 
• specific changes in the electrocardiogram (QT prolongation) 
• certain types of arrhythmia (including ventricular fibrillation, torsade de pointes, and 

bradycardia) 
• eye inflammation causing eye pain and possibly eyesight problems 
• inflammation of the skin causing red scaly patches due to an immune system illness 
 
Very rare (may affect up to 1 in 10,000 people): 
• 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 medac 
 
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. The 
expiry date refers to the last day of that month. 
 
For Aluminium-aluminium blisters: 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


54 

This medicine does not require any special storage conditions. 
 
For PVC/PVdC-aluminium blisters: 
Do not store above 30 °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 medac contains 
 
• The active substance is capecitabine. 
 

Each 150 mg film-coated tablet contains 150 mg capecitabine 
Each 300 mg film-coated tablet contains 300 mg capecitabine 
Each 500 mg film-coated tablet contains 500 mg capecitabine 

 
• The other ingredients are: 

Tablet core: anhydrous lactose, croscarmellose sodium (E468), hypromellose (E464), 
microcrystalline cellulose (E460), magnesium stearate (E572) – see section 2 “Capecitabine 
medac contains lactose”. 

 
Tablet coating: 
Capecitabine medac 150 mg film-coated tablets 
Hypromellose (E464), titanium dioxide (E171), yellow iron oxide (E172), red iron oxide 
(E172), talc 
Capecitabine medac 300 mg film-coated tablets 
Hypromellose (E464), titanium dioxide (E171), talc 
Capecitabine medac 500 mg film-coated tablets  
Hypromellose (E464), titanium dioxide (E171), yellow iron oxide (E172), red iron oxide 
(E172), talc 

 
What Capecitabine medac looks like and contents of the pack 
 
Capecitabine medac 150 mg film-coated tablets  
Light peach coloured, oblong shaped, biconvex tablet, debossed with ‘150’ on the one side and plain 
on the other side. 
 
Capecitabine medac 300 mg film-coated tablets 
White to off-white, oblong shaped, biconvex tablet, debossed with ‘300’ on the one side and plain on 
the other side. 
 
Capecitabine medac 500 mg film-coated tablets  
Peach coloured, oblong shaped, biconvex tablet, debossed with ‘500’ on the one side and plain on the 
other side. 
  
Capecitabine medac is available in blisters (Aluminium-Aluminium or PVC/PVdC-Aluminium). 
Each pack contains 28, 30, 56, 60, 84, 112, or 120 film-coated tablets.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
medac 
Gesellschaft für klinische 



55 

Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
Manufacturer 
Pharmacare Premium Ltd 
HHF 003, Hal Far Industrial Estate Birzebbugia 
BBG 3000, Malta 
 
LABORATORI FUNDACIÓ DAU  
C/ C, 12-14 Pol. Ind. Zona Franca, Barcelona 
08040 Barcelona 
Spain 
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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