Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CAPTERO  
Dosage form and strength: Each film coated tablet contains 150 mg and 500 mg capecitabine respectively  
APPROVED PROFESSIONAL INFORMATION FOR CAPTERO  
WARNING  
CAPTERO-Warfarin interaction: Patients receiving concomitant capecitabine and oral coumarin-  
derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time)  
monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important  
CAPTERO-Warfarin interaction was demonstrated in a clinical pharmacology trail. Altered  
coagulation parameters and/or bleeding, including death, have been reported in patients taking  
CAPTERO concomitantly with warfarin. Post-marketing reports have shown clinically significant  
increases in prothrombin time (PT) and INR in patients who were stabilised on anticoagulants at the  
time CAPTERO was introduced. These events occurred with several days and up to several months  
after initiating CAPTERO therapy and, in few cases, within one month after stopping CAPTERO.  
These events occurred in patients with and without liver metastases. Age greater than 60 and a  
diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.  
SCHEDULING STATUS  
S4  
1.  
NAME OF THE MEDICINE  
CAPTERO 150 film-coated tablets  
CAPTERO 500 film-coated tablets  
2.  
QUALITATIVE AND QUANTITATIVE COMPOSITION  
CAPTERO 150: Each film-coated tablet contains 150 mg capecitabine.  
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Product proprietary name: CAPTERO  
Dosage form and strength: Each film coated tablet contains 150 mg and 500 mg capecitabine respectively  
CAPTERO 500: Each film-coated tablet contains 500 mg capecitabine.  
Excipient with known effect:  
Contains sugar (lactose)  
CAPTERO 150: Each film-coated tablet contains 15,6 mg lactose.  
CAPTERO 500: Each film-coated tablet contains 52 mg lactose.  
For the full list of excipients, see section 6.1.  
3.  
PHARMACEUTICAL FORM  
Film-coated tablets.  
CAPTERO 150: Light peach coloured, capsule shaped, biconvex, film-coated tablets, debossed with  
“6” on one side and “H” on the other side.  
CAPTERO 500: Peach coloured, oval shaped, biconvex, film-coated tablets, debossed with “3” on  
one side and “H” on the other side.  
4.  
CLINICAL PARTICULARS  
Therapeutic indications  
4.1  
Breast cancer:  
Metastatic breast cancer (combination therapy): CAPTERO in combination with docetaxel is  
indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of  
cytotoxic chemotherapy which should have included an anthracycline.  
Metastatic breast cancer (monotherapy): CAPTERO is indicated as monotherapy for the treatment  
of patients with locally advanced or metastatic breast cancer after failure of taxanes and an  
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Product proprietary name: CAPTERO  
Dosage form and strength: Each film coated tablet contains 150 mg and 500 mg capecitabine respectively  
anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not  
indicated.  
Colorectal cancer:  
Colon cancer: CAPTERO is indicated as adjuvant treatment after surgery, of patients with Dukes C  
colon cancer.  
Metastatic colorectal cancer: CAPTERO is indicated as treatment of patients with metastatic  
colorectal adenocarcinoma. The benefit relates to time to progression, while overall survival was not  
influenced.  
Gastric cancer:  
CAPTERO is indicated as first line treatment of patients with advanced gastric adenocarcinoma in  
combination with other anti-chemotherapeutic regimen. The benefit relates to time to progression,  
while overall survival was not influenced.  
4.2  
Posology and method of administration  
CAPTERO should only be prescribed by a qualified physician experienced in the utilisation of  
antineoplastic medicines. CAPTERO tablets should be swallowed with water within 30 minutes after a  
meal. 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 1 250  
mg/m2 and 1 000 mg/m2 are provided in Tables 1 and 2, respectively.  
CAPTERO doses are calculated according to body surface area.  
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Dosage form and strength: Each film coated tablet contains 150 mg and 500 mg capecitabine respectively  
Posology  
Adults  
Monotherapy:  
Colon, colorectal and breast cancer: The recommended monotherapy dose of CAPTERO 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. For the CAPTERO dose schedule during monotherapy,  
please refer to Table 1.  
Adjuvant treatment in patients with Stage Ill colon cancer is recommended for a maximum of six  
months.  
Combination therapy:  
Colorectal and gastric cancer: In combination treatment, the starting dose of CAPTERO should be  
reduced to 1 000 mg/m2 when administered twice daily for 14 days, followed by a 7-day rest period.  
For the CAPTERO dose schedule during combination therapy (in colorectal and gastric cancer),  
please refer to Table 2.  
The inclusion of biological medicines in a combination regimen has no effect on the starting dose of  
CAPTERO.  
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin prescribing  
information should be started prior to cisplatin administration for patients receiving the CAPTERO plus  
cisplatin combination.  
Breast cancer: In combination with docetaxel for locally advanced or metastatic breast cancer, the  
recommended dose of CAPTERO is 1 250 mg/m2 twice daily for 14 days, followed by a 7-day rest  
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Dosage form and strength: Each film coated tablet contains 150 mg and 500 mg capecitabine respectively  
period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. For the  
CAPTERO dose schedule during combination therapy (in breast cancer), please refer to Table 1.  
Pre-medication with an oral corticosteroid such as dexamethasone according to the docetaxel  
prescribing information should be started prior to docetaxel administration for patients receiving the  
CAPTERO plus docetaxel combination.  
Table 1: Standard and reduced dose calculations according to body surface area for a starting  
dose of CAPTERO of 1 250 mg/m2 (twice daily)  
Body  
Full dose  
Number of 150 mg  
tablets and/or  
Reduced dose  
(75 %)  
Reduced dose  
(50 %)  
surface area  
(m2)  
(1 250 mg/m2)  
500 mg tablets per  
administration (each  
administration to be  
given morning and  
evening)  
950  
625  
mg/m2  
mg/m2  
Dose per  
admini-stration  
(mg)  
150 mg  
500 mg  
Dose per admini-  
stration (mg)  
Dose per admini-  
stration (mg)  
≤ 1,26  
1 500  
-
3
3
3
4
4
4
1 150  
1 300  
1 450  
1 500  
1 650  
1 800  
800  
800  
1,27 – 1,38  
1,39 – 1,52  
1,53 – 1,66  
1,67 – 1,78  
1,79 – 1,92  
1 650  
1
2
-
1 800  
950  
2 000  
1 000  
1 000  
1 150  
2 150  
1
2
2 300  
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1,93 – 2,06  
2,07 – 2,18  
≥ 2,19  
2 500  
2 650  
2 800  
-
5
5
5
1 950  
2 000  
2 150  
1 300  
1 300  
1 450  
1
2
Table 2: Standard and reduced dose calculations according to body surface area for a starting  
dose of CAPTERO of 1 000 mg/m2 (twice daily)  
Body  
Full dose  
Number of 150 mg  
tablets and/or  
Reduced dose  
(75 %)  
Reduced dose  
(50 %)  
surface area  
(m2)  
(1 000 mg/m2)  
500 mg tablets per  
administration (each  
administration to be  
given morning and  
evening)  
750 mg/m2  
500 mg/m2  
Dose per  
admini-  
stration (mg)  
1 150  
150 mg  
500 mg  
Dose per admini-  
stration (mg)  
Dose per admini-  
stration (mg)  
≤ 1,26  
1
2
3
4
5
2
-
2
2
2
2
2
3
4
4
800  
600  
600  
1,27 – 1,38  
1,39 – 1,52  
1,53 – 1,66  
1,67 – 1,78  
1,79 – 1,92  
1,93 – 2,06  
2,07 – 2,18  
1 300  
1 000  
1 100  
1 200  
1 300  
1 400  
1 500  
1 600  
1 450  
750  
1 600  
800  
1 750  
800  
1 800  
900  
2 000  
1 000  
1 050  
2 150  
1
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Dosage form and strength: Each film coated tablet contains 150 mg and 500 mg capecitabine respectively  
≥ 2,19  
2 300  
2
4
1 750  
1 100  
Dose adjustments during treatment:  
Patients should be carefully monitored for toxicity. Toxicity due to CAPTERO administration may be  
managed by symptomatic treatment and/or modification of the CAPTERO dose (treatment interruption  
or dose reduction).  
Dosage modifications are not recommended for Grade 1 events. Therapy with CAPTERO should be  
interrupted upon the occurrence of Grade 2 or 3 adverse experiences. Once the adverse event has  
resolved or decreased in intensity to Grade 1, then CAPTERO therapy may be restarted at full dose  
or adjusted according to the table below. If a Grade 4 experience occurs, therapy should be  
discontinued or interrupted until resolved or decreased to Grade 1, and therapy can then be restarted  
at 50 % of the original dose.  
Patients taking CAPTERO should be informed of the need to interrupt treatment immediately if  
moderate or worse toxicity occurs.  
Doses of CAPTERO omitted for toxicity are not replaced or restored; instead the patient should  
resume the planned treatment cycles. Once the dose has been reduced it should not be increased at  
a later time.  
The following table shows the recommended dose modifications following toxicity with CAPTERO:  
Table 3: CAPTERO dose reduction schedule following toxicity (3-weekly cycle or continuous  
treatment)  
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Toxicity NCIC grades*  
Dose changes within a  
treatment cycle  
Dose adjustment for next  
cycle/dose  
(% of starting dose)  
Maintain dose level  
• Grade 1  
Maintain dose level  
• Grade 2  
1st appearance  
Interrupt until resolved to Grade  
100 %  
75 %  
50 %  
0 – 1  
Interrupt until resolved to Grade  
0 – 1  
2nd appearance  
3rd appearance  
4th appearance  
Interrupt until resolved to Grade  
0 – 1  
Discontinue treatment  
permanently  
• Grade 3  
1st appearance  
Interrupt until resolved to Grade  
0 – 1  
75 %  
50 %  
2nd appearance  
3rd appearance  
Interrupt until resolved to Grade  
0 – 1  
Discontinue treatment  
permanently  
Grade 4  
1st appearance  
Discontinue treatment  
50 %  
permanently  
or  
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If physician deems it to be in  
the patient's best interest to  
continue, interrupt until  
resolved to Grade 0 – 1  
2nd appearance  
Discontinue treatment  
permanently  
*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 CAPTERO. If unscheduled laboratory assessments during a treatment  
cycle show Grade 3 or 4 haematologic toxicity, treatment with CAPTERO should be interrupted.  
Dose modifications for toxicity when CAPTERO is used as a 3-weekly cycle in combination with other  
medicines:  
Dose modifications for toxicity when CAPTERO is used as a 3-weekly cycle in combination with other  
medicines should be made according to Table 3 above for CAPTERO and according to the  
appropriate prescribing information for the other medicine(s) used. At the beginning of a treatment  
cycle, if a treatment delay is indicated for either CAPTERO or the other medicine(s), then  
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administration of all medicines should be delayed until the requirements for restarting all medicines  
are met.  
During a treatment cycle for those toxicities considered by the treating physician not to be related to  
CAPTERO, CAPTERO should he continued, and the dose of the other medicines should be adjusted  
according to the appropriate prescribing information.  
If the other medicine(s) has(ve) to be discontinued permanently, CAPTERO treatment can be  
resumed when the requirements for restarting CAPTERO are met.  
This advice is applicable to all indications and to all special populations.  
Dose modifications for toxicity when CAPTERO is used continuously in combination with other  
medicines:  
Dose modifications for toxicity when CAPTERO is used continuously in combination with other  
medicines should be made according to Table 3 above for CAPTERO and according to the  
appropriate prescribing information for the other medicine(s).  
Special populations  
Patients with hepatic impairment due to liver metastases:  
In patients with mild to moderate hepatic impairment due to liver metastases, no starting dose  
adjustment is necessary. However, such patients should be carefully monitored. Patients with severe  
hepatic impairment have not been studied (see section 4.3).  
Patients with renal impairment:  
CAPTERO is contraindicated in patients with severe renal impairment (creatinine clearance below  
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30 mL/min) (see section 4.3).  
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 (creatinine clearance 30 – 50 mL/min) 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), no adjustment in starting dose is  
recommended. Careful monitoring and prompt treatment interruption is recommended if the patient  
develops a Grade 2, 3 or 4 adverse event, with subsequent dose adjustment as outlined in the table  
above. The dose adjustment recommendations for patients with moderate renal impairment apply  
both to monotherapy and combination use (see sections 4.3 and 5.2).  
Children:  
Safety and efficacy in children have not been established.  
Elderly:  
No adjustment of the starting dose is needed for CAPTERO monotherapy. However, severe Grade 3  
or 4 treatment-related adverse events were more frequent in patients over 60 years of age compared  
to younger patients. Careful monitoring of elderly patients is advisable.  
For treatment with CAPTERO:  
•
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. For patients 60 years of age or more treated with the combination of CAPTERO plus  
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docetaxel, a starting dose reduction of CAPTERO to 75 % (950 mg/m2 twice daily) is  
recommended. If no toxicity is observed in patients ≥ 60 years of age treated with a reduced  
CAPTERO starting dose in combination with docetaxel, the dose of CAPTERO may be cautiously  
escalated to 1 250 mg/m2 twice daily.  
•
In combination with irinotecan: For patients 65 years of age or more treated with the combination  
of CAPTERO and irinotecan, a starting dose reduction of CAPTERO to 800 mg/m2 twice daily is  
recommended.  
Method of administration  
CAPTERO should be swallowed whole with water within 30 minutes after a meal.  
CAPTERO should not be crushed or cut (see section 4.4).  
4.3  
Contraindications  
•
•
•
•
Hypersensitivity to capecitabine or to any of the excipients listed in section 6.1.  
Patients with a known hypersensitivity to 5-fluorouracil (5-FU, a capecitabine metabolite).  
History of severe and unexpected reactions to fluoropyrimidine therapy.  
Patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see  
section 4.4).  
•
•
•
•
•
During pregnancy and lactation (see section 4.6).  
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 sorivudine or its chemically related analogues, such as  
brivudine (see sections 4.4 and 4.5 for medicine-medicine interaction).  
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•
If contraindications exist to any of the medicines in the combination regimen, that combination  
medicine 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 erythrodysaesthesia). 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 CAPTERO is given  
concomitantly with known nephrotoxic medicines. Acute renal failure secondary to dehydration might  
be potentially fatal. If Grade 2 (or higher) dehydration occurs, CAPTERO treatment should be  
immediately interrupted and the dehydration corrected. Treatment should not be restarted until the  
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patient is rehydrated and any precipitating causes have been corrected or controlled. Dose  
modifications should be applied for the precipitating adverse event as necessary (see section 4.2).  
Hand-foot syndrome:  
Hand-foot syndrome is also known as hand-foot skin reaction or palmar-plantar erythrodysaesthesia  
or chemotherapy-induced acral erythema. Grade 1 hand-foot syndrome is defined as numbness,  
dysaesthesia/paraesthesia, tingling, painless swelling or erythema of the hands and/or feet and/or  
discomfort which does not disrupt the patient's normal activities.  
Grade 2 hand-foot syndrome is painful erythema and swelling of the hands and/or feet and/or  
discomfort affecting the patient's activities of daily living. Persistent or severe hand-foot syndrome  
(Grade 2 and above) can eventually lead to loss of fingerprints which could impact patient  
identification. Grade 3 hand-foot syndrome is defined as moist desquamation, ulceration, blistering or  
severe pain of the hands and/or feet and/or severe discomfort that cause the patient to be unable to  
work or perform activities of daily living.  
If Grade 2 or 3 hand-foot syndrome occurs, administration of CAPTERO should be interrupted until  
the event resolves or decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome,  
subsequent doses of CAPTERO should be decreased. When capecitabine and cisplatin are used in  
combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary  
prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the  
efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome  
prophylaxis in patients treated with CAPTERO.  
Cardiotoxicity:  
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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 dysrhythmias (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, dysrhythmias 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 isoenzyme 2C9 system by capecitabine. Patients receiving concomitant  
capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant  
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response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted  
accordingly (see section 4.5).  
Sorivudine and analogues:  
Sorivudine or its chemically related analogues, such as brivudine, must not be administered  
concomitantly with CAPTERO. Fatal cases have been reported following concomitant use of  
CAPTERO and brivudine. There must be at least a 4-week waiting period between end of treatment  
with brivudine and start of CAPTERO. Treatment with brivudine can be started 24 hours after the last  
dose of CAPTERO (see sections 4.3 and 4.5). In the event of accidental administration of brivudine  
to patients being treated with CAPTERO, effective measures should be taken to reduce the toxicity of  
CAPTERO. 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, CAPTERO should be  
carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or  
absence of liver metastasis.  
Hyperbilirubinaemia:  
CAPTERO can induce hyperbilirubinaemia. Administration of CAPTERO 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 may be resumed when bilirubin  
decreases to ≤ 3,0 x ULN or hepatic aminotransferases decreases 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:  
Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and  
neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity.  
Patients with low or absent DPD activity, an enzyme involved in fluorouracil degradation, are at  
increased risk for severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although  
DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or  
certain compound heterozygous mutations in the DPYD gene locus (e.g. DPYD*2A, c.1679T>G,  
c.2846A>T and c.1236G>A/HapB3 variants), which can cause complete or near complete absence of  
DPD enzymatic activity (as determined from laboratory assays), have the highest risk of life-  
threatening or fatal toxicity and should not be treated with CAPTERO (see section 4.3). No dose has  
been proven safe for patients with complete absence of DPD activity.  
Patients with certain heterozygous DPYD variants (including DPYD*2A, c.1679T>G, c.2846A>T and  
c.1236G>A/HapB3 variants) have been shown to have increased risk of severe toxicity when treated  
with capecitabine.  
The frequency of the heterozygous DPYD*2A 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. Genotyping for these alleles is recommended to identify patients at increased risk for  
severe toxicity. Data on the frequency of these DPYD variants in populations other than Caucasian is  
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limited. It cannot be excluded that other rare variants may also be associated with an increased risk of  
severe toxicity.  
For patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD  
gene) and where the benefits of CAPTERO are considered to outweigh the risks (taking into account  
the suitability of an alternative nonfluoropyrimidine chemotherapeutic regimen), these patients must  
be treated with extreme caution and frequent monitoring, with dose adjustment according to toxicity. A  
reduction of the starting dose in these patients may be considered to avoid serious toxicity. There is  
insufficient data to recommend a specific dose in patients with partial DPD activity as measured by  
specific test. It has been reported that the DPYD*2A, c.1679T>G variants lead to a greater reduction  
in enzymatic activity than the other variants, with a higher risk of side effects. The consequences of a  
reduced dose for efficacy are currently uncertain. Therefore, in the absence of serious toxicity the  
dose could be increased while carefully monitoring the patient.  
The patients who tested negative for the above-mentioned alleles may still have a risk of severe  
adverse events.  
In patients with unrecognised DPD deficiency treated with capecitabine as well as in those patients  
who test negative for specific DPYD variations, life-threatening toxicities manifesting as acute  
overdose may occur (see section 4.9). In the event of Grade 2 – 4 acute toxicity, treatment must be  
discontinued immediately. Permanent discontinuation should be considered based on clinical  
assessment of the onset, duration and severity of the observed toxicities.  
Ophthalmological complications:  
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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:  
CAPTERO can induce severe skin reactions, such as Stevens-Johnson syndrome and toxic  
epidermal necrolysis. CAPTERO should be permanently discontinued in patients who experience a  
severe skin reaction during treatment.  
Lactose:  
As CAPTERO contains anhydrous lactose as an excipient, patients with rare hereditary problems of  
galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take  
CAPTERO.  
CAPTERO tablets should not be crushed or cut. In case of exposure of either patient or caregiver to  
crushed or cut CAPTERO, adverse drug reactions (ADRs) could occur (see section 4.8).  
4.5  
Interaction with other medicines 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 CAPTERO (see  
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sections 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 CAPTERO.  
Cytochrome P-450 2C9 substrates: Other than warfarin, no formal interaction studies between  
capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when  
CAPTERO 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 CAPTERO 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 CAPTERO.  
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 CAPTERO 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 CAPTERO with phenytoin.  
Patients taking phenytoin concomitantly with CAPTERO should be regularly monitored for increased  
phenytoin plasma concentrations.  
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Folinic acid (leucovorin)/folic acid: A combination study with capecitabine and folinic acid  
(leucovorin) 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 CAPTERO alone  
using the intermittent regimen is 3 000 mg/m2 per day, whereas it is only 2 000 mg/m2 per day when  
CAPTERO was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant  
when switching from 5-FU/leucovorin 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.  
Antacids: The effect of an antacid containing aluminium hydroxide and magnesium hydroxide on the  
pharmacokinetics of capecitabine was investigated. There was a small increase in plasma  
concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3 major  
metabolites (5'-DFUR, 5-FU and FBAL).  
Allopurinol: Interactions with allopurinol have been observed for 5-FU, with possible decreased  
efficacy of 5-FU. Concomitant use of allopurinol with CAPTERO should be avoided.  
Interferon alpha: The MTD of CAPTERO 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 CAPTERO was used alone.  
Radiotherapy: The MTD of CAPTERO alone using the intermittent regimen is 3 000 mg/m2 per day,  
whereas, when combined with radiotherapy for rectal cancer, the MTD of CAPTERO 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.  
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Oxaliplatin: No clinically significant differences in exposure to CAPTERO or its metabolites, free  
platinum or total platinum occurred when CAPTERO was administered in combination with oxaliplatin  
or in combination with CAPTERO and bevacizumab.  
Bevacizumab: There was no clinically significant effect of bevacizumab on the pharmacokinetic  
parameters of capecitabine or its metabolites in the presence of oxaliplatin.  
Food interaction:  
In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal.  
Since current safety and efficacy data are based upon administration with food, it is recommended  
that capecitabine be administered with food. Administration with food decreases the rate of  
capecitabine absorption (see section 5.2).  
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  
CAPTERO may cause foetal harm if administered to pregnant women. In reproductive toxicity studies  
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in animals, capecitabine administration caused embryolethality and teratogenicity. These findings are  
expected effects of fluoropyrimidine derivatives. CAPTERO is contraindicated during pregnancy (see  
section 4.3).  
Lactation  
It is not known whether CAPTERO 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, breastfeeding should be discontinued while  
receiving treatment with capecitabine and for 2 weeks after the final dose (see section 4.3).  
Fertility  
There is no data on CAPTERO 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.  
4.7  
Effects on ability to drive and use machines  
CAPTERO has minor or moderate influence on the ability to drive and use machines. CAPTERO may  
cause dizziness, fatigue and nausea.  
4.8  
Undesirable effects  
Summary of the safety profile  
The overall safety profile of CAPTERO is based on data from over 3 000 patients treated with  
capecitabine as monotherapy, or capecitabine in combination with different chemotherapy regimens in  
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multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer,  
metastatic colorectal cancer and adjuvant colon cancer populations are comparable.  
The most frequently reported and/or clinically relevant treatment-related adverse drug reactions  
(ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain,  
stomatitis), hand-foot syndrome (palmar-plantar erythrodysaesthesia), fatigue, asthenia, anorexia,  
cardiotoxicity, increased renal dysfunction in those with pre-existing compromised renal function, and  
thrombosis/embolism.  
Tabulated list of adverse reactions  
ADRs considered by the investigator to be possibly, probably, or remotely related to the administration  
of CAPTERO are listed in Table 4 for CAPTERO given as monotherapy and in Table 5 for CAPTERO  
given in combination with different chemotherapy regimens in multiple indications.  
CAPTERO monotherapy:  
Table 4: Summary of related ADRs reported in patients treated with CAPTERO monotherapy  
System organ class  
Frequent  
Less frequent  
Severe and/or life-threatening  
(Grade 3 – 4) or considered  
medically  
All grades  
relevant and those reported  
during  
post-marketing  
experience*  
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Infections and  
infestations  
Herpes viral infection  
Nasopharyngitis  
Sepsis  
Urinary tract infection Cellulitis  
Tonsillitis  
Lower respiratory tract infection  
Pharyngitis  
Oral candidiasis  
Influenza  
Gastroenteritis  
Fungal infection  
Infection  
Tooth abscess  
Lipoma  
Neoplasm benign,  
malignant and  
unspecified (including cysts  
and polyps)  
Blood and  
Neutropenia  
Anaemia  
Febrile neutropenia  
Pancytopenia  
lymphatic system  
disorders  
Granulocytopenia  
Thrombocytopenia  
Leukopenia  
Haemolytic anaemia  
International normalised ratio  
(INR) increased  
Prothrombin time prolonged  
Hypersensitivity  
Immune system  
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disorders  
Metabolism and  
Anorexia  
Diabetes  
nutrition disorders  
Dehydration  
Weight decreased  
Hypokalaemia  
Appetite disorder  
Malnutrition  
Hypertriglyceridaemia  
Confusional state  
Panic attack  
Psychiatric  
disorders  
Insomnia  
Depression  
Depressed mood  
Libido decreased  
Aphasia  
Nervous system  
disorders  
Headache  
Lethargy  
Memory impairment  
Ataxia  
Dizziness  
Paraesthesia  
Dysgeusia  
Syncope  
Balance disorder  
Sensory disorder  
Neuropathy peripheral  
Toxic leukoencephalopathy*  
Visual acuity reduced  
Diplopia  
Eye disorders  
Lacrimation increased,  
Conjunctivitis  
Eye irritation  
Lacrimal duct stenosis*  
Corneal disorders* Keratitis*  
Punctate keratitis*  
Vertigo  
Ear and labyrinth  
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disorders  
Ear pain  
Cardiac disorders  
Angina unstable  
Angina pectoris Myocardial  
ischaemia/infarction  
Atrial fibrillation  
Dysrhythmia  
Tachycardia  
Sinus tachycardia  
Palpitations  
Ventricular fibrillation*  
QT prolongation*  
Torsade de pointes*  
Bradycardia*  
Vasospasm*  
Vascular  
disorders  
Thrombophlebitis  
Deep vein thrombosis  
Hypertension  
Petechiae  
Hypotension  
Hot flushes  
Peripheral coldness  
Pulmonary embolism  
Pneumothorax  
Haemoptysis  
Respiratory,  
thoracic and  
mediastinal  
disorders  
Dyspnoea  
Epistaxis  
Cough  
Rhinorrhoea  
Asthma  
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Dyspnoea exertional  
Gastrointestinal  
disorders  
Diarrhoea  
Intestinal obstruction  
Ascites  
Vomiting  
Nausea  
Enteritis  
Stomatitis  
Gastritis  
Abdominal pain  
Gastrointestinal  
haemorrhage  
Constipation  
Upper abdominal pain  
Dyspepsia  
Dysphagia  
Abdominal pain lower,  
Oesophagitis  
Abdominal discomfort  
Gastroesophageal reflux  
disease  
Flatulence  
Colitis  
Dry mouth  
Blood in stool  
Jaundice  
Hepatobiliary  
disorders  
Hyperbilirubinaemia  
Liver function test  
abnormalities  
Palmar-plantar  
erythrodysaesthesia  
syndrome  
Hepatic failure*  
Cholestatic hepatitis*  
Blister  
Skin and  
subcutaneous  
tissue disorders  
Skin ulcer  
Rash  
Rash  
Urticaria  
Alopecia  
Photosensitivity reaction  
Palmar erythema  
Swelling face  
Purpura  
Erythema  
Dry skin  
Pruritus  
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Skin hyperpigmentation Rash  
macular  
Radiation recall syndrome  
Cutaneous lupus  
erythematosus*  
Skin desquamation  
Dermatitis  
Severe skin reactions* such as  
Stevens-Johnson  
syndrome and toxic  
epidermal necrolysis (see  
section 4.4)  
Pigmentation disorder Nail  
disorder  
Musculoskeletal  
and connective  
tissue disorders  
Pain in extremity  
Back pain  
Joint swelling  
Bone pain  
Arthralgia  
Facial pain  
Musculoskeletal stiffness  
Muscular weakness  
Hydronephrosis  
Renal and urinary  
disorders  
Urinary incontinence  
Haematuria  
Nocturia  
Blood creatinine increased  
Vaginal haemorrhage  
Reproductive  
system and  
breast disorders  
General disorders  
and  
Fatigue  
Asthenia  
Pyrexia  
Oedema  
Chills  
administration site  
Influenza-like illness Rigors  
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conditions  
Oedema peripheral Malaise  
Chest pain  
Body temperature increased  
* Side effects reported during post-marketing experience  
** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia  
syndrome can eventually lead to loss of fingerprints (see section 4.4)  
CAPTERO in combination therapy:  
Table 5 lists ADRs associated with the use of CAPTERO in combination with different chemotherapy  
regimens in multiple indications. ADRs are added to the appropriate frequency grouping 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 CAPTERO monotherapy or seen at a higher frequency grouping  
compared to CAPTERO monotherapy (see Table 4). ADRs reported less frequently for CAPTERO in  
combination therapy are consistent with the ADRs reported for CAPTERO monotherapy or reported  
for monotherapy with the combination medicine (in literature and/or respective summary of product  
characteristics).  
Some of the ADRs are reactions frequently seen with the combination medicine (e.g. peripheral  
sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab). However, an  
exacerbation by CAPTERO therapy cannot be excluded.  
Table 5: Summary of related ADRs reported in patients treated with CAPTERO in combination  
treatment in addition to those seen with CAPTERO monotherapy or seen at a higher frequency  
grouping compared to CAPTERO monotherapy  
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System organ class  
Frequent  
Frequency unknown  
All grades  
(Post-marketing experience)  
Infections and  
infestations  
Herpes zoster  
Urinary tract infection Oral  
candidiasis  
Upper respiratory tract infection  
Rhinitis  
Influenza  
Infection  
Oral herpes  
Blood and lymphatic system  
disorders  
+Neutropenia  
+Leucopenia  
+Anaemia  
+Neutropenic fever  
Thrombocytopenia  
Bone marrow depression  
+Febrile neutropenia  
Hypersensitivity  
Appetite decreased  
Hypokalaemia Hyponatraemia  
Hypomagnesaemia  
Hypocalcaemia  
Immune system disorders  
Metabolism and nutrition  
disorders  
Hyperglycaemia  
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Psychiatric disorders  
Sleep disorder  
Anxiety  
Nervous system  
disorders  
Paraesthesia  
Dysaesthesia  
Peripheral neuropathy  
Peripheral sensory  
neuropathy  
Dysgeusia  
Headache  
Neurotoxicity  
Tremor  
Neuralgia  
Hypaesthesia  
Lacrimation increased  
Visual disorders  
Dry eye  
Eye disorders  
Eye pain  
Visual impairment  
Vision blurred  
Tinnitus  
Ear and labyrinth  
disorders  
Hypoacusis  
Cardiac disorders  
Atrial fibrillation  
Cardiac ischaemia/infarction  
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Vascular disorders  
Lower limb oedema  
Hypertension  
+Embolism and  
thrombosis  
Flushing  
Hypotension  
Hypertensive crisis  
Hot flush  
Phlebitis  
Respiratory, thoracic and  
Sore throat  
mediastinal system disorders  
Dysaesthesia pharynx  
Hiccups Pharyngolaryngeal  
pain  
Dysphonia  
Gastrointestinal  
disorders  
Constipation  
Dyspepsia  
Upper gastrointestinal  
haemorrhage  
Mouth ulceration Gastritis  
Abdominal distension  
Gastroesophageal reflux  
disease  
Oral pain  
Dysphagia  
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Rectal haemorrhage Abdominal  
pain lower Oral dysaesthesia  
Paraesthesia oral  
Hypoaesthesia oral Abdominal  
discomfort  
Hepatobiliary disorders  
Skin and subcutaneous  
tissue disorders  
Hepatic function abnormal  
Alopecia  
Nail disorder  
Hyperhidrosis  
Rash erythematous Urticaria  
Night sweats  
Musculoskeletal and  
Myalgia  
connective tissue disorders  
Arthralgia  
Pain in extremity  
Pain in jaw  
Muscle spasms Trismus  
Muscular weakness  
Haematuria  
Renal and urinary  
disorder  
Acute renal failure secondary to  
dehydration  
Proteinuria  
Creatinine renal clearance  
decreased Dysuria  
Pyrexia  
General disorders and  
administration site conditions  
Weakness  
+Lethargy  
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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  
Investigations  
Blood pressure increased  
Confusion  
Injury, poisoning and  
procedural complications  
+ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”,  
the frequency count was based on Grade 3 – 4 ADRs. ADRs are added according to the highest  
incidence seen in any of the major combination trials.  
Description of selected adverse reactions  
Hand-foot syndrome (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 CAPTERO monotherapy trials (comprising studies in  
adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast  
cancer). A frequency of 63 % was observed in the capecitabine/docetaxel arm for the treatment of  
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metastatic breast cancer. For the CAPTERO 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 clinical trials of 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 43 % of patients after a median time of  
239 [95 % CI 201, 288] days after starting treatment with capecitabine. In all studies combined, the  
following covariates were statistically significantly associated with an increased risk of developing  
HFS: increasing capecitabine starting dose (gramme), decreasing cumulative capecitabine dose  
(0,1*kg), increasing relative dose intensity in the first six weeks, increasing duration of study treatment  
(weeks), increasing age (by 10 year increments), female gender, and good ECOG performance status  
at baseline (0 versus ≥ 1).  
Diarrhoea (see section 4.4):  
CAPTERO can induce the occurrence of diarrhoea, which has been observed in up to 50 % of  
patients. The results of a meta-analysis of 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 (gramme), 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):  
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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 (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, encephalopathy was also associated with the use of capecitabine monotherapy  
with an incidence of less than 0,1 %.  
Exposure to crushed or cut CAPTERO tablets:  
In the instance of exposure to crushed or cut CAPTERO tablets, the following adverse drug reactions  
have been reported: eye irritation, eye swelling, skin rash, headache, paraesthesia, diarrhoea,  
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.  
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The results of a meta-analysis of 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 patients treated with capecitabine showed that in all studies  
combined, female gender was statistically significantly associated with an increased risk of developing  
HFS and diarrhoea and with a decreased risk of developing neutropenia.  
Patients with renal impairment (see sections 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, 41 % in mild and 54 % in moderate renal impairment, 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 CAPTERO is important. It allows  
continued monitoring of the benefit/risk balance of CAPTERO. Healthcare providers are asked to  
report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions  
Reporting Form”, found online under SAHPRA’s publications:  
https://www.sahpra.org.za/Publications/Index/8.  
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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  
Pharmacodynamic properties  
5.1  
Category and class: A 26 – Cytostatic agents.  
Pharmacotherapeutic group: Cytostatic (antimetabolite).  
ATC code: L01BC06.  
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate in vitro, which functions as an orally  
administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU) in vivo. Capecitabine is activated  
via several enzymatic steps (see section 5.2). The enzyme involved in the final conversion to 5-FU,  
thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeit  
usually at lower levels. In human cancer xenograft models capecitabine demonstrated a synergistic  
effect in combination with docetaxel, which may be related to the upregulation of thymidine  
phosphorylase by docetaxel.  
There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation  
reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of  
deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein  
synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to  
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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.  
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'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-  
fluorouridine (5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30 % – 35 %  
higher on day 14. Capecitabine dose reduction decreases systemic exposure to 5-FU more than  
dose-proportionally, due to non-linear pharmacokinetics for the active metabolite.  
Absorption  
After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive  
conversion to the metabolites, 5'-DFCR and 5’-DFUR. Administration with food decreases the rate of  
capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of  
the subsequent metabolite 5-FU. At the dose of 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  
α-fluoro-β-alanine (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.  
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Biotransformation  
Capecitabine is first metabolised by hepatic carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-DFCR),  
which is then converted to 5'-deoxy -5-fluorouridine (5'-DFUR) by cytidine deaminase, principally  
located in the liver and tumour tissues. Further catalytic activation of 5'-DFUR then occurs by  
thymidine phosphorylase (dThyPase) to form 5-FU. Formation of 5-FU occurs preferentially at the  
tumor site by the tumour associated angiogenic factor dThdPase.  
The metabolites of capecitabine become cytotoxic after conversion to 5-FU and anabolites of 5-FU. 5-  
FU is further catabolised to the inactive metabolites dihydro-5-fluoruracil (FUH2), 5-fluoro-  
ureidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL) via dihydropyrimidine dehydrogenase  
(DPD), which is rate limiting.  
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. 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, but did  
not increase subsequently (day 22). At therapeutic doses, the pharmacokinetics of capecitabine and  
its metabolites were dose proportional; except for 5-FU. After oral administration capecitabine  
metabolites are primarily recovered in the urine. 95,5 % of administered capecitabine dose is  
recovered in urine. Faecal excretion is minimal (2,6 %). The major metabolite excreted in urine is  
FBAL, which represents 57 % of the administered dose. About 3 % of the administered dose is  
excreted in urine as unchanged active ingredient, capecitabine. The interpatient variability in Cmax and  
AUC of 5-FU was greater than 85 %.  
Combination therapy  
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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 (the most important metabolite of capecitabine).  
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, ASAT and ALAT  
had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.  
Patients with hepatic impairment due to liver metastases:  
According to a pharmacokinetic study in cancer patients with mild to moderate liver impairment due to  
liver metastases, the bioavailability of capecitabine and exposure to 5-FU may increase compared to  
patients with no liver impairment. There are no pharmacokinetic data on patients with severe hepatic  
impairment.  
Patients with renal impairment:  
Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no  
evidence for an effect of creatinine clearance on the pharmacokinetics of intact medicine 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:  
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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  
No further information of relevance available.  
6.  
PHARMACEUTICAL PARTICULARS  
List of excipients  
6.1  
Tablet core:  
Lactose anhydrous  
Croscarmellose sodium  
Hypromellose (E464)  
Microcrystalline cellulose  
Magnesium stearate.  
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Film-coating:  
Opadry Pink consisting of:  
Hypromellose (E464)  
Titanium dioxide (E171)  
Talc (E553b)  
Iron oxide red (E172)  
Iron oxide yellow (E172).  
6.2  
Incompatibilities  
Not applicable.  
6.3  
Shelf life  
24 months.  
6.4  
Special precautions for storage  
Store at or below 25 °C.  
Protect from light and moisture.  
HDPE bottles and blister strips are enclosed in an outer carton.  
Keep the blister strips in outer carton until required for use.  
Keep the HDPE container tightly closed.  
6.5  
Nature and contents of container  
HDPE bottle:  
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White opaque high-density polyethylene (HDPE) bottle, closed with a child resistant plastic cap with  
pulp liner, containing desiccant 1,0 gramme silica gel canister.  
Pack sizes:  
CAPTERO 150: 60 tablets.  
CAPTERO 500: 112 or 120 tablets.  
Blister strips:  
Alu-alu blister strip of cold PVC/aluminium/OPA forming foil and plain aluminium lidding foil, containing  
10 tablets per blister strip,  
Or  
Blister strip of clear PVC/PE/PVdc forming foil and plain aluminium lidding foil, containing 10 tablets  
per blister strip.  
Pack size: 10 tablets per blister. 3 or 6 blisters packed in a box.  
Not all pack sizes may be marketed.  
6.6  
Special precautions for disposal and other handling  
Procedures for safe handling of cytotoxic medicines should be followed.  
7.  
HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Jean Park Chambers  
252 Jean Avenue  
Building 6, Unit 17 & 18  
Centurion 0157  
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8.  
REGISTRATION NUMBER  
CAPTERO 150: 55/26/0425.423  
CAPTERO 500: 54/26/0267.265  
9.  
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
CAPTERO 150: 12 October 2021  
CAPTERO 500: 13 March 2021  
10.  
DATE OF REVISION OF THE TEXT  
01 September 2020  
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