4.1. Therapeutic indications

Capecitabine is indicated for the treatment of:

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

- metastatic colorectal cancer (see section 5.1).

- 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 should only be prescribed by a qualified physician experienced in the utilisation of anti-neoplastic medicinal products. Careful monitoring during the first cycle of treatment is recommended for all patients.

Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard and reduced dose calculations according to body surface area for starting doses of Capecitabine of 1250 mg/m2 and 1000 mg/m2 are provided in tables 1 and 2, respectively.

Posology

Recommended posology (see section 5.1):

Monotherapy

Colon, colorectal and breast cancer

Given as monotherapy, the recommended starting dose for capecitabine in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.

Combination therapy

Colon, colorectal and gastric cancer

In combination treatment, the recommended starting dose of capecitabine should be reduced to 800 – 1000 mg/m2 when administered twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m2 twice daily when administered continuously (see section 5.1). For combination with irinotecan, the recommended starting dose is 800 mg/m² when administered twice daily for 14 days followed by a 7-day rest period combined with irinotecan 200 mg/m² on day 1. The inclusion of bevacizumab in a combination regimen has no effect on the starting dose of capecitabine. Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of product characteristics should be started prior to cisplatin administration for patients receiving the capecitabine plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the capecitabine plus oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended for a duration of 6 months.

Breast cancer

In combination with docetaxel, the recommended starting dose of capecitabine in the treatment of metastatic breast cancer is 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period, combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Premedication with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for patients receiving the capecitabine plus docetaxel combination.

Capecitabine Dose Calculations

Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of capecitabine of 1250 mg/m2

Dose level 1250 mg/m2 (twice daily)

Full dose

1250 mg/m2

Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)

Reduced dose (75%)

950 mg/m2

Reduced dose (50%)

625 mg/m2

Body Surface Area (m2)

Dose per administration (mg)

150 mg

500 mg

Dose per administration (mg)

Dose per administration (mg)

≤1.26

1500

-

3

1150

800

1.27 - 1.38

1650

1

3

1300

800

1.39 - 1.52

1800

2

3

1450

950

1.53 - 1.66

2000

-

4

1500

1000

1.67 - 1.78

2150

1

4

1650

1000

1.79 - 1.92

2300

2

4

1800

1150

1.93 - 2.06

2500

-

5

1950

1300

2.07 - 2.18

2650

1

5

2000

1300

≥2.19

2800

2

5

2150

1450

Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of capecitabine of 1000 mg/m2

Dose level 1000 mg/m2 (twice daily)

Full dose

1000 mg/m2

Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)

Reduced dose (75%)

750 mg/m2

Reduced dose (50%)

500 mg/m2

Body Surface Area (m2)

Dose per administration (mg)

150 mg

500 mg

Dose per administration (mg)

Dose per administration (mg)

≤1.26

1150

1

2

800

600

1.27 - 1.38

1300

2

2

1000

600

1.39 - 1.52

1450

3

2

1100

750

1.53 - 1.66

1600

4

2

1200

800

1.67 - 1.78

1750

5

2

1300

800

1.79 - 1.92

1800

2

3

1400

900

1.93 - 2.06

2000

-

4

1500

1000

2.07 - 2.18

2150

1

4

1600

1050

≥2.19

2300

2

4

1750

1100

Posology adjustments during treatment:

General

Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time. For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. Patients taking capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of capecitabine omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity:

Table 3 Capecitabine dose reduction schedule (3-weekly cycle or continuous treatment)

Toxicity grades*

Dose changes within a treatment cycle

Dose adjustment for next cycle/dose

(% of starting dose)

• Grade 1

Maintain dose level

Maintain dose level

• Grade 2

-1st appearance

Interrupt until resolved to grade 0-1

100%

-2nd appearance

75%

-3rd appearance

50%

-4th appearance

Discontinue treatment permanently

Not applicable

• Grade 3

-1st appearance

Interrupt until resolved to grade 0-1

75%

-2nd appearance

50%

-3rd appearance

Discontinue treatment permanently

Not applicable

• Grade 4

-1st appearance

Discontinue permanently

or

If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1

50%

-2nd appearance

Discontinue permanently

Not applicable

*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 4.0. For hand-foot syndrome and hyperbilirubinemia, see section 4.4.

Haematology

Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of <100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below 1.0 x 109/L or that the platelet count drops below 75 x 109/L, treatment with capecitabine should be interrupted.

Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with other medicinal products

Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination with other medicinal products should be made according to table 3 above for capecitabine and according to the appropriate summary of product characteristics for the other medicinal product(s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the other medicinal product(s), then administration of all therapy should be delayed until the requirements for restarting all medicinal products are met.

During a treatment cycle for those toxicities considered by the treating physician not to be related to capecitabine, capecitabine should be continued and the dose of the other medicinal product should be adjusted according to the appropriate Prescribing Information.

If the other medicinal product(s) have to be discontinued permanently, capecitabine treatment can be resumed when the requirements for restarting capecitabine are met.

This advice is applicable to all indications and to all special populations.

Dose modifications for toxicity when capecitabine is used continuously in combination with other medicinal products:

Dose modifications for toxicity when capecitabine is used continuously in combination with other medicinal products should be made according to table 3 above for capecitabine and according to the appropriate summary of product characteristics for the other medicinal product(s).

Posology adjustments for special populations:

Hepatic impairment

Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.

Renal impairment

Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m2 is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m2. In patients with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose adjustment as outlined in table 3 above. If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, capecitabine should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use (see also section “Elderly” below).

Elderly

During capecitabine monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment related adverse reactions were more frequent in patients ≥60 years of age compared to younger patients.

When capecitabine was used in combination with other medicinal products, elderly patients (≥65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to discontinuation, compared to younger patients. Careful monitoring of patients ≥60 years of age is advisable.

In combination with docetaxel: an increased incidence of grade 3 or 4 treatment related adverse reactions and treatment related serious adverse reactions were observed in patients 60 years of age or more (see section 5.1). For patients 60 years of age or more, a starting dose reduction of capecitabine to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in patients ≥60 years of age treated with a reduced capecitabine starting dose in combination with docetaxel, the dose of capecitabine may be cautiously escalated to 1250 mg/m2 twice daily.

Paediatric population

There is no relevant use of capecitabine in the paediatric population in the indications colon, colorectal, gastric and breast cancer.

Method of administration

Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal.

Capecitabine tablets should not be crushed or cut.

4.3. Contraindications

• History of severe and unexpected reactions to fluoropyrimidine therapy,

• Hypersensitivity to capecitabine 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 include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.

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 (also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema). Grade 1 hand-foot syndrome is defined as numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patient's normal activities.

Grade 2 hand- foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living.

Grade 3 hand- foot syndrome is moist desquamation, ulceration, blistering and severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-foot syndrome (Grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand- foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1.

Following grade 3 hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated with capecitabine.

Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsade de pointes, and bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine. Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris (see section 4.8).

Hypo- or hypercalcaemia. Hypo- or hypercalcaemia has been reported during capecitabine treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia (see section 4.8).

Central or peripheral nervous system disease. Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy (see section 4.8).

Diabetes mellitus or electrolyte disturbances. Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment.

Coumarin-derivative anticoagulation. In a interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly (see section 4.5).

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. 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 (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 is recommended despite uncertainties regarding optimal pre-treatment testing methodologies. Consideration should be given to applicable clinical guidelines.

Impaired kidney function can lead to increased blood uracil levels with risk for misdiagnosis of DPD deficiency in patients with moderate renal impairment. Capecitabine is contraindicated in patients with severe renal impairment (see section 4.3).

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 variants) 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.

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. Blood uracil levels should be interpreted with caution in patients with impaired kidney function (see 'Testing for DPD deficiency' above).

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.

As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Capecitabine tablets should not be crushed or cut. In case of exposure of either patient or caregiver to crushed or cut capecitabine 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 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 capecitabine is co-administered with 2C9 substrates (e.g., phenytoin). See also interaction with coumarin-derivative anticoagulants below, and section 4.4.

Coumarin-derivative anticoagulants: altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These reactions occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within one month after stopping capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for 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 3000 mg/m2 per day whereas it is only 2000 mg/m2 per day when capecitabine was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV to a capecitabine regimen. This may also be relevant with folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid.

Antacid: the effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'- DFUR, 5-FU and FBAL).

Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided.

Interferon alpha: the MTD of capecitabine was 2000 mg/m2 per day when combined with interferon alpha- 2a (3 MIU/m2 per day) compared to 3000 mg/m2 per day when capecitabine was used alone.

Radiotherapy: the MTD of capecitabine alone using the intermittent regimen is 3000 mg/m2 per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2000 mg/m2 per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy.

Oxaliplatin: no clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.

Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.

Food interaction

In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food. Administration with food decreases the rate of capecitabine absorption (see section 5.2).

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 3000 patients treated with capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable. See section 5.1 for details of major studies, including study designs and major efficacy results.

The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.

Tabulated 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 a monotherapy and in table 5 for capecitabine given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Capecitabine Monotherapy:

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

Table 4 Summary of related ADRs reported in patients treated with capecitabine monotherapy

Body System

Very Common

All grades

Common

All grades

Uncommon

Severe and/or Life-threatening (grade 3-4) or considered medically relevant

Rare/Very Rare

(Post-Marketing Experience)

Infections and Infestations

-

Herpes viral infection, Nasopharyngitis, Lower respiratory tract infection

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

Neoplasm benign, malignant and unspecified

-

-

Lipoma

Blood and lymphatic system disorders

-

Neutropenia, Anaemia

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

Immune system disorders

-

-

Hypersensitivity

Angioedema (rare)

Metabolism and nutrition disorders

Anorexia

Dehydration, Weight decreased

Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia,

Psychiatric disorders

-

Insomnia, Depression

Confusional state, Panic attack, Depressed mood, Libido decreased

Nervous system disorders

-

Headache, Lethargy Dizziness, Parasthesia Dysgeusia

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

Toxic 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/ infarction, 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, Blood in stool

Hepatobiliary disorders

-

Hyperbilirubinemia, 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.)

Muskuloskeletal 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 3000 patients. ADRs are added to the appropriate frequency grouping (Very common or Common) according to the highest incidence seen in any of the major clinical trials and are only added when they were seen in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy (see table 4). Uncommon ADRs reported for capecitabine in combination therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for monotherapy with the combination medicinal product (in literature and/or respective summary of product characteristics).

Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however an exacerbation by capecitabine therapy cannot 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 disorders

Sore throat, Dysaesthesia pharynx

Hiccups, Pharyngolaryngeal pain, Dysphonia

Gastrointestinal disorders

Constipation, Dyspepsia

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

Hepatobiliary disorders

-

Hepatic function abnormal

Skin and subcutaneous tissue disorders

Alopecia, Nail disorder

Hyperhidrosis, Rash erythematous, Urticaria, Night sweats

Musculoskeletal and connective tissue disorders

Myalgia, Arthralgia, Pain in extremity

Pain in jaw , Muscle spasms, Trismus, Muscular weakness

Renal and urinary disorder

-

Haematuria, Proteinuria, Creatinine renal clearance decreased, Dysuria

Acute renal failure secondary to dehydration (rare)

General disorders and administration site conditions

Pyrexia, Weakness, +Lethargy, Temperature intolerance

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

Injury, poisoning and procedural complications

-

Contusion

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

Description of selected adverse reactions

Hand-foot syndrome (see section 4.4):

For the capecitabine dose of 1250 mg/m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 53% to 60% of all-grades HFS was observed in capecitabine monotherapy trials (comprising studies in adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast cancer) and a frequency of 63% was observed in the capecitabine/docetaxel arm for the treatment of metastatic breast cancer. For the capecitabine dose of 1000 mg/m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination therapy

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment with capecitabine. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female gender, and good ECOG performance status at baseline (0 versus ≥1).

Diarrhoea (see section 4.4):

Capecitabine can induce the occurrence of diarrhoea, which has been observed in up to 50% of patients.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhoea: increasing capecitabine starting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 year increments), and female gender. The following covariates were statistically significantly associated with a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) and increasing relative dose intensity in the first six weeks.

Cardiotoxicity (see section 4.4) :

In addition to the ADRs described in tables 4 and 5, the following ADRs with an incidence of less than 0.1% were associated with the use of capecitabine monotherapy based on a pooled analysis from clinical safety data from 7 clinical trials including 949 patients (2 phase III and 5 phase II clinical trials in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, cardiac failure, sudden death, and ventricular extrasystoles.

Encephalopathy:

In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis from clinical safety data from 7 clinical trials, encephalopathy was also associated with the use of Capecitabine monotherapy with an incidence of less than 0.1%.

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 4700 patients treated with capecitabine showed that in all studies combined, increasing age (by 10 year increments) was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Gender

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Patients with renal impairment (see section 4.2, 4.4, and 5.2):

An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) with baseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions compared to patients with normal renal function (36% in patients without renal impairment n=268, vs. 41% in mild n=257 and 54% in moderate n=59, respectively) (see section 5.2). Patients with moderately impaired renal function show an increased rate of dose reduction (44%) vs. 33% and 32% in patients with no or mild renal impairment and an increase in early withdrawals from treatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mild renal impairment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.