Capecitabine is indicated for the treatment of:

·         For the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer.

·         Metastatic colorectal cancer.

·         First-line treatment of advanced gastric cancer in combination with a platinum-basedregimen.

·         In combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included ananthracycline.

·         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.

Standard Dosage

Capecitabine SPC tablets should be swallowed with water within 30 minutes after the end of a meal.

Monotherapy - Colon, colorectal, breast cancer

The recommended monotherapy starting dose of Capecitabine SPC is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 7 day rest period; given as 3 week cycles.

Combination therapy - Breast cancer

In combination with docetaxel, the recommended starting dose of Capecitabine SPC is 1250 mg/m2 administered twice daily for 2 weeks followed by a 7 day rest period, combined with docetaxel 75 mg/m2 administered as a 1 hour intravenous infusion every 3 weeks.

Pre-medication, according to the docetaxel product information, should be started prior to docetaxel administration for patients receiving capecitabine plus docetaxel combination.

Combination therapy - Colorectal cancer

In combination with oxaliplatin with or without bevacizumab the recommended starting dose of Capecitabine SPC is 1000 mg/m2 twice daily for 2 weeks followed by a 7 day rest period. The first dose of Capecitabine SPC is given on the evening of day 1 and the last dose is given on the morning of day 15. Given as a 3-week cycle, on day 1 every 3 weeks bevacizumab is administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes followed by oxaliplatin administered as a 130 mg/m2 intravenous infusion over 2 hours.

Combination therapy – Adjuvant colon cancer

In combination with oxaliplatin the recommended starting dose of Capecitabine SPC is 1000 mg/m2 twice daily for 2 weeks followed by a 7 day rest period. The first dose of Capecitabine SPC is given on the evening of day 1 and the last dose is given on the morning of day 15. Given as a 3 week cycle, on day 1 oxaliplatin is administered as a 130 mg/m2 intravenous infusion over 2 hours.

Premedication to maintain adequate anti-emesis according to the oxaliplatin product information should be started prior to oxaliplatin administration for patients receiving the Capecitabine SPC plus oxaliplatin combination.

Combination therapy - Oesophagogastric cancer

In triplet combination with epirubicin and cisplatin/oxaliplatin for oesophagogastric cancer, the recommended starting dose of Capecitabine SPC is 625 mg/m2 twice daily as a continuous regimen. Epirubicin is administered as a 50 mg/m2 intravenous bolus on day 1 of a 3 week cycle. Platinum therapy should consist of either cisplatin administered at a dose of 60 mg/m2 given as a 2 hour intravenous infusion on day 1 of a 3 week cycle; or oxaliplatin administered at a dose of 130 mg/m2 given as a 2 hour intravenous infusion on day 1 of a 3 week cycle.

In doublet combination with cisplatin for gastric cancer, the recommended starting dose of Capecitabine SPC is 1000 mg/m2 twice daily for 2 weeks followed by a 7-day rest period. The first dose of Capecitabine SPC is given on the evening of day 1 and the last dose is given on the morning of day 15. Cisplatin is administered at a dose of 80 mg/m2 as a 2 hour intravenous infusion on day 1 of a 3-week cycle.

Pre-medication to maintain adequate hydration and anti-emesis should be started prior to oxaliplatin/cisplatin administration for patients receiving Capecitabine SPC in combination with one of these agents.

The Capecitabine SPC dose is calculated according to body surface area. The following tables show examples of the standard and reduced dose calculations for a starting dose of Capecitabine SPC of 1250 mg/m2 or 1000 mg/m2.

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

Capecitabine SPC of 1250 mg/m2

Table : Standard and reduced dose calculations according to body surface area for a starting dose of Capecitabine SPC of 1000 mg/m2

Duration of Treatment

For metastatic disease, Capecitabine SPC is intended for long-term administration unless clinically inappropriate. In the adjuvant setting, treatment duration is recommended for 24 weeks.

Dosage Adjustment During Treatment

General

Toxicity due to Capecitabine SPC administration may be managed by symptomatic treatment and/or modification of the Capecitabine SPC dose (treatment interruption or dose reduction). Once dose has been reduced, it should not be increased at a later time.

Dosage modifications are not recommended for Grade 1 events. Therapy with Capecitabine SPC should be interrupted if a Grade 2 or 3 adverse experience occurs. Once the adverse event has resolved or decreased in intensity to Grade 1, Capecitabine SPC therapy may be restarted at full dose or as adjusted according to Table. 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 Capecitabine SPC should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Capecitabine SPC omitted for toxicity are not replace

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 SPC. If unscheduled laboratory assessments during a treatment cycle show Grade 3 or 4 haematologic toxicity, treatment with Capecitabine SPC should be interrupted.

The following table shows the recommended dose modifications following toxicity related to Capecitabine SPC.

Table: Capecitabine SPC dose reduction schedule

# 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 3.0). For hand-foot syndrome and hyperbilirubinaemia see PRECAUTIONS.

General combination therapy

Dose modifications for toxicity when Capecitabine SPC is used in combination with other therapies

should be made according to the table above for Capecitabine SPC, and according to the appropriate product information for the other agent(s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either Capecitabine SPC or the other agent(s), then administration of all agents 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 Capecitabine SPC [for example, neurotoxicity, ototoxicity, neurosensory toxicity, fluid retention (pleural effusion, pericardial effusion or ascites), bleeding, gastrointestinal perforations, proteinuria, hypertension], then Capecitabine SPC should be continued and the dose of the other agent adjusted according to the appropriate product information.

If the other agent(s) have to be discontinued permanently, Capecitabine SPC treatment can be resumed when the requirements for restarting Capecitabine SPC are met.

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

Dosage Adjustments in Special Populations

Hepatic Impairment due to liver metastases: Patients with mild to moderate hepatic impairment due to liver metastases, should be carefully monitored when Capecitabine SPC is administered. No starting dose reduction is necessary. Patients with severe hepatic impairment have not been studied.

Renal Impairment: In metastatic colorectal and breast cancer clinical trials, patients with renal impairment had a greater incidence of Grade 3 or 4 adverse reactions than other patients, the incidence increasing with the degree of renal impairment from 35% in patients with normal renal function to 55% in patients with moderate renal impairment (creatinine clearance 30-50 mL/min). Based on the pharmacokinetic data, a dose reduction to 75% is recommended in moderate renal impairment for both monotherapy and combination use. No initial dose reduction is recommended in patients with mild renal impairment (creatinine clearance 51-80 mL/min). Further dose reductions should be made if adverse reactions occur. Capecitabine SPC is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Capecitabine SPC is contraindicated in patients with creatinine clearance below 30 mL/min (see CONTRAINDICATIONS).

Elderly: For Capecitabine SPC monotherapy, no adjustment of the starting dose is needed. However, severe Grade 3 or 4 treatment-related adverse reactions were more frequent in patients over 80 years of age compared to younger patients. When Capecitabine SPC was used in combination with other agents, elderly patients (≥ 65 years of age) experienced more Grade 3 and Grade 4 adverse drug reactions (ADRs), and ADRs that led to discontinuation, compared to younger patients. Careful moving of elderly patients is advisable. For treatment with Capecitabine SPC 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 Capecitabine SPC plus docetaxel, a starting dose reduction of Capecitabine SPC to 75% (950 mg/m2 twice daily) is recommended. For dosage calculations, see Tables.

Dose limiting toxicities

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 nephrotoxicmedicinal 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 Xeloda.

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 section4.8).

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 capecitabinetreatment.

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 iPf atgrea8tment- 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: 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, 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 Xeloda (see section 4.3). No dose has been proven safe for patients with complete absence of DPD activity.

For patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the benefits of Xeloda are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution and frequent monitoring with dose adjusment according to toxicity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by specific test.

In patients with unrecognised DPD deficiency treated with capecitabine, life-threatening toxicities manifesting as acute overdose may occur (see section 4.9). In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities.

Ophthalmologic complications: Patients should be carefully monitored for ophthalmological complications such as keratitis and corneal disorders, especially if they have a prior history of eye disorders. Treatment of eye disorders should be initiated as clinically appropriate.

Severe skin reactions: Xeloda can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Xeloda 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Post marketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time Capecitabine was introduced.

These events occurred within several days and up to several months after initiating Capecitabine therapy and, in a few cases, within 1 month after stopping Capecitabine. 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.

In 251 patients with metastatic breast cancer who received combination of Capecitabine SPC and docetaxel, Grade 3 hyperbilirubinaemia occurred in 6.8% (n = 17) and Grade 4 hyperbilirubinaemia occurred in 2% (n = 5).

Use in Children

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

Use in the Elderly

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

Table: Summary of the occurrence (%) of treatment related Grade 3 and 4 adverse reactions by age

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

Carcinogenicity, Mutagenicity and Impairment of Fertility

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

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

Impairment of Fertility: Impairment of fertility was observed in female mice receiving Capecitabine SPC at 760 mg/kg/day (2292 mg/m2/day) - a disruption in the oestrous cycle occurred with a subsequent failure of mating. A reduction in live litter size, decreased foetal weight and foetal abnormalities were observed in mice dosed at 380 mg/kg/day (1174 mg/m2/day) before implantation. At the no effect dose of 190 mg/kg/day (587 mg/m2/day), plasma Cmax for 5’- DFUR was similar to that observed in humans at the recommended dose, while the AUC value was 4-fold lower than that in humans. The effect of Capecitabine SPC on female fertility was reversible after a drug-free period.

In male mice, degenerative changes and a decrease in the number of spermatocytes and spermatids were noted at 760 mg/kg/day (2401 mg/m2/day). At the no-effect dose of 380 mg/kg/day (1201 mg/m2/day), plasma Cmax for 5’-DFUR was slightly greater than that observed in humans at the recommended dose, while the AUC was about half that in humans.

Use in Pregnancy – CATEGORY D

Capecitabine SPC may cause foetal harm when administered to pregnant women. Women of child bearing potential should be advised to avoid becoming pregnant while receiving treatment with Capecitabine SPC. There are no adequate and well-controlled studies in pregnant women using Capecitabine SPC. If the medicine is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be advised of the potential hazard to the foetus.

Studies Conducted in Animals

Mice: Capecitabine SPC and/or its metabolites have been shown to cross the placenta in mice. Capecitabine SPC was shown to be teratogenic and embryolethal when administered orally to mice during organogenesis at a dose of 198 mg/kg/day (676 mg/m2/day). Teratogenic findings included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilatation of cerebral ventricles. The non- teratogenic dose level in mice was 50 mg/kg/day (approximately 170 mg/m2/day). Systemic exposure to 5’- DFUR at the 50 mg/kg/day dose level was not assessed in any studies; however, this dose level is estimated to be about 20 times lower than that in patients dosed at 2510 mg/m2/day, based on plasma AUC values.

Capecitabine SPC administered to mice dams for the period following organogenesis through to weaning at doses up to 400 mg/kg/day (1428 mg/m2/day) was not associated with any adverse effects on the dams or offspring. In separate studies, this dose produced 5’-DFUR Cmax and AUC values about 1.4 and 0.43 times, respectively, of the corresponding values in patients administered 2510 mg/m2/day.

Monkeys: Capecitabine SPC was embryolethal when administered to dams during organogenesis at a dose of 90 mg/kg/day equivalent to 1095 mg/m2/day. However, no teratogenic effects were observed in those fetuses that did survive at that dose level. The no-effect dose was 45 mg/kg/day (560 mg/m2/day), which produced a plasma 5’- DFUR AUC value that was about one third of the corresponding value in patients at the recommended dose.

Use in Lactation

It is not known whether Capecitabine SPC and its metabolites are excreted in human milk. In a study of single oral administration of Capecitabine SPC in lactating mice, a significant amount of Capecitabine SPC metabolites was detected in the milk. No effects were observed on the offspring of lactating mice dosed orally with Capecitabine SPC at 400 mg/kg/day (1428 mg/m2/day). However, plasma AUC for 5’-DFUR at this dose was lower than that in patients receiving the recommended dose of the medicine. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving Capecitabine SPC therapy.

Interaction with Food

The effect of food on the pharmacokinetics of Capecitabine SPC was investigated in 11 cancer patients. The rate and extent of absorption of Capecitabine SPC is decreased when administered with food. The effect on AUC0-∞ of the 3 main metabolites in plasma (5’DFUR, 5-FU, FBAL) is minor. In all clinical trials, patients were instructed to administer Capecitabine SPC within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that Capecitabine SPC be administered with food.

Interaction studies have only been performed in adults.

Interaction with other medicinal products

Brivudine: a clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5- Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with capecitabine (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of capecitabine.

Cytochrome P450 2C9 Substrates: Other than warfarin, no formal interaction studies with capecitabine and other medicines known to be metabolised by the cytochrome P450 2C9 isoenzyme have been conducted. Care should be exercised when capecitabine is 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 occur when capecitabine and oxaliplatin were administered in combination, with or without bevacizumab.

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

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.

Breastfeeding

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, breastfeeding 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).

Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause dizziness, fatigue and nausea.

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 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

** 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

+ 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, 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.

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 submitting completed forms to: npc.drug@sfda.gov.sa.

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.

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

Bioactivation

Capecitabine SPC is a fluoropyrimidine carbamate derivative that was designed as an orally administered, tumour- activated and tumour-selective cytotoxic agent. Capecitabine SPC is non- cytotoxic in vitro.

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

Figure 1:                                       Metabolic Pathway of Capecitabine to5-FU

Mechanism of Action

Both normal and tumour cells metabolise 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5- fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor N5-10 methylenetetrahydrofolate bind covalently to thymidylate

synthase (TS) to form a covalently bound ternary complex. This binding prevents formation of thymidylate from uracil, the necessary precursor of thymidine triphosphate that is required for DNA synthesis. A deficiency of thymidine triphosphate can inhibit cell division. The second mechanism results from the incorporation of FUTP into RNA in place of UTP, thereby preventing the correct nuclear processing of ribosomal RNA and messenger RNA. These effects are most marked on rapidly proliferating cells, such as tumour cells, which utilise 5-FU at a higher rate.

Pharmacokinetics in Tumours and Adjacent Healthy Tissue

A pharmacokinetic study in 19 colorectal patients was conducted investigating the tumour selectivity of Capecitabine SPC comparing 5-FU concentrations in tumour, healthy tissue and plasma. Following oral administration of Capecitabine SPC (1250 mg/m2 twice daily, 5 to 7 days before surgery), concentrations of 5- FU were significantly greater in primary tumour than in adjacent healthy tissue (geometric mean ratio 2.5; 95% CI: [1.5 to 4.1]) and plasma (geometric mean ratio14).

Thymidine phosphorylase activity was four times greater in primary tumour tissue (colon) than in normal tissue.

Human Pharmacokinetics

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

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

Distribution: In vitro human plasma studies have determined that Capecitabine SPC, 5’-DFCR, 5’- DFUR and 5- FU are 54%, 10%, 62% and 10% protein bound respectively, mainly to albumin

Metabolism: Capecitabine SPC is first metabolised by hepatic carboxylesterase to 5’-DFCR, which is then converted to 5’-DFUR by cytidine deaminase, principally located in the liver and tumour tissues. Formation of 5-FU occurs preferentially at the tumour site by the tumour-associated angiogenic factor dThdPase, thereby minimising the exposure of healthy body tissues to systemic 5-FU.

The plasma AUC of 5-FU is 6 to 22 times lower than that following an IV bolus of 5-FU (Dose of 600 mg/m2). The metabolites of Capecitabine SPC become cytotoxic only after conversion to 5-FU and anabolites of 5-FU. 5-FU is further catabolised to the inactive metabolites dihydro-5- fluorouracil (FUH2), 5-fluoro- ureidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL) via dihydropyrimidine dehydrogenase (DPD), which is rate limiting.

Elimination: After oral administration, Capecitabine SPC metabolites are primarily recovered in the urine. Most (95.5%) of administered Capecitabine SPC dose is recovered in urine. Faecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the administered dose. About 3% of the administered dose is excreted in the urine as unchanged drug.

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

0.76 hours, respectively.

Pharmacokinetic parameters estimated on Day 14 after administration of Capecitabine SPC (1250 mg/m2 twice daily) in 8 cancer patients

# Median values (min-max) are reported for tmax

Combination therapy: Phase I studies evaluating the effect of Capecitabine SPC on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by Capecitabine SPC on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5’-DFUR.

Pharmacokinetics in Special Populations

See also PRECAUTIONS and DOSAGE AND ADMINISTRATION for recommendations regarding the use of Capecitabine SPC in (i) the elderly; (ii) patients with hepatic impairment and (iii) patients with renal impairment.

A population pharmacokinetic analysis was carried out after Capecitabine SPC treatment of 505 patients with colorectal cancer dosed at 1250 mg/m2 twice daily. Gender, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, AST/ALT had no statistically significant effect on the pharmacokinetics of 5’-DFUR, 5-FU and FBAL.

Elderly: A population pharmacokinetic analysis which included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65 years of age, found age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal function.

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

Hepatic Impairment: Capecitabine SPC has been evaluated in patients with mild to moderate hepatic impairment due to liver metastases as defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase. Cmax of Capecitabine SPC, 5’-DFUR and 5-FU were increased by 49%, 33% and 28%, respectively. AUC0-∞ of Capecitabine SPC 5’-DFUR and 5-FU were increased by 48%, 20% and 15%, respectively. Conversely, Cmax and AUC of 5’-DFCR decreased by 29% and 35%, respectively. Therefore, bioactivation of Capecitabine SPC is not affected.

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

CLINICAL TRIALS 

Colon and Colorectal Cancer

Monotherapy - adjuvant colon cancer

Data from an open-label, multicenter, randomised, phase III clinical trial investigated the efficacy and safety of Capecitabine SPC for the adjuvant treatment in patients who underwent surgery for Dukes’ stage C colon cancer (XACT: study M66001). In this trial, 1987 patients were randomised to treatment with Capecitabine SPC (1250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles for 24 weeks) or 5- FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin intravenous (IV) followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks).

The major efficacy parameters assessed were disease free survival (DFS, primary endpoint) and overall survival (OS). The median follow up at the time of the analysis was 6.9 years. Capecitabine SPC was shown to be at least equivalent to 5-FU/leucovorin in DFS and OS.

Table Adjuvant colon cancer efficacy results monotherapy1

1  All-randomised population

2  For disease free survival event = death, relapse or new occurrence of colon cancer (NOCC); for relapse free survival event = death related to treatment or to disease progression, relapse or NOCC; for overall survival event = death (all causes)

3  Hazard Ratio Capecitabine SPC vs. 5-FU/leucovorin. Non-inferiority criterion: 95% CI upper bound≤1.25

4    Wald chi-square test

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

Combination therapy - adjuvant colon cancer

Data from a multicentre, randomised, controlled phase III clinical trial in patients with stage III (Dukes’ C) colon cancer supports the use of Capecitabine SPC in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer (NO16968). In this trial, 944 patients were randomised to 3 week cycles for 24 weeks with Capecitabine SPC (1000 mg/m2 twice daily for 2 weeks followed by a 7 day rest period) in combination with oxaliplatin (130 mg/m2 intravenous infusion over 2 hours on day 1 every 3 weeks); 942 patients were randomised to bolus 5-FU and leucovorin. In the primary analysis (ITT population), median observation time was 57 months for DFS and 59 months for OS. XELOX was shown to be significantly superior to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of relapse free survival (RFS) supports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5-FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486). The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV.

Monotherapy - metastatic colorectal cancer

A phase II open label, multicentre, randomised clinical trial was conducted to explore the efficacy and safety of three different treatment regimens in patients with advanced and/or metastatic colorectal cancer. These were continuous therapy with Capecitabine SPC (1331 mg/m2/day, n = 39) over 12 weeks; intermittent therapy with Capecitabine SPC (1250 mg/m2 twice daily, n = 34) 2 weeks treatment followed by a 1 week rest period, given as 3 week cycles over 12 weeks and intermittent therapy with Capecitabine SPC in combination with oral leucovorin (Capecitabine SPC 1657 mg/m2/day; leucovorin 60 mg/day, n = 35). The objective response rate was 22% in the continuous arm, 25% in the intermittent arm and 24% in the combinationarm.

Data from two identically-designed, multicenter, randomised, controlled phase III clinical trials (SO14695; SO14796) conducted in 120 centres internationally, compared Capecitabine SPC with 5-FU in combination with leucovorin (Mayo regimen) as first-line chemotherapy in patients with advanced and/or metastatic colorectal cancer. In these trials, 603 patients were randomised to treatment with Capecitabine SPC at a daily dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles over 30 weeks. A total of 604 patients were randomised to treatment with 5-FU/leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days). The mean durationPoagfet2re6atment was 139 days for Capecitabine SPC treated patients and 140 days for 5-FU/leucovorin treated patients.

The major efficacy endpoints assessed were time to disease progression (primary endpoint), objective response rate and OS. The objective response rate included partial and complete responses. The results from the two phase III trials were similar; the pooled efficacy data from both trials are given in the tablebelow.

Table : Metastatic colorectal cancer pooled trials efficacy results monotherapy1

1  All-randomised population, investigator assessment

2  Hazard Ratio Capecitabine SPC /5-FU leucovorin. Non-inferiority criterion: 95% CI upper bound ≤ 1.20

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

Combination therapy - first-line treatment of metastatic colorectal cancer

Data from a multicenter, randomised, controlled phase III clinical study (NO16966) support the use of Capecitabine SPC in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab (BV) for the first-line treatment of metastastic colorectal cancer. The study contained two parts: an initial 2-arm part in which patients were randomised to two different treatment groups, XELOX or FOLFOX-4, and a subsequent 2x2 factorial part with four different treatment groups, XELOX + placebo (P), FOLFOX-4 + P, XELOX+BV, and FOLFOX-4 + BV. The treatment regimens are summarised in the tablebelow.

Table : Treatment regimens in study NO16966

Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival (PFS) in the eligible per-protocol

population (EPP), with progression determined by the study investigators who were not blinded to treatment allocation (see Table). The criterion set for concluding non- inferiority was that the upper limit of the 97.5% confidence interval for the hazard ratio for PFS was less than 1.23. The results for OS are similar to those reported for PFS. A comparison of XELOX plus BV versus FOLFOX-4 plus BV was a pre-specified exploratory analysis. In this treatment subgroup comparison, XELOX plus BV was similar compared to FOLFOX-4 plus BV in terms of PFS (hazard ratio 1.01 [97.5% CI 0.84, 1.22]). The median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses following an additional 1 year of follow up are included in Table.

Table: Key non-inferiority efficacy results for the primary analysis and 1 year follow-up data (EPP population, Study NO16966) PRIMARY ANALYSIS

ADDITIONAL 1 YEAR OF FOLLOW UP

# EPP=eligible patient population

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

Combination therapy - second- line treatment of metastatic colorectal cancer

Data from a multicenter, randomised, controlled phase III clinical study (NO16967) support the use of Capecitabine SPC in combination with oxaliplatin for the second-line treatment of metastastic colorectal cancer. In this trial, 627 patients with metastatic colorectal cancer who have received prior treatment with irinotecan in combination with a fluoropyrimidine regimen as first-line therapy were randomised to treatment with XELOX or FOLFOX-4. The treatment regimens used in study NO16967 are summarised in the table below.

Table: Treatment regimens in Study NO16967

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

Table : Key non-inferiority efficacy results for the primary analysis and 6-month follow-up data of Study NO16967 (PPP population)

PRIMARY ANALYSIS

# PPP = per-protocol population

A pooled analysis of the efficacy data from first-line (study NO16966; initial 2-arm part) and second line treatment (study NO 16967) further support the non-inferiority results of XELOX versus FOLFOX-4 as obtained in the individual studies: PFS in the per-protocol population (hazard ratio 1.00 [95% CI: 0.88; 1.14]) with a median PFS of 193 days (XELOX; 508 patients) versus 204 days (FOLFOX-4; 500 patients). The results also indicate that XELOX is comparable to FOLFOX-4 in terms of OS (hazard ratio 1.01 [95% CI: 0.87; 1.17]) with a median OS of 468 days (XELOX) versus 478 days(FOLFOX-4).

Combination therapy - oesophagogastric cancer

Two multicentre, randomised, controlled phase III clinical trials were conducted to evaluate the safety and efficacy of Capecitabine SPC in patients with previously untreated advanced or metastatic oesophagogastric.

Data from a multicentre, open-label, randomised, controlled phase III clinical trial (ML17032,) supports the use of Capecitabine SPC in this setting. In this trial, 160 patients with previously untreated advanced or metastatic gastric cancer were randomised to treatment with Capecitabine SPC (1000 mg/m2 twice daily for 2 weeks followed by a 1 week rest period) and cisplatin (80 mg/m2 as a 2 hour IV infusion every 3 weeks).

A total of 156 patients were randomised to treatment with 5- FU (800 mg/m2 per day, continuous infusion on days 1 to 5 every 3 weeks) and cisplatin (80 mg/m2  as a 2 hour IV infusion on day 1, every 3 weeks).

Patients received treatment for at least 6 weeks (2 cycles) and were treated until disease progression or unacceptable toxicity.

The primary objective of the study was met, Capecitabine SPC in combination with cisplatin was at least equivalent to 5-FU in combination with cisplatin in terms of PFS in the per-protocol analysis. Duration of survival (overall survival) with the combination of Capecitabine SPC and cisplatin was also at least equivalent to that of 5-FU and cisplatin.

Table: Summary of results for key efficacy parameters (PPP, Study ML17032)

# Unadjusted treatment effect in Cox proportional model

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

Table : Treatment regimens in the REAL-2 Study

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

Colon, colorectal and advanced gastric cancer: meta-analysis

A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, ML17032) supports Capecitabine SPC replacing 5-FU in mono- and combination treatment in gastrointestinal cancer. The pooled analysis includes 3097 patients treated with Capecitabine SPC - containing regimens and 3074 patients treated with 5-FU-containing regimens. The hazard ratio for OS was 0.94 (95% CI: 0.89; 1.00, p=0.0489) indicating that Capecitabine SPC -containing regimens are comparable to 5-FU containing regimens.

Monotherapy - Breast cancer

Two phase II open label, multicenter trials were conducted to evaluate the efficacy and safety of Capecitabine SPC in patients with locally advanced and/or metastatic breast cancer who had been previously treated with taxanes. Capecitabine SPC was administered at a dose of 1250 mg/m2 twice daily for 2 weeks treatment followed by a 1 week rest period, given as 3 week cycles.

In the first trial, 162 female outpatients were selected from an investigator’s current practice or from referred patients. This heavily pre-treated patient population was refractory to previous paclitaxel therapy (77% resistant, 23% failed). Additionally, most patients were resistant (41%) or had failed (26%) previous anthracycline therapy and 82% had been exposed to 5-FU.

In the second trial, 74 patients were treated; all but three had received prior treatment with taxanes (paclitaxel and/or docetaxel). In addition, over 95% had previously been treated with an anthracycline- based chemotherapy.

Table : Breast cancer monotherapy efficacy results1

1 Intent to Treat population

A prospectively defined clinical benefit response score (pain, analgesic consumption and Karnofsky Performance Status) was used to assess the effect of treatment on tumour-associated morbidity. The overall clinical benefit response was positive in 29 patients (20%) in the first trial and 8 patients (15%) in the second trial, 45 patients (31%) and 22 patients (41%), respectively, remained stable.

Of the 51 patients with baseline pain ≥ 20 mm on the visual analogue scale in the first trial, 24 patients (47%) had a positive response in pain intensity (greater than or equal to 50% decrease lasting for at least 4 weeks), similar analysis in the second trial showed 7/27 patients (26%) had a positive pain response.

Combination therapy - Breast cancer

The dose of Capecitabine SPC used in the phase III clinical trial in combination with Docetaxel Based on the results of a phase I trial, where a range of doses of docetaxel given every 3 weeks in combination with an intermittent regimen of Capecitabine SPC (2 weeks treatment followed by a 1 week rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of docetaxel 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks in combination with 1250 mg/m2 twice daily for 2 weeks of Capecitabine SPC administered every 3 weeks for at least 6 weeks. The approved dose of 100 mg/m2 of docetaxel administered every 3 weeks was the control arm of the phase III study.

Capecitabine SPC in combination with docetaxel was assessed in an open label, multicenter, randomised trial. A total of 511 patients with locally advanced and/or metastatic breast cancer resistant to, or recurring after an anthracycline containing therapy, or relapsing during or recurring within two years of completing an anthracycline containing adjuvant therapy were enrolled. In this trial, 255 patients were randomised to receive Capecitabine SPC in combination with docetaxel and 256 patients received docetaxel alone.

Capecitabine SPC in combination with docetaxel resulted in statistically significant improvements in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table and Figures 2 and 3. Health related quality of life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ; C30 version 2, including Breast Cancer Module BR23). HRQoL was similar in the two treatment groups.

Table : Breast cancer combination treatment efficacy results1

1.   All-randomised population, Investigator assessment

2.   Hazard Ratio

3.   Figure 2.Kaplan-Meier Estimates for Time to Disease Progression Capecitabine SPC and Docetaxel vs. Docetaxel

Figure 3. Kaplan-Meier Estimates of Survival Capecitabine SPC and Docetaxel vs. Docetaxel

In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised by degenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepatic and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing (1379 mg/m²/day).

A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.

During standard fertility studies, impairment of fertility was observed in female mice receiving capecitabine; however, this effect was reversible after a drug-free period. In addition, during a 13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; however these effects were reversible after a drug-free period (see section 4.6).

In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of teratogenicity.

Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).

·        lactose

·        croscarmellose sodium

·        hypromellose

·        microcrystalline cellulose

·        magnesium stearate

Not applicable.

Capecitabine SPC tablets should be stored below 30°C. Capecitabine SPC tablets should not be taken after the expiry date imprinted on the pack label.

Blister pack

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.