ECANSYA 150mg tablets medication leaflet

Ecansya 150 mg film-coated tablets

Ecansya 300 mg film-coated tablets

Ecansya 500 mg film-coated tablets

Ecansya 150 mg film-coated tablets

Each film-coated tablet contains 150 mg capecitabine.

Each film-coated tablet contains 7 mg lactose.

Ecansya 300 mg film-coated tablets

Each film-coated tablet contains 300 mg capecitabine.

Each film-coated tablet contains 15 mg lactose.

Ecansya 500 mg film-coated tablets

Each film-coated tablet contains 500 mg capecitabine.

Each film-coated tablet contains 25 mg lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Ecansya 150 mg film-coated tablets

The tablets are light peach colored, oblong shaped, biconvex tablets of 11.4 mm in length and 5.3 mmin width, debossed with '150' on one side and plain on other side.

Ecansya 300 mg film-coated tablets

The tablets are white to off white, oblong shaped, biconvex tablets of 14.6 mm in length and 6.7 mmin width, debossed with '300' on one side and plain on other side.

Ecansya 500 mg film-coated tablets

The tablets are peach colored, oblong shaped, biconvex tablets of 15.9 mm in length and 8.4 mm inwidth, debossed with '500' on one side and plain on other side.

Ecansya is indicated for the treatment of:

- for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) coloncancer (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 locallyadvanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapyshould have included an anthracycline.

- as monotherapy for the treatment of patients with locally advanced or metastatic breast cancerafter failure of taxanes and an anthracycline containing chemotherapy regimen or for whomfurther anthracycline therapy is not indicated.

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

Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standardand reduced dose calculations according to body surface area for starting doses of Ecansya of1250 mg/m2 and 1000 mg/m2 are provided in tables 1 and 2, respectively.

Recommended posology (see section 5.1):

Colon, colorectal and breast cancer

Given as monotherapy, the recommended starting dose for capecitabine in the adjuvant treatment ofcolon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastaticbreast cancer is 1250 mg/m2 administered twice daily (morning and evening; equivalent to2500 mg/m2 total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment inpatients with stage III colon cancer is recommended for a total of 6 months.

Colon, colorectal and gastric cancer

In combination treatment, the recommended starting dose of capecitabine should be reduced to800 - 1000 mg/m2 when administered twice daily for 14 days followed by a 7-day rest period, or to625 mg/m2 twice daily when administered continuously (see section 5.1). For combination withirinotecan, the recommended starting dose is 800 mg/m2 when administered twice daily for 14 daysfollowed by a 7-day rest period combined with irinotecan 200 mg/m2 on day 1. The inclusion ofbevacizumab 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 ofproduct characteristics should be started prior to cisplatin administration for patients receiving thecapecitabine plus cisplatin combination. Premedication with antiemetics according to the oxaliplatinsummary of product characteristics is recommended for patients receiving the capecitabine plusoxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommendedfor a duration of 6 months.

Breast cancer

In combination with docetaxel, the recommended starting dose of capecitabine in the treatment ofmetastatic 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. Premedicationwith an oral corticosteroid such as dexamethasone according to the docetaxel summary of productcharacteristics should be started prior to docetaxel administration for patients receiving thecapecitabine plus docetaxel combination.

Ecansya dose calculations

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

Dose level 1250 mg/m2 (twice daily)

Full dose Number of 150 mg tablets, Reduced dose Reduced dose300 mg tablets and/or (75%) (50%)500 mg tablets peradministration (each1250 mg/m2 administration to be given 950 mg/m2 625 mg/m2morning and evening)

Body Dose per 150 mg 300 mg 500 mg Dose per Dose per

Surface administration administration administration

Area (m2) (mg) (mg) (mg)≤ 1.26 1500 - - 3 1150 8001.27 - 1.38 1650 1 - 3 1300 8001.39 - 1.52 1800 - 1 3 1450 9501.53 - 1.66 2000 - - 4 1500 10001.67 - 1.78 2150 1 - 4 1650 10001.79 - 1.92 2300 - 1 4 1800 11501.93 - 2.06 2500 - - 5 1950 13002.07 - 2.18 2650 1 - 5 2000 1300≥ 2.19 2800 - 1 5 2150 1450

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

Dose level 1000 mg/m2 (twice daily)

Full dose Number of 150 mg tablets, Reduced dose Reduced dose300 mg tablets and/or 500 mg (75%) (50%)tablets per administration1000 mg/m2 (each administration to be 750 mg/m2 500 mg/m2given morning and evening)

Body Dose per 150 mg 300 mg 500 mg Dose per Dose per

Surface administration administration administration

Area (m2) (mg) (mg) (mg)≤ 1.26 1150 1 - 2 800 6001.27 - 1.38 1300 - 1 2 1000 6001.39 - 1.52 1450 1 1 2 1100 7501.53 - 1.66 1600 - 2 2 1200 8001.67 - 1.78 1750 1 2 2 1300 8001.79 - 1.92 1800 - 1 3 1400 9001.93 - 2.06 2000 - - 4 1500 10002.07 - 2.18 2150 1 - 4 1600 1050≥ 2.19 2300 - 1 4 1750 1100

Posology adjustments during treatment

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

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

Toxicity grades* Dose changes within a treatment Dose adjustment for nextcycle 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 50%or

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

- 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) ofthe Cancer Therapy Evaluation Program, US National Cancer Institute, version 4.0. For hand-footsyndrome and hyperbilirubinemia, see section 4.4.

Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of <100 x 109/Lshould not be treated with capecitabine. If unscheduled laboratory assessments during a treatmentcycle show that the neutrophil count drops below 1.0 x 109/L or that the platelet count drops below75 x 109/L, treatment with capecitabine should be interrupted.

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

Dose modifications for toxicity when capecitabine is used as a 3 weekly cycle in combination withother medicinal products should be made according to table 3 above for capecitabine and according tothe 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 theother medicinal product(s), then administration of all therapy should be delayed until the requirementsfor restarting all medicinal products are met.

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

If the other medicinal product(s) have to be discontinued permanently, capecitabine treatment can beresumed 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 othermedicinal products

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

Posology adjustments for special populations

Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a doseadjustment recommendation. No information is available on hepatic impairment due to cirrhosis orhepatitis.

Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions inpatients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increasedcompared to the overall population. In patients with moderate renal impairment at baseline, a dosereduction to 75% for a starting dose of 1250 mg/m2 is recommended. In patients with moderate renalimpairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m2. In patientswith mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of thestarting dose is recommended. Careful monitoring and prompt treatment interruption is recommendedif the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent doseadjustment as outlined in table 3 above. If the calculated creatinine clearance decreases duringtreatment to a value below 30 ml/min, Ecansya should be discontinued. These dose adjustmentrecommendations for renal impairment apply both to monotherapy and combination use (see alsosection 'Elderly' below).

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

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

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

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

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

Ecansya tablets should not be crushed or cut.

- 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-druginteraction),

- If contraindications exist to any of the medicinal products in the combination regimen, thatmedicinal product should not be used.

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 anddo not require permanent discontinuation of therapy, although doses may need to be withheld orreduced.

Diarrhoea. Patients with severe diarrhoea should be carefully monitored and given fluid andelectrolyte 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/dayor nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence andmalabsorption. Grade 4 diarrhoea is an increase of ≥10 stools/day or grossly bloody diarrhoea or theneed 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 acuterenal failure, especially in patients with pre-existing compromised renal function or when capecitabineis given concomitantly with known nephrotoxic medicinal products. Acute renal failure secondary todehydration might be potentially fatal. If grade 2 (or higher) dehydration occurs, capecitabinetreatment should be immediately interrupted and the dehydration corrected. Treatment should not berestarted 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 (seesection 4.2).

Hand-foot syndrome (also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia orchemotherapy 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/ordiscomfort 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/ordiscomfort affecting the patient’s activities of daily living.

Grade 3 hand-foot syndrome is moist desquamation, ulceration, blistering and severe pain of the handsand/or feet and/or severe discomfort that causes the patient to be unable to work or perform activitiesof daily living. Persistent or severe hand-foot syndrome (Grade 2 and above) can eventually lead toloss of fingerprints which could impact patient identification. If grade 2 or 3 hand-foot syndromeoccurs, administration of capecitabine should be interrupted until the event resolves or decreases inintensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of capecitabine shouldbe 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-footsyndrome, because of published reports that it may decrease the efficacy of cisplatin. There is someevidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated with

Ecansya.

Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, includingmyocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death andelectrocardiographic changes (including very rare cases of QT prolongation). These adverse reactionsmay 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, myocardialinfarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine.

Caution must be exercised in patients with history of significant cardiac disease, arrhythmias andangina 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 orperipheral 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 diabetesmellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment.

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

Brivudine. Brivudine must not be administered concomitantly with capecitabine. Fatal cases have beenreported following this drug interaction. There must be at least a 4-week waiting period between endof treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started24 hours after the last dose of capecitabine (see section 4.3 and 4.5). In the event of accidentaladministration of brivudine to patients being treated with capecitabine, effective measures should betaken to reduce the toxicity of capecitabine. Immediate admission to hospital is recommended. Allmeasures 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 beinterrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations inhepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with capecitabinemonotherapy may be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferasesdecrease to ≤ 2.5 x ULN.

Renal impairment. The incidence of grade 3 or 4 adverse reactions in patients with moderate renalimpairment (creatinine clearance 30-50 ml/min) is increased compared to the overall population (seesections 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 DPDdeficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for examplestomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.

DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after doseincrease.

Complete DPD deficiency

Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Patients with complete DPD deficiencyare at high risk of life-threatening or fatal toxicity and must not be treated with Ecansya (see section4.3).

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 reducedstarting dose should be considered to limit this toxicity. DPD deficiency should be considered as aparameter 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 Ecansya is recommendeddespite uncertainties regarding optimal pre-treatment testing methodologies. Consideration should begiven 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 inpatients 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 enzymaticactivity. Other rare variants may also be associated with an increased risk of severe or life-threateningtoxicity.

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 knownto 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>Tand c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated withfluoropyrimidines.

The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients isaround 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% forc.1679T>G.

Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. Atthe 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 levelsof the endogenous DPD substrate uracil (U) in plasma is recommended.

Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despiteuncertainties 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 associatedwith an increased risk for fluoropyrimidine toxicity. A blood uracil level ≥ 150 ng/ml should beconsidered indicative of complete DPD deficiency and associated with a risk for life-threatening orfatal fluoropyrimidine toxicity. Blood uracil levels should be interpreted with caution in patients withimpaired kidney function (see ‘Testing for DPD deficiency’ above).

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

Severe skin reactions: Ecansya can induce severe skin reactions such as Stevens-Johnson syndromeand Toxic Epidermal Necrolysis. Ecansya should be permanently discontinued in patients whoexperience a severe skin reaction during treatment.

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

Ecansya tablets should not be crushed or cut. In case of exposure of either patient or caregiver tocrushed or cut Ecansya tablets adverse drug reactions could occur (see Section 4.8).

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 dihydropyrimidinedehydrogenase by brivudine, has been described. This interaction, which leads to increasedfluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administeredconcomitantly with capecitabine (see section 4.3 and 4.4). There must be at least a 4-week waitingperiod between end of treatment with brivudine and start of capecitabine therapy. Treatment withbrivudine can be started 24 hours after the last dose of capecitabine.

Cytochrome P-450 2C9 substrates: Other than warfarin, no formal interaction studies betweencapecitabine and other CYP2C9 substrates have been conducted. Care should be exercised whencapecitabine is co-administered with 2C9 substrates (e.g., phenytoin). See also interaction withcoumarin-derivative anticoagulants below, and section 4.4.

Coumarin-derivative anticoagulants: altered coagulation parameters and/or bleeding have beenreported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants suchas warfarin and phenprocoumon. These reactions occurred within several days and up to severalmonths after initiating capecitabine therapy and, in a few cases, within one month after stoppingcapecitabine. 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 foralterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjustedaccordingly.

Phenytoin: increased phenytoin plasma concentrations resulting in symptoms of phenytoinintoxication in single cases have been reported during concomitant use of capecitabine with phenytoin.

Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increasedphenytoin plasma concentrations.

Folinic acid/folic acid: a combination study with capecitabine and folinic acid indicated that folinicacid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinicacid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced byfolinic acid: the maximum tolerated dose (MTD) of capecitabine alone using the intermittent regimenis 3000 mg/m2 per day whereas it is only 2000 mg/m2 per day when capecitabine was combined withfolinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LVto a capecitabine regimen. This may also be relevant with folic acid supplementation for folatedeficiency due to the similarity between folinic acid and folic acid.

Antacid: the effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on thepharmacokinetics of capecitabine was investigated. There was a small increase in plasmaconcentrations of capecitabine and one metabolite (5’-DFCR); there was no effect on the 3 majormetabolites (5’-DFUR, 5-FU and FBAL).

Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreasedefficacy 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 interferonalpha-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/m2per day using either a continuous schedule or given daily Monday through Friday during a 6-weekcourse of radiotherapy.

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

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

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 thatcapecitabine be administered with food. Administration with food decreases the rate of capecitabineabsorption (see section 5.2).

Women of childbearing potential should be advised to avoid becoming pregnant while receivingtreatment with capecitabine. If the patient becomes pregnant while receiving capecitabine, thepotential hazard to the foetus must be explained. An effective method of contraception should be usedduring treatment and for 6 months after the last dose of capecitabine.

Based on genetic toxicity findings, male patients with female partners of reproductive potential shoulduse effective contraception during treatment and for 3 months following the last dose of capecitabine.

There are no studies in pregnant women using capecitabine; however, it should be assumed thatcapecitabine may cause foetal harm if administered to pregnant women. In reproductive toxicitystudies in animals, capecitabine administration caused embryolethality and teratogenicity. Thesefindings are expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated duringpregnancy.

It is not known whether capecitabine is excreted in human breast milk. No studies have beenconducted to assess the impact of capecitabine on milk production or its presence in human breastmilk. 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 discontinuedwhile receiving treatment with capecitabine and for 2 weeks after the final dose.

There is no data on Ecansya and impact on fertility. The Ecansya pivotal studies included females ofchildbearing potential and males only if they agreed to use an acceptable method of birth control toavoid 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).

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

The overall safety profile of capecitabine is based on data from over 3000 patients treated withcapecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens inmultiple 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 fordetails 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, andthrombosis/embolism.

ADRs considered by the investigator to be possibly, probably, or remotely related to theadministration of capecitabine are listed in table 4 for capecitabine given as monotherapy and in table5 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 ofsafety 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 incidencefrom the pooled analysis.

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

Body System Very Common Common Uncommon Rare/Very Rare(Post-Marketing

All grades All grades Severe and/or Life- Experience)threatening (grade 3-4) or consideredmedically relevant

Infections and - Herpes viral Sepsis, Urinary tractinfestations infection, infection, Cellulitis,

Nasopharyngitis, Tonsillitis,

Lower respiratory Pharyngitis, Oraltract infection candidiasis, Influenza,

Gastroenteritis, Fungalinfection, Infection,

Tooth abscess

Neoplasm - - Lipomabenign,malignant andunspecified

Blood and - Neutropenia, Febrile neutropenia,lymphatic Anaemia Pancytopenia,system disorders Granulocytopenia,

Thrombocytopenia,

Leukopenia,

Haemolytic anaemia,

International

Normalised Ratio(INR) increased/

Prothrombin timeprolonged

Immune system - - Hypersensitivity Angioedema (rare)

Body System Very Common Common Uncommon Rare/Very Rare(Post-Marketing

All grades All grades Severe and/or Life- Experience)threatening (grade 3-4) or consideredmedically relevantdisorders

Metabolism and Anorexia Dehydration, Diabetes,nutrition Weight decreased Hypokalaemia,disorders Appetite disorder,

Malnutrition,

Hypertriglyceridaemia

Psychiatric - Insomnia, Confusional state,disorders Depression Panic attack,

Depressed mood,

Libido decreased

Nervous system - Headache, Aphasia, Memory Toxicdisorders Lethargy impairment, Ataxia, leukoencephalopathy

Dizziness, Syncope, Balance (very rare)

Paraesthesia, disorder, Sensory

Dysgeusia disorder, Neuropathyperipheral

Eye disorders - Lacrimation Visual acuity reduced, Lacrimal ductincreased, Diplopia stenosis (rare),

Conjunctivitis, Corneal

Eye irritation disorders(rare),keratitis (rare),punctate keratitis(rare)

Ear and - - Vertigo, Ear painlabyrinthdisorders

Cardiac - - Angina unstable, Ventriculardisorders Angina pectoris, fibrillation (rare),

Myocardial QT prolongationischaemia/infarction, (rare), Torsade de

Atrial fibrillation, pointes (rare),

Arrhythmia, Bradycardia (rare),

Tachycardia, Sinus Vasospasm (rare)tachycardia,

Palpitations

Vascular - Thrombophlebitis Deep vein thrombosis,disorders Hypertension,

Petechiae,

Hypotension, Hotflush, Peripheralcoldness

Respiratory, - Dyspnoea, Pulmonary embolism,thoracic and Epistaxis, Cough, Pneumothorax,mediastinal Rhinorrhoea Haemoptysis, Asthma,disorders Dyspnoea exertional

Gastrointestinal Diarrhoea, Gastrointestinal Intestinal obstruction,disorders Vomiting, haemorrhage, Ascites, Enteritis,

Nausea, Constipation, Gastritis, Dysphagia,

Stomatitis, Upper abdominal Abdominal pain

Abdominal pain, Dyspepsia, lower, Oesophagitis,

Body System Very Common Common Uncommon Rare/Very Rare(Post-Marketing

All grades All grades Severe and/or Life- Experience)threatening (grade 3-4) or consideredmedically relevantpain Flatulence, Dry Abdominalmouth discomfort,

Gastrooesophagealreflux disease, Colitis,

Blood in stool

Hepatobiliary - Hyperbilirubinemi Jaundice Hepatic failure (rare),disorders a, Liver function Cholestatic hepatitistest abnormalities (rare)

Skin and Palmar-plantar Rash, Alopecia, Blister, Skin ulcer, Cutaneous lupussubcutaneous erythrodysaest Erythema, Dry Rash, Urticaria, erythematosus (rare),tissue disorders hesia skin, Pruritus, Photosensitivity Severe skin reactionssyndrome** Skin reaction, Palmar such ashyper-pigmentatio erythema, Swelling Stevens-Johnsonn, Rash macular, face, Purpura, Syndrome and toxic

Skin Radiation recall Epidermal Necrolysisdesquamation, syndrome (very rare) (see

Dermatitis, section 4.4.)

Pigmentationdisorder, Naildisorder

Muskuloskeletal - Pain in extremity, Joint swelling, Boneand connective Back pain, pain, Facial pain,tissue disorders Arthralgia Musculoskeletalstiffness, Muscularweakness

Renal and - - Hydronephrosis,urinary Urinary incontinence,disorders Haematuria, Nocturia,

Blood creatinineincreased

Reproductive - - Vaginal haemorrhagesystem andbreast disorders

General Fatigue, Pyrexia, Oedema Oedema, Chills,disorders and Asthenia peripheral, Influenza like illness,administration Malaise, Chest Rigors, Bodysite conditions pain temperature increased

** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesiasyndrome 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 differentchemotherapy regimens in multiple indications based on safety data from over 3000 patients. ADRsare added to the appropriate frequency grouping (Very common or Common) according to the highestincidence seen in any of the major clinical trials and are only added when they were seen in additionto those seen with capecitabine monotherapy or seen at a higher frequency grouping compared tocapecitabine monotherapy (see table 4). Uncommon ADRs reported for capecitabine in combinationtherapy are consistent with the ADRs reported for capecitabine monotherapy or reported formonotherapy with the combination medicinal product (in literature and/or respective summary ofproduct 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 combinationtreatment in addition to those seen with capecitabine monotherapy or seen at a higherfrequency grouping compared to capecitabine monotherapy

Body System Very Common Common Rare/Very

Rare

All grades All grades (Post-

Marketing

Experience)

Infections and - Herpes zoster, Urinary tractinfestations infection, Oral candidiasis, Upperrespiratory tract infection,

Rhinitis, Influenza, +Infection,

Oral herpes

Blood and lymphatic +Neutropenia, Bone marrow depression, +Febrilesystem disorders +Leucopenia, +Anaemia, Neutropenia+Neutropenic fever,

Immune system - Hypersensitivitydisorders

Metabolism and Appetite decreased Hypokalaemia, Hyponatraemia,nutrition disorders Hypomagnesaemia,

Hypocalcaemia, Hyperglycaemia

Psychiatric disorders - Sleep disorder, Anxiety

Nervous system Paraesthesia, Neurotoxicity, Tremor, Neuralgia,disorders Dysaesthesia, Peripheral Hypersensitivity reaction,neuropathy, Peripheral Hypoaesthesiasensory neuropathy,

Dysgeusia, Headache

Eye disorders Lacrimation increased Visual disorders, Dry eye, Eyepain, Visual impairment, Visionblurred

Ear and labyrinth - Tinnitus, Hypoacusisdisorders

Cardiac disorders - Atrial fibrillation, Cardiacischaemia/infarction

Vascular disorders Lower limb oedema, Flushing, Hypotension,

Hypertension, Hypertensive crisis, Hot flush,+Embolism and Phlebitisthrombosis

Respiratory, thoracic Sore throat, Hiccups, Pharyngolaryngeal pain,and mediastinal Dysaesthesia pharynx Dysphoniasystem disorders

Gastrointestinal Constipation, Dyspepsia Upper gastrointestinaldisorders haemorrhage, Mouth ulceration,

Gastritis, Abdominal distension,

Gastroesophageal reflux disease,

Oral pain, Dysphagia, Rectalhaemorrhage, Abdominal painlower, Oral dysaesthesia,

Paraesthesia oral, Hypoaesthesiaoral, Abdominal discomfort

Hepatobiliary - Hepatic function abnormal

Body System Very Common Common Rare/Very

Rare

All grades All grades (Post-

Marketing

Experience)disorders

Skin and subcutaneous Alopecia, Nail disorder Hyperhidrosis, Rashtissue disorders erythematous, Urticaria, Nightsweats

Musculoskeletal and Myalgia, Arthralgia, Pain in jaw, Muscle spasms,connective tissue Pain in extremity Trismus, Muscular weaknessdisorders

Renal and urinary - Haematuria, Proteinuria, Acute renaldisorders Creatinine renal clearance failuredecreased, Dysuria secondary todehydration(rare)

General disorders and Pyrexia, Weakness, Mucosal inflammation, Pain inadministration site +Lethargy, Temperature limb, Pain, Chills, Chest pain,conditions intolerance Influenza-like illness, +Fever,

Infusion related reaction, Injectionsite reaction, Infusion site pain,

Injection site pain

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

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 of53% to 60% of all-grades HFS was observed in capecitabine monotherapy trials (comprising studies inadjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breastcancer) and a frequency of 63% was observed in the capecitabine/docetaxel arm for the treatment ofmetastatic breast cancer. For the capecitabine dose of 1000 mg/m2 twice daily on days 1 to 14 every 3weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combinationtherapy.

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabinemonotherapy or capecitabine in combination with different chemotherapy regimens in multipleindications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment withcapecitabine. In all studies combined, the following covariates were statistically significantlyassociated 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 sixweeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), femalegender, 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% ofpatients.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated withcapecitabine showed that in all studies combined, the following covariates were statisticallysignificantly associated with an increased risk of developing diarrhoea: increasing capecitabinestarting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 yearincrements), and female gender. The following covariates were statistically significantly associatedwith a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) andincreasing 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 than0.1% were associated with the use of capecitabine monotherapy based on a pooled analysis fromclinical safety data from 7 clinical trials including 949 patients (2 phase III and 5 phase II clinical trialsin metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, cardiac failure, suddendeath, and ventricular extrasystoles.

In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis fromclinical safety data from 7 clinical trials, encephalopathy was also associated with the use ofcapecitabine 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 reactionshave been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea,gastric irritation, and vomiting.

Elderly (see section 4.2):

An analysis of safety data in patients ≥ 60 years of age treated with capecitabine monotherapy and ananalysis of patients treated with capecitabine plus docetaxel combination therapy showed an increasein the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related seriousadverse reactions compared to patients < 60 years of age. Patients ≥ 60 years of age treated withcapecitabine plus docetaxel also had more early withdrawals from treatment due to adverse reactionscompared to patients < 60 years of age.

The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated withcapecitabine showed that in all studies combined, increasing age (by 10 year increments) wasstatistically significantly associated with an increased risk of developing HFS and diarrhoea and with adecreased risk of developing neutropenia.

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

Renal impairment (see section 4.2, pct. 4.4, and 5.2):

An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) withbaseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4adverse reactions compared to patients with normal renal function (36% in patients without renalimpairment 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 fromtreatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mildrenal impairment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The manifestations of acute overdose include nausea, vomiting, diarrhoea, mucositis, gastrointestinalirritation and bleeding, and bone marrow depression.

Medical management of overdose should include customary therapeutic and supportive medicalinterventions aimed at correcting the presenting clinical manifestations and preventing their possiblecomplications.

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, ATC code: L01BC06.

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orallyadministered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated viaseveral enzymatic steps (see section 5.2). The enzyme involved in the final conversion to 5-FU,thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeitusually at lower levels. In human cancer xenograft models capecitabine demonstrated a synergisticeffect in combination with docetaxel, which may be related to the upregulation of thymidinephosphorylase by docetaxel.

There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylationreaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis ofdeoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and proteinsynthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may beto create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of

DNA and RNA deprivation are most marked on those cells which proliferate more rapidly and whichmetabolise 5-FU at a more rapid rate.

Colon and colorectal cancer:

Monotherapy with capecitabine in adjuvant colon cancer

Data from one multicentre, randomised, controlled phase III clinical trial in patients with stage III(Dukes’ C) colon cancer supports the use of capecitabine for the adjuvant treatment of patients withcolon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment withcapecitabine (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo Clinic regimen: 20 mg/m2 leucovorinintravenous followed by 425 mg/m2 intravenous bolus 5-FU, on days 1 to 5, every 28 days for 24weeks). Capecitabine was at least equivalent to intravenous 5-FU/LV in disease-free survival in perprotocol population (hazard ratio 0.92; 95% CI 0.80-1.06). In the all-randomised population, tests fordifference of capecitabine vs 5-FU/LV in disease-free and overall survival showed hazard ratios of0.88 (95% CI 0.77 - 1.01; p = 0.068) and 0.86 (95% CI 0.74 - 1.01; p = 0.060), respectively. Themedian follow up at the time of the analysis was 6.9 years. In a preplanned multivariate Cox analysis,superiority of capecitabine compared with bolus 5-FU/LV was demonstrated. The following factorswere pre-specified in the statistical analysis plan for inclusion in the model: age, time from surgery torandomization, gender, CEA levels at baseline, lymph nodes at baseline, and country. In the all-randomised population, capecitabine was shown to be superior to 5FU/LV for disease-free survival(hazard ratio 0.849; 95% CI 0.739 - 0.976; p = 0.0212), as well as for overall survival (hazard ratio0.828; 95% CI 0.705 - 0.971; p = 0.0203).

Combination therapy in adjuvant colon cancer

Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III(Dukes’ C) colon cancer supports the use of capecitabine in combination with oxaliplatin (XELOX)for the adjuvant treatment of patients with colon cancer (NO16968 study). In this trial, 944 patientswere randomised to 3-week cycles for 24 weeks with capecitabine (1000 mg/m2 twice daily for 2weeks followed by a 1-week rest period) in combination with oxaliplatin (130 mg/m2 intravenousinfusion over 2-hours on day 1 every 3 weeks); 942 patients were randomised to bolus 5-FU andleucovorin. In the primary analysis for DFS in the ITT population, XELOX was shown to besignificantly superior to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS ratewas 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of RFSsupports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5-FU/LV.

XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486)which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus74% for 5-FU/LV. The efficacy data is based on a median observation time of 59 months for OS and57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOXcombination therapy arm (21%) as compared with that of the 5-FU/LV monotherapy arm (9%) in the

ITT population.

Monotherapy with capecitabine in metastatic colorectal cancer

Data from two identically-designed, multicentre, randomised, controlled phase III clinical trials(SO14695; SO14796) support the use of capecitabine for first line treatment of metastatic colorectalcancer. In these trials, 603 patients were randomised to treatment with capecitabine (1250 mg/m2 twicedaily for 2 weeks followed by a 1-week rest period and given as 3-week cycles). 604 patients wererandomised to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin intravenousfollowed by 425 mg/m2 intravenous bolus 5-FU, on days 1 to 5, every 28 days). The overall objectiveresponse rates in the all-randomised population (investigator assessment) were 25.7% (capecitabine)vs. 16.7% (Mayo regimen); p <0.0002. The median time to progression was 140 days (capecitabine)vs. 144 days (Mayo regimen). Median survival was 392 days (capecitabine) vs. 391 days (Mayoregimen). Currently, no comparative data are available on capecitabine monotherapy in colorectalcancer in comparison with first line combination regimens.

Combination therapy in first-line treatment of metastatic colorectal cancer

Data from a multicentre, randomised, controlled phase III clinical study (NO16966) support the use ofcapecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab forthe first-line treatment of metastatic colorectal cancer. The study contained two parts: an initial 2-armpart in which 634 patients were randomised to two different treatment groups, including XELOX or

FOLFOX-4, and a subsequent 2x2 factorial part in which 1401 patients were randomised to fourdifferent treatment groups, including XELOX plus placebo, FOLFOX-4 plus placebo, XELOX plusbevacizumab, and FOLFOX-4 plus bevacizumab. See table 6 for treatment regimens.

Table 6 Treatment regimens in study NO16966 (mCRC)

Treatment Starting Dose Schedule

FOLFOX-4 Oxaliplatin 85 mg/m2 Oxaliplatin on Day 1, every 2 weeksor intravenous 2 hr Leucovorin on Days 1 and 2, every 2

FOLFOX-4 + weeks

Bevacizumab Leucovorin 200 mg/m2 5-fluorouracil intravenousintravenous 2 hr bolus/infusion, each on Days 1 and 2,every 2 weeks5-Fluorouracil 400 mg/m2intravenous bolus,followed by 600 mg/m2 intravenous 22 hr

Placebo or 5 mg/kg intravenous Day 1, prior to FOLFOX-4, every

Bevacizumab 30-90 mins 2 weeks

Treatment Starting Dose Schedule

XELOX Oxaliplatin 130 mg/m2 Oxaliplatin on Day 1, every 3 weeksor intravenous 2 hr Capecitabine oral twice daily for 2

XELOX+ weeks (followed by 1 week off-

Bevacizumab Capecitabine 1000 mg/m2 oral treatment)twice daily

Placebo or 7.5 mg/kg Day 1, prior to XELOX, every 3 weeks

Bevacizumab intravenous 30-90mins5-Fluorouracil: intravenous bolus injection immediately after leucovorin

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

Table 7 Key efficacy results for the non-inferiority analysis of Study NO16966

PRIMARY ANALYSIS

XELOX/XELOX+P/ FOLFOX-4/FOLFOX-4+P/

XELOX+BV FOLFOX-4+BV(EPP*: N=967; ITT**: (EPP*: N=937; ITT**:

N=1017) N=1017)

HR

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

Parameter: Progression-free Survival

EPP 241 259 1.05 (0.94; 1.18)

ITT 244 259 1.04 (0.93; 1.16)

Parameter: Overall Survival

EPP 577 549 0.97 (0.84; 1.14)

ITT 581 553 0.96 (0.83; 1.12)

ADDITIONAL 1 YEAR OF FOLLOW UP

HR

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

Parameter: Progression-free Survival

EPP 242 259 1.02 (0.92; 1.14)

ITT 244 259 1.01 (0.91; 1.12)

Parameter: Overall Survival

EPP 600 594 1.00 (0.88; 1.13)

ITT 602 596 0.99 (0.88; 1.12)

*EPP=eligible patient population; **ITT=intent-to-treat population

In a randomised, controlled phase III study (CAIRO), the effect of using capecitabine at a starting doseof 1000 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment ofpatients with metastatic colorectal cancer was studied. 820 patients were randomised to receive eithersequential treatment (n=410) or combination treatment (n=410). Sequential treatment consisted offirst-line capecitabine (1250 mg/m2 twice daily for 14 days), second-line irinotecan (350 mg/m2 on day1), and third-line combination of capecitabine (1000 mg/m2 twice daily for 14 days) with oxaliplatin(130 mg/m2 on day 1). Combination treatment consisted of first-line capecitabine (1000 mg/m2 twicedaily for 14 days) combined with irinotecan (250 mg /m2 on day 1) (XELIRI) and second-linecapecitabine (1000 mg/m2 twice daily for 14 days) plus oxaliplatin (130 mg/m2 on day 1). Alltreatment cycles were administered at intervals of 3 weeks. In first-line treatment the medianprogression-free survival in the intent-to-treat population was 5.8 months (95%CI 5.1 - 6.2 months)for capecitabine monotherapy and 7.8 months (95%CI 7.0 - 8.3 months; p=0.0002) for XELIRI.

However this was associated with an increased incidence of gastrointestinal toxicity and neutropeniaduring first-line treatment with XELIRI (26% and 11% for XELIRI and first line capecitabinerespectively).

The XELIRI has been compared with 5-FU + irinotecan (FOLFIRI) in three randomised studies inpatients with metastatic colorectal cancer. The XELIRI regimens included capecitabine 1000 mg/m2twice daily on days 1 to 14 of a three-week cycle combined with irinotecan 250 mg/m2 on day1. In thelargest study (BICC-C), patients were randomised to receive either open label FOLFIRI (n=144),bolus 5-FU (mIFL) (n=145) or XELIRI (n=141) and were additionally randomised to receive eitherdouble-blind treatment with celecoxib or placebo. Median PFS was 7.6 months for FOLFIRI, 5.9months for mIFL (p=0.004) for the comparison with FOLFIRI), and 5.8 months for XELIRI(p=0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p=0.09), and 18.9months for XELIRI (p=0.27). Patients treated with XELIRI experienced excessive gastrointestinaltoxicity compared with FOLFIRI (diarrhoea 48% and 14% for XELIRI and FOLFIRI respectively).

In the EORTC study patients were randomised to receive either open label FOLFIRI (n=41) or

XELIRI (n=44) with additional randomisation to either double-blind treatment with celecoxib orplacebo. Median PFS and overall survival (OS) times were shorter for XELIRI versus FOLFIRI (PFS5.9 versus 9.6 months and OS 14.8 versus 19.9 months), in addition to which excessive rates ofdiarrhoea were reported in patients receiving the XELIRI regimen (41% XELIRI, 5.1% FOLFIRI).

In the study published by Skof et al, patients were randomised to receive either FOLFIRI or XELIRI.

Overall response rate was 49% in the XELIRI and 48% in the FOLFIRI arm (p=0.76). At the end oftreatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were withoutevidence of the disease (p=0.56). Toxcity was similar between treatments with the exception ofneutropenia reported more commonly in patients treated with FOLFIRI.

Montagnani et al used the results from the above three studies to provide an overall analysis ofrandomised studies comparing FOLFIRI and XELIRI treatment regimens in the treatment of mCRC.

A significant reduction in the risk of progression was associated with FOLFIRI (HR, 0.76; 95%CI,0.62-0.95; P <0.01), a result partly due to poor tolerance to the XELIRI regimens used.

Data from a randomised clinical study (Souglakos et al, 2012) comparing FOLFIRI + bevacizumabwith XELIRI + bevacizumab showed no significant differences in PFS or OS between treatments.

Patients were randomised to receive either FOLFIRI plus bevacizumab (Arm-A, n=167) or XELIRIplus bevacizumab (Arm-B, n-166). For Arm B, the XELIRI regimen used capecitabine 1000 mg/m2twice daily for 14 days + irinotecan 250 mg/m2 on day 1. Median progression-free survival (PFS) was10.0 and 8.9 months; p=0.64, overall survival 25.7 and 27.5 months; p=0.55 and response rates 45.5and 39.8%; p=0.32 for FOLFIRI-Bev and XELIRI-Bev, respectively. Patients treated with XELIRI +bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-footskin reactions than patients treated with FOLFIRI + bevacizumab with significantly increasedtreatment delays, dose reductions and treatment discontinuations.

Data from a multicentre, randomised, controlled phase II study (AIO KRK 0604) supports the use ofcapecitabine at a starting dose of 800 mg/m2 for 2 weeks every 3 weeks in combination with irinotecanand bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. 120 Patientswere randomised to a modified XELIRI regimen with capecitabine 800 mg/m2 twice daily for twoweeks followed by a 7-day rest period), irinotecan (200 mg/m2 as a 30 minute infusion on day 1 every3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks); 127patients were randomised to treatment with capecitabine (1000 mg/m2 twice daily for two weeksfollowed by a 7-day rest period), oxaliplatin (130 mg/m2 as a 2 hour infusion on day 1 every 3 weeks),and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). Following a meanduration of follow-up for the study population of 26.2 months, treatment responses were as shownbelow:

Table 8 Key efficacy results for AIO KRK study

XELOX + bevacizumab Modified XELIRI+ Hazard ratiobevacizumab 95% CI(ITT: N=127) (ITT: N= 120) P value

Progression-free Survival after 6 months

ITT 76% 84%

- 95% CI 69 - 84% 77 - 90%

Median progression free survival

ITT 10.4 months 12.1 months 0.9395% CI 9.0 - 12.0 10.8 - 13.2 0.82 - 1.07

P=0.30

Median overall survival

ITT 24.4 months 25.5 months 0.9095% CI 19.3 - 30.7 21.0 - 31.0 0.68 - 1.19

P=0.45

Combination therapy in second-line treatment of metastatic colorectal cancer

Data from a multicentre, randomised, controlled phase III clinical study (NO16967) support the use ofcapecitabine in combination with oxaliplatin for the second-line treatment of metastastic colorectalcancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received priortreatment with irinotecan in combination with a fluoropyrimidine regimen as first line therapy wererandomised to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and

FOLFOX-4 (without addition of placebo or bevacizumab), refer to table 6. XELOX was demonstratedto be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol populationand intent-to-treat population (see table 9). The results indicate that XELOX is equivalent to

FOLFOX-4 in terms of overall survival (see table 9). The median follow up at the time of the primaryanalyses in the intent-to-treat population was 2.1 years; data from analyses following an additional 6months of follow up are also included in table 9.

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

PRIMARY ANALYSIS

XELOX FOLFOX-4(PPP*: N=251; ITT**: (PPP*: N=252; ITT**:

N=313) N=314)

HR

Population Median Time to Event (Days) (95% CI)

Parameter: Progression-free Survival

PPP 154 168 1.03 (0.87; 1.24)

ITT 144 146 0.97 (0.83; 1.14)

Parameter: Overall Survival

PPP 388 401 1.07 (0.88; 1.31)

ITT 363 382 1.03 (0.87; 1.23)

ADDITIONAL 6 MONTHS OF FOLLOW UP

HR

Population Median Time to Event (Days) (95% CI)

Parameter: Progression-free Survival

PPP 154 166 1.04 (0.87; 1.24)

ITT 143 146 0.97 (0.83; 1.14)

Parameter: Overall Survival

PPP 393 402 1.05 (0.88; 1.27)

ITT 363 382 1.02 (0.86; 1.21)

*PPP=per-protocol population; **ITT=intent-to-treat population

Advanced gastric cancer:

Data from a multicentre, randomised, controlled phase III clinical trial in patients with advancedgastric cancer supports the use of capecitabine for the first-line treatment of advanced gastric cancer(ML17032). In this trial, 160 patients were randomised to treatment with capecitabine (1000 mg/m2twice daily for 2 weeks followed by a 7-day rest period) and cisplatin (80 mg/m2 as a 2-hour infusionevery 3 weeks). A total of 156 patients were randomised to treatment with 5-FU (800 mg/m2 per day,continuous infusion on days 1 to 5 every 3 weeks) and cisplatin (80 mg/m2 as a 2-hour infusion on day1, every 3 weeks). Capecitabine in combination with cisplatin was non-inferior to 5-FU incombination with cisplatin in terms of progression-free survival in the per protocol analysis (hazardratio 0.81; 95% CI 0.63 - 1.04). The median progression-free survival was 5.6 months (capecitabine +cisplatin) versus 5.0 months (5-FU + cisplatin). The hazard ratio for duration of survival (overallsurvival) was similar to the hazard ratio for progression-free survival (hazard ratio 0.85; 95% CI 0.64 -1.13). The median duration of survival was 10.5 months (capecitabine + cisplatin) versus 9.3 months(5-FU + cisplatin).

Data from a randomised multicentre, phase III study comparing capecitabine to 5-FU and oxaliplatinto cisplatin in patients with advanced gastric cancer supports the use of capecitabine for the first-linetreatment of advanced gastric cancer (REAL-2). In this trial, 1002 patients were randomised in a 2x2factorial design to one of the following 4 arms:

- ECF: epirubicin (50 mg/ m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a twohour infusion on day 1 every 3 weeks) and 5-FU (200 mg/m2 daily given by continuous infusionvia a central line).

- ECX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a twohour infusion on day 1 every 3 weeks), and capecitabine (625 mg/m2 twice daily continuously).

- EOF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given asa 2 hour infusion on day 1 every three weeks), and 5-FU (200 mg/m2 daily given by continuousinfusion via a central line).

- EOX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given asa 2 hour infusion on day 1 every three weeks), and capecitabine (625 mg/m2 twice dailycontinuously).

The primary efficacy analyses in the per protocol population demonstrated non-inferiority in overallsurvival for capecitabine- vs 5-FU-based regimens (hazard ratio 0.86; 95% CI 0.8 - 0.99) and foroxaliplatin- vs cisplatin-based regimens (hazard ratio 0.92; 95% CI 0.80 - 1.1). The median overallsurvival was 10.9 months in capecitabine-based regimens and 9.6 months in 5-FU based regimens.

The median overall survival was 10.0 months in cisplatin-based regimens and 10.4 months inoxaliplatin-based regimens.

Capecitabine has also been used in combination with oxaliplatin for the treatment of advanced gastriccancer. Studies with capecitabine monotherapy indicate that capecitabine has activity in advancedgastric cancer.

Colon, colorectal and advanced gastric cancer: meta-analysis

A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967,

M17032) supports capecitabine replacing 5-FU in mono- and combination treatment in gastrointestinalcancer. The pooled analysis includes 3097 patients treated with capecitabine-containing regimens and3074 patients treated with 5-FU-containing regimens. Median overall survival time was 703 days(95% CI: 671; 745) in patients treated with capecitabine-containing regimens and 683 days (95% CI:646; 715) in patients treated with 5-FU-containing regimens. The hazard ratio for overall survival was0.94 (95% CI: 0.89; 1.00, p=0.0489) indicating that capecitabine-containing regimens are non-inferiorto 5-FU-containing regimens.

Breast cancer

Combination therapy with capecitabine and docetaxel in locally advanced or metastatic breast cancer

Data from one multicentre, randomised, controlled phase III clinical trial support the use ofcapecitabine in combination with docetaxel for treatment of patients with locally advanced ormetastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In thistrial, 255 patients were randomised to treatment with capecitabine (1250 mg/m2 twice daily for 2weeks followed by 1-week rest period and docetaxel 75 mg/m2 as a 1 hour intravenous infusion every3 weeks). 256 patients were randomised to treatment with docetaxel alone (100 mg/m2 as a 1 hourintravenous infusion every 3 weeks). Survival was superior in the capecitabine + docetaxelcombination arm (p=0.0126). Median survival was 442 days (capecitabine + docetaxel) vs. 352 days(docetaxel alone). The overall objective response rates in the all-randomised population (investigatorassessment) were 41.6% (capecitabine + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time toprogressive disease was superior in the capecitabine + docetaxel combination arm (p<0.0001). Themedian time to progression was 186 days (capecitabine + docetaxel) vs. 128 days (docetaxel alone).

Monotherapy with capecitabine after failure of taxanes, anthracycline containing chemotherapy, andfor whom anthracycline therapy is not indicated

Data from two multicentre phase II clinical trials support the use of capecitabine monotherapy fortreatment of patients after failure of taxanes and an anthracycline-containing chemotherapy regimen orfor whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients weretreated with capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). Theoverall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial).

The median time to progression was 93 and 98 days. Median survival was 384 and 373 days.

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabinemonotherapy or capecitabine in combination with different chemotherapy regimens in multipleindications (colon, colorectal, gastric and breast cancer) showed that patients on capecitabine whodeveloped hand-foot syndrome (HFS) had a longer overall survival compared to patients who did notdevelop HFS: median overall survival 1100 days (95% CI 1007;1200) vs 691 days (95% CI 638;754)with a hazard ratio of 0.61 (95% CI 0.56; 0.66).

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing capecitabine in all subsets of the paediatric population inadenocarcinoma of the colon and rectum, gastric adenocarcinoma and breast carcinoma (see section4.2 for information on paediatric use).

The pharmacokinetics of capecitabine have been evaluated over a dose range of 502-3514 mg/m2/day.

The parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine(5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30%-35% higher on day14. Capecitabine dose reduction decreases systemic exposure to 5-FU more than dose-proportionally,due to non-linear pharmacokinetics for the active metabolite.

After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensiveconversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate ofcapecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC ofthe subsequent metabolite 5-FU. At the dose of 1250 mg/m2 on day 14 with administration after foodintake, the peak plasma concentrations (Cmax in µg/ml) for capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and

FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 respectively. The time to peak plasma concentrations (Tmaxin hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0- values in g-h/ml were 7.75, 7.24, 24.6,2.03 and 36.3.

In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are54%, 10%, 62% and 10% protein bound, mainly to albumin.

Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to5-DFUR by cytidine deaminase, principally located in the liver and tumour tissues. Further catalyticactivation of 5'-DFUR then occurs by thymidine phosphorylase (ThyPase). The enzymes involved inthe catalytic activation are found in tumour tissues but also in normal tissues, albeit usually at lowerlevels. The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higherconcentrations within tumour tissues. In the case of colorectal tumours, 5-FU generation appears to bein large part localised in tumour stromal cells. Following oral administration of capecitabine topatients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumours to adjacenttissues was 3.2 (ranged from 0.9 to 8.0). The ratio of 5-FU concentration in tumour to plasma was 21.4(ranged from 3.9 to 59.9, n=8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0to 25.8, n=8). Thymidine phosphorylase activity was measured and found to be 4 times greater inprimary colorectal tumour than in adjacent normal tissue. According to immunohistochemical studies,thymidine phosphorylase appears to be in large part localised in tumour stromal cells.

5-FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much lesstoxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield5-fluoro-ureidopropionic acid (FUPA). Finally, -ureido-propionase cleaves FUPA to-fluoro--alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD)activity is the rate limiting step. Deficiency of DPD may lead to increased toxicity of capecitabine (seesection 4.3 and 4.4).

The elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were0.85, 1.11, 0.66, 0.76 and 3.23 respectively. Capecitabine and its metabolites are predominantlyexcreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Faecal excretion isminimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of theadministered dose. About 3% of the administered dose is excreted in urine unchanged.

Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel orpaclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel orpaclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of5’-DFUR.

A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patientswith colorectal cancer dosed at 1250 mg/m2 twice daily. Gender, presence or absence of livermetastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and

ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Hepatic impairment due to liver metastases.

According to a pharmacokinetic study in cancer patients with mild to moderate liver impairment dueto liver metastases, the bioavailability of capecitabine and exposure to 5-FU may increase compared topatients with no liver impairment. There are no pharmacokinetic data on patients with severe hepaticimpairment.

Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is noevidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU.

Creatinine clearance was found to influence the systemic exposure to 5’-DFUR (35% increase in AUCwhen creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinineclearance decreases by 50%). FBAL is a metabolite without antiproliferative activity.

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

Ethnic factors.

Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients(n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than Caucasian patients(n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than

Caucasian patients. The clinical relevance of these differences is unknown. No significant differencesoccurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).

In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys andmice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical forfluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised bydegenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepaticand CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable incynomolgus 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 receivingcapecitabine; however, this effect was reversible after a drug-free period. In addition, during a13-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 andteratogenicity 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 mousebone marrow micronucleus tests (in vivo).

Microcrystalline cellulose (E460)

Croscarmellose sodium

Hypromellose (E-5)

Magnesium stearate

- Ecansya 150 mg film-coated tablets

Hypromellose (6cps)

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

- Ecansya 300 mg film-coated tablets

Hypromellose (6cps)

Talc

Titanium dioxide (E171)

- Ecansya 500 mg film-coated tablets

Hypromellose (6cps)

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Not applicable.

3 years

Aluminium/aluminium blisters

This medicinal product does not require any special storage conditions.

PVC/PVdC/aluminium blisters

Do not store above 30°C.

Aluminium/aluminium or PVC/PVdC/aluminium blister containing 10 film-coated tablets. Each packcontains 30, 60 or 120 film-coated tablets.

Not all pack sizes may be marketed.

Procedures for safe handling of cytotoxic drugs should be followed.

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Ecansya 150 mg film-coated tablets

- Aluminium/aluminium blisters30 film-coated tablets: EU/1/12/763/00160 film-coated tablets: EU/1/12/763/002120 Film-coated tablets: EU/1/12/763/003

- PVC/PVdC/aluminium blisters30 film-coated tablets: EU/1/12/763/00460 film-coated tablets: EU/1/12/763/005120 film-coated tablets: EU/1/12/763/006

Ecansya 300 mg film-coated tablets

- Aluminium/aluminium blisters30 film-coated tablets: EU/1/12/763/00760 film-coated tablets: EU/1/12/763/008120 film-coated tablets: EU/1/12/763/009

- PVC/PVdC/aluminium blisters30 film-coated tablets: EU/1/12/763/01060 film-coated tablets: EU/1/12/763/011120 film-coated tablets: EU/1/12/763/012

Ecansya 500 mg film-coated tablets

- Aluminium/aluminium blisters30 film-coated tablets: EU/1/12/763/01360 film-coated tablets: EU/1/12/763/014120 film-coated tablets: EU/1/12/763/015

- PVC/PVdC/aluminium blisters30 film-coated tablets: EU/1/12/763/01660 film-coated tablets: EU/1/12/763/017120 film-coated tablets: EU/1/12/763/018

Date of first authorisation: 20 April 2012

Date of latest renewal: 9 December 2016

Detailed information on this medicinal product is available on the website of the European Medicines

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