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4.4      Special warnings and precautions for use

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

Diarrhoea. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of ³10 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. If Grade 2 (or higher) dehydration occurs, Xeloda 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. If grade 2 or 3 hand- foot syndrome occurs, administration of Xeloda should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand- foot syndrome, subsequent doses of Xeloda should be decreased. When Xeloda 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.

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 Xeloda. 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 Xeloda treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia (see section 4.8).

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

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

Coumarin-derivative anticoagulation. In a drug 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 Xeloda 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).

Hepatic impairment. In the absence of safety and efficacy data in patients with hepatic impairment, Xeloda use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of Xeloda should be interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with Xeloda 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 section 4.2 and 4.3).

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.

4.6      Fertility, Ppregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Xeloda. If the patient becomes pregnant while receiving Xeloda, the potential hazard to the foetus must be explained.

Pregnancy

There are no studies in pregnant women using Xeloda; however, it should be assumed that Xeloda may cause foetal harm if administered to pregnant women. In reproductive toxicity studies in animals, Xeloda administration caused embryolethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Xeloda is contraindicated during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Xeloda. If the patient becomes pregnant while receiving Xeloda, the potential hazard to the foetus must be explained.

Breastfeeding

It is not known whether Xeloda is excreted in human breast milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. Breast-feeding should be discontinued while receiving treatment with Xeloda.

4.8      Undesirable effects

Post-Marketing Experience:

The following additional serious adverse reactions have been identified during post-marketing exposure:

-           Very rare: lacrimal duct stenosis

-           Very rare: hepatic failure and cholestatic hepatitis have been reported during clinical trials and post-marketing exposure

-           Very rare: ventricular fibrillation, QT prolongation, torsade de pointes and bradycardia

4.2     Posology and method of administration

Combination therapy

Colon, Ccolorectal and gastric cancer

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

4.8     Undesirable effects

Xeloda in combination therapy:

Table 5 lists ADRs associated with the use of Xeloda in combination with different chemotherapy regimens in multiple indications based on safety data from over 14003000 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 Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy (see Table 4). Uncommon ADRs reported for Xeloda in combination therapy are consistent with the ADRs reported for Xeloda monotherapy or reported for monotherapy with the combination agent (in literature and/or respective summary of product characteristics).

Table 5   Summary of related ADRs reported in patients treated with Xeloda in combination treatment in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda 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.

c. Description of selected adverse reactions

A meta-analysis of 143 clinical trials with data from over 348700 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 20661788 (473%) patients after a median time of 155239 [95% CI 201135, 187288] 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 ³1).

Diarrhoea (see section 4.4):

The results of a meta-analysis of 134 clinical trials with data from over 348700 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhea:  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 diarrhea:  increasing cumulative capecitabine dose (0.1*kg) and increasing relative dose intensity in the first six weeks.   

d. Special populations

Elderly patients (see section 4.2):

The results of a meta-analysis of 134 clinical trials with data from over 437800 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 diarrhea and with a decreased risk of developing neutropenia. 

Gender

The results of a meta-analysis of 134 clinical trials with data from over 437800 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhea and with a decreased risk of developing neutropenia.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Colon and colorectal cancer:

Monotherapy with Xeloda in Aadjuvant Therapy with Xeloda in 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 Xeloda for the adjuvant treatment of patients with colon cancer (XACT Study; M66001). In this trial, 1987 patients were randomised to treatment with Xeloda (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 leucovorin IV followed by 425 mg/m² IV bolus 5‑FU, on days 1 to 5, every 28 days for 24 weeks). Xeloda was at least equivalent to IV 5-FU/LV in disease-free survival in per protocol population (hazard ratio 0.92; 95% CI 0.80-1.06). In the all-randomised population, tests for difference of Xeloda vs 5-FU/LV in disease-free and overall survival showed hazard ratios of 0.88 (95% CI 0.77 – 1.01; p = 0.068) and 0.86 (95% CI 0.74 – 1.01; p = 0.060), respectively. The median follow up at the time of the analysis was 6.9 years. In a preplanned multivariate Cox analysis, superiority of Xeloda compared with bolus 5-FU/LV was demonstrated. The following factors were pre-specified in the statistical analysis plan for inclusion in the model: age, time from surgery to randomisation, gender, CEA levels at baseline, lymph nodes at baseline, and country. In the all-randomised population, Xeloda 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 ratio 0.828; 95% CI 0.705 - 0.971; p = 0.0203). Currently, data on the use of Xeloda in combination with other chemotherapeutic agents in adjuvant therapy of colon cancer is not available.

Combination therapy in adjuvant colon cancer

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 Xeloda in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer (NO16968 study). In this trial, 944 patients were randomised to 3-week cycles for 24 weeks with Xeloda (1000 mg/m² twice daily for 2 weeks followed by a 1-week rest period) in combination with oxaliplatin (130 mg/m² intravenous infusion over 2-hours on day 1 every 3 weeks); 942 patients were randomized to bolus 5-FU and leucovorin. In the primary analysis for DFS in the ITT population, XELOX was shown to be significantly superior to 5-FU/LV (HR=0.80, 95% CI=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of RFS supports these results with a HR of 0.78 (95% CI=[0.67; 0.92]; p=0.0024) for XELOX vs. 5-FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI=[0.72; 1.05]; p=0.1486) which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV. The efficacy data is based on a median observation time of 59 months for OS and 57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOX combination therapy are (21 %) as compared with that of the 5-FU/LV monotherapy arm (9 %) in the ITT population.

Colon, colorectal and advanced gastric cancer: meta-analysis

A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, M17032) supports Xeloda replacing 5-FU in mono- and combination treatment in gastrointestinal cancer. The pooled analysis includes 3097 patients treated with Xeloda-containing regimens and 3074 patients treated with 5-FU-containing regimens. Median overall survival time was 703 days (95% CI: 671; 7435) in patients treated with Xeloda-containing regimens and 683 days (95% CI: 6486; 715) in patients treated with 5-FU-containing regimens. The hazard ratio for overall survival was 0.964 (95% CI: 0.9089; 1.020, p=0.0489) indicating that Xeloda-containing regimens are superior  equivalent to 5-FU-containing regimens.

All indications:

A meta-analysis of 134 clinical trials with data from over 438700 patients treated with Xeloda monotherapy or Xeloda in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that patients on Xeloda who developed hand-foot syndrome (HFS) had a longer overall survival compared to patients who did not develop HFS: median overall survival 29.0 months 1100 days (95% CI 26.0; 31.61007;1200) vs 15.9 months691 days (95% CI 638;75415.0; 17.0) with a hazard ratio of 0.6591 (95% CI 0.546; 0.646). 

10.     DATE OF REVISION OF THE TEXT

31 October 2008 23 March 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.ema.europa.eu/

Underlined text has been added, text with strike through deleted:

4.8     Undesirable effects

a. Summary of the safety profile

The overall safety profile of Xeloda is based on data adverse drug reactions considered by the investigator to be possibly, probably, or remotely related to the administration of Xeloda have been obtained from clinical studies in >over 3000 patients  conductedtreated  with Xeloda as monotherapy (in adjuvant therapy of colon cancer, in metastatic colorectal cancer and metastatic breast cancer),or  Xeloda in combination with different chemotherapy regimens in multiple indications. The safety profiles of Xeloda monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable. docetaxel in metastatic breast cancer after failure of cytotoxic chemotherapy, Xeloda in combination with oxaliplatin with or without bevacizumab in metastatic colorectal cancer and Xeloda in combination with various agents in advanced gastric cancer. The safety data from the clinical trial population for monotherapy and combination therapy are presented in this section. For post marketing experience, see below. 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), fatigue and hand-foot syndrome (palmar-plantar erythrodysesthesia), .fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.

b. Tabulated summary of adverse reactions

ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of Xeloda are listed in Table 4 for Xeloda given as a single agent and in Table 5 for Xeloda given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRsadverse drug reactions by frequency: vVery common (³ 1/10), common (³ 1/100, < 1/10) and uncommon (³ 1/1,000, < 1/100). Within each frequency grouping, ADRsadverse drug reactions  are presented in order of decreasing seriousness.

Xeloda Monotherapy:

Table 4 lists ADRs associated with the use of Xeloda monotherapy based on a pooled analysis of safety data from three major studies including over Safety data for Xeloda monotherapy has been obtained from >1900 patients (studies M66001, SO14695, and SO14796).  Table 4 lists adverse drug reactions associated with the use of Xeloda monotherapy in three major clinical trials in adjuvant treatment for colon cancer and for metastatic colorectal cancer. Each aADRsdverse drug reaction has been  are added to the appropriate frequency grouping according to the overall incidence from athe pooled analysis.

 of the safety data from these three major clinical studies in colorectal cancer. 

The most frequently reported treatment-related adverse drug reactions were gastrointestinal disorders, especially diarrhoea, nausea, vomiting, stomatitis, and hand-foot syndrome (palmar-plantar erythrodysesthesia). The safety profiles of Xeloda monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable.

Table 4   Summary of related ADRsadverse drug reactions  reported in patients treated with Xeloda monotherapy in adjuvant treatment for colon cancer and metastatic colorectal cancer

Laboratory Abnormalities observed with Xeloda Monotherapy:

Table 5 lists laboratory abnormalities of all grades observed with Xeloda monotherapy in three major trials in adjuvant treatment for colon cancer and for metastatic colorectal cancer. Each laboratory abnormality has been added to the appropriate frequency grouping according to the overall incidence from a pooled analysis of the safety data from these three major clinical studies in colorectal cancer. 

Table 5   Laboratory abnormalities observed in patients treated with Xeloda monotherapy

Xeloda in combination therapy:

Tables 56, 7, and 8 lists those ADRs associated with the use ofadverse drug reactions reported in patients treated with Xeloda in combination with different chemotherapy regimens in multiple indications based on safety data from over 1400 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 another agent that were seen in addition to those seen with Xeloda monotherapy (see Table 4) or seen at a higher frequency grouping compared to Xeloda monotherapy (see Table 4). Uncommon ADRs reported for Xeloda in combination therapy are consistent with the ADRs reported for Xeloda monotherapy or reported for monotherapy with the combination agent (in literature and/or respective summary of product characteristics)..

Some of the ADRs are reactions commonly seen with the combination agent (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however an exacerbation by Xeloda therapy can not be excluded.

Table 9 lists those adverse drug reactions reported in patients treated with Xeloda in combination with two agents (oxaliplatin and bevacizumab) that were seen in addition to those seen with Xeloda monotherapy and those seen with Xeloda in combination with oxaliplatin (see Table 8) or seen at a higher frequency grouping compared to Xeloda monotherapy and Xeloda in combination with oxaliplatin (see Table 8).

Each adverse drug reaction has been added to the appropriate frequency grouping according to the incidence seen in the major clinical trial (for combination with cisplatin, with docetaxel, and with oxaliplatin and bevacizumab) or in the pooled safety analysis (for combination with oxaliplatin).

Uncommon adverse drug reactions reported for the combination therapy of Xeloda with the combination agent are consistent with the adverse drug reactions reported for Xeloda monotherapy or reported for monotherapy with the combination agent (in literature and/or respective summary of product characteristics).

Xeloda in combination with cisplatin:

Safety data for Xeloda in combination with cisplatin has been obtained from >150 patients. Table 6 lists adverse drug reactions associated with the use of Xeloda in combination with cisplatin in the major clinical trial in gastric cancer. The incidence of hand-foot syndrome for Xeloda plus cisplatin was 22% (all grades) and 4% (grade 3) in study ML17032 (see section 5.1).

Table 56 Summary of related ADRsadverse drug reactions  reported in patients treated with Xeloda in combination treatment with cisplatin in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy

Xeloda in combination with docetaxel:

Safety data for Xeloda in combination with docetaxel has been obtained from >250 patients. Table 7 lists adverse drug reactions associated with the use of Xeloda in combination with docetaxel in the major clinical trial in metastatic breast cancer.

Table 7   Summary of related adverse drug reactions reported in patients treated with Xeloda in combination with docetaxel in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy

Xeloda in combination with oxaliplatin:

Safety data for Xeloda in combination with oxaliplatin has been obtained from >900 patients. Table 8 lists adverse drug reactions associated with the use of Xeloda in combination with oxaliplatin from a pooled analysis of the safety data from two major clinical trials in first- and second-line treatment of metastatic colorectal cancer.

Table 8   Summary of related adverse drug reactions reported in patients treated with Xeloda in combination with oxaliplatin for the first-line and second-line treatmtent of metastatic colorectal cancer. The adverse drug reactions shown are those that were seen in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy

Xeloda in combination with oxaliplatin and bevacizumab:

Safety data for Xeloda in combination with oxaliplatin and bevacizumab has been obtained from >350 patients. Table 9 lists adverse drug reactions associated with the use of Xeloda in combination with oxaliplatin and bevacizumab in a clinical trial in the first-line treatment of metastatic colorectal cancer.

Table 9   Summary of related adverse drug reactions reported in patients who received Xeloda in combination with oxaliplatin and bevacizumab for the first-line treatmtent of metastatic colorectal cancer.  The adverse drug reactions shown are those that were seen in addition to those seen with Xeloda monotherapy and Xeloda in combination with oxaliplatin or seen at a higher frequency grouping compared to Xeloda monotherapy and Xeloda in combination with oxaliplatin

⁺ 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.

Xeloda in combination with irinotecan:

Adverse drug reactions reported in patients treated with Xeloda in combination with irinotecan in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy include: Very common,  all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity reaction, cardiac ischemia/infarction; Common, grade 3 and grade 4 adverse drug reactions: febrile neutropenia.

Xeloda in combination with irinotecan and bevacizumab:

Grade 3 and Grade 4 adverse drug reactions reported in patients treated with Xeloda in combination with irinotecan and bevacizumab in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy include: Common, grade 3 and grade 4 adverse drug reactions: neutropenia, thrombosis/embolism, hypertension, and cardiac ischemia/infarction.

Xeloda in combination with epirubicin and oxaliplatin:

Grade 3 and Grade 4 adverse drug reactions reported in patients treated with Xeloda in combination with epirubicin and oxaliplatin in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy include: Very common, grade 3 and grade 4 adverse drug reactions: leukopenia, neutropenia, lethargy; Common, grade 3 and grade 4 adverse drug reactions: anaemia, thrombocytopenia, febrile neutropenia, peripheral neuropathy, infection, fever, thromboembolism.

Xeloda in combination with epirubicin and cisplatin:

Grade 3 and Grade 4 adverse drug reactions reported in patients treated with Xeloda in combination with epirubicin and cisplatin in addition to those seen with Xeloda monotherapy or seen at a higher frequency grouping compared to Xeloda monotherapy include: Very common, grade 3 and grade 4 adverse drug reactions: leukopenia, neutropenia, anaemia, lethargy, thromboembolism; Common, grade 3 and grade 4 adverse drug reactions: thrombocytopenia, febrile neutropenia, peripheral neuropathy, infection, fever.

Post-Marketing Experience:

The following additional serious adverse reactions have been identified during post-marketing exposure:

-        Very rare: lacrimal duct stenosis

-        Very rare: hepatic failure and cholestatic hepatitis have been reported during clinical trials and post-marketing exposure

c. 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 13 clinical trials with data from over 3800 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 1788 (47%) patients after a median time of 155 [95% CI 135, 187] 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 ³1).

Diarrhoea (see section 4.4):

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

The results of a meta-analysis of 13 clinical trials with data from over 3800 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhea:  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 diarrhea:  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 Xeloda 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 Xeloda monotherapy with an incidence of less than 0.1%.

d. Special populations

Elderly patients (see section 4.2):

An analysis of safety data in patients ³60 years of age treated with Xeloda monotherapy and an analysis of patients treated with Xeloda 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 ³60 years of age treated with Xeloda 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 13 clinical trials with data from over 3800 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 diarrhea and with a decreased risk of developing neutropenia. 

Gender

The results of a meta-analysis of 13 clinical trials with data from over 3800 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhea 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 Xeloda 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.

Section 4.2

The text in red has been added:

The recommended dose for Xeloda in the treatment of metastatic colorectal cancer and locally advanced or metastatic breast cancer is 1250 mg/m² administered twice daily (morning and evening; equivalent to 2500mg/m² total daily dose) for 14 days followed by a seven day rest period. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months, i.e. Xeloda 1250 mg/m² administered twice daily for 14 days followed by a seven day rest period, given as 3-week cycles for a total of 8 cycles (24 weeks).

Section 4.8

The text in red has been added:

The safety profiles of Xeloda monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable.

In table 6:

Skin and subcutaneous tissue disorders: dermatitis has changed from 1% to 2%

Gastrointestinal disorders: gastrointestinal haemorrhage (2%) has been added.

General disorders and administration site conditions: non-cardiac chest pain (1%) has been added

Investigations: liver function test abnormalities (1%) has been added

Infections and infestations: lower respiratory tract infection (1%) has been added

Vascular disorders: Thrombophlebitis (2%) has been added

After table 6

Underlined text has been added, text with strike through has been deleted:

The following related uncommon adverse reactions have been reported as severe and/or life-threatening or are considered to be medically relevant:

Skin and subcutaneous tissue disorders (uncommon): Skin ulcer, rash, urticaria, photosensitivity reaction, palmar erythema, swelling face, purpura penile ulceration, onycholysis, skin lesion, rash pruritic, pruritus generalized, urticaria, photosensitivity reaction, dermatitis exfoliative, eczema, skin fissures, rash vesicular, plantar erythema, palmar erythema, rash erythematous, rash generalized, rash maculo-papular, rash papular, rash scaly, skin inflammation, exanthema, onychorrhexis, nail dystrophy, hyperhidrosis, hypotrichosis, swelling face, night sweats, nail discolouration, nail ridging, actinic keratosis, localised exfoliation, nail pigmentation, onychomadesis, hyperkeratosis, purpura, skin discolouration

Gastrointestinal disorders(uncommon): Gastrointestinal haemorrhage, iIntestinal obstruction, small intestinal obstruction, ascites, enteritis, gastritis, dysphagia, abdominal pain lower, oesophagitis, abdominal discomfort, gastro-oesophageal reflux disease, colitis haematemesis, melaena, rectal haemorrhage, diarrhoea haemorrhagic, ascites, haematochezia, enterocolitis, oral pain, gastritis, dysphagia, dry lip, lip ulceration, abdominal pain lower, abdominal distension, oesophagitis, chapped lips, lip pain, abdominal discomfort, gastrooesophageal reflux disease, cheilitis, haemorrhoids, aphthous stomatitis, proctalgia, colitis, glossodynia, proctitis, salivary hypersecretion, frequent bowel movements, gingival pain, pruritus ani, eructation, lip blister, aptyalism, enteritis, stomach discomfort, epigastric discomfort, abdominal tenderness, hypoaesthesia oral, rectal discharge, tongue ulceration, anal fissure, bowel sounds abnormal

General disorders and administration site conditions (uncommon): Chest pain, oOedema, pitting oedema, chills, influenza like illness, non-cardiac chest pain, pain, rigors, ill-defined disorder, thirst, chest discomfort, feeling cold, feeling hot, facial pain, tenderness

Metabolism and nutrition disorders (uncommon): Appetite disorder, Cachexia, malnutrition, diabetes, hypokalaemia,  mellitus, diabetes mellitus inadequate control, hypoalbuminaemia, hypokalemia, appetite disorder, hypertriglyceridaemia

Nervous System Disorders (uncommon): Aphasia, amnesia, memory impairment, ataxia, syncope, balance disorder, hypoaesthesia, peripheral sensory neuropathy, sensory disorder, neuropathy peripheral hyperaesthesia, burning sensation, paresthesia oral, dysaethesia, ageusia, disturbance in attention, somnolence, parosmia, tremor, neuropathy peripheral, dizziness postural

Eye disorders (uncommon): Visual acuity reduced, diplopiaEye pain, vision blurred, keratoconjunctivitis sicca, dry eye, eye pruritus, visual acuity reduced, eye discharge, eye redness, diplopia, conjunctival haemorrhage, eyelid pain

Respiratory, thoracic and mediastinal disorders (uncommon): Pulmonary embolism, pneumothorax

haemoptysis, asthma, dyspnoea exertional,

 wheezing, pharyngolaryngeal pain, hiccups, rhinitis, nasal passage irritation, dry throat, nasal ulcer, hoarseness, productive cough, nasal discomfort, postnasal drip, throat irritation

Muskuloskeletal and connective tissue disorders (uncommon): Myalgia, jJoint swelling, muscle cramp, bone pain, flank pain, facial pain, neck pain, musculoskeletal stiffness, muscular weakness

Investigations (uncommon): International normalised ratio increased, blood creatinine increased, haemoglobin decreased, blood potassium decreased, hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, liver function test abnormal, body temperature increased, weight increased, blood in stool

Psychiatric disorders (uncommon): Confusional state, panic attack, anxiety, depressed mood, sleep disorder, nightmare, libido decreased, anger, nervousness, irritability, restlessness, mood altered

Hepatobiliary disorders (uncommon): Hepatic steatosis, hepatomegaly, jJaundice, hepatic pain

Infections and infestations (uncommon): Sepsis, urinary tract infection, cellulites, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, herpes infection, infection,  tooth abscess pneumonia, lower respiratory tract infection, urinary tract infection, wound infection, cellulitis, cystitis, tonsillitis, upper respiratory tract infection, localized infection, pharyngitis, vaginal candidiasis, candidiasis, oral candidiasis, influenza, nail infection, bronchitis, gastroenteritis, folliculitis, rhinitis, vaginitis, fungal skin infection, paronychia, fungal infection, herpes virus infection, herpes zoster, infection, tooth abscess, onychomycosis

Vascular disorders (uncommon): Deep vein thrombosis, hypertension, petechiae, hypotension, hot flush, peripheral coldnessvenous thrombosis limb, phlebothrombosis, thrombophlebitis, thrombophlebitis superficial, phlebitis, hypertension, petechiae, hypotension, orthostatic hypotension, hot flush, flushing, peripheral coldness

Injury, poisoning and procedural complications (uncommon): Blister, contusion, sunburn, overdose, stoma site reaction

Reproductive system and breast disorders (uncommon): Vaginal haemorrhage, vaginal burning sensation, genital erythema, genital pruritus male, phimosis, balanitis

Renal and urinary disorders (uncommon): Hydronephrosis, urinary incontinence, haematuria, dysuria, pollakiuria, chromaturia, nocturia