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Drug details for : XELODA 150 mg and 500 mg film-coated tablets
| Drug class description : | Cytostatic (antimetabolite) |
| Generic Name : | Capecitabine |
| Drug description : | Film-coated tablet |
| Presentation : | 150 mg or 500 mg capecitabine |
| Indications : | Xeloda is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer. Xeloda is indicated for first line monotherapy of metastatic colorectal cancer. Xeloda in combination with docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Xeloda is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. |
| Adult Dosage : | Xeloda should only be prescribed by a qualified physician experienced in the utilisation of anti-neoplastic agents. Recommended posology: The recommended dose is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 14 days followed by a seven day rest period. Xeloda tablets should be swallowed with water within 30 minutes after a meal. Treatment should be discontinued if progressive disease or intolerable toxicity is observed. In combination with docetaxel, the recommended dose of Xeloda is 1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Pre-medication with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for patients receiving the Xeloda plus docetaxel combination. Table 1: Xeloda dose calculation according to body surface area, standard starting dose Dose level 1250 mg/m2 (twice daily) Number of tablets administered in the morning Number of tablets administered in the evening Body Surface Area (m2 ) Dose per administration (mg) 150 mg 500 mg 150 mg 500 mg 1.26 1500 - 3 - 3 1.27 - 1.38 1650 1 3 1 3 1.39 - 1.52 1800 2 3 2 3 1.53 - 1.66 2000 - 4 - 4 1.67 - 1.78 2150 1 4 1 4 1.79 - 1.92 2300 2 4 2 4 1.93 - 2.06 2500 - 5 - 5 2.07 - 2.18 2650 1 5 1 5 2.19 2800 2 5 2 5 Table 2: Calculated Xeloda dose, reduced to 75% of the standard starting dose Dose level 950 mg/m2 (twice daily) Number of tablets administered in the morning Number of tablets administered in the evening Body Surface Area (m2 ) Dose per administration (mg) 150 mg 500 mg 150 mg 500 mg 1.26 1150 1 2 1 2 1.27 - 1.38 1300 2 2 2 2 1.39 - 1.52 1450 3 2 3 2 1.53 - 1.66 1500 - 3 - 3 1.67 - 1.78 1650 1 3 1 3 1.79 - 1.92 1800 2 3 2 3 1.93 - 2.06 1950 3 3 3 3 2.07 - 2.18 2000 - 4 - 4 2.19 2150 1 4 1 4 Table 3: Calculated Xeloda dose, reduced to 50% of the standard starting dose Dose level 625 mg/m2 (twice daily) Number of tablets administered in the morning Number of tablets administered in the evening Body Surface Area (m2 ) Dose per administration (mg) 150 mg 500 mg 150 mg 500 mg 1.38 800 2 1 2 1 1.39 - 1.52 950 3 1 3 1 1.53 - 1.66 1000 - 2 - 2 1.67 - 1.78 1000 - 2 - 2 1.79 - 1.92 1150 1 2 1 2 1.93 - 2.06 1300 2 2 2 2 2.07 - 2.18 1300 2 2 2 2 2.19 1450 3 2 3 2 Posology adjustments during treatment: Toxicity due to Xeloda administration may be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time. Patients taking Xeloda should be informed of the need to interrupt treatment immediately if moderate or worse toxicity occurs. Doses of Xeloda omitted for toxicity are not replaced or restored, instead the patient should resume the planned treatment cycle. The following are the recommended dose modifications for toxicity: Table 4: Xeloda Monotherapy Dose Reduction Schedule Toxicity NCIC grades* During a course of therapy Dose adjustment for next cycle (% 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 Interrupt until resolved to grade 0-1 75% -3rd appearance Interrupt until resolved to grade 0-1 50% -4th appearance Discontinue treatment permanently •Grade 3 -1st appearance Interrupt until resolved to grade 0-1 75% -2nd appearance Interrupt until resolved to grade 0-1 50% -3rd appearance Discontinue treatment permanently •Grade 4 -1st appearance Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 50% *National Cancer Institute of Canada (NCIC) Common Toxicity Criteria (version 1) were used except for hand-foot syndrome. The following are the recommended dose modifications for toxicity when Xeloda and docetaxel are used in combination: Table 5: Xeloda (X) in Combination with Docetaxel (Taxotere®, T) Dose Reduction Schedule for Non-Haematological Toxicities (for dose modifications due to haematological toxicities, see section on haematological toxicity after the table) Recommended Dose Modifications Xeloda dose changes within a treatment cycle Dose adjustment on resumption of treatment Toxicity grade1 Grade 1 100% of starting dose (no interruption) X: 100% of starting dose T: 100% (75mg/m2 ) Toxicity grade1 Grade 2 1st appearance Interrupt until resolved to grade 0-1 X: 100% of starting dose T: 100% (75mg/m2 ) 2nd appearance of same toxicity Interrupt until resolved to (grade 0-1) X:75% of starting dose T: Reduce to 55mg/m2 3rd appearance of same toxicity Interrupt until resolved (grade 0-1) X: 50% of starting dose T: Discontinue permanently 4th appearance of same toxicity Discontinue permanently Toxicity grade1 Grade 3 1st appearance Interrupt until resolved (grade 0-1) X: 75% of starting dose T: Reduce to 55mg/m2 2nd appearance Interrupt until resolved (grade 0-1) X: 50% of starting dose T: Discontinue permanently 3rd appearance Discontinue permanently Toxicity grade1 Grade 4 1st appearance Discontinue permanently or (if physician deems it to be in the best interest of the patient) interrupt until resolved (grade 0-1) X: Reduce to 50% T: Discontinue permanently 2nd appearance Discontinue permanently 1. National Cancer Institute of Canada Common Toxicity Criteria (NCIC CTC), version 1.0 revised December 1994. Specific dose adjustment in combination with docetaxel: Xeloda and/or docetaxel dose modifications should be made according to the general dose modification scheme above, if nothing else is stated regarding specific dose adjustments. For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. At the beginning of a treatment cycle, if either a docetaxel or a Xeloda treatment delay is indicated, both docetaxel and Xeloda administration should be delayed until the requirements for restarting both drugs are met. For further information about docetaxel see also the summary of product characteristics for docetaxel (Taxotere®). Haematology: Xeloda treatment may continue throughout a grade 3 neutropenic episode. However, the patient should be closely monitored and administration of Xeloda should be interrupted if any grade 2 clinical event (eg diarrhoea, stomatitis, fever) coincides with the grade 3 neutropenic episode. If grade 4 neutropenia occurs treatment with Xeloda should be interrupted until recovery to grade 0-1. Treatment should only be re-administered when the neutrophil count is 1.5 x 109/L (Grade 0 - 1). Docetaxel dosage should be reduced from 75 mg/m2 to 55 mg/m2 in patients with neutropenia <0.5 x 109/l (grade 4) for more than 1 week, or febrile ( > 38°C) neutropenia. Docetaxel should be discontinued if grade 4 neutropenia or febrile neutropenia occurs at a dose of 55 mg/m2 docetaxel. Patients with baseline neutrophil counts of <1.5 x 109/l and/or thrombocyte counts of <100 x 109/l should not be treated with the Xeloda/docetaxel combination. Hypersensitivity: Patients who develop severe hypersensitivity reactions (hypotension with a decrease of 20 mm Hg, or bronchospasm, or generalised rash/erythema) should stop treatment immediately and be given appropriate therapy. These patients should not be rechallenged with the drug suspected to have caused hypersensitivity. Peripheral neuropathy: For 1st appearance of grade 2 toxicity, reduce the docetaxel dose to 55 mg/m2. If grade 3 toxicity appears, discontinue docetaxel treatment. In both instances follow the above dose modification scheme for Xeloda. Fluid retention: Severe (grade 3 or 4) toxicity such as pleural effusion, pericardial effusion or ascites which is possibly related to docetaxel should be closely monitored. In case of appearance of such toxicity docetaxel treatment should be discontinued, Xeloda treatment may be continued without dose modification. Hepatic impairment: Docetaxel should generally not be given to patients with serum bilirubin above the upper limit of normal. The following modifications should be applied to the docetaxel dose in the event of abnormal values for ASAT, ALAT, and/or alkaline phosphatase levels; ASAT and/or ALAT values Alkaline phosphatase values Docetaxel Dose modification 1.5 x ULN AND 5 x ULN no dose modification >1.5 x ULN - 2.5 x ULN AND 2.5 x ULN no dose modification >2.5 x ULN - 5 x ULN AND 2.5 x ULN reduce by 25% (not below 55 mg/m2 ) >1.5 x ULN - 5 x ULN AND >2.5 x ULN - 5 x ULN reduce by 25% (not below 55 mg/m2 ) >5 x ULN OR >5 x ULN (unless bone metastasis are present in the absence of any liver disorder) delay dose by a maximum of 2 weeks. If no recovery, discontinue docetaxel. Once the docetaxel dose is reduced for a given cycle, no further dose reduction is recommended for subsequent cycles unless worsening of the parameters is observed. In case of recovery of liver function tests after previous reduction of the docetaxel dose, the docetaxel dose can be re-escalated to the previous dose level. Diarrhoea: Follow the general dose modification scheme above (see also section 4.4). 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 those for the precipitating adverse event in accordance with the above guidelines. Posology adjustments for special populations: Hepatic impairment: Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis. Renal impairment: Xeloda is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min [Cockroft and Gault] at baseline). The incidence of grade 3 or 4 adverse events in patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% of starting dose is recommended. In patients with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose adjustment as outlined in the table above. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use. |
| Child Dosage : | Children (under 18 years): The safety and efficacy of Xeloda in children has not been studied. |
| Elderly Dosage : | Elderly: No adjustment of the starting dose is needed during Xeloda monotherapy. However, grade 3 or 4 treatment-related adverse events were more frequent in patients 60 years of age compared to younger patients. Careful monitoring of patients 60 years of age is advisable. In combination with docetaxel, an increased incidence of grade 3 or 4 treatment-related adverse events and treatment-related serious adverse events were observed in patients 60 years of age or more. For patients 60 years of age or more treated with the combination of Xeloda plus docetaxel, a starting dose reduction of Xeloda to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in patients 60 years of age treated with a reduced Xeloda starting dose in combination with docetaxel, the dose of Xeloda may be cautiously escalated to 1250 mg/m2 twice daily. |
| Contra Indications : | History of severe and unexpected reactions to fluoropyrimidine therapy, Known hypersensitivity to capecitabine, fluorouracil or any of the excipients, In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, During pregnancy and lactation, In patients with severe leucopenia, neutropenia, or thrombocytopenia, In patients with severe hepatic impairment, In patients with severe renal impairment (creatinine clearance below 30 ml/min), Treatment with sorivudine or its chemically related analogues, such as brivudine. Contraindications for docetaxel also apply to the Xeloda plus docetaxel combination. |
| Special Precautions : | Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse events are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced. Diarrhoea. Xeloda can induce the occurrence of diarrhoea, which has been observed in 50% of patients. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of 10 stools/day or grossly bloody diarrhoea or the need for parenteral support. If grade 2, 3 or 4 diarrhoea occurs, administration of Xeloda should be immediately interrupted until the diarrhoea resolves or decreases in intensity to grade 1. Following grade 3 or 4 diarrhoea, subsequent doses of Xeloda should be decreased or treatment discontinued permanently (grade 4). 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. Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes. These adverse events may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias, 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 Adverse Reactions). 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 Adverse Reactions). 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 Adverse Reactions). 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. 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. For combination treatment with Xeloda and docetaxel, see also Adult Dosage. Renal impairment. The incidence of grade 3 or 4 adverse events in patients with moderate renal impairment (creatinine clearance 30-50 ml/min) is increased compared to the overall population (See Adult Dosage and Contraindications). |
| Interactions : | Interaction with other medicinal products: Coumarin-derivative anticoagulants: Altered coagulation parameters and/or bleeding have been reported in patients taking Xeloda concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating Xeloda therapy and, in a few cases, within one month after stopping Xeloda. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, Xeloda 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 Xeloda should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anti-coagulant dose adjusted accordingly. Phenytoin: Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of Xeloda with phenytoin. Patients taking phenytoin concomitantly with Xeloda should be regularly monitored for increased phenytoin plasma concentrations. Folinic acid: A combination study with Xeloda and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of Xeloda and its metabolites. However, folinic acid has an effect on the pharmacodynamics of Xeloda: the maximum tolerated dose (MTD) of Xeloda alone using the intermittent regimen is 3000 mg/m2 per day whereas it is only 2000 mg/ m2 per day when Xeloda was combined with folinic acid (30 mg orally bid). Sorivudine and analogues: A clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, Xeloda must not be administered with sorivudine or its chemically related analogues, such as brivudine (See Contraindications). Antacid: The effect of an aluminum hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL). Allopurinol: Interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU. Concomitant use of allopurinol with Xeloda should be avoided. Interaction with cytochrome P-450: For potential interactions with isozymes 1A2, 2C9 and 3A4, see interactions with coumarin-derivative anticoagulation. Interferon alpha: The MTD of Xeloda was 2000 mg/m2 per day when combined with interferon alpha-2a (3 MIU/m2 per day) compared to 3000 mg/m2 per day when Xeloda was used alone. Radiotherapy: The MTD of Xeloda alone using the intermittent regimen is 3000 mg/m2 per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of Xeloda is 2000 mg/m2 per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy. Food Interaction: In all clinical trials, patients were instructed to administer Xeloda within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that Xeloda be administered with food. Administration with food decreases the rate of capecitabine absorption. |
| Adverse Reactions : | The adverse reactions considered to be possibly, probably, or remotely related to the administration of Xeloda have been obtained from clinical studies conducted with Xeloda monotherapy (in adjuvant therapy of colon cancer, in metastatic colorectal cancer and metastatic breast cancer) and Xeloda in combination with docetaxel in metastatic breast cancer after failure of cytotoxic chemotherapy. The most commonly reported treatment-related adverse events were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), fatigue and hand-foot syndrome (palmar-plantar erythrodysesthesia). Safety data of Xeloda monotherapy in adjuvant treatment for colon cancer (995 patients) and metastatic colorectal cancer (596 patients) were reported in three phase III trials (Table 6). The most frequently reported treatment-related adverse reactions in these trials were gastrointestinal disorders, especially diarrhoea, nausea, vomiting, stomatitis, and hand-foot syndrome (palmar-plantar erythrodysesthesia). The safety profile of Xeloda monotherapy for the breast cancer and colorectal cancer populations is comparable. The following headings are used to rank the undesirable effects by frequency: Very common (>1/10), common (>1/100, < 1/10) and uncommon (>1/1,000, < 1/100 ). Table 6: Summary of related adverse events reported in patients treated with Xeloda monotherapy in adjuvant treatment for colon cancer and metastatic colorectal cancer (total of 1591 patients) Body System Adverse Event Very Common Common Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome (57%) Rash (7%), alopecia (6%), erythema (6%), dry skin (5%), pruritus (2%), skin hyper-pigmentation (2%), rash macular (1%); skin desquamation (1%), dermatitis (1%), pigmentation disorder (1%), nail disorder (1%) Gastrointestinal disorders Diarrhoea (47%), nausea (35%), stomatitis (23%), vomiting (18%), abdominal pain (11%) Constipation (6%), upper abdominal pain (6%), dyspepsia (5%), flatulence (3%), dry mouth (3%), loose stools (2%), General disorders and administration site conditions Fatigue (16%), asthenia (10%) Pyrexia (6%), lethargy (6%), oedema peripheral (3%), malaise (1%) Metabolism and nutrition disorders Anorexia (10%), Dehydration (3%), decreased appetite (2%) Nervous System Disorders (none) Dysgeusia (5%), dizziness (5%), headache (4%), paresthesia (3 %), lethargy (1%) Eye disorders (none) Lacrimation increased (5%), conjunctivitis (4%), eye irritation (1%) Hepatobiliary Disorders (none) Hyperbilirubinemia/blood bilirubin/blood bilirubin increased (3%) Respiratory, thoracic and mediastinal disorders (none) Dyspnoea (3%), epistaxis (2%), cough (1%), rhinorrhea (1%) Muskuloskeletal and connective tissue disorders (none) Pain in extremity (3%), back pain (2%), arthralgia (2%) Investigations Weight decreased (2%) Blood and lymphatic system disorders (none) Neutropenia (2%), anaemia (2%) Psychiatric disorders (none) Insomnia (2%), depression (1%) Infections and infestations (none) Herpes simplex (1%), nasopharyngitis (1%) Skin and subcutaneous tissue disorders ( uncommon): Rash pruritic, skin discolouration, photosensitivity reaction, rash erythematous, dermatitis exfoliative, exanthema, onychorrhexis, hyperhidrosis, hypotrichosis, eczema, skin fissures, swelling face, onycholysis, palmar erythema, night sweats, skin ulcer, nail discolouration, nail ridging, rash generalised, rash maculo-papular, rash papular, penile ulceration, plantar erythema, skin lesion, actinic keratosis, localised exfoliation,nail dystrophy, pruritus generalised, rash vesicular, nail pigmentation, onychomadesis, urticaria, hyperkeratosis, purpura, rash scaly, skin inflammation. Gastrointestinal disorders(uncommon): Oral pain, gastritis, dysphagia, dry lip, lip ulceration, abdominal pain lower, abdominal distension, oesophagitis, chapped lips, lip pain, rectal haemorrhage, abdominal discomfort, gastrooesophageal reflux disease, cheilitis, haemorrhoids, aphthous stomatitis, proctalgia, colitis, glossodynia, proctitis, salivary hypersecretion, frequent bowel movements, gingival pain, intestinal obstruction, pruritus ani, eructation, gastrointestinal haemorrhage, lip blister, small intestinal obstruction, aptyalism, enteritis, stomach discomfort, epigastric discomfort, abdominal tenderness, hypoaesthesia oral, rectal discharge, tongue ulceration, anal fissure, enterocolitis, haematochezia, melaena, ascites, bowel sounds abnormal, diarrhoea haemorrhagic, haematemesis. General disorders and administration site conditions (uncommon): Chills, influenza like illness, non-cardiac chest pain, chest pain, pain, rigors, ill-defined disorder, thirst, chest discomfort, oedema, feeling cold, feeling hot, facial pain, pitting oedema, tenderness. Metabolism and nutrition disorders (uncommon): Hypokalemia, cachexia, appetite disorder, diabetes mellitus inadequate control, hypertriglyceridaemia, malnutrition, diabetes mellitus, hypoalbuminaemia. Nervous System Disorders (uncommon): Hypoaesthesia, paresthesia oral, ageusia, disturbance in attention, syncope, hyperaesthesia, burning sensation, balance disorder, somnolence, amnesia, memory impairment, dysaethesia, ataxia, parosmia, tremor, neuropathy peripheral, dizziness postural, aphasia, peripheral sensory neuropathy. Eye disorders (uncommon): Eye 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): Pharyngolaryngeal pain, hiccups, dyspnoea exertional, rhinitis, nasal passage irritation, dry throat, nasal ulcer, pulmonary embolism, hoarseness, haemoptysis, productive cough, wheezing, asthma, nasal discomfort, postnasal drip, throat irritation, pneumothorax. Muskuloskeletal and connective tissue disorders (uncommon): Myalgia, joint swelling, muscle cramp, bone pain, flank pain, facial pain, neck pain, musculoskeletal stiffness, muscular weakness. Blood and lymphatic system disorders (uncommon): Febrile neutropenia, leucopenia, thrombocytopenia, granulocytopenia, haemolytic anaemia, pancytopenia. Investigations (uncommon): Alanine aminotransferase increased, weight increased, hepatic enzyme increased, body temperature increased, aspartate aminotransferase increased, blood potassium decreased, haemoglobin decreased, liver function test abnormal, blood alkaline phosphatase increased, blood in stool, gamma-glutamyltransferase increased, international normalised ratio increased, blood creatinine increased. Psychiatric disorders (uncommon): Anxiety, nervousness, confusional state, depressed mood, irritability, restlessness, mood altered, sleep disorder, anger, libido decreased, nightmare, panic attack. Hepatobiliary disorders (uncommon): Hepatic steatosis, hepatomegaly, jaundice, hepatic pain. Infections and infestations (uncommon): Oral candidiasis, urinary tract infection, upper respiratory tract infection, lower respiratory tract infection, localized infection, cystitis, pneumonia, pharyngitis, vaginal candidiasis, candidiasis, influenza, nail infection, bronchitis, gastroenteritis, sepsis, folliculitis, rhinitis, vaginitis, wound infection, fungal skin infection, paronychia, fungal infection, herpes virus infection, herpes zoster, infection, tooth abscess, cellulitis, onychomycosis, tonsillitis. Vascular disorders (uncommon): Flushing, phlebitis, deep vein thrombosis, hypertension, hypotension, thrombophlebitis, hot flush, orthostatic hypotension, petechiae, thrombophlebitis superficial, peripheral coldness, phlebothrombosis, venous thrombosis limb. Cardiac disorders (uncommon): Angina pectoris, palpitations, artrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, angina unstable, myocardial ischaemia. Injury, poisoning and procedural complications (uncommon): Blister, contusion, sunburn, overdose, stoma site reaction. Reproductive system and breast disorders (uncommon): Balanitis, vaginal haemorrhage, vaginal burning sensation, genital erythema, genital pruritus male, phimosis. Renal and urinary disorders (uncommon): Dysuria, pollakiuria, haematuria, chromaturia, urinary incontinence, hydronephrosis, nocturia. Ear and labyrinth disorders (uncommon): Vertigo, ear pain. Immune system disorders (uncommon): Hypersensitivity. Neoplasm benign, malignant and unspecified (uncommon): Lipoma. Table 7: Laboratory abnormalities reported in patients treated with Xeloda monotherapy in adjuvant treatment for colon cancer and metastatic colorectal cancer (total 1591 patients) Patients with grade 1 to 4 abnormality (%) Patients with grade 3/4 (%) Patients with grade 4 (%) Decreased haemoglobin 73.3 1.4 0.4 Decreased neutrophils/granulocytes 25.4 2.4 1.6 Decreased platelets 18.8 1.0 0.6 Decreased lymphocytes 83.5 21.9 4.0 Decreased sodium 26.0 0.6 0.1 Decreased potassium 24.3 0.6 0.1 Increased calcium 6.4 0.9 0.8 Decreased calcium 16.7 1.8 1.5 Increased bilirubin 49.4 21.06 2.6 Increased alkaline phosphatase 44.3 1.3 0.1 Increased ALAT (SGPT) 29.9 1.2 0.1 Increased ASAT (SGOT) 33.9 0.8 0.1 Xeloda and docetaxel in combination: The most frequent treatment-related undesirable effects (5%) reported in a phase III trial in breast cancer patients failing anthracycline treatment are presented in Table 8. Treatment-related undesirable effects reported in the comparator arm of this trial, using the standard dose of docetaxel, are also presented. Rare or uncommon undesirable effects, as described in the section on Xeloda monotherapy, can be expected for combination therapy as well. These are not listed in the following table. Table 8: Summary of adverse events reported in patient treated with Xeloda in combination with docetaxel for metastatic breast cancer after failure of cytotoxic chemotherapy Adverse Event Xeloda 1250 mg/m2 /bid with Docetaxel 75 mg/m2 /3 weeks (n=251) Docetaxel 100 mg/m2 / 3 weeks (n=255) Body System/Adverse Event Total % Grade 3 / 4 % Total % Grade 3 / 4 % Gastrointestinal Stomatitis Diarrhoea Nausea Vomiting Constipation Abdominal pain Dyspepsia Abdominal pain upper Dry mouth 67 64 43 33 14 14 12 9 5 18 14 6 4 1 2 - - - 42 45 35 22 12 9 5 6 4 5 5 2 1 - 1 <1 1 - Skin and Subcutaneous Hand-foot syndrome Alopecia Nail disorder Dermatitis Rash erythematous Nail discolouration Onycholysis 63 41 14 8 8 6 5 24 6 2 - <1 - 1 7 42 15 9 4 4 5 1 7 - 1 - <1 1 General Asthenia Pyrexia Fatigue Weakness Pain in limb Lethargy Pain 23 21 21 13 9 6 6 3 1 4 1 <1 - - 22 29 25 9 8 5 2 5 <1 5 2 <1 1 - Blood & lymphatic system Neutropenic fever 16 16 21 21 Neurological Taste disturbance Paresthesia Dizziness Headache Peripheral neuropathy 15 11 9 7 5 <1 <1 - <1 - 14 15 6 8 10 <1 1 <1 1 1 Metabolism Anorexia Appetite decreased Dehydration Weight decreased 12 10 8 6 1 - 2 - 10 4 5 4 1 - 1 - Eye Lacrimation increased 12 - 5 - Musculoskeletal Myalgia Arthralgia Back pain 14 11 7 2 1 1 24 18 6 2 2 1 Cardiovascular Lower limb oedema 14 1 12 1 Respiratory Sore throat Dyspnoea Cough Epistaxis 11 7 6 5 2 1 <1 <1 7 9 9 5 <1 <1 - - Infection Oral candidiasis 6 <1 7 <1 Table 9: Laboratory abnormalities: Xeloda in combination with docetaxel in metastatic breast cancer after failure of cytotoxic chemotherapy Adverse Event Xeloda 1250 mg/m2 /bid with Docetaxel 75 mg/m2 /3 weeks (n=251) Docetaxel 100 mg/m2 / 3 weeks (n=255) Laboratory Abnormalities (according to NCIC/CTC) Grade 3 / 4 % Grade 3 / 4 % Lymphopenia Leucocytopenia Neutropenia Anaemia Thrombocytopenia Hyperbilirubinemia 89 61 63 10 3 9 84 75 72 6 3 3 Post-Marketing Experience The following additional serious adverse events have been identified during post-marketing exposure: - Very rare: lacrimal duct stenosis. |
| Manufacturer : | Roche |
| Drug Availability : | (POM) |
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