Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Roche Registration Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom
Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.
Diarrhoea: Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of ≥10 stools/day or grossly bloody diarrhoea or the need for parenteral support. Dose reduction should be applied as necessary (see section 4.2).
Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. 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.
Interaction studies have only been performed in adults.
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 reactions 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 and its toxicity may be enhanced by folinic acid: 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 concomitantly with sorivudine or its chemically related analogues, such as brivudine (see section 4.3). There must be at least a 4-week waiting period between end of treatment with sorivudine or its chemically related analogues such as brivudine and start of Xeloda therapy.
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.
Oxaliplatin: no clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.
Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.
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 (see section 5.2).
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.
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.
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.
Xeloda has minor or moderate influence on the ability to drive and use machines. Xeloda may cause dizziness, fatigue and nausea.
The overall safety profile of Xeloda is based on data from over 3000 patients treated with Xeloda as monotherapy 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. See section 5.1 for details of major studies, including study designs and major efficacy results.
The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.
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 ADRs by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10) and uncommon (≥ 1/1,000, < 1/100). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
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 1900 patients (studies M66001, SO14695, and SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis.
Table 4 – Summary of related ADRs reported in patients treated with Xeloda monotherapy:
| Body System | Very Common-All grades | Common-All grades | Uncommon-Severe and/or Life-threatening (grade 3-4) or considered medically relevant |
|---|---|---|---|
| Infections and infestations | - | Herpes viral infection, Nasopharyngitis, Lower respiratory tract infection | Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Influenza, Gastroenteritis, Fungal infection, Infection, Tooth abscess |
| Neoplasm benign, malignant and unspecified | - | - | Lipoma |
| Blood and lymphatic system disorders | - | Neutropenia, Anaemia | Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leucopenia, Haemolytic anaemia, International Normalised Ratio (INR) increased/Prothrombin time prolonged |
| Immune system disorders | - | - | Hypersensitivity |
| Metabolism and nutrition disorders | Anorexia | Dehydration, Decreased appetite, Weight decreased | Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia |
| Psychiatric disorders | - | Insomnia, Depression | Confusional state, Panic attack, Depressed mood, Libido decreased |
| Nervous system disorders | - | Headache, Lethargy Dizziness, Parasthesia Dysgeusia | Aphasia, Memory impairment, Ataxia, Syncope, Balance disorder, Sensory disorder, Neuropathy peripheral |
| Eye disorders | - | Lacrimation increased, Conjunctivitis, Eye irritation | Visual acuity reduced, Diplopia |
| Ear and labyrinth disorders | - | - | Vertigo, Ear pain |
| Cardiac disorders | - | - | Angina unstable, Angina pectoris, Myocardial ischaemia, Atrial fibrillation, Arrhythmia, Tachycardia, Sinus tachycardia, Palpitations |
| Vascular disorders | - | Thrombophlebitis | Deep vein thrombosis, Hypertension, Petechiae, Hypotension, Hot flush, Peripheral coldness |
| Respiratory, thoracic and mediastinal disorders | - | Dyspnoea, Epistaxis, Cough, Rhinorrhea | Pulmonary embolism, Pneumothorax, Haemoptysis, Asthma, Dyspnoea exertional |
| Gastrointestinal disorders | Diarrhoea, Vomiting, Nausea, Stomatitis, Abdominal pain | Gastrointestinal haemorrhage, Constipation, Upper abdominal pain, Dyspepsia, Flatulence, Dry mouth | Intestinal obstruction, Ascites, Enteritis, Gastritis, Dysphagia, Abdominal pain lower, Oesophagitis, Abdominal discomfort, Gastrooesophageal reflux disease, Colitis, Blood in stool |
| Hepatobiliary Disorders | - | Hyperbilirubinemia , Liver function test abnormalities | Jaundice |
| Skin and subcutaneous tissue disorders | Palmar-plantar erythrodysaesthesia syndrome | Rash, Alopecia, Erythema, Dry skin, Pruritus, Skin hyper-pigmentation, Rash macular, Skin desquamation, Dermatitis, Pigmentation disorder, Nail disorder | Skin ulcer, Rash, Urticaria, Photosensitivity reaction, Palmar erythema, Swelling face, Purpura |
| Muskuloskeletal and connective tissue disorders | - | Pain in extremity, Back pain, Arthralgia | Joint swelling, Bone pain, Facial pain, Musculoskeletal stiffness, Muscular weakness |
| Renal and urinary disorders | - | - | Hydronephrosis, Urinary incontinence, Haematuria, Nocturia, Blood creatinine increased |
| Reproductive system and breast disorders | - | - | Vaginal haemorrhage |
| General disorders and administration site conditions | Fatigue, Asthenia | Pyrexia, Lethargy, Oedema peripheral, Malaise, Chest pain | Oedema, Chills, Influenza like illness, Rigors, Body temperature increased |
| Injury, poisoning and procedural complications | - | - | Blister, Overdose |
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 3000 patients. ADRs are added to the appropriate frequency grouping (Very common or Common) according to the highest incidence seen in any of the major clinical trials and are only added when they were seen in addition to those seen with 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).
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.
| Body System | Very common-All grades | Common-All grades |
|---|---|---|
| Infections and infestations | - | Herpes zoster, Urinary tract infection, Oral candidiasis, Upper respiratory tract infection , Rhinitis, Influenza, +Infection, Oral herpes |
| Blood and lymphatic system disorders | +Neutropenia, +Leucopenia, +Anaemia, +Neutropenic fever, Thrombocytopenia | Bone marrow depression, +Febrile Neutropenia |
| Immune system disorders | - | Hypersensitivity |
| Metabolism and nutrition disorders | Appetite decreased | Hypokalaemia, Hyponatremia, Hypomagnesaemia, Hypocalcaemia, Hyperglycaemia |
| Psychiatric disorders | - | Sleep disorder, Anxiety |
| Nervous system disorders | Taste disturbance, Paraesthesia and dysaesthesia, Peripheral neuropathy, Peripheral sensory neuropathy, Dysgeusia, Headache | Neurotoxicity, Tremor, Neuralgia, Hypersensitivity reaction, Hypoaesthesia |
| Eye disorders | Lacrimation increased | Visual disorders, Dry eye, Eye pain, Visual impairment, Vision blurred |
| Ear and labyrinth disorders | - | Tinnitus, Hypoacusis |
| Cardiac disorders | - | Atrial fibrillation, Cardiac ischemia/infarction |
| Vascular disorders | Lower limb oedema, Hypertension, +Embolism and thrombosis | Flushing, Hypotension, Hypertensive crisis, Hot flush, Phlebitis |
| Respiratory, thoracic and mediastinal system disorders | Sore throat, Dysaesthesia pharynx | Hiccups, Pharyngolaryngeal pain, Dysphonia |
| Gastrointestinal disorders | Constipation, Dyspepsia | Upper gastrointestinal haemorrhage, Mouth ulceration, Gastritis, Abdominal distension, Gastroesophageal reflux disease, Oral pain, Dysphagia, Rectal haemorrhage, Abdominal pain lower, Oral dysaesthesia, Paraesthesia oral, Hypoaesthesia oral, Abdominal discomfort |
| Hepatobiliary disorders | - | Hepatic function abnormal |
| Skin and subcutaneous tissue disorders | Alopecia, Nail disorder | Hyperhidrosis, Rash erythematous, Urticaria, Night sweats |
| Musculoskeletal and connective tissue disorders | Myalgia, Arthralgia, Pain in extremity | Pain in jaw , Muscle spasms, Trismus, Muscular weakness |
| Renal and urinary disorder | - | Haematuria, Proteinuria, Creatinine renal clearance decreased, Dysuria |
| General disorders and administration site conditions | Pyrexia, Weakness, +Lethargy, Temperature intolerance | Mucosal inflammation, Pain in limb, Pain, Chills, Chest pain, Influenza-like illness, +Fever, Infusion related reaction, Injection site reaction, Infusion site pain, Injection site pain |
| Injury, poisoning and procedural complications | - | Contusion |
+ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”, the frequency count was based on grade 3-4 ADRs. ADRs are added according to the highest incidence seen in any of the major combination trials.
The following additional serious adverse reactions have been identified during post-marketing exposure:
Hand-foot syndrome (see section 4.4): For the capecitabine dose of 1250 mg/m² twice daily on days 1 to 14 every 3 weeks, a frequency of 53% to 60% of all-grades HFS was observed in capecitabine monotherapy trials (comprising studies in adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast cancer) and a frequency of 63% was observed in the capecitabine/docetaxel arm for the treatment of metastatic breast cancer. For the capecitabine dose of 1000 mg/m² twice daily on days 1 to 14 every 3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination therapy
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment with capecitabine. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female gender, and good ECOG performance status at baseline (0 versus ≥1).
Diarrhoea (see section 4.4): Xeloda can induce the occurrence of diarrhoea, which has been observed in up to 50% of patients.
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing 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%.
Elderly patients (see section 4.2): An analysis of safety data in patients ≥60 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 ≥60 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 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, increasing age (by 10 year increments) was statistically significantly associated with an increased risk of developing HFS and diarrhea and with a decreased risk of developing neutropenia.
Gender: The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and 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.
Not applicable.
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