Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 30 April 2018

Indication(s)

1 INDICATIONS AND USAGE XELODA (capecitabine) is a nucleoside metabolic inhibitor with antineoplastic activity indicated for: Adjuvant Colon Cancer (1.1) –Patients with Dukes' C colon cancer Metastatic Colorectal Cancer (1.1) –First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred Metastatic Breast Cancer (1.2) –In combination with docetaxel after failure of prior anthracycline-containing therapy –As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen 1.1 Colorectal Cancer XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent XELODA in the adjuvant treatment of Dukes' C colon cancer. XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage. 1.2 Breast Cancer XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. XELODA monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

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Advisory information

contraindications
4 CONTRAINDICATIONS Severe Renal Impairment (4.1) Hypersensitivity (4.2) 4.1 Severe Renal Impairment XELODA is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 4.2 Hypersensitivity XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.
Adverse reactions
6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. (6) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adjuvant Colon Cancer Table 4 shows the adverse reactions occurring in ≥5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV. Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. Table 4 Percent Incidence of Adverse Reactions Reported in ≥5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1969) XELODA (N=995) 5-FU/LV (N=974) Body System/Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal Pain 14 3 16 2 Constipation 9 - 11 <1 Upper Abdominal Pain 7 <1 7 <1 Dyspepsia 6 <1 5 - Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome 60 17 9 <1 Alopecia 6 - 22 <1 Rash 7 - 8 - Erythema 6 1 5 <1 General Disorders and Administration Site Conditions Fatigue 16 <1 16 1 Pyrexia 7 <1 9 <1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Nervous System Disorders Dizziness 6 <1 6 - Headache 5 <1 6 <1 Dysgeusia 6 - 9 - Metabolism and Nutrition Disorders Anorexia 9 <1 11 <1 Eye Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 Respiratory Thoracic and Mediastinal Disorders Epistaxis 2 - 5 - Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse Event XELODA (n=995) Grade 3/4 % IV 5-FU/LV (n=974) Grade 3/4 % Increased ALAT (SGPT) 1.6 0.6 Increased calcium 1.1 0.7 Decreased calcium 2.3 2.2 Decreased hemoglobin 1.0 1.2 Decreased lymphocytes 13.0 13.0 Decreased neutrophilsThe incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5-FU/LV arm. 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 1.0 0.7 Increased bilirubinIt should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN. 20 6.3 6.2 Metastatic Colorectal Cancer Monotherapy Table 6 shows the adverse reactions occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV. Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of Patients Adverse Event XELODA (n=596) 5-FU/LV (n=593) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable Number of Patients With > One Adverse Event 96 52 9 94 45 9 Body System/Adverse Event GI Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Abdominal Pain 35 9 <1 31 5 – Gastrointestinal Motility Disorder 10 <1 – 7 <1 – Constipation 14 1 <1 17 1 – Oral Discomfort 10 – – 10 – – Upper GI Inflammatory Disorders 8 <1 – 10 1 – Gastrointestinal Hemorrhage 6 1 <1 3 1 – Ileus 6 4 1 5 2 1 Skin and Subcutaneous Hand-and-Foot Syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Skin Discoloration 7 <1 – 5 – – Alopecia 6 – – 21 <1 – General Fatigue/Weakness 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Chest Pain 6 1 – 6 1 <1 Neurological Peripheral Sensory Neuropathy 10 – – 4 – – Headache 10 1 – 7 – – DizzinessExcluding vertigo 8 <1 – 8 <1 – Insomnia 7 – – 7 – – Taste Disturbance 6 1 – 11 <1 1 Metabolism Appetite Decreased 26 3 <1 31 2 <1 Dehydration 7 2 <1 8 3 1 Eye Eye Irritation 13 – – 10 <1 – Vision Abnormal 5 – – 2 – – Respiratory Dyspnea 14 1 – 10 <1 1 Cough 7 <1 1 8 – – Pharyngeal Disorder 5 – – 5 – – Epistaxis 3 <1 – 6 – – Sore Throat 2 – – 6 – – Musculoskeletal Back Pain 10 2 – 9 <1 – Arthralgia 8 1 – 6 1 – Vascular Venous Thrombosis 8 3 <1 6 2 – Psychiatric Mood Alteration 5 – – 6 <1 – Depression 5 – – 4 <1 – Infections Viral 5 <1 – 5 <1 – Blood and Lymphatic Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 6.3 Breast Cancer In Combination with Docetaxel The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8 . In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients. Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event XELODA 1250 mg/m2/bid With Docetaxel 75 mg/m2/3 weeks Docetaxel 100 mg/m2/3 weeks (n=251) (n=255) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8 Body System/Adverse Event GI Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Constipation 20 2 – 18 – – Abdominal Pain 30 <3 <1 24 2 – Dyspepsia 14 – – 8 1 – Dry Mouth 6 <1 – 5 – – Skin and Subcutaneous Hand-and-Foot Syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail Disorder 14 2 – 15 – – Dermatitis 8 – – 11 1 – Rash Erythematous 9 <1 – 5 – – Nail Discoloration 6 – – 4 <1 – Onycholysis 5 1 – 5 1 – Pruritus 4 – – 5 – – General Pyrexia 28 2 – 34 2 – Asthenia 26 4 <1 25 6 – Fatigue 22 4 – 27 6 – Weakness 16 2 – 11 2 – Pain in Limb 13 <1 – 13 2 – Lethargy 7 – – 6 2 – Pain 7 <1 – 5 1 – Chest Pain (non-cardiac) 4 <1 – 6 2 – Influenza-like Illness 5 – – 5 – – Neurological Taste Disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Insomnia 8 – – 10 <1 – Peripheral Neuropathy 6 – – 10 1 – Hypoaesthesia 4 <1 – 8 <1 – Metabolism Anorexia 13 1 – 11 <1 – Appetite Decreased 10 – – 5 – – Weight Decreased 7 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation Increased 12 – – 7 <1 – Conjunctivitis 5 – – 4 – – Eye Irritation 5 – – 1 – – Musculoskeletal Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Bone Pain 8 <1 – 10 2 – Cardiac Edema 33 <2 – 34 <3 1 Blood Neutropenic Fever 16 3 13 21 5 16 Respiratory Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Epistaxis 7 <1 – 6 – – Rhinorrhea 5 – – 3 – – Pleural Effusion 2 1 – 7 4 – Infection Oral Candidiasis 7 <1 – 8 <1 – Urinary Tract Infection 6 <1 – 4 – – Upper Respiratory Tract 4 – – 5 1 – Vascular Flushing 5 – – 5 – – Lymphoedema 3 <1 – 5 1 – Psychiatric Depression 5 – – 5 1 – Table 8 Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event XELODA 1250 mg/m2/bid With Docetaxel 75 mg/m2/3 weeks Docetaxel 100 mg/m2/3 weeks (n=251) (n=255) Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Hematologic Leukopenia 91 37 24 88 42 33 Neutropenia/Granulocytopenia 86 20 49 87 10 66 Thrombocytopenia 41 2 1 23 1 2 Anemia 80 7 3 83 5 <1 Lymphocytopenia 99 48 41 98 44 40 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Monotherapy The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness. Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable GI Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal Pain 20 4 – Constipation 15 1 – Dyspepsia 8 – – Skin and Subcutaneous Hand-and-Foot Syndrome 57 11 NA Dermatitis 37 1 – Nail Disorder 7 – – General Fatigue 41 8 – Pyrexia 12 1 – Pain in Limb 6 1 – Neurological Paresthesia 21 1 – Headache 9 1 – Dizziness 8 – – Insomnia 8 – – Metabolism Anorexia 23 3 – Dehydration 7 4 1 Eye Eye Irritation 15 – – Musculoskeletal Myalgia 9 – – Cardiac Edema 9 1 – Blood Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Anemia 72 3 1 Lymphopenia 94 44 15 Hepatobiliary Hyperbilirubinemia 22 9 2 6.4 Clinically Relevant Adverse Events in <5% of Patients Clinically relevant adverse events reported in <5% of patients treated with XELODA either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%) Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%) General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%) Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%) Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%) Psychiatric: depression, confusion (0.1%) Renal: renal impairment (0.6%) Ear: vertigo Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests Immune System: drug hypersensitivity (0.1%) Postmarketing: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)] , persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7) ] XELODA In Combination With Docetaxel (Metastatic Breast Cancer) Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%) Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%) Cardiac: supraventricular tachycardia (0.4%) Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%) Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%) Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%) Renal: renal failure (0.4%) Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%) Immune System: hypersensitivity (1.2%)

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Take XELODA with water within 30 min after a meal (2.1) Monotherapy: 1250 mg/m2 twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles (2.2) Adjuvant treatment is recommended for a total of 6 months (8 cycles) (2.2) In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m2 as a 1-hour IV infusion every 3 weeks (2.2) XELODA dosage may need to be individualized to optimize patient management (2.3) Reduce the dose of XELODA by 25% in patients with moderate renal impairment (2.4) 2.1 Important Administration Instructions XELODA tablets should be swallowed whole with water within 30 minutes after a meal. XELODA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If XELODA tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. XELODA dose is calculated according to body surface area. 2.2 Standard Starting Dose Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) The recommended dose of XELODA is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1 ). Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months [ie, XELODA 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)]. Table 1 XELODA Dose Calculation According to Body Surface Area Dose Level 1250 mg/m2 Twice a Day Number of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area (m2) Total Daily DoseTotal Daily Dose divided by 2 to allow equal morning and evening doses (mg) 150 mg 500 mg ≤ 1.25 3000 0 3 1.26-1.37 3300 1 3 1.38-1.51 3600 2 3 1.52-1.65 4000 0 4 1.66-1.77 4300 1 4 1.78-1.91 4600 2 4 1.92-2.05 5000 0 5 2.06-2.17 5300 1 5 ≥ 2.18 5600 2 5 In Combination With Docetaxel (Metastatic Breast Cancer) In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. Table 1 displays the total daily dose of XELODA by body surface area and the number of tablets to be taken at each dose. 2.3 Dose Management Guidelines General XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced, it should not be increased at a later time. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles. The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA [see Drug Interactions (7.1)]. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) XELODA dose modification scheme as described below (see Table 2 ) is recommended for the management of adverse reactions. Table 2 Recommended Dose Modifications of XELODA Toxicity NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)]. During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) Grade 1 Maintain dose level Maintain dose level Grade 2 -1st appearance Interrupt until resolved to grade 0-1 100% -2nd appearance 75% -3rd appearance 50% -4th appearance Discontinue treatment permanently - Grade 3 -1st appearance Interrupt until resolved to grade 0-1 75% -2nd appearance 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% In Combination With Docetaxel (Metastatic Breast Cancer) Dose modifications of XELODA for toxicity should be made according to Table 2 above for XELODA. At the beginning of a treatment cycle, if a treatment delay is indicated for either XELODA or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met. The dose reduction schedule for docetaxel when used in combination with XELODA for the treatment of metastatic breast cancer is shown in Table 3 . Table 3 Docetaxel Dose Reduction Schedule in Combination with XELODA Toxicity NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5)]. Grade 2 Grade 3 Grade 4 1st appearance Delay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m2 docetaxel Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel 2nd appearance Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel - 3rd appearance Discontinue treatment with docetaxel - - 2.4 Adjustment of Starting Dose in Special Populations Renal Impairment No adjustment to the starting dose of XELODA is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both XELODA monotherapy and XELODA in combination use with docetaxel. Cockroft and Gault Equation: (140 - age [yrs]) (body wt [kg]) Creatinine clearance for males = —————————————— (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value Geriatrics Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide a dosage recommendation.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of XELODA. Advise males with female partners of reproductive potential to use effective contraception. (8.3) Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5) Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6) Renal Impairment: Reduce XELODA starting dose in patients with moderate renal impairment (2.4, 8.7, 12.3) 8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, XELODA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data]. Apprise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5'-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose. 8.2 Lactation Risk Summary There is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with XELODA and for 2 weeks after the final dose. Data Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating XELODA. Contraception Females XELODA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of XELODA. Males Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of XELODA [see Nonclinical Toxicology (13.1)]. Infertility Based on animal studies, XELODA may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of XELODA in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to XELODA was similar. The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation. The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials. The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%). 8.5 Geriatric Use Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly [see Warnings and Precautions (5.11)]. 8.6 Hepatic Insufficiency Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with XELODA. The effect of severe hepatic dysfunction on XELODA is not known [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)]. 8.7 Renal Insufficiency Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-DFUR, and FBAL than in those with normal renal function [see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. (5.2, 7.1) Phenytoin: Monitor phenytoin levels in patients taking XELODA concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1) Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1) CYP2C9 substrates: Care should be exercised when XELODA is coadministered with CYP2C9 substrates. (7.1) Food reduced both the rate and extent of absorption of capecitabine. (2, 7.1, 12.3) 7.1 Drug-Drug Interactions Anticoagulants Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning]. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin [see Clinical Pharmacology (12.3)]. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites. Phenytoin The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced [see Dosage and Administration (2.3)]. Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites. Leucovorin The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. CYP2C9 substrates Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates. 7.2 Drug-Food Interaction Food was shown to reduce both the rate and extent of absorption of capecitabine [see Clinical Pharmacology (12.3)]. In all clinical trials, patients were instructed to administer XELODA within 30 minutes after a meal. It is recommended that XELODA be administered with food [see Dosage and Administration (2)].

More information

Category Value
Authorisation number NDA020896
Agency product number 6804DJ8Z9U
Orphan designation No
Product NDC 0004-1100,0004-1101
Date Last Revised 23-04-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED. XELODA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.
Marketing authorisation holder Genentech, Inc.
Warnings WARNING: XELODA-WARFARIN INTERACTION XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. WARNING: XELODA-WARFARIN INTERACTION See full prescribing information for complete boxed warning. Patients receiving concomitant XELODA and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use. Occurrence: Within several days and up to several months after initiating XELODA therapy; may also be seen within 1 month after stopping XELODA Predisposing factors: age>60 and diagnosis of cancer