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Xeloda

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Xeloda

Side Effects
Interactions

SIDE EFFECTS

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.

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)

Body System/Adverse Event Adjuvant Treatment for Colon Cancer
(N=1969)
XELODA
(N=995)
5-FU/LV
(N=974)
All Grades Grade 3/4 All Grades Grade 3/4
GastrointestinalDisorders
  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 SubcutaneousTissue 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 neutrophils* 2.2 26.2
Decreased neutrophils/granulocytes 2.4 26.4
Decreased platelets 1.0 0.7
Increased bilirubin** 20 6.3
*The 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.
**It 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 x upper limit of normal (ULN) range, and grade 4 a value of > 3.0 x ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of > 3.0 to 10.0 x ULN, and grade 4 values > 10.0 x ULN.

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/m l2e 2u covorin IV followed by 425 mg/m 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
%
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/W eakness 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 - -
  Dizziness* 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
- Not observed
* Excluding vertigo
NA = Not Applicable

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/m 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/m 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 (n=251) Docetaxel 100 mg/m²/3 weeks (n=255)
Total
%
Grade 3
%
Grade 4
%
Total
%
Grade 3
%
Grade 4
%
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 -
- Not observed
NA = Not Applicable

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 Docetaxel75 mg/m²/3 weeks
(n=251)
Docetaxel 100 mg/m²/3 weeks
(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/m 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
%
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
- Not observed
NA = Not Applicable

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 docetaxol 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

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%)

Read the Xeloda (capecitabine) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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 singledose warfarin administration, there was a significant increase in the mean AUC of S-warfarin [see CLINICAL PHARMACOLOGY]. 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]. 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.

Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of capecitabine [see CLINICAL PHARMACOLOGY]. 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].

Read the Xeloda Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 12/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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Xeloda - User Reviews

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