Mild (grade 1 or 2) insomnia was reported in 7% to 8% of patients with metastatic colorectal or breast cancer treated with capecitabine monotherapy (n = 758) or in combination with docetaxel (n = 251) in 3 clinical trials; mood alteration (5% or less) and depression (5%) were also reported. Irritability (less than 5%), sedation (less than 5%), and confusion (grade 3 or 4, 0.1%) were additionally reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials.[44458]

Palmar-plantar erythrodysesthesia (hand and foot syndrome) is a dose-limiting toxicity of capecitabine and has been reported more often in patients receiving capecitabine monotherapy (n = 1,753) or in combination with docetaxel (54% to 63%; grade 3, 11% to 24%) compared with fluorouracil/leucovorin (n = 1,567) (6% to 9%; grade 3, 1% or less) in clinical trials.[64032] [44458] The median time to onset of palmar-plantar erythrodysesthesia was 79 days. Alopecia was more common in patients treated with fluorouracil/leucovorin (6% vs. 21% to 22%; grade 3 or 4, 0% vs. less than 1%). Dermatitis (27% to 37%; grade 3, 1%), skin discoloration (7%; grade 3, less than 1%), rash (7%), nail disorder (7%; grade 3 or 4, 0.1%), erythema (6%; grade 3 or 4, 1%), skin ulcer (less than 5%), pruritus (less than 5%), radiation recall reaction (grade 3 or 4, 0.2%), hyperhidrosis (grade 3 or 4, 0.1%), and photosensitivity reaction (grade 3 or 4, 0.1%) were also reported in patients treated with capecitabine monotherapy in clinical trials. The addition of capecitabine to docetaxel (n = 251) in patients with metastatic breast cancer did not meaningfully increase the incidence of dermatologic adverse reactions compared with docetaxel alone (n = 255) in a randomized clinical trial, including alopecia (41% vs. 42%; grade 3, 6% vs. 7%), nail disorder (14% vs. 15%; grade 3, 2% vs. 0%), dermatitis (8% vs. 11%; grade 3, 0% vs. 1%), erythematous rash (9% vs. 5%; grade 3, less than 1% vs. 0%), nail discoloration (6% vs. 4%; grade 3, less than 1%), onycholysis (5% vs. 5%; grade 3, 1% vs. 1%), pruritus (4% vs. 5%). Grade 3 or 4 hypersensitivity reactions occurred in 0.1% of patients receiving capecitabine monotherapy and in 1.2% of patients receiving capecitabine in combination with docetaxel. Lupus-like symptoms (cutaneous lupus erythematosus) and severe skin reactions such as Stevens-Johnson Syndrome and toxic epidermal necrolysis have additionally been reported in postmarketing experience with capecitabine.[44458]

Hyperbilirubinemia has been reported in patients (48% or less; grade 3 or 4, 11% to 23%) treated with capecitabine monotherapy in clinical trials (n = 1,870) and is a dose-limiting toxicity. The incidence of hyperbilirubinemia in patients receiving treatment with fluorouracil/leucovorin (n = 1,567) was much lower (17% or less; grade 3 or 4, 6% to 6.3%). In patients with metastatic breast or colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was higher in patients with hepatic metastases at baseline (n = 566) compared to those without hepatic metastases at baseline (n = 309) (22.8% vs. 12.3%). Of the patients who developed grade 3 or 4 hyperbilirubinemia, 18.6% also had postbaseline elevations in alkaline phosphatase and 27.5% had elevated hepatic enzymes postbaseline; most of these patients (64.5% and 71.7%, respectively) had liver metastases at baseline. Also, 57.5% of patients who developed grade 3 or 4 hyperbilirubinemia had both pre- and postbaseline increases in alkaline phosphatase (grade 3 or 4, 7.8%) and 35.3% had both pre- and postbaseline increases in transaminases (grade 3 or 4, 3%). The median time to onset for grade 3 or 4 hyperbilirubinemia patients with colorectal cancer was 64 days. Abnormal liver function tests in general were reported in less than 5% of patients treated with capecitabine monotherapy, along with ascites (grade 3 or 4, 0.1%), hepatic fibrosis (grade 3 or 4, less than 0.1%), hepatitis (grade 3 or 4, 0.1%), and cholestasis/cholestatic hepatitis (grade 3 or 4, 0.1%). Hyperbilirubinemia was reported in 20% (grade 3 or 4, 9%) of patients with metastatic breast cancer treated with capecitabine plus docetaxel (n = 251); grade 3 or 4 hepatotoxicity (0.4%), jaundice (0.4%), abnormal liver function tests (0.4%), and hepatic failure (0.4%) were also reported in these patients. Increased ALT was reported in 75% and hypoalbuminemia in 55% of children treated with capecitabine.[44458]

Cardiotoxicity has been reported with capecitabine treatment, including myocardial infarction/ischemia, angina, dysrhythmias or arrhythmia exacerbation, cardiac arrest, heart failure, cardiomyopathy, ECG changes, and sudden death. Clinically relevant atrial fibrillation, bradycardia, extrasystoles, ventricular extrasystoles, and pericardial effusion were each reported in less than 5% of patients treated with capecitabine monotherapy in clinical trials; grade 3 or 4 sinus tachycardia (0.1%) and myocarditis (0.1%) were also reported. Supraventricular tachycardia (SVT) (grade 3 or 4, 0.4%) was reported in patients with metastatic breast cancer receiving capecitabine in combination with docetaxel.[44458]

Neutropenia has been reported across clinical trials of patients treated with capecitabine, although it is less common than with fluorouracil/leucovorin treatment in comparative trials. Neutropenia or decreased neutrophils/granulocytes was reported in 13% to 26% (grade 3 or 4, 2.2% to 4%) patients receiving capecitabine monotherapy as adjuvant or metastatic treatment for colorectal cancer or treatment for metastatic breast cancer (n = 1,753) compared with 46% or fewer (grade 3 or 4, 21% to 26.4%) patients receiving fluorouracil/leucovorin (n = 1,567). Anemia or decreased hemoglobin occurred with a similar frequency in patients with adjuvant or metastatic colorectal cancer or metastatic breast cancer receiving capecitabine versus fluorouracil/leucovorin (72% to 80%; grade 3 or 4, 4% or less). Lymphopenia occurred in 94% (grade 3 or 4, 59%) of patients with metastatic breast cancer receiving capecitabine monotherapy in a phase 2 clinical trial (n = 162) and thrombocytopenia was reported in 24% (grade 3 or 4, 4%). Grade 3 or 4 decreases in lymphocytes (13%) and platelets (1%) occurred less often in a large clinical trial of patients receiving adjuvant capecitabine monotherapy for colorectal cancer (n = 995). Additional hematologic adverse reactions reported with capecitabine monotherapy across adjuvant and metastatic indications include idiopathic thrombocytopenic purpura (grade 3 or 4, 1%), leukopenia (grade 3 or 4, 0.2%), bone marrow depression (grade 3 or 4, 0.1%), and pancytopenia (grade 3 or 4, 0.1%). In a randomized clinical trial of patients with metastatic breast cancer, the addition of capecitabine to docetaxel (n = 251) increased the incidence of thrombocytopenia compared with docetaxel alone (n = 255) (41% vs. 23%; grade 3 or 4, 3% vs. 3%), but other hematologic adverse reactions were similar between study arms including lymphopenia (99% vs. 98%; grade 3 or 4, 89% vs. 84%), leukopenia (91% vs. 88%; grade 3 or 4, 61% vs. 75%), neutropenia/granulocytopenia (86% vs. 87%; grade 3 or 4, 69% vs. 77%), and anemia (80% vs. 83%; grade 3 or 4, 10% vs. less than 6%). Grade 3 or 4 agranulocytosis was also reported in 0.4% of metastatic breast cancer patients who received capecitabine plus docetaxel. Laboratory abnormalities were more common in 2 clinical trials of pediatric patients receiving capecitabine with radiation therapy (n = 56), including lymphopenia (73%), leukopenia (73%), thrombocytopenia (57%), neutropenia (50%), and anemia (50%). Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including neutropenia.[44458]

Nausea (34% to 43% vs. 47% to 51%; grade 3 or 4, 2% to 4% vs. 2% or less), stomatitis (22% to 25% vs. 60% to 62%; grade 3 or 4, less than 3% vs. 14% to 15%) and vomiting (15% to 27% vs. 21% to 30%; grade 3 or 4, less than 5% vs. less than 5%) were less common in patients with colorectal cancer receiving adjuvant or metastatic treatment with capecitabine monotherapy (n = 1,591) compared to treatment with fluorouracil/leucovorin (n = 1,567). Nausea (53%; grade 3, 4%) and vomiting (37%; grade 3, 4%) were more common in patients with metastatic breast cancer receiving capecitabine monotherapy in a single-arm, phase 2 trial (n = 162); stomatitis occurred at a similar incidence as the colorectal trials (24%; grade 3, 7%). Abdominal pain (7% to 35%; grade 3 or 4, less than 10%), constipation (9% to 15%; grade 3 or 4, less than 2%), GI motility disorder (10%; grade 3, less than 1%), oral discomfort (10%), upper GI inflammatory disorders (8%; grade 3, less than 1%), GI bleeding (6%; grade 3 or 4, less than 2%), ileus (6%; grade 3 or 4, 0.3% to 5%), abdominal distension (less than 5%), proctalgia (less than 5%), toxic dilation of intestine (less than 5%), and peptic ulcer (grade 3 or 4, 0.1%) have also been reported with capecitabine monotherapy. Stomatitis (67% vs. 43%; grade 3 or 4, less than 18% vs. 5%), nausea (45% vs. 36%; grade 3, 7% vs. 2%), vomiting (35% vs. 24%; grade 3 or 4, 5% vs. 2%), constipation (20% vs. 18%; grade 3 or 4, 2% vs. 0%), and abdominal pain (30% vs. 24%; grade 3 or 4, less than 4% vs. 2%) occurred more often in patients with metastatic breast cancer treated with docetaxel plus capecitabine (n = 251) compared with docetaxel alone (n = 255) in a randomized clinical trial; grade 3 or 4 ileus (0.4%) and esophageal ulceration (0.4%) were also reported. Geriatric patients may be at an increased risk for some GI adverse reactions, with grade 3 or 4 nausea (1.3% to 13.1%), vomiting (1.5% to 9.5%), and stomatitis (3% to 30%) reported at an increased incidence in these patients (n = 429) in clinical trials of patients receiving capecitabine monotherapy or in combination with docetaxel. Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including mucositis.[44458]

Diarrhea which can sometimes be severe is a dose-limiting toxicity of capecitabine and occurs in 47% to 57% (grade 3 or 4, 12% to 15%) of patients with breast cancer or colorectal cancer who received capecitabine monotherapy in several clinical trials (n = 1,753), and in 67% (grade 3 or 4, less than 15%) of breast cancer patients treated with capecitabine plus docetaxel in another clinical trial (n = 251).[64032] [44458] Grade 3 or 4 gastroenteritis has also been reported in 0.1% of patients receiving capecitabine monotherapy in clinical trials. Grade 3 or 4 necrotizing enterocolitis (typhlitis) (0.4%) and hemorrhagic diarrhea (0.8%) have also been reported in patients with metastatic breast cancer treated with capecitabine in combination with docetaxel. Geriatric patients may be at an increased risk, with grade 3 or 4 diarrhea reported in 13.1% to 30% of these patients (n = 429) in clinical trials of patients receiving capecitabine monotherapy or in combination with docetaxel. Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including diarrhea. Carefully monitor patients with diarrhea and replace fluids and electrolytes if needed; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. In patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy (n = 875), the median time to first occurrence of grade 2 to 4 diarrhea was 34 days, with a median duration of grade 3 to 4 diarrhea of 5 days.[44458]

Anorexia or decreased appetite has been reported in 9% to 26% (grade 3 or 4, less than 4%) of patients treated with capecitabine monotherapy in clinical trials (n = 1,753); dyspepsia (8% or less; grade 3 or 4, less than 1%), dysgeusia or taste disturbance (6%; grade 3 or 4, 1% or less), dysphagia (less than 5%), and cachexia (grade 3 or 4, 0.4%) has also been reported in patients receiving capecitabine monotherapy. Taste disturbance (16% vs. 14%; grade 3, less than 1% vs. less than 1%), dyspepsia (14% vs. 8%; grade 3 or 4, 0% vs. 1%), anorexia (13% vs. 11%; grade 3, 1% vs. less than 1%), decreased appetite (10% vs. 5%), xerostomia (6% vs. 5%; grade 3, less than 1% vs. 0%), and weight loss (7% vs. 5%) were also reported more often in patients with metastatic breast cancer who received docetaxel in combination with capecitabine (n = 251) compared with docetaxel alone (n = 255).[44458]

Dehydration has been reported in patients treated with capecitabine (7% to 10%; grade 3 or 4, 5% or less), which may cause acute renal failure. Monitor patients to prevent dehydration and quickly correct it if it occurs; an interruption of therapy and intravenous fluids may be needed. Do not be restart therapy until the patient is rehydrated and any precipitating causes have been corrected or controlled.[44458]

Severe (grade 3 or 4) renal impairment (0.6%) and renal failure (unspecified) (0.4%) have been reported in patients treated with capecitabine as monotherapy or in combination with docetaxel during clinical trials. Acute renal failure secondary to dehydration (including fatal outcome) has been reported in postmarketing experience with capecitabine.[44458]

Fever was reported in 7% to 18% (grade 3 or 4, 1% or less) of patients with colorectal or breast cancer treated with capecitabine monotherapy in clinical trials (n = 1,753). Infection has also been reported in patients receiving capecitabine monotherapy, including viral infections (5%; grade 3, less than 1%) as well as grade 3 or 4 laryngitis (1%), sepsis (0.3%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), and fungal infections including candidiasis (0.2%). The incidence of infection was similar between treatment arms in patients with metastatic breast cancer randomized to treatment with capecitabine plus docetaxel (n = 251) vs. docetaxel alone (n = 255), including fever (28%; grade 3, 2%), neutropenic fever (16%; grade 3 or 4, 16%), influenza-line illness (5%), oral candidiasis (7%; grade 3, less than 1%), urinary tract infection (6%; grade 3, less than 1%), and upper respiratory tract infection (4%); grade 3 or 4 neutropenic sepsis (2.4%), sepsis (0.4%), and bronchopneumonia (0.4%) were also reported in these patients.[44458]

Fatigue, asthenia, and lethargy occurred with a similar frequency in patients treated with capecitabine versus fluorouracil/leucovorin in clinical trials. In a randomized clinical trial of patients receiving adjuvant treatment for colorectal cancer with either capecitabine (n = 995) or fluorouracil/leucovorin (n = 974), fatigue (16% vs. 16%; grade 3 or 4, less than 1% vs. 1%), asthenia (10% vs. 10%; grade 3 or 4, less than 1% vs. 1%), and lethargy (10% vs. 9%; grade 3 or 4, less than 1% vs. less than 1%) were reported with similar frequencies between arms. Fatigue/weakness occurred in 42% (grade 3, 4%) of patients with metastatic colorectal cancer receiving capecitabine monotherapy (n = 596) compared with 46% (grade 3, 4%) of those treated with fluorouracil/leucovorin (n = 593). Fatigue occurred in a similar percentage of patients with metastatic breast cancer receiving capecitabine monotherapy in a phase 2 clinical trial (n = 162) (41%; grade 3, 8%). Muscle weakness was reported in less than 5% of patients receiving capecitabine monotherapy in clinical trials. The addition of capecitabine to docetaxel in patients with metastatic breast cancer (n = 251) did not increase the incidence of these adverse reactions compared with docetaxel alone (n = 255) in a randomized clinical trial, including asthenia (26% vs. 25%; grade 3 or 4, 4% to 5% vs. 6%), fatigue (22% vs. 27%; grade 3, 4% vs. 6%), weakness (16% vs. 11%; grade 3, 2% vs. 2%), and lethargy (7% vs. 6%; grade 3, 0% vs. 2%).[44458]

Mild (grade 1 or 2) ocular irritation was reported in 13% to 15% of patients with metastatic breast or colorectal cancer treated with capecitabine monotherapy in 2 clinical trials (n = 758). Abnormal vision/visual impairment (5%), conjunctivitis (5%; grade 3 or 4, less than 1%), and keratoconjunctivitis (less than 5%) have been reported in patients receiving capecitabine monotherapy. Increased lacrimation (12%), conjunctivitis (5%), and eye irritation (5%) were reported in patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel (n = 251). There have been reports of lacrimal duct stenosis and corneal disorders including keratitis in postmarketing experience with capecitabine.[44458]

Hypercalcemia (1.1%; grade 3 or 4, 0.7%) and hypocalcemia (2.3%; grade 3 or 4, 2.2%) were reported in patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 995) in a randomized clinical trial. Hypokalemia (less than 5%), hypomagnesemia (less than 5%), and hypertriglyceridemia (grade 3 or 4, 0.1%) were additionally reported in patients receiving capecitabine monotherapy for the treatment of colorectal or breast cancer. The adverse reaction profile of capecitabine in pediatric patients (n = 56) was consistent with adult patients with the exception of laboratory abnormalities, which were more common in pediatric patients including hypokalemia (68%), hypocalcemia (48%), hypophosphatemia (45%), and hyponatremia (45%).[44458]

Generally mild epistaxis has been reported in clinical trials of patients receiving capecitabine monotherapy as adjuvant or metastatic treatment for colorectal cancer (n = 1,591) (2% to 3%; grade 3, less than 1%); the incidence was slightly higher when administered in combination with docetaxel (n = 251) to patients with metastatic breast cancer (7%; grade 3, less than 1%). Hemorrhage (bleeding) and hemoptysis were each reported in less than 5% of patients receiving capecitabine monotherapy; grade 3 or 4 coagulopathy (0.1%) was also reported. Grade 3 or 4 decreases in prothrombin time occurred in 0.4% of metastatic breast cancer patients receiving capecitabine plus docetaxel.[44458]

Musculoskeletal adverse reactions occurred with a similar frequency in patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 596) compared with fluorouracil/leucovorin (n = 593) in a randomized clinical trial, including pain (12% vs. 10%; grade 3, 1% vs. 1%), chest pain (unspecified) (6% vs. 6%; grade 3 or 4, 1% vs. less than 2%), back pain (10% vs. 9%; grade 3, 2% vs. less than 1%), and arthralgia (8% vs. 6%; grade 3, 1% vs. 1%). Limb pain 6%; grade 3, 1%) and myalgia (9%) were also reported in a phase 2 trial of capecitabine monotherapy for the treatment of metastatic breast cancer (n = 162). Grade 3 or 4 chest pain (0.2%) and pain (0.1%) were reported across clinical trials of patients with colorectal or breast cancer receiving capecitabine monotherapy in clinical trials. The incidence of musculoskeletal adverse reactions were similar when capecitabine was added to docetaxel in patients with metastatic breast cancer (n = 251), including limb pain (13%; grade 3, less than 1%), pain (7%; grade 3, less than 1%), non-cardiac chest pain (4%; grade 3, less than 1%), arthralgia (13%; grade 3, 2%), myalgia (13%; grade 3, 2%), back pain (12%; grade 3, less than 1%), and bone pain (8%; grade 3, less than 1%); bone pain (grade 3 or 4, 0.1%) and arthritis (grade 3 or 4, 0.1%) have also been reported.[44458]

Headache (5% to 10%; grade 3 or 4, 1% or less) and dizziness (6% to 8%; grade 3 or 4, less than 1%) of patients with colorectal or breast cancer receiving capecitabine monotherapy (n = 1,753); vertigo was reported in less than 5% of patients receiving capecitabine monotherapy. The occurrence of headache (15%; grade 3, 3%) and dizziness (12%) was slightly higher when capecitabine was administered with docetaxel (n = 251) to patients with metastatic breast cancer in a randomized clinical trial, although the incidences were similar to docetaxel monotherapy (n = 255); grade 3 or 4 migraine was reported in 0.4% of patients receiving combination therapy.[44458]

Mild (grade 1 or 2) peripheral neuropathy was reported in 10% of patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 596) compared with 4% of those receiving fluorouracil/leucovorin (n = 593) in a randomized clinical trial. In a phase 2 single-arm trial of patients with metastatic breast cancer (n = 162), paresthesias occurred in 21% (grade 3, 1%) of patients receiving capecitabine monotherapy. In a randomized clinical trial of patients with metastatic breast cancer, paresthesias (12% vs. 16%; grade 3, less than 1% vs. 1%), peripheral neuropathy (6% vs. 10%; grade 3, 0% vs. 1%), and hypoesthesia (4% vs. 8%; grade 3, less than 1% vs. less than 1%) occurred less often in patients receiving capecitabine plus docetaxel (n = 251) compared with docetaxel alone (n = 255); grade 3 or 4 polyneuropathy was reported in 0.4% of patients receiving combination therapy. Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including neurotoxicity.[44458]

Edema was reported in 9% to 15% (grade 3, 1%) of patients with metastatic colorectal or breast cancer treated with capecitabine monotherapy in 2 clinical trials (n = 758). Edema (less than 5%), weight gain (less than 5%), and lymphedema (grade 3 or 4, 0.1%) have also been reported across clinical trials of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. In patients with metastatic breast cancer randomized to treatment with docetaxel plus capecitabine (n = 251) or docetaxel alone (n = 255), the incidence of edema was higher than with capecitabine monotherapy, but similar between treatment arms (33% vs. 34%; grade 3, less than 2% vs. less than 4%); lymphedema was reported in 3% (grade 3, less than 1%) versus 5% (grade 3, 1%) of these patients, respectively.[44458]

Respiratory adverse reactions including dyspnea (14%; grade 3, 1% to 3%), cough (7% to 13%; grade 3 or 4, less than 2%), pharyngeal disorder (5%), and sore throat (2% to 12%; grade 3, 2% or less) were reported in patients with metastatic colorectal cancer receiving capecitabine monotherapy (n = 596) or metastatic breast cancer receiving capecitabine plus docetaxel (n = 251); the incidence was similar to patients receiving fluorouracil/leucovorin alone (n = 593). Hoarseness (less than 5%), dyspnea (less than 5%), as well as grade 3 or 4 asthma (0.2%), cough (0.1%), and respiratory distress (0.1%) were also reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. In patients receiving combination therapy with capecitabine and docetaxel, rhinorrhea (5%) and pleural effusion (2%; grade 3, 1%) were reported.[44458]

Venous thrombosis was reported in 8% (grade 3 or 4, 3% to 4%) of patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 596) compared with 6% (grade 3, 2%) of those treated with fluorouracil/leucovorin (n = 593). Pulmonary embolism (grade 3 or 4, 0.2%) and cerebrovascular accident/stroke (grade 3 or 4, 0.1%) were also reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. Grade 3 or 4 venous phlebitis and thrombophlebitis were additionally reported in 0.4% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in a randomized clinical trial.[44458]

Hot flashes were reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials. Flushing was also reported in 5% of patients with metastatic breast cancer treated with capecitabine plus docetaxel; the incidence was similar to patients receiving docetaxel alone.[44458]

Difficulty walking, abnormal coordination, impaired balance, and tremor were each reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. Additionally, grade 3 or 4 ataxia (0.5%), loss of consciousness (0.2%), and encephalopathy (0.1%) were reported. Grade 3 or 4 syncope (1.2%) and ataxia (0.4%) were also reported in patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel. Toxic leukoencephalopathy was reported in postmarketing experience with capecitabine therapy.[44458]

Hypotension (grade 3 or 4, 0.2%) and hypertension (grade 3 or 4, 0.1%) were reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials. Additionally, grade 3 or 4 hypotension (1.2%) and postural hypotension (0.8%) occurred in patients with metastatic breast cancer who received combination therapy with capecitabine plus docetaxel.[44458]

Polydipsia was reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials.[44458]

Dysarthria and dysphasia were each reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials.[44458]

Angioedema has been reported with capecitabine use in postmarketing experience.[44458]

Diarrhea, sometimes severe, has been reported with capecitabine therapy. Carefully monitor patients with severe diarrhea and administer standard antidiarrheal treatments (e.g., loperamide) if necessary; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Administer fluid and electrolyte replacement if patients become dehydrated; dehydration may cause acute renal insufficiency or failure which can be fatal. Patients with anorexia, asthenia, nausea/vomiting, or diarrhea may rapidly become dehydrated. Monitor patients to prevent and correct the causes of dehydration. If grade 2 or higher dehydration occurs, interrupt capecitabine therapy until dehydration is corrected and precipitating causes are corrected or controlled.[44458]

Capecitabine is contraindicated in patients with severe renal impairment or renal failure (creatinine clearance (CrCL) less than 30 mL/min). Patients with moderate renal impairment (CrCL 30 to 50 mL/min) require a reduced starting dose of capecitabine. Patients with pre-existing renal impairment or who are receiving concomitant nephrotoxic agents are at an increased risk of renal failure which has been reported in conjunction with dehydration. Closely monitor patients with mild and moderate renal impairment at baseline for adverse reactions; promptly interrupt therapy and reduce the dose of capecitabine as recommended if grade 2 to 4 adverse reactions occur.[44458]

Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or with fluorouracil hypersensitivity. Capecitabine has not been proven safe for patients with dihydropyrimidine dehydrogenase (DPD) deficiency at any dose, and there is insufficient data regarding capecitabine dosing in patients with partial DPD activity. Dihydropyrimidine dehydrogenase (DPD) is responsible for the metabolism of fluorouracil, the active metabolite of capecitabine, and deficiency of this enzyme leads to elevated concentrations of fluorouracil due to decreased clearance. Administration of capecitabine to individuals with DPD deficiency can lead to enhanced early-onset toxicity and severe, life-threatening or fatal adverse reactions including mucositis, neutropenia, neutropenic fever, neurotoxicity, abdominal pain, diarrhea, vomiting, and chills. Hold or permanently discontinue capecitabine in patients with acute early-onset or unusually severe toxicities, which may indicate near complete or total absence of DPD activity.[44458]

Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm³ or platelet counts below 100,000 cells/mm³; patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy are at increased risk of bone marrow suppression during capecitabine treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be needed if myelosuppression occurs during the course of treatment. Patients with an active infection should be treated prior to receiving capecitabine. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.[44458]

Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or PT) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Post-marketing reports have shown clinically significant increases in PT and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within one month after stopping capecitabine. 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.[44458]

Use capecitabine with caution in patients with cardiac disease or a prior history of coronary artery disease. Capecitabine therapy has been associated with cardiotoxicity including myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, electrocardiogram changes, cardiomyopathy, and sudden death; patients with a prior history of coronary artery disease may be at increased risk.[44458]

Patients with mild to moderate hepatic disease due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is unknown. Serious elevations in bilirubin, resulting in jaundice, have been reported with capecitabine therapy. Monitor liver function tests; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.[44458]

Closely monitor geriatric patients for an increased incidence of adverse reactions, as they may experience more grade 3 or 4 adverse reactions compared with younger patients; insufficient data are available to provide a dosage recommendation. In a study of capecitabine monotherapy, 62% of patients aged 80 years and older (n = 21) experienced a treatment-related grade 3 or 4 adverse event including diarrhea (28.6%), nausea (14.3%), hand-and-foot syndrome (14.3%), and vomiting (9.5%). In patients age 70 and older receiving capecitabine plus docetaxel (n = 10), 30% experienced grade 3 or 4 diarrhea and stomatitis, and 40% experienced grade 3 hand-and-foot syndrome. The incidence of grade 3 or 4 treatment-related adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions, and treatment discontinuations within the first 2 treatment cycles was higher in patients age 60 and older who received capecitabine plus docetaxel (n = 67) compared to patients younger than 60 years of age. Of 398 patients age 65 or older receiving adjuvant capecitabine for Dukes' C colon cancer, 41% experienced a treatment-related grade 3 or 4 adverse event, including hand-and-foot syndrome (18.8%), diarrhea (13.1%), stomatitis (3%), neutropenia/granulocytopenia (2.8%), vomiting (1.5%), and nausea (1.3%).[44458]

Serious mucocutaneous reactions and skin disease, some with fatal outcome, have been reported with capecitabine therapy including toxic epidermal necrolysis and Stevens-Johnson syndrome. Palmar-plantar erythrodysesthesia (hand and foot syndrome) has also occurred with capecitabine treatment; persistent or severe hand and foot syndrome can lead to loss of fingerprints, which could impact patient identification. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for skin toxicity. Permanently discontinue capecitabine in patients who develop a severe mucocutaneous reaction possibly associated with capecitabine therapy.[44458]

Pregnancy should be avoided by females of reproductive potential during capecitabine treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, capecitabine can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving capecitabine should be apprised of the potential hazard to the fetus. When capecitabine was given to pregnant animals during organogenesis, teratogenesis and embryolethality were observed in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC), respectively, in patients receiving the recommended dose. Teratogenic malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles.[44458]

Counsel patients about the reproductive risk and contraception requirements during capecitabine treatment. Capecitabine can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with capecitabine. Females of reproductive potential should undergo pregnancy testing prior to initiation of capecitabine. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose. Women who become pregnant while receiving capecitabine should be apprised of the potential hazard to the fetus. In addition, capecitabine reversibly disturbed estrus in female mice and caused degenerative changes in the testes of male mice (including decreases in the number of spermatocytes and spermatids), resulting in impaired fertility or infertility.[44458]

Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether capecitabine is present in human milk, although many drugs are excreted in human milk.[44458]