Insomnia, depression, and confusion were each reported in fewer than 10% of patients treated with capecitabine monotherapy in a pooled safety population. A general alteration in mood was also reported in less than 10% of patients who received capecitabine monotherapy in 1 randomized clinical trial.[44458]

Palmar-plantar erythrodysesthesia (hand and foot syndrome) is a dose-limiting toxicity of capecitabine and occurred in 54% to 63% (grade 3 or 4, 11% to 24%) of patients treated with capecitabine as monotherapy or in combination with docetaxel across clinical trials; persistent or severe palmar-plantar erythrodysesthesia can eventually lead to the loss of fingerprints. In patients with metastatic breast or colorectal cancer who received capecitabine monotherapy, the median time to onset of grade 1 to 3 palmar-plantar erythrodysesthesia was 2.6 months (range, 11 days to 1 year). Dermatitis was additionally reported in 27% to 37%; grade 3, 1% of patients treated with capecitabine monotherapy in clinical trials. Additional dermatologic adverse reactions reported in less than 10% of patients treated with capecitabine monotherapy include alopecia, erythema, hyperhidrosis, nail disorder, photosensitivity reaction, pruritus, radiation recall reaction, rash, skin discoloration, and skin ulcer. Nail discoloration and onycholysis were each reported in less than 10% of patients treated with capecitabine and docetaxel in a clinical trial; the addition of capecitabine to docetaxel did not increase the incidence of alopecia (41% vs. 42%; grade 3, 6% vs. 7%) or nail disorders (14% vs. 15%; grade 3, 2% vs. 0%) compared with docetaxel alone. Cutaneous lupus erythematosus (lupus-like symptoms) and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported in postmarketing experience with capecitabine; permanently discontinue capecitabine for SCARs.[44458]

Hyperbilirubinemia occurred in 48% of patients with metastatic colorectal cancer treated with capecitabine compared with 17% of those who received fluorouracil/leucovorin in a randomized clinical trial (grade 3 or 4, 23% vs. 6%); the incidence of grade 3 or 4 increases in bilirubin was similar (20%) in another clinical trial of patients with colorectal cancer receiving adjuvant treatment with capecitabine therapy. In a single-arm trial of patients with metastatic breast cancer, hyperbilirubinemia occurred in 22% of patients who received monotherapy (grade 3 or 4, 11%). Hyperbilirubinemia was more common in metastatic breast cancer patients treated with capecitabine plus docetaxel compared with docetaxel alone (20% vs. 6%; grade 3 or 4, 9% vs. 4%). In patients with metastatic breast or colorectal cancer, the incidence of patients who developed grade 3 or 4 hyperbilirubinemia was higher in those with hepatic metastases at baseline compared to those without (23% vs. 12%). The median total bilirubin increased from 8 micromol/liter at baseline to 13 micromol/liter during therapy; the median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days. Of patients with grade 3 or 4 hyperbilirubinemia, 58% (grade 3 or 4, 8%) had both pre- and postbaseline increases in alkaline phosphatase and 19% had only postbaseline increases in alkaline phosphatase; 35% (grade 3 or 4, 3%) had both pre- and postbaseline elevated hepatic enzymes and 28% only had postbaseline transaminitis. Grade 3 or 4 increases in ALT were reported in 1.6% of patients who received capecitabine monotherapy in one noncomparative trial. Hepatic fibrosis, hepatitis, cholestasis, and abnormal liver function tests were also each reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population, while jaundice, abnormal liver function tests, hepatic failure, hepatic coma, and hepatotoxicity were reported in less than 10% of patients treated with capecitabine plus docetaxel in 1 clinical trial. Hepatic failure was also reported in postmarketing experience with capecitabine. Increased ALT (75%) and hypoalbuminemia (55%) were more common in pediatric patients compared to adult patients. Monitor patients with hepatic disease more frequently for adverse reactions; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if hyperbilirubinemia occurs.[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. Sinus tachycardia, bradycardia, atrial fibrillation, and myocarditis were each reported in less than 10% of patients who received capecitabine monotherapy in a pooled safety population; chest pain was additionally reported in less than 10% of capecitabine-treated patients in 1 randomized clinical trial. Fewer than 10% of breast cancer patients treated with capecitabine plus docetaxel experienced supraventricular tachycardia (SVT) in another randomized clinical trial. Use capecitabine with caution in patients with cardiac disease or a prior history of coronary artery disease. If cardiotoxicity occurs, interrupt therapy with capecitabine as clinically appropriate; the safety of resuming capecitabine therapy after cardiotoxicity has occurred has not been established.[44458]

Bone marrow suppression can occur with capecitabine treatment. Lymphopenia (94%; grade 3 or 4, 59%), anemia (72%; grade 3 or 4, 4%), neutropenia (26%; grade 3 or 4, 4%), and thrombocytopenia (24%; grade 3 or 4, 4%) were reported in a single-arm clinical trial of patients treated with capecitabine. In pooled data from 2 randomized clinical trials, anemia occurred with a similar frequency in patients treated with capecitabine to those who received fluorouracil and leucovorin (80% vs. 79%; grade 3 or 4, 2% to 3% vs. 1% to 2%); however, neutropenia occurred in 13% of patients who received capecitabine compared with 46% of those in the fluorouracil/leucovorin arm (grade 3 or 4, 3% vs. 21%). In another trial, the incidence of grade 3 or 4 decreases from baseline in lymphocytes (13% vs. 13%), hemoglobin (1% vs. 1.2%), and platelets (1% vs. 0.7%) were similar in patients treated with capecitabine compared with fluorouracil/leucovorin; grade 3 or 4 decreases from baseline in neutrophils/granulocytes (2.4% vs. 26%) and neutrophils (2.2% vs. 26%) were again more common in the fluorouracil/leucovorin arm. In a pooled safety population, bone marrow depression, leukopenia, and pancytopenia each occurred in less than 10% of patients who received capecitabine monotherapy. The addition of capecitabine to docetaxel resulted in a similar incidence of lymphopenia (99% vs. 98%; grade 3 or 4, 89% vs. 84%), leukopenia (91% vs. 88%; grade 3 or 4, 61% vs. 75%), neutropenia (86% vs. 87%; grade 3 or 4, 69% vs. 76%), anemia (80% vs. 83%; grade 3 or 4, 10% vs. 5% to 6%), and febrile neutropenia (16% vs. 21%; grade 3 or 4, 16% vs. 21%) compared to those who received docetaxel alone in a randomized clinical trial; thrombocytopenia was reported in 41% versus 23% of patients, respectively (grade 3 or 4, 3% vs. 3%). Agranulocytosis and neutropenic sepsis were each reported in less than 10% of patients who received capecitabine and docetaxel. Lymphopenia (73%), thrombocytopenia (57%), neutropenia (50%), and low hematocrit (50%) were more common in the pediatric population compared to adults. Monitor complete blood counts at baseline and prior to each cycle. Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm³ or platelet counts below 100,000 cells/mm³. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary if grade 3 or 4 myelosuppression occurs during the course of treatment.[44458]

Nausea (34% to 53%; grade 3 or higher, 2% to 4%), vomiting (15% to 37%; grade 3 or higher, 2% to less than 5%), abdominal pain (14% to 35%; grade 3 or higher, 3% to less than 10%), stomatitis (22% to 25%; grade 3 or higher, 2% to 7%), and constipation (15% or less; grade 3 or higher, less than 2%), were reported in patients treated with capecitabine monotherapy across clinical trials; grade 1 or 2 oral discomfort was also reported in capecitabine-treated patients in 1 trial. Less than 10% of patients who received capecitabine monotherapy in a pooled safety population reported abdominal distention, gastric ulcer (peptic ulcer), ileus, and proctalgia. The incidence of stomatitis was higher in a clinical trial of patients who received docetaxel plus capecitabine (67%; grade 3 or higher, 17% to 18%), but the incidence of nausea (45% (grade 3, 7%), vomiting (35%; grade 3 or higher, 5%), abdominal pain (30%; grade 3 or higher, 3% to 4%), constipation (20%; grade 3, 2%), and ileus (less than 10%) were similar to capecitabine monotherapy. Sore throat was additionally reported in 12% (grade 3, 2%) of those who received capecitabine and docetaxel, as well as esophageal ulceration (less than 10%). 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 was reported in 47% to 67% (grade 3 or 4, 12% to 15%) of patients treated with capecitabine as monotherapy or in combination with docetaxel or oxaliplatin in clinical trials; the incidence of diarrhea was higher when used as a component of chemoradiotherapy. Gastroenteritis was reported in less than 10% of patients receiving capecitabine monotherapy in a pooled safety population. An upper GI inflammatory disorder (less than 10%) and a GI motility disorder (10%; grade 3, less than 1%) were reported in a clinical trial of patients with advanced colorectal cancer who received capecitabine monotherapy. Necrotizing enterocolitis (typhlitis) developed in less than 10% of metastatic breast cancer patients treated with capecitabine plus docetaxel; consider typhlitis in patients with fever, neutropenia, and abdominal pain. Monitor hydration status and renal function at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for grade 2 or higher diarrhea or dehydration.[64032] [44458]

Anorexia or decreased appetite (26% or less; grade 3 or higher, 3% to 4%), dysgeusia (less than 10%), dysphagia (less than 10%), and dyspepsia (14% or less) were reported in patients treated with capecitabine as monotherapy or in combination with docetaxel across clinical trials. Dyspepsia and cachexia were each additionally reported in less than 10% of patients who received capecitabine monotherapy while weight loss and xerostomia were each reported in less than 10% of patients treated with capecitabine plus docetaxel.[44458]

Dehydration was reported in 10% or fewer patients treated with capecitabine as monotherapy or in combination with docetaxel in clinical trials (grade 3, 2% or less). Deaths from severe dehydration have been reported in elderly patients treated with weekly fluorouracil and leucovorin. Renal impairment occurred in less than 10% of patients who received capecitabine in clinical trials, with acute renal failure secondary to dehydration (including fatal outcome) reported in postmarketing experience with capecitabine. Optimize hydration prior to starting therapy. Monitor renal function and hydration status at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if dehydration or renal impairment occur.[44458]

Fever was reported in 18% or fewer patients treated with capecitabine monotherapy across clinical trials (grade 3 or 4, 1% or less). Various types of infection including bronchitis, fungal infections, influenza-like illnesses, pneumonia, sepsis, and other viral infections have each been reported in less than 10% of patients who received capecitabine monotherapy.[44458]

Fatigue (16% to 42% vs. 16% to 46%; grade 3 or 4, 8% or less vs. 1% to 4%), asthenia (10% vs. 10%; less than 1% vs. 1%), and lethargy (10% vs. 9%; grade 3 or 4, less than 1% vs. less than 1%) occurred with a similar frequency in patients treated with capecitabine monotherapy versus fluorouracil/leucovorin in clinical trials. Muscle weakness was also reported in fewer than 10% of patients who received capecitabine monotherapy in a pooled safety population. The addition of capecitabine to docetaxel in patients with metastatic breast cancer did not increase the incidence of asthenia (26% vs. 25%; grade 3 or 4, 4% to 5% vs. 6%) or fatigue (22% vs. 27%; grade 3 or 4, 4% vs. 6%) compared with docetaxel alone. Weakness was reported in 16% of patients who received capecitabine plus docetaxel compared with 11% of those who received docetaxel alone (grade 3, 2% vs. 2%); lethargy was reported in less than 10% of patients in the capecitabine arm.[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. Additionally, abnormal vision/visual impairment, conjunctivitis, and keratoconjunctivitis have each been reported in fewer than 10% of patients receiving capecitabine monotherapy. Increased lacrimation was reported in 12% of patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel compared with 7% (grade 3, less than 1%) of those receiving docetaxel alone; conjunctivitis and eye irritation were also each reported in fewer than 10% of patients in the capecitabine arm. There have been reports of lacrimal duct stenosis and corneal disorders including keratitis in postmarketing experience with capecitabine.[44458]

Hypercalcemia and hypocalcemia have been reported in patients with metastatic colorectal cancer treated with capecitabine monotherapy in a randomized clinical trial, including grade 3 or 4 decreases (2.3%) and increases (1.1%) from baseline in calcium levels. Hypokalemia, hypomagnesemia, and hypertriglyceridemia were also each reported in fewer than 10% of patients receiving capecitabine monotherapy in a pooled safety population. Hypokalemia (68%), hypocalcemia (48%), hypophosphatemia (45%), and hyponatremia (45%) were more common in pediatric patients compared to adult patients.[44458]

Hemorrhage (bleeding), coagulopathy, and epistaxis were each reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population; GI bleeding was additionally reported in less than 10% of patients treated with capecitabine monotherapy in 1 randomized clinical trial. Hemorrhagic diarrhea, decreased prothrombin, and epistaxis were also reported in less than 10% of patients treated with capecitabine plus docetaxel in a randomized clinical trial.[44458]

Musculoskeletal adverse reactions reported with capecitabine treatment when administered as monotherapy or in combination with docetaxel include arthralgia (15% or less; grade 3, 2% or less), arthritis (less than 10%), back pain (12% or less; grade 3, 2% or less), myalgia (15 or less%; grade 3, 2% or less), noncardiac chest pain (unspecified) (less than 10%), generalized pain (12% or less; grade 3, 1% or less), limb pain (13% or less; grade 3, less than 1%), and myalgia (less than 10%). Bone pain was reported in fewer than 10% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in 1 randomized clinical trial.[44458]

Headache (15% or less; grade 3, 3% or less), dizziness (12% or less), and vertigo (less than 10%) have been reported in patients treated with capecitabine as monotherapy or in combination with docetaxel across clinical trials; migraine was additionally reported in fewer than 10% of patients treated with capecitabine plus docetaxel in 1 randomized clinical trial.[44458]

Paresthesias (12% to 21%; grade 3, 1% or less), peripheral neuropathy (10% or less), hypoesthesia (less than 10%), and polyneuropathy (less than 10%) were reported in patients treated with capecitabine monotherapy across clinical trials. 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 15% or fewer patients treated with capecitabine monotherapy across clinical trials (grade 3, 1%). The addition of capecitabine to docetaxel did not increase the incidence of edema compared to docetaxel alone in 1 randomized clinical trial (33% vs. 34%; grade 3 or 4, less than 2% vs. less than 4%). Lymphedema was reported in less than 10% of patients treated with capecitabine as monotherapy or in combination with docetaxel in clinical trials.[44458]

Dyspnea (14% or less; grade 3, less than 3%), cough (13% or less; grade 3, 1% or less), respiratory distress (less than 10%), and a nonspecific pharyngeal disorder (less than 10%) were reported in patients treated with capecitabine as monotherapy or in combination with docetaxel in clinical trials. Pleural effusion and rhinorrhea each occurred in fewer than 10% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in 1 clinical trial.[44458]

Venous thrombosis and pulmonary embolism were each reported in less than 10% of patients treated with capecitabine monotherapy in clinical trials. Venous phlebitis and thrombophlebitis were each reported in less than 10% of metastatic breast cancer patients who received capecitabine plus docetaxel in 1 clinical trial.[44458]

Hot flashes were reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population. Flushing was also reported in less than 10% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in 1 clinical trial.[44458]

Ataxia, impaired balance, encephalopathy, syncope, and tremor were each reported in less than 10% of patients treated with capecitabine monotherapy across clinical trials. Toxic leukoencephalopathy was reported in postmarketing experience with capecitabine therapy.[44458]

Hypotension and hypertension were each reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population.[44458]

Thirst (polydipsia) was reported in less than 10% 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 10% of patients receiving capecitabine monotherapy in a pooled safety population.[44458]

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

Optimize hydration prior to starting therapy with capecitabine. 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. Dehydration can occur with capecitabine therapy and patients with anorexia, asthenia, nausea/vomiting, or diarrhea may be at increased risk. Monitor hydration status and renal function at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for grade 2 or higher diarrhea or dehydration.[44458]

Use capecitabine with caution in patients with renal impairment; a dose reduction is necessary for patients with creatinine clearance (CrCl) 30 to 50 mL/min, and capecitabine has not been studied in patients with CrCl less than 30 mL/min. Serious cases of renal failure, some fatal, can occur with capecitabine treatment. Optimize hydration prior to starting therapy. Monitor renal function at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if renal impairment or renal failure occurs.[44458]

Capecitabine is not recommended for patients with certain homozygous or compound heterozygous variants in the DPYD gene that result in complete dihydropyrimidine dehydrogenase deficiency (DPD deficiency) due to an increased risk of acute early-onset toxicities and serious adverse reactions that can result in death (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity); patients with partial DPD deficiency may also have an increased risk of serious adverse reactions. Capecitabine has not been proven safe for patients with complete DPD deficiency at any dose, and there is insufficient data regarding capecitabine dosing in patients with partial DPD activity. Consider testing for DPD deficiency prior to starting therapy if clinically appropriate. There is not an FDA-approved test to detect DPYD mutations; currently available tests may vary in accuracy and design. 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]

Bone marrow suppression can occur with capecitabine treatment. Monitor complete blood counts at baseline and prior to each cycle. Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm³ or platelet counts below 100,000 cells/mm³. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary if grade 3 or 4 myelosuppression occurs during the course of treatment.[44458]

Monitor the INR more frequently in patients receiving concomitant capecitabine and vitamin K antagonist anticoagulant therapy and adjust the anticoagulant dose as clinically appropriate. Clinically significant increases in PT and INR and/or bleeding events, including fatalities, have been reported in patients taking capecitabine concomitantly with oral vitamin K antagonists such as warfarin, occurring within several days and up to several months after initiating capecitabine therapy; patients included those with and without liver metastases, as well as those who were on stable doses of oral vitamin K antagonists at the time capecitabine was introduced.[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 history of coronary artery disease may be at increased risk. If cardiotoxicity occurs, interrupt therapy with capecitabine as clinically appropriate; the safety of resuming capecitabine therapy after cardiotoxicity has occurred has not been established.[44458]

Monitor patients with hepatic disease more frequently for adverse reactions. Capecitabine exposure increases in patients with mild to moderate hepatic impairment, while the effect of severe hepatic impairment on the safety and pharmacokinetics of capecitabine is unknown. Hyperbilirubinemia has been reported with capecitabine treatment and is more common in patients with hepatic metastases at baseline; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if hyperbilirubinemia occurs.[44458]

Monitor geriatric patients (65 years or older) for an increased incidence of capecitabine-related gastrointestinal adverse reactions compared to younger patients. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil in clinical trials.[44458]

Severe cutaneous adverse reactions (SCARs) (serious rash and skin disease) have been reported with capecitabine therapy including toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS), which can be fatal. 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. Monitor patients for new or worsening skin conditions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for skin toxicity, depending on the severity of the reaction. Permanently discontinue capecitabine for SCARs.[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. Due to the risk of male-mediated teratogenicity, 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. Although there are no data regarding the effect of capecitabine on human fertility, male and female infertility has been observed in animal studies.[44458]

Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether capecitabine is present in human milk, although many drugs are excreted in human milk.[44458]