(ka pe SITE a been)
US labeling:
Breast cancer, metastatic:
Monotherapy: Treatment of metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing regimen or resistant to paclitaxel in patients for whom further anthracycline therapy is not indicated
Combination therapy: Treatment of metastatic breast cancer (in combination with docetaxel) after failure of a prior anthracycline-containing regimen
Colorectal cancer: First-line treatment of metastatic colorectal cancer when treatment with a fluoropyrimidine alone is preferred; adjuvant therapy of Dukes C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred
Canadian labeling:
Colorectal cancer (combination therapy): Treatment of metastatic colorectal cancer (in combination with oxaliplatin) after failure of a prior irinotecan-containing regimen.
Known hypersensitivity to capecitabine, fluorouracil, or any component of the formulation; severe renal impairment (CrCl <30 mL/minute)
Canadian labeling: Additional contraindications (not in US labeling): Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity; concomitant administration with sorivudine or chemically related analogues (eg, brivudine).
Frequently monitor the anticoagulant response (international normalized ratio [INR] or prothrombin time [PT]) of patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy in order to adjust the anticoagulant dose accordingly. A clinically important capecitabine-warfarin drug interaction was demonstrated in a clinical pharmacology trial. 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. Postmarketing 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 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age older than 60 years and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
Breast cancer, metastatic: Oral: 1,250 mg/m2 twice daily for 2 weeks, every 21 days (as either monotherapy or in combination with docetaxel)
Breast cancer, metastatic (off-label dosing): Oral: 1,000 mg/m2 twice daily (in combination with ixabepilone) on days 1 to 14 of a 3-week cycle until disease progression or unacceptable toxicity (Thomas, 2007)
Breast cancer, metastatic, HER2+ (off-label dosing): Oral: 1,000 mg/m2 twice daily (in combination with lapatinib) on days 1 to 14 of a 3-week cycle until disease progression or unacceptable toxicity (Geyer, 2006) or 1,250 mg/m2 twice daily (in combination with trastuzumab) on days 1 to 14 of a 3-week cycle (Bartsch, 2007)
Breast cancer, metastatic, HER2+ with brain metastases, first-line therapy (off-label dosing): Oral: 1,000 mg/m2 twice daily (in combination with lapatinib) on days 1 to 14 of a 3-week cycle until disease progression or unacceptable toxicity (Bachelot, 2012)
Colorectal cancer, metastatic: Oral: 1,250 mg/m2 twice daily for 2 weeks, every 21 days. Note: Capecitabine toxicities, particularly hand-foot syndrome, may be higher in North American populations; therapy initiation at doses of 1,000 mg/m2 twice daily (for 2 weeks every 21 days) may be considered (Haller, 2008).
Colorectal cancer (Canadian labeling; off-label combination in the US): Oral: 1,000 mg/m2 twice daily (in combination with oxaliplatin) on days 1 to 14 of a 3-week cycle for 8 or 16 cycles (Cassidy, 2008; Haller, 2011; Schmoll, 2007)
Dukes C colon cancer, adjuvant therapy: Oral: 1,250 mg/m2 twice daily for 2 weeks, every 21 days, for a recommended total duration of 24 weeks (8 cycles of 2 weeks of drug administration and 1 week rest period).
Esophageal and gastric cancers (off-label uses): Oral:
Preoperative or definitive chemoradiation: 800 mg/m2 twice daily (in combination with cisplatin and radiation) on days 1 to 5 weekly for 5 weeks (Lee, 2007) or 625 mg/m2 twice daily (in combination with oxaliplatin and radiation) on days 1 to 5 weekly for 5 weeks (Javle, 2009)
Postoperative chemoradiation: 625 to 825 mg/m2 twice daily during radiation therapy (Lee, 2006)
Locally advanced or metastatic (chemoradiation not indicated): 1,000 to 1,250 mg/m2 twice daily (monotherapy or in combination with cisplatin with or without trastuzumab) on days 1 to 14 of a 3-week cycle (Bang, 2010; Hong, 2004; Kang, 2009) or 625 mg/m2 twice daily (in combination with epirubicin and cisplatin or oxaliplatin) on days 1 to 21 of a 3-week cycle for up to 8 cycles (Cunningham, 2008; Sumpter, 2005)
Hepatobiliary cancers, advanced (off-label use): Oral: 650 mg/m2 twice daily (in combination with gemcitabine) on days 1 to 14 of a 3-week cycle (Knox, 2005) or 1,000 mg/m2 twice daily (in combination with oxaliplatin) on days 1 to 14 of a 3-week cycle (Nehls, 2008) or 1,250 mg/m2 twice daily (in combination with cisplatin) on days 1 to 14 of a 3-week cycle (Kim, 2003); all regimens continued until disease progression or unacceptable toxicity
Neuroendocrine (pancreatic/islet cell) tumors, metastatic or unresectable (off label use): Oral: 750 mg/m2 twice daily (in combination with temozolomide) on days 1 to 14 of a 4-week cycle (Strosberg, 2011)
Ovarian, fallopian tube, or peritoneal cancer, platinum-refractory (off label use): Oral: 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle until disease progression or unacceptable toxicity (Wolf, 2006)
Pancreatic cancer, metastatic (off-label use): Oral: 1,250 mg/m2 twice daily on days 1 to 14 of a 3-week cycle (Cartwright , 2002) or 830 mg/m2 twice daily (in combination with gemcitabine) on days 1 to 21 of a 4-week cycle until disease progression or unacceptable toxicity (Cunningham, 2009)
Unknown primary cancer (off-label use): Oral: 1,000 mg/m2 twice daily (in combination with oxaliplatin) on days 1 to 14 of a 3-week cycle for up to 6 cycles or until disease progression (Hainsworth, 2010) or 800 mg/m2 twice daily (in combination with carboplatin and gemcitabine) on days 1 to 14 of a 3-week cycle for up to 8 cycles or until disease progression or unacceptable toxicity (Schneider, 2007)
The elderly may be more sensitive to the toxic effects of fluorouracil. Insufficient data are available to provide dosage modifications.
Note: Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes.
Renal impairment at treatment initiation:
CrCl ≥51 mL/minute: Initial: No dosage adjustment necessary.
CrCl 30 to 50 mL/minute: Initial: Administer 75% of usual dose (Cassidy, 2002; Poole, 2002; Xeloda prescribing information, 2015)
CrCl <30 mL/minute: Use is contraindicated (Poole, 2002; Xeloda prescribing information, 2015)
Renal toxicity during treatment: Refer to dosage adjustment for toxicity.
Hepatic impairment at treatment initiation:
Mild to moderate impairment: No starting dose adjustment necessary (Ecklund, 2005; Superfin, 2007); however, carefully monitor patients.
Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer 's labeling (has not been studied).
Hepatotoxicity during treatment:
US labeling: Hyperbilirubinemia, grade 3 or 4: Interrupt treatment until bilirubin ≤3 times ULN; refer to dosage adjustment for toxicity for dosage recommendations.
Canadian labeling: Hyperbilirubinemia, grades 2, 3 or 4: Interrupt treatment until resolution to grade 1 (bilirubin ≤1.5 times ULN); refer to dosage adjustment for toxicity for dosage recommendations.
Usually administered in 2 divided doses taken 12 hours apart. Doses should be taken with water within 30 minutes after a meal. Swallow tablets whole; do not cut or crush.
Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single gloving for administration of intact tablets. If it is necessary to manipulate the tablets (eg, to prepare an oral solution), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).
Store at 25 � �C (77 � �F); excursions are permitted between 15 � �C and 30 � �C (59 � �F and 86 � �F). Keep bottle tightly closed.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Xeloda: 150 mg, 500 mg
Generic: 150 mg, 500 mg
Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating tablets, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).
A 10 mg/mL oral solution may be made with tablets. Crush four 500 mg tablets in a mortar and reduce to a fine powder; add to 200 mL water. Capecitabine tablets are water soluble (data on file from Roche). Administer immediately after preparation, 30 minutes after a meal.
Judson IR, Beale PJ, Trigo JM, et al, "A Human Capecitabine Excretion Balance and Pharmacokinetic Study After Administration of a Single Oral Dose of 14C-Labelled Drug, " � Invest New Drugs, 1999, 17(1):49-56.[PMID: 10555122]Alitretinoin (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP2C9 inhibitor. Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Bosentan: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy
Cannabis: May increase the serum concentration of CYP2C9 Inhibitors (Strong). More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy
Carvedilol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy
Cimetidine: May increase serum concentrations of the active metabolite(s) of Capecitabine. Specifically, concentrations of fluorouracil may be increased. Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
CYP2C9 Substrates: CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates. Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Diclofenac (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used together with a strong CYP2C9 inhibitor. Arthrotec (diclofenac and misoprostol) labeling specifically recommends limiting the total daily dose to a maximum of 50 mg twice/day. Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Dronabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Fosphenytoin: Capecitabine may increase the serum concentration of Fosphenytoin. Consider therapy modification
Gimeracil: May increase serum concentrations of the active metabolite(s) of Capecitabine. Specifically, gimeracil may increase concentrations of fluorouracil. Avoid combination
Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
Lacosamide: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification
Leucovorin Calcium-Levoleucovorin: May enhance the adverse/toxic effect of Capecitabine. Monitor therapy
MetroNIDAZOLE (Systemic): May increase serum concentrations of the active metabolite(s) of Capecitabine. Monitor therapy
MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification
Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ospemifene: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy
Parecoxib: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy
Phenytoin: Capecitabine may increase the serum concentration of Phenytoin. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Ramelteon: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tetrahydrocannabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination
Vitamin K Antagonists (eg, warfarin): Capecitabine may increase the serum concentration of Vitamin K Antagonists. Consider therapy modification
Renal function should be estimated at baseline to determine initial dose. During therapy, CBC with differential, hepatic function, and renal function should be monitored. Monitor INR closely if receiving concomitant warfarin. Monitor for diarrhea, dehydration, hand-foot syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, stomatitis, and cardiotoxicity.
Frequency listed derived from monotherapy trials. Incidence reported for all indications and usage, unless otherwise noted. Frequency not always defined.
>10%:
Cardiovascular: Edema ( ≤15%)
Central nervous system: Fatigue ( ≤42%), paresthesia (stage IV breast cancer: 21%; grades 3/4: 1%), pain ( ≤12%)
Dermatologic: Palmar-plantar erythrodysesthesia (54% to 60%; grades ≥3: 11% to 17%), dermatitis (27% to 37%, grades ≥3: 1%)
Gastrointestinal: Diarrhea (47% to 57%, grades 3/4: 2% to 13%), nausea (34% to 43%; stage IV breast cancer: 53%), vomiting (metastatic colorectal cancer, stage IV breast cancer: 27% to 37%; Dukes C colon cancer: 15%), abdominal pain (metastatic colorectal cancer: 35%; stage IV breast cancer: 20%; Dukes' C colon cancer: 14%), decreased appetite (26%), stomatitis (22% to 25%), anorexia (stage IV breast cancer: 23%; Dukes' C colon cancer: 9%), constipation (9% to 15%)
Hematologic & oncologic: Lymphocytopenia (stage IV breast cancer: 94%; stage IV breast cancer, grades 3/4: 15% to 44%), anemia (72% to 80%, grades 3/4: ≤3%), neutropenia ( ≤26%, grades 3/4: ≤3%), thrombocytopenia (stage IV breast cancer: 24%; all: grades 3/4: 1% to 3%)
Hepatic: Hyperbilirubinemia (Metastatic colorectal cancer: 48%; stage IV breast cancer: 22%; all: grades 3/4: 2% to 23%)
Neuromuscular & skeletal: Weakness ( ≤42%)
Ophthalmic: Eye irritation (13% to 15%)
Miscellaneous: Fever (7% to 18%)
1% to 10%:
Cardiovascular: Venous thrombosis (8%), chest pain ( ≤6%), atrial fibrillation (<5%), bradycardia (<5%), collapse (<5%), extrasystoles (<5%), pericardial effusion (<5%), ventricular premature contractions (<5%), angina pectoris, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG changes, ischemic heart disease, myocardial infarction
Central nervous system: Lethargy (10%), peripheral sensory neuropathy (10%), headache (5% to 10%), insomnia ( ≤8%), dizziness (6% to 8%), ataxia (<5%), depression ( ≤5%), mood changes (5%), abnormal gait (<5%), brain disease (<5%), dysarthria (<5%), dysphasia (<5%), equilibrium disturbance (<5%), irritability (<5%), myasthenia (<5%), sedation (<5%), vertigo (<5%)
Dermatologic: Nail disease ( ≤7%), skin discoloration (7%), skin rash (7%), alopecia (6%), erythema (6%), dermal ulcer (<5%), pruritus (<5%)
Endocrine & metabolic: Dehydration (7%), hot flash (<5%), hypokalemia (<5%), hypomagnesemia (<5%), increased thirst (<5%), weight gain (<5%), decreased serum calcium (Dukes' C colon cancer: grades 3/4: 2%), increased serum calcium (Dukes' C colon cancer: grades 3/4: 1%)
Gastrointestinal: Gastrointestinal motility disorder (10%), GI inflammation (upper: 8%), oral discomfort (grades 3/4: 10%), dyspepsia (6% to 8%), upper abdominal pain (7%), intestinal obstruction ( ≤6%), dysgeusia (6%), gastrointestinal hemorrhage (6%), abdominal distention (<5%), dysphagia (<5%), rectal pain (<5%), toxic dilation of intestine (<5%), increased serum alanine aminotransferase (Dukes' C colon cancer: grades 3/4: 2%), sore throat (2%), necrotizing enterocolitis
Hematologic & oncologic: Hemorrhage (<5%), lymphedema (<5%), granulocytopenia (Dukes' C colon cancer: grades 3/4: 3%), immune thrombocytopenia (1%)
Hepatic: Abnormal hepatic function tests (<5%)
Hypersensitivity: Drug-induced hypersensitivity (<5%)
Infection: Viral infection (metastatic colorectal cancer: 5%)
Neuromuscular & skeletal: Back pain (10%), myalgia ( ≤9%), arthralgia (8%), limb pain (stage IV breast cancer: 6%), tremor (<5%)
Ophthalmic: Visual disturbance (metastatic colorectal cancer: 5%), conjunctivitis ( ≤5%), keratoconjunctivitis (<5%)
Respiratory: Cough ( ≤7%), chest mass (<5%), dyspnea (<5%), flu-like symptoms (<5%), hemoptysis (<5%), hoarseness (<5%), pharyngeal disease (metastatic colorectal cancer: 5%), epistaxis ( ≤3%), laryngitis (1%)
<1% (limited to important or life-threatening): Acute renal failure, ascites, blood coagulation disorder, bronchitis, bronchospasm, cachexia, cerebrovascular accident, cholestatic hepatitis, confusion, cutaneous lupus erythematosus, ecchymoses, esophagitis, fibrosis, fungal infection, gastric ulcer, gastroenteritis, gastrointestinal perforation, hemorrhage, hepatic failure, hepatic fibrosis, hepatitis, hypersensitivity, hypertension, hypertriglyceridemia, hypotension, keratitis, lacrimal stenosis, leukoencephalopathy, loss of consciousness, myocarditis, nocturia, ostealgia, pancytopenia, phlebitis (venous), photophobia, pneumonia, pulmonary embolism, radiation recall phenomenon, respiratory distress, sepsis, Stevens-Johnson syndrome, syncope, tachycardia, toxic epidermal necrolysis
In moderate-to-severe renal function impairment, there is increased exposure to inactive metabolites (FBAL and 5 '-DFUR) and a 25% increase in exposure to capecitabine.
In mild-to-moderate hepatic dysfunction due to liver metastases, capecitabine AUC and Cmax increased 60%; 5-FU was not affected. The effect of severe hepatic dysfunction is not known.
In a study of patients ranging from ages 27 to 86 years, age had no significant influence on the pharmacokinetics of 5 '-DFUR, 5-FU; a 20% increase in age resulted in a 15% increase in the AUC of FBAL.
Concerns related to adverse effects:
- Bone marrow suppression: Bone marrow suppression may occur, hematologic toxicity is more common when used in combination therapy; use with caution; dosage adjustments may be required. The product labeling recommends that patients with baseline platelets <100,000/mm3 and/or neutrophils <1,500/mm3 not receive capecitabine therapy and also to withhold therapy for grade 3 or 4 hematologic toxicity during treatment.
- Cardiotoxicity: Cardiotoxicity has been observed with capecitabine, including myocardial infarction, ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. These adverse events may be more common in patients with a history of coronary artery disease.
- Dermatologic toxicity: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) have been reported (some fatal); permanently discontinue capecitabine if a severe dermatologic or mucocutaneous reaction occurs.
- Gastrointestinal toxicity: May cause diarrhea (may be severe); median time to first occurrence of grade 2 to 4 diarrhea was 34 days and median duration of grades 3 or 4 diarrhea was 5 days. Withhold treatment for grades 2 to 4 diarrhea; subsequent doses should be reduced after grade 3 or 4 diarrhea or recurrence of grade 2 diarrhea. Antidiarrheal therapy (eg, loperamide) is recommended. Dehydration may occur rapidly in patients with diarrhea, nausea, vomiting, anorexia, and/or weakness; adequately hydrate prior to treatment initiation. Elderly patients may be at higher risk for dehydration. Interrupt treatment for grade 2 or higher dehydration; correct precipitating factors and ensure rehydration prior to resuming therapy; may require dose modification (based on precipitating factor). Necrotizing enterocolitis (typhlitis) has been reported.
- Hand-and-foot syndrome: May cause hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema); characterized by numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering, and severe pain. The median onset is 79 days (range: 11 to 360 days). If grade 2 or 3 hand-and-foot syndrome occurs, interrupt administration of capecitabine until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, decrease subsequent doses of therapy.
- Hepatotoxicity: Grade 3 and 4 hyperbilirubinemia have been observed in patients with and without hepatic metastases at baseline (median onset: 64 days). Transaminase and alkaline phosphatase elevations have also been reported. If capecitabine-related grade 3 or 4 hyperbilirubinemia occurs, interrupt treatment until bilirubin ≤3 times ULN. The Canadian labeling recommends treatment interruption for grades 2, 3, or 4 hyperbilirubinemia; may resume with resolution to grade 1. Bilirubin elevations may also require dose reductions.
Disease-related concerns:
- Dihydropyrimidine dehydrogenase deficiency: Patients with certain homozygous or heterozygous mutations of the dihydropyrimidine dehydrogenase (DPD) enzyme are at increased risk for acute early-onset (potentially severe, life-threatening, or fatal) toxicity due to total or near total absence of DPD activity. Toxicity may include mucositis/stomatitis, diarrhea, neutropenia, and neurotoxicity. Patients with partial DPD activity are also at risk for severe, life-threatening, or fatal toxicity. May require therapy interruption or permanent discontinuation, depending on the onset, duration, and severity of toxicity observed. No capecitabine dose has been shown to be safe in patients with complete DPD deficiency; data is insufficient to recommend a dose in patients with partial DPD activity. The Canadian labeling contraindicates use in patients with a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity.
- Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment due to liver metastases. The effect of severe hepatic impairment has not been studied.
- Renal impairment: Dehydration may occur, resulting in acute renal failure (may be fatal); concomitant use with nephrotoxic agents and baseline renal dysfunction may increase the risk. Use with caution in patients with mild to moderate renal impairment; reduce dose with moderate impairment (exposure to capecitabine and metabolites is increased) and carefully monitor and reduce subsequent dose (with any grade 2 or higher adverse effect) with mild to moderate impairment. Use is contraindicated in severe impairment.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Fluorouracil/leucovorin (FU/LV): In patients with colorectal cancer, treatment with capecitabine immediately following 6 weeks of FU/LV therapy has been associated with an increased incidence of grade ≥3 toxicity, when compared to patients receiving the reverse sequence, capecitabine (two 3-week courses) followed by FU/LV (Hennig, 2008).
- Warfarin: [US Boxed Warning]: Capecitabine may increase the anticoagulant effects of warfarin; bleeding events, including death, have occurred with concomitant use. Clinically significant increases in prothrombin time (PT) and INR have occurred within several days to months after capecitabine initiation (in patients previously stabilized on anticoagulants), and may continue up to 1 month after capecitabine discontinuation. May occur in patients with or without liver metastases. Monitor PT and INR frequently and adjust anticoagulation dosing accordingly. An increased risk of coagulopathy is correlated with a cancer diagnosis and age >60 years.
Special populations:
- Elderly: Use with caution in patients ≥60 years of age; the incidence of treatment-related adverse events may be higher.
Special handling:
- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).
Other warnings/precautions:
- Fluoropyrimidine overdose: Uridine triacetate (formerly called vistonuridine), has been studied in cases of fluoropyrimidine overdose. In a clinical study of 98 patients who received uridine triacetate for fluorouracil toxicity (due to overdose, accidental capecitabine ingestion, or possible DPD deficiency), 96 patients recovered fully (Bamat, 2013). Of 17 patients receiving uridine triacetate beginning within 8 to 96 hours after fluorouracil overdose, all patients fully recovered (von Borstel, 2009). An additional case report describes accidental capecitabine ingestion by a 22-month-old child; uridine triacetate was initiated approximately 7 hours after exposure. The patient received uridine triacetate every 6 hours for a total of 20 doses through nasogastric tube administration; he was asymptomatic throughout his course and was discharged with normal laboratory values (Kanie, 2011). Refer to Uridine Triacetate monograph.
D
Adverse effects were observed in animal reproduction studies. Fetal harm may occur if administered during pregnancy. Women of childbearing potential should use effective contraceptives to avoid pregnancy during treatment.
Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues to form fluorouracil which is the active moiety. Fluorouracil is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and S phases of the cell cycle.
Rapid and extensive (rate and extent reduced by food)
Hepatic: Inactive metabolites: 5 " �-deoxy-5-fluorocytidine, 5 " �-deoxy-5-fluorouridine; Tissue: Enzymatically metabolized to fluorouracil, which is then metabolized to active metabolites, 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2 '-deoxyuridine-5 '-O-monophosphate (F-dUMP)
Urine (96%, 57% asα-fluoro- � �-alanine; <3% as unchanged drug); feces (<3%)
1.5 hours; Fluorouracil: 2 hours
~0.75 hour
<60%; ~35% to albumin
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, dizziness, insomnia, nail changes, lack of appetite, constipation, loss of strength and energy, dry skin, back pain, joint pain, or muscle pain. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea or vomiting), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), shortness of breath, swelling of arm or leg, excessive weight gain, angina, arrhythmia, severe nausea, vomiting, severe or bloody diarrhea, burning or numbness feeling, severe skin irritation, mouth sores, vision changes, eye pain, severe eye irritation, severe abdominal pain, or redness or irritation of palm or soles of feet (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.