Skip to Content
Top of Page: How to talk to a doctor about advanced ovarian cancer >>

Capecitabine

Pronunciation

Pronunciation

(ka pe SITE a been)

Index Terms

  • CAPE

Dosage Forms

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

Brand Names: U.S.

  • Xeloda

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Pharmacology

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.

Absorption

Rapid and extensive (rate and extent reduced by food)

Metabolism

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)

Excretion

Urine (96%, 57% as α-fluoro-β-alanine; <3% as unchanged drug); feces (<3%)

Time to Peak

1.5 hours; Fluorouracil: 2 hours

Half-Life Elimination

~0.75 hour

Protein Binding

<60%; ~35% to albumin

Special Populations: Renal Function Impairment

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.

Special Populations: Hepatic Function Impairment

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.

Special Populations: Elderly

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.

Use: Labeled Indications

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

Use: Unlabeled

Treatment of CNS lesions from metastatic breast cancer, esophageal cancer, gastric cancer, hepatobiliary cancers (advanced), neuroendocrine (pancreatic/islet cell) tumors (metastatic or unresectable), ovarian cancer (platinum-refractory), pancreatic cancer (metastatic), unknown primary cancer

Contraindications

Known hypersensitivity to capecitabine, fluorouracil, or any component of the formulation; severe renal impairment (CrCl <30 mL/minute)

Dosage

Breast cancer, metastatic: Adults: 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): Adults: 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): Adults: 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): Adults: 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: Adults: 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 (off-label dosing): Adults: 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: Adults: 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): Adults: 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): Adults: 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): Adults: 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): Adults: 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): Adults: 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): Adults: 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)

Elderly: The elderly may be more sensitive to the toxic effects of fluorouracil. Insufficient data are available to provide dosage modifications.

Dosage adjustment in renal impairment: 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.

Dosage adjustment in hepatic impairment:

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: Hyperbilirubinemia, grade 3 or 4: Interrupt treatment until bilirubin ≤3 times ULN; refer to dosage adjustment for toxicity for dosage recommendations.

Dosing in obesity: ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Dosage adjustment for toxicity: See table (Note: Capecitabine dosing recommendations apply to both monotherapy and when used in combination therapy with docetaxel).

Monitor carefully for toxicity and adjust dose as necessary. Doses reduced for toxicity should not be increased at a later time. For combination therapy, also refer to docetaxel product labeling for docetaxel dose modifications. If treatment delay is required for either capecitabine or docetaxel, withhold both agents until appropriate to resume combination treatment.

Recommended Capecitabine Dose Modifications

Toxicity Grades

During a Course of Therapy

Dose Adjustment for Next Cycle (% of starting dose)

Grade 1

Maintain dose level

Maintain dose level

Grade 2

1st appearance

Interrupt until resolved to grade 0 to 1

100%

2nd appearance

Interrupt until resolved to grade 0 to 1

75%

3rd appearance

Interrupt until resolved to grade 0 to 1

50%

4th appearance

Discontinue treatment permanently

Grade 3

1st appearance

Interrupt until resolved to grade 0 to 1

75%

2nd appearance

Interrupt until resolved to grade 0 to 1

50%

3rd appearance

Discontinue treatment permanently

Grade 4

1st appearance

Discontinue permanently

or

If in the patient's best interest to continue, interrupt until resolved to grade 0 to 1

50%

Table has been converted to the following text.

Recommended Capecitabine Dosage Adjustments

Note: Capecitabine dosing recommendations apply to both monotherapy and when used in combination therapy with docetaxel. Monitor carefully for toxicity and adjust dose as necessary. Doses reduced for toxicity should not be increased at a later time. For combination therapy, also refer to docetaxel product labeling for docetaxel dose modifications. If treatment delay is required for either capecitabine or docetaxel, withhold both agents until appropriate to resume combination treatment.

Grade 1 toxicity:

• Maintain dose level during course of therapy and for next cycle.

Grade 2 toxicity:

• 1st appearance: Interrupt therapy until resolved to grade 0 to 1 during course of therapy; administer 100% of starting dose for next cycle.

• 2nd appearance: Interrupt therapy until resolved to grade 0 to 1 during course of therapy; administer 75% of starting dose for next cycle.

• 3rd appearance: Interrupt therapy until resolved to grade 0 to 1 during course of therapy; administer 50% of starting dose for next cycle.

• 4th appearance: Discontinue treatment permanently.

Grade 3 toxicity:

• 1st appearance: Interrupt therapy until resolved to grade 0 to 1 during course of therapy; administer 75% of starting dose for next cycle.

• 2nd appearance: Interrupt therapy until resolved to grade 0 to 1 during course of therapy; administer 50% of starting dose for next cycle.

• 3rd appearance: Discontinue treatment permanently.

Grade 4 toxicity:

• 1st appearance: Discontinue permanently, or, if in the patient's best interest to continue, interrupt until resolved to grade 0 to 1; administer 50% of starting dose for next cycle.

Dosage adjustments for hematologic toxicity in combination therapy with ixabepilone:

Neutrophils <500/mm3 for ≥7 days or neutropenic fever: Hold for concurrent diarrhea or stomatitis until neutrophils recover to >1,000/mm3, then continue at same dose

Platelets <25,000/mm3 (or <50,000/mm3 with bleeding): Hold for concurrent diarrhea or stomatitis until platelets recover to >50,000/mm3, then continue at same dose

Extemporaneously Prepared

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):49-56.10555122

Administration

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]). 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).

Storage

Store at room temperature of 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed.

Drug Interactions

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

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

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

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

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

Adverse Reactions

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

ALERT: U.S. Boxed Warning

Warfarin interaction:

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.

Warnings/Precautions

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. Note: The Canadian labeling recommends treatment interruption for dehydration requiring IV hydration lasting <24 hours or dosage reduction if IV hydration required for ≥24 hours; correct precipitating factors and ensure rehydration prior to resuming therapy. 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.

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.

• 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: An investigational uridine prodrug, uridine triacetate (formerly called vistonuridine), has been studied in a limited number of cases of fluoropyrimidine overdose. Of 17 patients receiving uridine triacetate beginning within 8 to 96 hours after fluorouracil overdose, all patients fully recovered (von Borstel, 2009). Updated data has described a total of 28 patients treated with uridine triacetate for fluorouracil overdose (including overdoses related to continuous infusions delivering fluorouracil at rates faster than prescribed), all of whom recovered fully (Bamat, 2010). 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.

Monitoring Parameters

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.

Pregnancy Risk Factor

D

Pregnancy Considerations

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.

Patient Education

• 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), 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.

Hide