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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.

Medication Safety Issues

Sound-alike/look-alike issues:

Xeloda® may be confused with Xenical®

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Pronunciation

(ka pe SITE a been)

U.S. Brand Names

• Xeloda®

Index Terms

• NSC-712807

Generic Available

No

Canadian Brand Names

• Xeloda®

Pharmacologic Category

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

Pharmacologic Category Synonyms

• Antimetabolite Antineoplastic
• Chemotherapy Agent, Antimetabolite

Use: Labeled Indications

Treatment of metastatic colorectal cancer; adjuvant therapy of Dukes' C colon cancer; treatment of metastatic breast cancer

Use: Unlabeled/Investigational

Treatment of gastric cancer, pancreatic cancer

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal studies have demonstrated teratogenicity and fetal loss. There are no adequate and well-controlled studies in pregnant women; however, fetal harm may occur. Women of childbearing potential should avoid pregnancy.

Lactation

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

It is not known if the drug is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving capecitabine therapy.

Contraindications

Hypersensitivity to capecitabine, fluorouracil, or any component of the formulation; known deficiency of dihydropyrimidine dehydrogenase (DPD); severe renal impairment (Cl_cr <30 mL/minute)

Warnings/Precautions

Boxed warnings:

• Warfarin: See “Concurrent drug therapy issues” below.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Cardiotoxicity: There has been cardiotoxicity associated with fluorinated pyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death, ECG changes, and cardiomyopathy. These adverse events may be more common in patients with a history of coronary artery disease.

• Diarrhea: Can cause severe diarrhea; median time to first occurrence is 34 days; subsequent doses should be reduced after grade 3 or 4 diarrhea or recurrence of grade 2 diarrhea.

• Hand-and-foot syndrome: May cause hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is characterized by numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering, and severe pain. 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.

• Necrotizing enterocolitis (typhlitis): Has been reported.

Disease-related concerns:

• Bone marrow suppression: Use with caution in patients with bone marrow suppression.

• Dihydropyrimidine dehydrogenase (DPD) deficiency: Rare and unexpected severe toxicity (stomatitis, diarrhea, neutropenia, neurotoxicity) may be attributed to dihydropyrimidine dehydrogenase (DPD) deficiency.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; reduce dose with moderate impairment and carefully monitor and reduce subsequent dose (with any grade 2 or higher adverse effect) with mild-to-moderate impairment.

Concurrent drug therapy issues:

• Alkylating therapy: Use with caution in patients who have received alkylating therapy.

• Warfarin: [U.S. Boxed Warning]: Capecitabine may increase the anticoagulant effects of warfarin; monitor closely.

Special populations:

• Elderly: Use with caution in patients ?80 years of age.

• Pediatrics: Safety and efficacy have not been established in children.

• Pelvic radiation therapy recipients: Use with caution in patients who have received extensive pelvic radiation.

Adverse Reactions

Frequency listed derived from monotherapy trials.

>10%:

Cardiovascular: Edema (9% to 15%)

Central nervous system: Fatigue (16% to 42%), fever (7% to 18%), pain (12%)

Dermatologic: Palmar-plantar erythrodysesthesia (hand-and-foot syndrome) (54% to 60%; grade 3: 11% to 17%; may be dose limiting), dermatitis (27% to 37%)

Gastrointestinal: Diarrhea (47% to 57%; may be dose limiting; grade 3: 12% to 13%; grade 4: 2% to 3%), nausea (34% to 53%), vomiting (15% to 37%), abdominal pain (7% to 35%), stomatitis (22% to 25%), appetite decreased (26%), anorexia (9% to 23%), constipation (9% to 15%)

Hematologic: Lymphopenia (94%; grade 4: 14%), anemia (72% to 80%; grade 4: <1% to 1%), neutropenia (2% to 26%; grade 4: 2%), thrombocytopenia (24%; grade 4: 1%)

Hepatic: Bilirubin increased (22% to 48%; grades 3/4: 11% to 23%)

Neuromuscular & skeletal: Paresthesia (21%)

Ocular: Eye irritation (13% to 15%)

Respiratory: Dyspnea (14%)

5% to 10%:

Cardiovascular: Venous thrombosis (8%), chest pain (6%)

Central nervous system: Headache (5% to 10%), lethargy (10%), dizziness (6% to 8%), insomnia (7% to 8%), mood alteration (5%), depression (5%)

Dermatologic: Nail disorder (7%), rash (7%), skin discoloration (7%), alopecia (6%), erythema (6%)

Endocrine & metabolic: Dehydration (7%)

Gastrointestinal: Motility disorder (10%), oral discomfort (10%), dyspepsia (6% to 8%), upper GI inflammatory disorders (colorectal cancer: 8%), hemorrhage (6%), ileus (6%), taste perversion (colorectal cancer: 6%)

Neuromuscular & skeletal: Back pain (10%), weakness (10%), neuropathy (10%), myalgia (9%), arthralgia (8%), limb pain (6%)

Ocular: Abnormal vision (colorectal cancer: 5%), conjunctivitis (5%)

Respiratory: Cough (7%)

Miscellaneous: Viral infection (colorectal cancer: 5%)

<5%: Abdominal distension, angina, appetite increased, arthritis, ascites, asthma, ataxia, atrial fibrillation, bone pain, bradycardia, bronchitis, bronchopneumonia, bronchospasm, cachexia, cardiac arrest, cardiac failure, cardiomyopathy, cerebral vascular accident, cholestasis, coagulation disorder, colitis, confusion, deep vein thrombosis, diaphoresis, duodenitis, dysarthria, dysphagia, dysrhythmia, ecchymoses, ECG changes, encephalopathy, epistaxis, esophagitis, fibrosis, fungal infection, gastric ulcer, gastritis, gastroenteritis, hematemesis, hemoptysis, hepatic fibrosis, hepatitis, hoarseness, hot flushes, hypokalemia, hypomagnesemia, hyper-/hypotension, hypersensitivity, hypertriglyceridemia, idiopathic thrombocytopenia purpura, ileus, impaired balance, infection, influenza-like illness, intestinal obstruction (~1%), irritability, joint stiffness, keratoconjunctivitis, laryngitis, leukopenia, loss of consciousness, lymphedema, MI, myocardial ischemia, myocarditis, necrotizing enterocolitis (typhlitis), nocturia, oral candidiasis, pericardial effusion, thrombocytopenic purpura, pancytopenia, photosensitivity reaction, pneumonia, proctalgia, pruritus, pulmonary embolism, radiation recall syndrome, renal impairment, respiratory distress, sedation, sepsis, skin ulceration, sore throat, tachycardia, thirst, thrombophlebitis, toxic megacolon, tremor, ventricular extrasystoles, vertigo, weight gain

Postmarketing and/or case reports: Hepatic failure, lacrimal duct stenosis, multifocal leukoencephalopathy

Drug Interactions

CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

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

Phenytoin: Capecitabine may increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination

Vitamin K Antagonists (eg, warfarin): Capecitabine may increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions

Food: Food reduced the rate and extent of absorption of capecitabine.

Storage

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

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Absorption: Rapid and extensive

Protein binding: <60%; ~35% to albumin

Metabolism:

Hepatic: Inactive metabolites: 5?-deoxy-5-fluorocytidine, 5?-deoxy-5-fluorouridine

Tissue: Active metabolite: Fluorouracil

Half-life elimination: 0.5-1 hour

Time to peak: 1.5 hours; Fluorouracil: 2 hours

Excretion: Urine (96%, 57% as ?-fluoro-?-alanine); feces (<3%)

Dosage

Oral:

Adults: Note: Capecitabine toxicities, particularly hand-foot syndrome, may be higher in North American populations (for the treatment of colorectal cancer); therapy initiation at doses of 1000 mg/m² twice daily (for 2 weeks every 21 days) may be considered (Haller, 2006; NCCN Colon Cancer Guidelines)

Metastatic breast cancer, metastatic colorectal cancer: 1250 mg/m² twice daily (morning and evening) for 2 weeks, every 21 days

Adjuvant therapy of Dukes' C colon cancer: Recommended for a total of 24 weeks (8 cycles of 2 weeks of drug administration and 1 week rest period.

Pancreatic cancer (unlabeled use): 1000-1250 mg/m² twice daily (morning and evening) for 2 weeks, every 21 days

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

Dosing adjustment in renal impairment:

Cl_cr 51-80 mL/minute: No adjustment of initial dose

Cl_cr 30-50 mL/minute: Administer 75% of normal dose

Cl_cr <30 mL/minute: Use is contraindicated

Dosing adjustment in hepatic impairment:

Mild-to-moderate impairment: No starting dose adjustment is necessary; however, carefully monitor patients

Severe hepatic impairment: Patients have not been studied

Dosage modification guidelines: See table.

Refer to package labeling for modifications when administered in combination with docetaxel.

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 >1000/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

Dosage: Combination Regimens

Biliary adenocarcinoma: Gemcitabine-Capecitabine

Breast cancer:

Bevacizumab-Capecitabine

Capecitabine + Docetaxcel (Breast Cancer)

Capecitabine + Lapatinib

Capecitabine-Trastuzumab

Ixabepilone-Capecitabine

TEX (Capecitabine + Docetaxel + Epirubicin)

Colorectal cancer: XelOx

Esophageal cancer: Epirubicin-Oxaliplatin-Capecitabine

Gastric cancer:

Capecitabine + Docetaxel (Gastric Cancer)

Epirubicin-Oxaliplatin-Capecitabine

Lung cancer (nonsmall cell): Capecitabine + Docetaxel (Nonsmall Cell Lung Cancer)

Pancreatic cancer: Gemcitabine-Capecitabine

Administration: Oral

Usually administered in 2 divided doses taken 12 hours apart. Doses should be taken with water within 30 minutes after a meal.

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.

Dietary Considerations

Because current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food. In all clinical trials, patients were instructed to take with water within 30 minutes after a meal.

Patient Education

Do not take any new medication during therapy unless approved by prescriber. Take with water within 30 minutes after meal. Avoid use of antacids within 2 hours of taking this medication. Do not crush, chew, or dissolve tablets. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause lethargy, dizziness, visual changes, confusion, anxiety (avoid driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, loss of appetite, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); loss of hair (will grow back when treatment is discontinued); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); or dry, itchy, skin, and dry or irritated eyes (avoid contact lenses). Report persistent diarrhea or abdominal pain; skin rash, pain, tenderness, or peeling (especially hands and feet); chills or fever, confusion, persistent or violent vomiting; respiratory difficulty; chest pain or palpitations; unusual bleeding or bruising; bone pain; muscle spasms/tremors; or vision changes immediately. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. Breast-feeding is not recommended.

Geriatric Considerations

Patients ?80 years of age may experience a greater incidence of grade 3 or 4 adverse events (diarrhea, hand-and-foot syndrome, nausea/vomiting).

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis, abnormal taste, and taste disturbance.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Sedation is common; may cause dizziness or insomnia

Mental Health: Effects on Psychiatric Treatment

Neutropenia is common; use caution with clozapine and carbamazepine

Nursing: Physical Assessment/Monitoring

Monitor coagulation parameters regularly for patients receiving an oral coumarin-derivative anticoagulant. Assess results of laboratory tests (renal and hepatic function, CBC with differential) at baseline and during therapy. Monitor therapeutic response and adverse reactions (eg, gastrointestinal disturbance [nausea, vomiting, pain, dehydration, or severe diarrhea that can occur at any time during therapy], hematologic [lymphopenia, anemia, thrombocytopenia], cardiovascular [edema, chest pain], and paresthesia) periodically during therapy. Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report.

Oncology: Emetic Potential

Low (10% to 30%)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:

Xeloda®: 150 mg, 500 mg

Pricing: U.S. (www.drugstore.com)

Tablets (Xeloda)

150 mg (60): $371.93

500 mg (120): $2408.11

References

Cartwright TH, Cohn A, Varkey JA, et al, “Phase II Study of Oral Capecitabine in Patients With Advanced or Metastatic Pancreatic Cancer,” J Clin Oncol, 2002, 20(1):160-4.

Cassidy J, Tabernero J, Twelves C, et al, "XELOX (Capecitabine Plus Oxaliplatin): Active First-Line Therapy for Patients With Metastatic Colorectal Cancer," J Clin Oncol, 2004, 22(11):2084-91.

Haller DG, Cassidy J, Clarke S, et al, “Tolerability of Fluoropyrimidines Appears to Differ by Region,” J Clin Oncol, 2006, 24(18S):3514 [abstract from 2006 ASCO Annual Meeting Proceedings]

Hoff PM, Ansari R, Batist G, et al, “Comparison of Oral Capecitabine Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Treatment in 605 Patients With Metastatic Colorectal Cancer: Results of a Randomized Phase III Study,” J Clin Oncol, 2001, 19(8):2282-92.

Ishitsuka H, “Capecitabine: Preclinical Pharmacology Studies,” Invest New Drugs, 2000, 18(4):343-54.

Johnston PG and Kaye S, “Capecitabine: A Novel Agent for the Treatment of Solid Tumors,” Anticancer Drugs, 2001, 12(8):639-46.

McGavin JK and Goa KL, “Capecitabine: A Review of Its Use in the Treatment of Advanced or Metastatic Colorectal Cancer,” Drugs, 2001, 61(15):2309-26.

National Comprehensive Cancer Network (NCCN), “Clinical Practice Guidelines in Oncology™: Prevention and Treatment of Colon Cancer,” Version 1, 2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf.

National Comprehensive Cancer Network (NCCN), “Clinical Practice Guidelines in Oncology™: Prevention and Treatment of Pancreatic Adenocarcinoma,” Version 1, 2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/pancreatic.pdf .

Schilsky RL, “Pharmacology and Clinical Status of Capecitabine,” Oncology, 2000, 14(9):1297-306.

Twelves C, Wong A, Nowacki MP, et al, “Capecitabine as Adjuvant Treatment for Stage III Colon Cancer,” N Engl J Med, 2005, 352(26):2696-704.

Van Cutsem E, Twelves C, Cassidy J, et al, “Oral Capecitabine Compared With Intravenous Fluorouracil Plus Leucovorin in Patients With Metastatic Colorectal Cancer: Results of a Large Phase III Study,” J Clin Oncol, 2001, 19(21):4097-106.

Videnovic A, Semenov I Chua-Adajar R, et al, “Capecitabine-Induced Multifocal Leukoencephalopathy: A Report of Five Cases,” Neurology, 2005, 65(11):1792-4.

International Brand Names

• Apecitab (AR)
• Xeloda (AR, AT, AU, BB, BE, BF, BG, BJ, BM, BR, BS, BZ, CH, CI, CL, CN, CO, CZ, DE, DK, EC, ES, ET, FI, FR, GB, GH, GM, GN, GR, GY, HK, HN, ID, IE, IL, IN, IS, IT, JM, KE, KP, LR, LU, MA, ML, MR, MU, MW, MX, NE, NG, NL, NO, PE, PH, PK, PL, PT, PY, RU, SC, SD, SE, SG, SL, SN, SR, TH, TN, TR, TT, TZ, UG, UY, VE, ZA, ZM, ZW)

Lexi-Comp.com

Last full review/revision September 2008

Content last modified September 2008