Capecitabine

Pronunciation

(ka pe SITE a been)

U.S. Brand Names

Xeloda®

Generic Available

Canadian Brand Names

Xeloda®

Use

Treatment of metastatic colorectal cancer, metastatic breast cancer

Pregnancy Risk Factor

Pregnancy Implications

There are no adequate and well-controlled studies using capecitabine in pregnant women; however, fetal harm may occur. Women of childbearing potential should avoid pregnancy.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

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

Warnings/Precautions

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution in patients with bone marrow suppression, poor nutritional status,

80 years of age, or renal or hepatic dysfunction. Use with caution in patients who have received extensive pelvic radiation or alkylating therapy. Use cautiously with warfarin; altered coagulation parameters and bleeding have been reported.

Capecitabine can cause severe diarrhea; median time to first occurrence is 31 days; subsequent doses should be reduced after grade 3 or 4 diarrhea

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 capecitabine.

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

Adverse Reactions

Frequency listed derived from monotherapy trials.

>10%:

Cardiovascular: Edema (9% to 15%)

Central nervous system: Fatigue (~40%), fever (12% to 18%), pain (colorectal cancer: 12%)

Dermatologic: Palmar-plantar erythrodysesthesia (hand-and-foot syndrome) (~55%, may be dose limiting), dermatitis (27% to 37%)

Gastrointestinal: Diarrhea (~55%, may be dose limiting), mild to moderate nausea (43% to 53%), vomiting (27% to 37%), stomatitis (~25%), decreased appetite (colorectal cancer: 26%), anorexia (23%), abdominal pain (20% to 35%), constipation (~15%)

Hematologic: Lymphopenia (94%), anemia (72% to 80%; Grade 3/4: <1% to 3%), neutropenia (13% to 26%; Grade 3/4: 1% to 2%), thrombocytopenia (24%; Grade 3/4: 1% to 3%)

Hepatic: Increased bilirubin (22% to 48%)

Neuromuscular & skeletal: Paresthesia (21%)

Ocular: Eye irritation (~15%)

Respiratory: Dyspnea (colorectal cancer: 14%)

5% to 10%:

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

Central nervous system: Headache (~10%), dizziness (~8%), insomnia (8%), mood alteration (colorectal cancer: 5%), depression (colorectal cancer: 5%)

Dermatologic: Nail disorders (7%), skin discoloration (colorectal cancer: 7%), alopecia (colorectal cancer: 6%)

Endocrine & metabolic: Dehydration (7%)

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

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

Respiratory: Cough (7%), sore throat (2%), epistaxis (3%)

Ocular: Abnormal vision (colorectal cancer: 5%)

Miscellaneous: Viral infection (colorectal cancer: 5%)

<5%: Abdominal distension, angina, appetite increased, arthritis, ascites, asthma, ataxia, atrial fibrillation, bronchitis, bone pain, bradycardia, bronchopneumonia, bronchospasm, cachexia, cardiac arrest, cardiac failure, cardiomyopathy, cerebral vascular accident, cholestasis, colitis, confusion, conjunctivitis, deep vein thrombosis, diaphoresis increased, duodenitis, dysarthria, dysphagia, dysrhythmia, ecchymoses, ECG changes, encephalopathy, esophagitis, fibrosis, fungal infection, gastric ulcer, gastritis, gastroenteritis, GI hemorrhage, hematemesis, hemoptysis, hepatitis, hepatic failure, hepatic fibrosis, hoarseness, hot flushes, hypokalemia, hypomagnesemia, hypotension, hypersensitivity, hypertension, 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, 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, toxic dilation of intestine, tachycardia, thirst, thrombophlebitis, tremor, weight gain, ventricular extrasystoles, vertigo

Overdosage/Toxicology

Symptoms of overdose include myelosuppression, nausea, vomiting, diarrhea, and alopecia. No specific antidote exists. Monitor hematologically for at least 4 weeks. Treatment is supportive.

Drug Interactions

Warfarin: Response to warfarin may be increased by capecitabine. Monitor INR closely.

Ethanol/Nutrition/Herb Interactions

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

Stability

Store tablets at room temperature of 25°C (77°F).

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%, 50% as -fluoro- -alanine)

Dosage

Oral:

Adults: 2500 mg/m² /day in 2 divided doses (~12 hours apart) at the end of a meal for 2 weeks followed by a 1- or 2-week rest period

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

Dosing adjustment in renal impairment:

Clcr 50-80 mL/minute: No adjustment of initial dose

Clcr 30-50 mL/minute: Reduce dose by 25%

Clcr<30 mL/minute: Do not use

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.

or

Recommended Dose Modifications

Toxicity NCI 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 0-1	100%
2nd appearance	Interrupt until resolved to grade 0-1	75%
3rd appearance	Interrupt until resolved to grade 0-1	50%
4th appearance	Discontinue treatment permanently
Grade 3
1st appearance	Interrupt until resolved to grade 0-1	75%
2nd appearance	Interrupt until resolved to grade 0-1	50%
3rd appearance	Discontinue treatment permanently
Grade 4
1st appearance	Discontinue permanently	50%
	or
	If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1

Administration

Capecitabine is administered orally, usually in two divided doses taken 12 hours apart. Doses should be taken after meals with water.

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 administer capecitabine within 30 minutes after a meal.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take with food or 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 will 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.

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

Oncology: Emetic Potential

Moderate

Oncology: Vesicant

Dosage Forms

Tablet: 150 mg, 500 mg

References

Budman DR, "Capecitabine," Invest New Drugs , 2000, 18(4):355-63.

Dooley M and Goa KL, "Capecitabine," Drugs , 199958(1):69-76.

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.

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

International Brand Names

Apecitab® (AR); Xeloda® (AR, AT, AU, BD, BE, BR, CA, CH, CL, CN, CO, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, ID, IE, IL, IN, IS, IT, KR, KW, LK, LT, LU, MA, MX, MY, NL, NO, NZ, PA, PE, PH, PL, PT, RO, RU, SE, SG, SI, SK, SV, TH, TW, UA, UY

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