No

Antineoplastic Agent, Antimetabolite

Treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (eg, patients who have received cumulative doses of 400 mg/m² of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

D

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.

Hypersensitivity to capecitabine, fluorouracil, or any component

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, or renal or hepatic dysfunction. The drug should be discontinued if intractable diarrhea, stomatitis, bone marrow suppression, or myocardial ischemia develop. Use with caution in patients who have received extensive pelvic radiation or alkylating therapy.

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 EKG changes. These adverse events may be more common in patients with a history of coronary artery disease.

>10%:

Central nervous system: Fatigue (41%), fever (12%)

Gastrointestinal: Diarrhea (57%), may be dose limiting; mild to moderate nausea (53%), vomiting (37%), stomatitis (24%), anorexia (23%), abdominal pain (20%), constipation (15%)

Dermatologic: Palmar-plantar erythrodysesthesia (hand-and-foot syndrome) (57%), may be dose limiting; dermatitis (37%)

Hematologic: Lymphopenia (94%), anemia (72%), neutropenia (26%), thrombocytopenia (24%)

Hepatic: Increased bilirubin (22%)

Neuromuscular & skeletal: Paresthesia (21%)

Ocular: Eye irritation (15%)

1% to 10%:

Central nervous system: Headache (9%), dizziness (8%), insomnia (8%)

Dermatologic: Nail disorders (7%)

Gastrointestinal: Intestinal obstruction (1.1%)

Endocrine & metabolic: Dehydration (7%)

Neuromuscular & skeletal: Myalgia (9%)

<1%: Chest pain, cardiomyopathy, hypotension, cerebral vascular accident, ataxia, encephalopathy, change in consciousness, confusion, photosensitization, radiation recall, alopecia, hypertriglyceridemia, necrotizing enterocolitis, gastritis, colitis, duodenitis, hematemesis, GI hemorrhage, esophagitis, cachexia, oral candidiasis, nocturia, thrombocytopenic purpura, pancytopenia, cholestasis, hepatitis, hepatic fibrosis, thrombophlebitis, deep vein thrombosis, bone pain, joint stiffness, dyspnea, epistaxis, bronchospasm, respiratory distress, pulmonary embolism, increased diaphoresis, infections, hypersensitivity, lymphedema

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

Increased effect: Taking capecitabine immediately before an aluminum hydroxide/magnesium hydroxide antacid, or a meal, increases the absorption of capecitabine. Phenytoin levels may be increased by capecitabine.

Increased toxicity: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. Warfarin: Altered coagulation parameters have been noted in cancer patients receiving coumarin derivatives concomitantly with capecitabine.

Tablets are stored at room temperature

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

Protein binding: <60% (35% to albumin)

Metabolism: Hepatic: Inactive metabolites: 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine; Tissues: Active metabolite: 5-fluorouracil

Half-life: Elimination: 0.5-1 hour

Elimination: Renal: 70%, 50% as a-fluoro-b-alanine

Oral:

Capecitabine dose calculation according to BSA table: The following can be used to determine the total daily dose (mg) based on a dosing level of 2500 mg/m²/day. (The number of tablets per dose, given morning and evening, are also listed):

Surface area less than or equal to 1.24 m²:

Total daily dose is 3000 mg (3 x 500 mg tablets per dose)

Surface area 1.25-1.36 m²:

Total daily dose is 3300 mg (1 x 150 mg tablet plus 3 x 500 mg tablets per dose)

Surface area 1.37-1.51 m²:

Total daily dose is 3600 mg (2 x 150 mg tablets plus 3 x 500 mg tablets per dose)

Surface area 1.52-1.64 m²:

Total daily dose is 4000 mg (4 x 500 mg tablets per dose)

Surface area 1.65-1.76 m²:

Total daily dose is 4300 mg (1 x 150 mg tablet plus 4 x 500 mg tablets per dose)

Surface area 1.77-1.91 m²:

Total daily dose is 4600 mg (2 x 150 mg tablets plus 4 x 500 mg tablets per dose)

Surface area 1.92-2.04 m²:

Total daily dose is 5000 mg (5 x 500 mg tablets per dose)

Surface area 2.05-2.17 m²:

Total daily dose is 5300 mg (1 x 150 mg tablets plus 5 x 500 mg tablets per dose)

Surface area greater than or equal to 2.18 m²:

Total daily dose is 5600 mg (2 x 150 mg tablets plus 5 x 500 mg tablets per dose)

Dosing adjustment in renal impairment: There is little experience in patients with renal impairment; use with caution. There is insufficient data to provide a dosage recommendation.

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

Dosing adjustment in elderly patients: The elderly may be pharmacodynamically more sensitive to the toxic effects of 5-fluorouracil. Use with caution in monitoring the effects of capecitabine. Insufficient data are available to provide dosage modifications.

Dosage modification guidelines: Carefully monitor patients for toxicity. Toxicity caused by capecitabine administration may be managed by symptomatic treatment, dose interruptions, and adjustment of dose. Once the dose has been reduced, it should not be increased at a later time.

Dosage reduction for toxicity: The starting dose may be reduced by 25% in patients experiencing significant adverse effects at the full starting dose if symptoms persist, a further reduction (to 50% of the starting dose) may be considered. These recommendations were based on clinical studies reported at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO).

Manufacturer-recommended dosage adjustments for various nonhematologic toxicities:

NCI Grade 1:

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

NCI Grade 2:

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

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

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

4th appearance: Discontinue treatment permanently

NCI Grade 3:

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

2nd appearance: Interrupt therapy until resolved to grade 0-1; administer 50% of initial dose for next cycle

3rd appearance: Discontinue treatment permanently

NCI Grade 4:

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

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

CBC with differential, hepatic function, renal function

Sedation is common; may cause dizziness or insomnia

Neutropenia is common; use caution with clozapine and carbamazepine

No information available to require special precautions

Relatively high incidence of stomatitis; oral candidiasis has been reported

Take with food or within 30 minutes after meal. Avoid use of antacids within 2 hours of taking capecitabine. Do not crush, chew, or dissolve tablets. You will need frequent blood tests while taking this medication. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). You may experience lethargy, dizziness, visual changes, confusion, anxiety (avoid driving or engaging in tasks requiring alertness until response to drug is known). For nausea, vomiting, loss of appetite, or dry mouth small, frequent meals, chewing gum, or sucking lozenges may help. You may experience loss of hair (will grow back when treatment is discontinued). You may experience photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). You may experience dry, itchy, skin, and dry or irritated eyes (avoid contact lenses). You will be more susceptible to infection; avoid crowds or infected persons. Report chills or fever, confusion, persistent or violent vomiting or stomach pain, persistent diarrhea, respiratory difficulty, chest pain or palpitations, unusual bleeding or bruising, bone pain, muscle spasms/tremors, or vision changes immediately. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication - both male and female should use appropriate barrier contraceptive measures. Do not give blood during this therapy or for 1 month following discontinuation of therapy. Do not breast-feed.

Tablet: 150 mg, 500 mg

Bajetta E, Carnaghi C, Somma L, et al, "A Pilot Safety Study of Capecitabine, A New Oral Fluoropyrimidine, in Patients With Advanced Neoplastic Disease," Tumori, 1996, 82(5):450-2.

Khoury P, Villalona-Calero M, Blum J, et al, "Phase I Study of Capecitabine in Combination With Paclitaxel in Patients With Previously Treated Metastatic Breast Cancer," Proc Am Soc Clin Oncol, 1998, 17:793 (abstract).

Pronk L, Vasey AP, Sparreboom A, et al, "A Matrix-Designed Phase I Dose-Finding and Pharmacokinetic Study of the Combination of Xeloda™ plus Taxotere™," Proc Am Soc Clin Oncol, 1998, 17:816 (abstract).

Rustum YM, Harstrick A, Cao S, et al, "Thymidylate Synthase Inhibitors in Cancer Therapy: Direct and Indirect Inhibitors," J Clin Oncol, 1997, 15(1):389-400. Much of the information included in this monograph is based on unpublished information provided by Roche Laboratories, Nutley, NJ.