Capecitabine

Trade Names:Xeloda- Tablets 150 mg- Tablets 500 mg

Pharmacology

Capecitabine is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by 2 different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

Pharmacokinetics

Absorption

T _max is approximately 1.5 h for capecitabine and 2 h for 5-FU. Food decreased C _max 60% and AUC 35% for capecitabine and decreased C _max 4.3% and AUC 21% for 5-FU. Food delayed T _max 1.5 h.

Distribution

Less than 60% protein bound (approximately 35% bound to albumin).

Metabolism

Enzymatically metabolized to 5-FU (active) in tissues; also metabolized to inactive metabolites in the liver.

Elimination

The t _½ is approximately 0.75 h (for capecitabine and 5-FU). Approximately 95.5% is excreted in urine (57% of the dose as inactive metabolite and 3% of the dose as unchanged drug); 2.6% is excreted in feces.

Special Populations

In moderate to severe renal function impairment, there is increased exposure to inactive metabolites and a 25% increase in exposure to capecitabine.

Capecitabine AUC and C _max increased 60%; 5-FU was not affected.

Indications and Usage

Treatment of resistant metastatic breast cancer alone or in combination with docetaxel; colorectal cancer.

Unlabeled Uses

Adjuvant treatment of pancreatic cancer.

Contraindications

Hypersensitivity to 5-FU; severe renal function impairment (Ccr below 30 mL/min); dihydropyrimidine dehydrogenase deficiency (DPD).

Dosage and Administration

PO 2,500 mg/m ² /day in 2 divided doses, approximately 12 h apart, for 2 wk. After a 1-wk rest period, this 3-wk cycle is repeated. Round to the nearest dose that gives a whole tablet size rather than cutting tablets in half. Dosing adjustments are needed for toxicities. Once the capecitabine dose is reduced, it should not be increased. See manufacturer's recommendations.

For moderate renal function impairment (30 to 50 mL/min), a dose reduction to 75% of the starting dose is recommended.

General Advice

Administer each dose with water within 30 min after a meal.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

May increase capecitabine levels.

May increase serum concentrations of fluorouracil and potentially increase toxicity.

Drug interactions have been reported with fluorouracil, the principal active metabolite of capecitabine.

May enhance GI toxicity of fluorouracil.

Risk of hepatotoxicity may be increased by coadministration with fluorouracil.

Levels may be elevated by capecitabine, increasing the risk of adverse reactions.

May alter warfarin's effects, increasing the risk of bleeding.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Venous thrombosis (8%).

CNS

Paresthesia (21%); headache, peripheral sensory neuropathy (10%); dizziness (8%); insomnia (7%); taste disturbances (6%); depression, mood alteration (5%).

Dermatologic

Hand-and-foot syndrome (54%); dermatitis (27%); nail disorder, skin discoloration (7%); alopecia (6%).

EENT

Eye irritation (15%); abnormal vision, pharyngeal disorder (5%); sore throat (2%); laryngitis (1%).

GI

Diarrhea (55%); nausea (43%); abdominal pain (35%); vomiting (27%); decreased appetite (26%); stomatitis (25%); constipation (14%); GI motility disorder, oral discomfort (10%); dyspepsia, upper GI inflammatory disorders (8%); GI hemorrhage, ileus (6%).

Hematologic

Lymphopenia (94%); anemia (80%); thrombocytopenia (24%); neutropenia (26%); idiopathic thrombocytopenia purpura (1%).

Hepatic

Hyperbilirubinemia (48%); hepatic failure (postmarketing).

Lab Tests

Increased bilirubin (20%); increased lymphocytes (13%); decreased calcium, decreased neutrophils, decreased neutrophils/granulocytes, increased ALT (2%); decreased Hgb, increased calcium (1%); decreased platelets (1%).

Metabolic

Dehydration (7%).

Respiratory

Dyspnea (14%); cough (7%); epistaxis (3%).

Miscellaneous

Fatigue/weakness (42%); pyrexia (18%); edema (15%); pain (12%); back pain (10%); myalgia (9%); arthralgia (8%); chest pain, pain in limb (6%); viral infections (5%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Patients 80 yr of age and older may experience a greater incidence of grade 3 or 4 adverse reactions.

Renal Function

Patients with moderate renal function impairment at baseline require dosage modification. Carefully monitor patients with mild or moderate renal function impairment for adverse reactions.

Hepatic Function

Carefully monitor patients with mild to moderate hepatic function impairment caused by liver metastases.

Cardiac effects

Cardiotoxicity has been associated with fluorinated pyrimidine therapy.

Contraception

Ensure women of childbearing potential use effective contraception before initiating therapy and for duration of treatment.

Diarrhea

Capecitabine can induce diarrhea, sometimes severe. If grade 2, 3, or 4 diarrhea occurs, immediately interrupt administration until the diarrhea resolves or decreases in intensity to grade 1. Following grade 3 or 4 diarrhea, decrease subsequent doses of capecitabine. Monitor patient for development of diarrhea. Consider use of antidiarrheal therapy (eg, loperamide) and be prepared to administer fluid and electrolyte replacement if severe.

DPD

Rarely, unexpected, severe toxicity (eg, diarrhea, neurotoxicity, neutropenia, stomatitis) associated with 5-FU has been attributed to a deficiency of DPD activity.

Hand-and-foot syndrome

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. Monitor patient for development of hand-and-foot syndrome (eg, discomfort of the hands and feet, numbness, redness, swelling), nausea, stomatitis, and vomiting. Inform health care provider if noted.

Hematologic

Grade 3 or 4 neutropenia, thrombocytopenia, or decreases in Hgb occur more frequently when capecitabine is used in combination with docetaxel.

Hyperbilirubinemia

If grade 2 to 4 elevations in bilirubin occur, immediately interrupt administration until the hyperbilirubinemia resolves or decreases in intensity to grade 1.

Overdosage

Symptoms

Bone marrow depression, diarrhea, GI irritation and bleeding, nausea, vomiting.

Patient Information

• Advise patient or caregiver to review patient information leaflet before starting therapy and with each refill.
• Review the following cyclic dosing schedule with patient or caregiver: twice daily for 2 wk, rest for 1 wk, then repeat cycle.
• Advise patient to take prescribed dose in the morning and evening with a glass of water and within 30 min after a meal.
• Advise patient or caregiver that if a dose is missed not to take the missed dose and not to double the next dose. Take the next dose at the regularly scheduled time.
• If patient is using a combination of different tablet strengths, ensure patient or caregiver can correctly identify the correct dose.
• Advise patient that medication may be used in combination with other chemotherapy agents to achieve max benefit possible.
• Advise patient to discontinue therapy and notify health care provider if any of the following occur: diarrhea with 4 to 6 stools/day or diarrhea at night, nausea or sores in the mouth that interfere with eating, vomiting 2 to 5 times within 24 h, redness, swelling, and pain of the hands or feet.
• Advise patient or caregiver that OTC antidiarrheals (eg, loperamide) can be used to treat mild diarrhea.
• Advise patient to report fever, chills, or other signs of an infection to health care provider immediately.
• Caution women of childbearing potential to avoid becoming pregnant while being treated.

Copyright © 2009 Wolters Kluwer Health.