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Therapeutic Classification: antineoplastics

Pharmacologic Classification: antimetabolites

• Adjuvant treatment of Stage III colon cancer (as monotherapy or in combination with other chemotherapy agents).
• Perioperative treatment of locally advanced rectal cancer (as component of chemoradiotherapy).
• Unresectable or metastatic colorectal cancer (as monotherapy or in combination with other chemotherapy agents).
• Advanced or metastatic breast cancer when an anthracycline- or taxane-containing chemotherapy is not indicated (as monotherapy).
• Advanced or metastatic breast cancer that has progressed despite prior therapy with an anthracycline-based chemotherapy regimen (in combination with docetaxel).
• Unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer (in combination with other chemotherapy agents).
• HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease (in combination with other agents).
• Adjuvant treatment of pancreatic adenocarcinoma (in combination with other chemotherapy agents).

• Converted in tissue to 5-fluorouracil, which inhibits DNA and RNA synthesis by preventing thymidine production.
• The enzyme responsible for the final step in the conversion to 5-fluorouracil may be found in higher concentrations in some tumors.

• Decreased spread of colorectal, breast, gastric, esophageal, gastroesophageal junction, and pancreatic cancer.

Absorption: Well absorbed after oral administration.

Distribution: Unknown.

Metabolism/Excretion: Metabolized mostly in tissue and by the liver to 5-fluorouracil; 5-fluorouracil is metabolized by dihydropyrimidine dehydrogenase to a less toxic compound; inactive metabolites are excreted primarily in urine.

Half-life: 45 min.

(plasma concentrations)

†Onset of antineoplastic effect is 6 wk.

†Peak 5-fluorouracil concentrations occur at 2 hr.

Contraindicated in:

• Hypersensitivity to capecitabine or 5-fluorouracil
• Severe renal impairment (CCr <30 mL/min)
• Complete dihydropyrimidine dehydrogenase deficiency (↑ risk of 5-fluorouracil toxicity)
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Partial dihydropyrimidine dehydrogenase deficiency
• Mild to moderate renal impairment (↓ initial dose for CCr 30–50 mL/min)
• Hepatic impairment
• Coronary artery disease
• Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety not established in children
• Geri: ↑risk of severe diarrhea in patients 80 yr.

CV: edema, arrhythmias, chest pain, HF, MYOCARDIAL ISCHEMIA/INFARCTION, SUDDEN CARDIAC DEATH.

Derm: dermatitis, hand-and-foot syndrome, nail disorder, alopecia, erythema, rash, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS.

EENT: eye irritation, epistaxis, rhinorrhea.

F and E: dehydration.

GI: abdominal pain, anorexia, constipation, diarrhea, hyperbilirubinemia, ↑liver enzymes, nausea, stomatitis, vomiting, dyspepsia, NECROTIZING ENTEROCOLITIS, xerostomia.

GU: acute renal failure, ↓ fertility.

Hemat: anemia, neutropenia, thrombocytopenia.

MS: arthralgia, myalgia.

Neuro: dysgeusia, fatigue, headache, dizziness, insomnia, peripheral neuropathy.

Resp: cough, dyspnea.
Misc: fever.

Drug-Drug:

• May ↑ risk of bleeding with warfarin; monitor INR frequently.
• Toxicity ↑ by concurrent leucovorin.
• Antacids may ↑ absorption.
• May ↑ levels and risk of toxicity from phenytoin (may need to ↓ phenytoin dose).
• ↑incidence of acute renal failure with other nephrotoxic drugs.
• Allopurinol may ↓ levels of capecitabine's active metabolite and its overall effectiveness; avoid concurrent use

Drug-Food:

• Food ↑ absorption, although capecitabine should be given within 30 min after a meal.

Colorectal Cancer

• PO (Adults): Monotherapy: 1250 mg/m² twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles. In combination with oxaliplatin: 1000 mg/m² twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles.

Advanced or Metastatic Breast Cancer

• PO (Adults): Monotherapy or in combination with docetaxel: 1000 mg/m² or 1250 mg/m² twice daily for the first 14 days of each 21-day cycle; continue until disease progression or unacceptable toxicity.

Gastric, Esophageal, or Gastroesophageal Junction Cancer

• PO (Adults): 625 mg/m² twice daily on Days 1–21 of each 21-day cycle for a maximum of 8 cycles (in combination with platinum-containing chemotherapy) OR 850 mg/m² or 1000 mg/m² twice daily for the first 14 days of each 21-day cycle (in combination with oxaliplatin); continue until disease progression or unacceptable toxicity.

Pancreatic Cancer

• PO (Adults): In combination with gemcitabine: 830 mg/m² twice daily for the first 21 days of each 28-day cycle; continue until disease progression, unacceptable toxicity, or a maximum of 6 cycles.

(Generic available)

• Tablets: 150 mg; 500 mg;

• Assess for signs of infection (fever, chills, sore throat, cough, hoarseness, pain in lower back or side, difficult or painful urination). Assess for bleeding (bleeding gums; bruising; petechiae; and guaiac-test stools, urine, and emesis). Avoid IM injections and taking rectal temperatures. Apply pressure to venipuncture sites for 10 min. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
• Assess mucous membranes, number and consistency of stools, and frequency of vomiting. Notify health care professional if symptoms of toxicity (stomatitis, uncontrollable vomiting, diarrhea, fever) occur; drug may need to be discontinued or dose decreased. Patients with severe diarrhea should be monitored carefully, administered antidiarrheal agents (loperamide) and given fluid and electrolyte replacements if they become dehydrated. Grade 2 diarrhea (4–6 stools/day or nocturnal stools), Grade 3 (7–9 stools/day or incontinence and malabsorption), Grade 4 (10 stools/day or grossly bloody diarrhea or need for parenteral support). If grade 2, 3, or 4 diarrhea occurs, immediately stop therapy until diarrhea resolves or decreases in intensity to Grade 1. Grade 3 or 4 diarrhea usually lasts 5 days.
• Assess patient for mucocutaneous and dermatologic toxicity (Stevens-Johnson syndrome, toxic epidermal necrolysis, hand-and-foot syndrome). Grade 1 (numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of hands and/or feet, and/or discomfort that does not disrupt normal activities). Grade 2 (painful erythema, swelling of hands and/or feet, and/or discomfort affecting the patient’s activities of daily living). Grade 3 (moist desquamation, ulceration, blistering or severe pain of hands and/or feet, and/or severe discomfort causing patient to be unable to work or perform activities of daily living). Persistent or severe hand-and-foot syndrome of Grade 2 and above can lead to loss of fingerprints, affecting patient identification. If Grade 2 or 3 occurs, interrupt therapy until Grade 1. Decrease doses following Grade 3.

• Verify negative pregnancy test before starting therapy.Consider testing for genetic variants of dihydropyrimidine dehydrogenase deficiency prior to initiating therapy to reduce risk of serious adverse reactions. Serious adverse reactions may still occur even if no dihydropyrimidine dehydrogenase deficiency variants are identified. An FDA-authorized test for the detection of genetic variants of dihydropyrimidine dehydrogenase deficiency to identify patients at risk of serious adverse reactions due to increased systemic exposure to capecitabine is not currently available. Currently available tests used to identify dihydropyrimidine dehydrogenase deficiency variants may vary in accuracy and design.Monitor CBC at baseline and before each cycle. If baseline neutrophil count <1.5 x 10⁹ /L or platelet count <100 x 10⁹ /L, therapy is not recommended. For grade 3 to 4 myelosuppression, hold dose and then resume at same or reduced dose, or permanently discontinue, based on occurrence.Monitor hepatic (serum alkaline phosphatase, AST, ALT, and bilirubin), and renal function before and periodically during therapy. May cause leukopenia, anemia, and thrombocytopenia. Leukopenia may require discontinuation of therapy. Therapy should be interrupted if serum bilirubin ↑ to 1.5 times normal or greater; may be reinstituted after bilirubin returns to normal.
  • Monitor INR frequently in patients receiving warfarin and capecitabine to adjust warfarin dose. May cause ↑ bleeding within a few days to several mo of initiation of therapy to 1 mo following discontinuation of therapy. Risk is greater in patients over 60 yr.

• High Alert:Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order and dose calculations.
• Dose modifications are based on degree of toxicity encountered. If Grade 2 adverse reaction occurs, hold dose until resolved to Grade 0–1. If adverse reaction recurs, decrease dose by 75%. If Grade 2 reaction occurs a 3rd time, decrease dose by 50%. If reaction occurs a 4th time, discontinue capecitabine permanently. If Grade 3 adverse reaction occurs, hold dose until resolved to grade 0–1 and decrease dose by 75%. If Grade 3 reaction recurs, decrease dose to 50%. If Grade 3 reaction occurs a 3rd time, permanently discontinue capecitabine. If Grade 4 adverse reaction occurs, permanently discontinue or hold dose until resolved to grade 0–1, then decrease dose by 50%. Once a dose has been reduced because of toxicity, do not be increase at a later time.
• PO: Administer every 12 hr for 2 wk, followed by a 1-wk rest period. Take tablets with water within 30 min after a meal.DNC: Swallow tablets whole; do not crush or cut. Capecitabine is a hazardous drug. Exposure to crushed tablets may cause eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting and nausea. Advise patients not to cut or crush tablets. If tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures.

• Instruct patient to take medication every 12 hr with water within 30 min after a meal. Missed doses should be omitted; continue regular schedule. If vomiting occurs, omit dose. Do not double dose. Advise patient to read Patient Information before starting and with each Rx refill in case of changes.
• Inform patient of the most common side effects. Instruct patient to notify health care provider immediately if any of the following occur: diarrhea (>4 bowel movements in a day or any diarrhea at night), vomiting (more than once in 24 hr), nausea (loss of appetite and significant decrease in daily food intake), stomatitis (pain, redness, swelling, or sore in mouth), hand-and-foot syndrome (pain, swelling, or redness of hands and/or feet), skin reactions (rash, blisters, peeling of skin), fever, or infection (temperature of 100.5° F or other signs of infection).
• Instruct patient to notify health care professional if fever; chills; sore throat; signs of infection; yellowing of skin or eyes; abdominal pain; joint or flank pain; swelling of feet or legs; bleeding gums; bruising; petechiae; or blood in urine, stool, or emesis occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor. Patients should be cautioned not to drink alcoholic beverages or take products containing aspirin or NSAIDs.
  • Advise patient to rinse mouth with clear water after eating and drinking and to avoid flossing to minimize stomatitis. Viscous lidocaine may be used if mouth pain interferes with eating. Stomatitis pain may require treatment with opioid analgesics.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Advise females of reproductive potential to use effective contraception during and for at least 6 mo after last dose. Advise males with female partners of reproductive potential to use effective contraception for at least 3 mo after last dose. Avoid breastfeeding during and for 1 wk after last dose. May impair fertility of female and male patients of reproductive potential.
  • Emphasize the importance of routine follow-up lab tests to monitor progress and to check for side effects.

• Decreased spread of colorectal, breast, gastric, esophageal, gastroesophageal junction, and pancreatic cancer.

Xeloda