Warfarin Interaction — Coagulopathy

• Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.
• A clinically important XELODA-warfarin drug interaction was demonstrated in a clinical pharmacology trial.
• Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.
• Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR have been observed in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy, and in some cases within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases.
• Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Dihydropyrimidine Dehydrogenase (DPD) Deficiency

• XELODA is contraindicated in patients with known DPD deficiency. Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of DPD activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.

Renal insufficiency

• XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]).
• Patients with moderate renal impairment at baseline require dose reduction. Patients with mild or moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in the Dosage and Administration section of the XELODA prescribing information.

Warnings and Precautions

Diarrhea

• XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated.
• If grade 2, 3, or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased. Standard antidiarrheal treatments are recommended.
• Necrotizing enterocolitis (typhlitis) has been reported.

Cardiotoxicity

• The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

Pregnancy Category D

• XELODA may cause fetal harm when given to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with XELODA. Because of the potential for serious adverse reactions in nursing infants from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Hand-and-Foot Syndrome

• Hand-and-Foot-Syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity.
• Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA monotherapy in the metastatic setting.
• If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased.

Hyperbilirubinemia

• If drug-related grade 3 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 x ULN.

Hematologic

• Patients with baseline neutrophil counts <1.5 x 10⁹/L and/or thrombocyte counts <100 x 10⁹/L should not be treated with XELODA. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with XELODA should be interrupted.

Geriatric Patients

• Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse events.

Hepatic Insufficiency

• Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known.

Drug Interactions

• Use of XELODA in combination with irinotecan has not been adequately studied.
• The level of phenytoin should be carefully monitored in patients taking XELODA and the dose of phenytoin may need to be reduced. Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels.
• 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.
• Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates.
• Food was shown to reduce both the rate of and extent of absorption of capecitabine.