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Xeloda (Capecitabine) - Warnings and Precautions

 
 



WARNING

XELODA Warfarin Interaction: 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 (see CLINICAL PHARMACOLOGY and PRECAUTIONS). 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 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 a few 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.

 

WARNINGS

Renal Insufficiency

Patients with moderate renal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION). Patients with mild and 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 Table 18 in DOSAGE AND ADMINISTRATION.

Coagulopathy

See Boxed WARNING.

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. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. 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 (see DOSAGE AND ADMINISTRATION). Standard antidiarrheal treatments (eg, loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

Geriatric Patients

Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use). In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 62% of the 21 patients ≥80 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

Among the 67 patients ≥60 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.

In 995 patients receiving XELODA as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for XELODA compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively.

PREGNANCY

XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. 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 of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

PRECAUTIONS

General

Patients receiving therapy with XELODA should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see DOSAGE AND ADMINISTRATION).

Combination With Other Drugs

Use of XELODA in combination with irinotecan has not been adequately studied.

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. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. 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 (see DOSAGE AND ADMINISTRATION).

Cardiotoxicity

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

Dihydropyrimidine Dehydrogenase Deficiency

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

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 (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 × ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.

In the 596 patients treated with XELODA as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of XELODA monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with XELODA. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel, grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 2% (n=5).

If drug-related grade 2 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. NCIC grade 2 hyperbilirubinemia is defined as 1.5 × normal, grade 3 hyperbilirubinemia as 1.5 to 3 × normal and grade 4 hyperbilirubinemia as >3 × normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.)

Hematologic

In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of XELODA in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Adequate studies investigating the carcinogenic potential of XELODA have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

Impairment of Fertility

In studies of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

Information for Patients (see Patient Package Insert)

Patients and patients' caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see DOSAGE AND ADMINISTRATION). Patients should be encouraged to recognize the common grade 2 toxicities associated with XELODA treatment.

Diarrhea

Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking XELODA immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.

Nausea

Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.

Vomiting

Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.

Hand-and-Foot Syndrome

Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking XELODA immediately.

Stomatitis

Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended (see DOSAGE AND ADMINISTRATION).

Fever and Neutropenia

Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician.

Drug-Food Interaction

In all clinical trials, patients were instructed to administer XELODA within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that XELODA be administered with food (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

Antacid

The effect of an aluminum hydroxide- and magnesium hydroxide-containing antacid (Maalox) on the pharmacokinetics of XELODA was investigated in 12 cancer patients. There was a small increase in plasma concentrations of XELODA and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL).

Anticoagulants

Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly (see Boxed WARNING and CLINICAL PHARMACOLOGY). Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites (see CLINICAL PHARMACOLOGY).

CYP2C9 substrates

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.

Phenytoin

The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced (see DOSAGE AND ADMINISTRATION: Dose Management Guidelines). Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites (see PRECAUTIONS: Drug-Drug Interactions: Anticoagulants).

Leucovorin

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.

Pregnancy

Teratogenic Effects

Category D (see WARNINGS). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

Nursing Women

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommended that nursing be discontinued when receiving XELODA therapy.

Pediatric Use

The safety and effectiveness of XELODA in persons <18 years of age have not been established.

Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see WARNINGS: Geriatric Patients).

Page last updated: 2006-06-12

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