Celabin Special Precautions

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 Capecitabine- Warfarin drug interaction was demonstrated in a clinical pharmacology trial. Altered coagulation parameters and/ or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinical significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. 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.
General: Patients receiving therapy with capecitabine should be monitored by a physician experienced in the use of cancer chemotherapeutic agents.
Dose-limiting toxicities include diarrhea, abdominal pain, nausea, stomatitis, and hand-and-foot syndrome. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
Diarrhea: Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. The median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days) following initiation of capecitabine therapy for metastatic breast or colorectal cancer and the median duration of grade 3 to 4 diarrhea was 5 days.
If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a recurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased. Standard antidiarrheal treatments (e.g., loperamide) should be initiated, as medically appropriate, as early as possible. Dose reduction should be applied as necessary (see Dosage & Administration).
Necrotizing enterocolitis (typhlitis) has been reported.
Dehydration: Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Dehydration may also cause acute renal failure which can be fatal. They should be prevented or corrected at the onset. Capecitabine tablets should be immediately interrupted and the dehydration corrected if Grade 2 (or higher) dehydration occurs. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary (see Dosage & Administration).
Mucocutaneous and Dermatologic Toxicity: Severe adverse drug reactions that may be fatal such as Stevens-Johnsons syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine. If patients experience these severe reactions possibly attributable to treatment with capecitabine, then the drug should be permanently discontinued.
Hand-and-foot syndrome, also called palmar-plantar erythrodysesthesia, is a cutaneous toxicity that is a side effect of some types of chemotherapy. 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 capecitabine monotherapy in the metastatic setting.
When patients experience grade 2 or grade 3 hand-foot syndrome, capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Subsequent doses of capecitabine should be decreased following grade 3 handfoot syndrome. If capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot syndrome because of published reports that it may decrease the efficacy of cisplatin.
Cardiotoxicity: Myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation) has been associated with fluoropyrimidine therapy and these adverse reactions may be increased in patients with a prior history of coronary artery disease. Patients should be monitored carefully during capecitabine therapy.
Dihydropyrimidine Dehydrogenase Deficiency: Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia, and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-FU therefore cannot be excluded.
Hyperbilirubinemia: Grade 3 to 4 hyperbilirubinemia has been reported in patients receiving capecitabine. If drug-related grade 2 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3 x upper limit of normal (ULN). Following grade 3 or 4 hyperbilirubinemia, subsequent doses of capecitabine should be decreased (see Dosage & Administration)
Hematologic Effects: In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m² administered two times a day as monotherapy for 14 days followed by a 7-day rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively.
Capecitabine should not be taken by patients with baseline neutrophil counts of <1.5 x 10⁹/L and/or thrombocyte counts of <100 x 10⁹/L.
Nausea and Vomiting: Patients experiencing ≥ grade 2 nausea or vomiting should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.
Special Populations: Exercise caution in patients with the following conditions: Pre-existing hypo- or hypercalcemia, as capecitabine may cause hypo- or hypercalcemia;
Central or peripheral nervous system disease (e.g., brain metastasis or neuropathy);
Diabetes mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment.
Carcinogenicity, Mutagenicity, Impairment of Fertility: Adequate studies investigating the carcinogenic potential of capecitabine 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 mutations in bacteria but was not clastogenic in vivo to mouse bone marrow (micronucleus test). 5-FU causes mutations in bacteria and yeast. 5-FU also causes chromosomal abnormalities in the mouse micronucleus test in vivo.
In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m²/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.
Hepatic impairment: Though there are no data on the safety and efficacy of capecitabine in patients with severe hepatic impairment, patients taking capecitabine with mild to moderate liver dysfunction regardless of the presence or absence of liver metastasis should be carefully monitored. Treatment with capecitabine should be interrupted if there is a treatment-related elevations in bilirubin (>3.0 x ULN) or aminotransferases (ALT, AST; >2.5 x ULN). Treatment may resume when bilirubin decreases to <3.0 x ULN or hepatic aminotransferases decrease to <2.5 x ULN.
Renal Impairment: There is an increase in adverse reactions in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) compared to the overall population. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions while those with moderate renal impairment at baseline require dose reduction. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2-4 adverse event.
Ophthalmologic complications: Patients, especially those with prior history of eye disorders, should be carefully monitored for opthalmological complications such as corneal disorders and keratitis.
Excipient: Anhydrous lactose is an excipient of this product. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on Ability to Drive or Use Machines: Though it may cause dizziness, fatigue and nausea, capecitabine has minor or moderate influence on the ability to drive and use machines.
Women of childbearing potential: Women should be advised to avoid becoming pregnant while receiving capecitabine. If in case the patient got pregnant, the potential hazard to the fetus must be explained.
Use in Pregnancy: Pregnancy Category D: There are no data on the safety of capecitabine in pregnant women; however, in animal studies, it caused embryolethality and teratogenicity that are expected effects of fluoropyrimidine derivatives. Thus, pregnancy should be avoided while receiving treatment with capecitabine.
Use in Lactation: In an animal study, capecitabine and its metabolites were found in the milk of lactating mice. In human breast milk, however, it is unknown. Hence, breastfeeding should be discontinued while receiving treatment with capecitabine.
Use in Children (<18 years old): There is no data on the use of capecitabine in children; safety and efficacy in pediatric patients have not been established.
Use in Elderly (>80 years old):Geriatric patients may experience increased frequency and severity of the toxic effects of capecitabine and its metabolites. Patients aged >80 years old that are being treated for metastatic breast cancer or metastatic colorectal cancer experience a greater incidence of grade 3 or 4 adverse effect, in particular, GI effects or severe hand-foot syndrome. Physicians should exercise caution in monitoring the effects of capecitabine in the elderly. Insufficient data are available to recommend dose adjustment of capecitabine in geriatric patients.