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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Cardiotoxicity: May be more common in patients with a prior history of coronary artery disease. Withhold capecitabine for cardiotoxicity as appropriate. The safety of resumption of capecitabine in patients with cardiotoxicity that has resolved has not been established. (2.5, 5.3) • Diarrhea : Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.4) • Dehydration : Optimize hydration before starting capecitabine. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine and then resume at same or reduced dose or permanently discontinue, based on severity and occurrence. (2.5, 5.5) • Renal Toxicity : Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine. Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.6) • Serious Skin Toxicities : Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine in patients who experience a severe cutaneous adverse reaction. (5.7) • Palmar-Plantar Erythrodysesthesia Syndrome : Withhold capecitabine then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. (2.5, 5.8) • Myelosuppression : Monitor complete blood count at baseline and before each cycle. Capecitabine is not recommended in patients with baseline neutrophil counts <1.5 x 10 9 /L or platelet counts <100 x 10 9 /L. For grade 3 or 4 myelosuppression, withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on occurrence. (2.5, 5.9) • Hyperbilirubinemia : Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (<3 x ULN), using the percent of current dose as shown in column 3 of Table 1 (2.5, 5.10) • Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.11, 8.1, 8.3) 5.1 Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase(DPD) Deficiency Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to capecitabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, or fatal, adverse reactions. Prior to initiating capecitabine, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD variants are identified. Avoid use of capecitabine in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Withhold or permanently discontinue capecitabine based on clinical assessment of the onset, duration, and severity of adverse reactions in patients with evidence of acute early-onset or unusually severe reactions. No capecitabine dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment. An FDA-authorized test for the detection of genetic variants of the DPYD gene to identify patients at risk of serious adverse reactions with capecitabine treatment is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify). 5.2 Increased Risk of Bleeding With Concomitant Use of Vitamin K Antagonists Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with vitamin K antagonists, such as warfarin. Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin K antagonists at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate [ see Drug Interactions (7.1)]. 5.3 Cardiotoxicity Cardiotoxicity can occur with capecitabine. Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported with capecitabine. These adverse reactions may be more common in patients with a prior history of coronary artery disease. Withhold capecitabine for cardiotoxicity as appropriate [ see Dosage and Administration (2.5)]. The safety of resumption of capecitabine in patients with cardiotoxicity that has resolved have not been established. 5.4 Diarrhea Diarrhea, sometimes severe, can occur with capecitabine. In 875 patients with metastatic breast or colorectal cancer who received capecitabine as a single agent, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range: 1 day to 1 year). The median duration of grade 3 to 4 diarrhea was 5 days. Withhold capecitabine and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)]. 5.5 Dehydration Dehydration can occur with capecitabine. Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be at an increased risk of developing dehydration with capecitabine. Optimize hydration before starting capecitabine. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)]. 5.6 Renal Toxicity Serious renal failure, sometimes fatal, can occur with capecitabine. Renal impairment or coadministration of capecitabine with other products known to cause renal toxicity may increase the risk of renal toxicity [see Drug Interactions (7.3)]. Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine. Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)]. 5.7 Serious Skin Toxicities Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN), which can be fatal, can occur with capecitabine [ see Adverse Reactions (6.2) ]. Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine for severe cutaneous adverse reactions. 5.8 Palmar-Plantar Erythrodysesthesia Syndrome Palmar-plantar erythrodysesthesia syndrome (PPES) can occur with capecitabine. In patients with metastatic breast or colorectal cancer who received capecitabine as a single agent, the median time to onset of grades 1 to 3 PPES was 2.6 months (range: 11 days to 1 year). Withhold capecitabine and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)]. 5.9 Myelosuppression Myelosuppression can occur with capecitabine. In the 875 patients with metastatic breast or colorectal cancer who received capecitabine as a single agent, 3.2% had grade 3 or 4 neutropenia, 1.7% had grade 3 or 4 thrombocytopenia, and 2.4% had grade 3 or 4 anemia. In the 251 patients with metastatic breast cancer who received capecitabine with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 10% had grade 3 or 4 anemia. Necrotizing enterocolitis (typhlitis) has been reported. Consider typhlitis in patients with fever, neutropenia and abdominal pain. Monitor complete blood count at baseline and before each cycle. Capecitabine is not recommended if baseline neutrophil count <1.5 x 10 9 /L or platelet count <100 x 10 9 /L. For grade 3 to 4 myelosuppression, withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on occurrence [ see Dosage and Administration (2.5) ]. 5.10 Hyperbilirubinemia Hyperbilirubinemia can occur with capecitabine. In the 875 patients with metastatic breast or colorectal cancer who received capecitabine as a single agent, grade 3 hyperbilirubinemia occurred in 15% of patients and grade 4 hyperbilirubinemia occurred in 3.9%. Of the 566 patients who had hepatic metastases at baseline and the 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 23% and 12%, respectively. Of these 167 patients with grade 3 or 4 hyperbilirubinemia, 19% had postbaseline increased alkaline phosphatase and 28% had postbaseline increased transaminases at any time (not necessarily concurrent). The majority of these patients with increased transaminases or alkaline phosphatase had liver metastases at baseline. In addition, 58% and 35% of the 167 patients with grade 3 or 4 hyperbilirubinemia had pre- and postbaseline increased alkaline phosphatase or transaminases (grades 1 to 4), respectively. Only 8% (n=13) and 3% (n=5) had grade 3 or 4 increased alkaline phosphatase or transaminases. In the 596 patients who received capecitabine for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to that observed for the pooled population of patients with metastatic breast and colorectal cancer. The median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with capecitabine. Of the 136 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 the 251 patients with metastatic breast cancer who received capecitabine with docetaxel, grade 3 hyperbilirubinemia occurred in 7% and grade 4 hyperbilirubinemia occurred in 2%. Withhold capecitabine and then resume at a same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)]. Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less than three times the upper limit of normal, using the percent of current dose as shown in Table 1 [see Dosage and Administration (2.5)]. 5.11 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and its mechanism of action, capecitabine can cause fetal harm when administered to a pregnant woman. Insufficient data is available on capecitabine use in pregnant women to evaluate a drug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the human exposure (AUC) in patients who received a dosage of 1,250 mg/m 2 twice daily, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with capecitabine and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine and for 3 months following the last dose [ see Use in Specific Populations (8.1, 8.3) ]. 5.12 Eye Irritation, Skin Rash, and Other Adverse Reactions from Exposure to Crushed Tablets In instances of exposure to crushed capecitabine tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting and nausea. Advise patients not to cut or crush tablets. If capecitabine 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 [see Dosage and Administration (2.7) ]. The safety and effectiveness have not been established for the administration of crushed capecitabine tablets.