Capecitabine is a nucleoside metabolic inhibitor indicated for: Colorectal Cancer ● adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 ) ● perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy.( 1.1 ) ● treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen.
( 1.1 ) Breast Cancer ● treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. ( 1.2 ) ● treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. ( 1.2 ) Gastric, Esophageal, or Gastroesophageal Junction Cancer ● treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen.
( 1.3 ) ● treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. ( 1.3 ) Pancreatic Cancer ● adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. ( 1.4 )
1.1Colorectal Cancer
Capecitabine tablets, USP are indicated for the: ● adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. ● perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. ● treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen.
1.2Breast Cancer
Capecitabine tablets USP are indicated for the: ● treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. ● treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy.
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1.3Gastric, Esophageal, or Gastroesophageal Junction Cancer
Capecitabine tablets USP are indicated for the: ● treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. ● treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen.
1.4Pancreatic Cancer
Capecitabine tablets USP are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.
Contraindications
Capecitabine is contraindicated in patients with history of severe hypersensitivity reaction to fluorouracil or capecitabine [see Adverse Reactions ( 6.1 )] . History of severe hypersensitivity reactions to fluorouracil or capecitabine ( 4 )
Warnings and precautions
● Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency: Patients with certain homozygous or compound heterozygous variants in the DPYD gene 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). Capecitabine is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity.
Withhold or permanently discontinue based on clinical assessment. No capecitabine dose has been proven safe in patients with complete absence of DPD activity. ( 5.2 ) ● 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 109/L or platelet counts <100 x 109/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 to 4 hyperbilirubinemia may resume treatment once the event isGrade 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 )
5.1Increased 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 )].
5.2Serious Adverse Reactions 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, including fatal, adverse reactions.
Capecitabine is not recommended for use in patients known to have 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 the observed adverse reactions in patients with evidence of acute early- onset or unusually severe reactions, which may indicate complete DPD deficiency.
No capecitabine dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency. Consider testing for genetic variants of DPYD prior to initiating capecitabine to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement [see Clinical Pharmacology( 12.5 )] .
Serious adverse reactions may still occur even if no DPYD variants are identified. An FDA-authorized test for the detection of genetic variants of DPYD 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 DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).
5.3Cardiotoxicity
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.
5.4Diarrhea
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)].
5.5Dehydration
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)].
5.6Renal 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 )].
5.7Serious Skin Toxicities
Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine [see Adverse Reactions (6.2) ] . Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine for severe cutaneous adverse reactions. .
5.8Palmar-Plantar Erythrodysesthesia Syndrome
Palmar-plantar erythrodysesthesia
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Interactions
● Allopurinol: Avoid concomitant use of allopurinol with capecitabine. ( 7.1 ) ● Leucovorin: Closely monitor for toxicities when capecitabine is coadministered with leucovorin. ( 7.1 ) ● CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine. ( 7.2 ) ● Vitamin K antagonists: Monitor INR more frequently and dose adjust oral vitamin K antagonist as appropriate ● Phenytoin: Closely monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin and adjust the phenytoin dose as appropriate.
( 7.2 ) ● Nephrotoxic drugs: Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs. ( 7.3 )
7.1Effect of Other Drugs on Capecitabine Allopurinol
Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see Clinical Pharmacology ( 12.3 )], which may decrease efficacy. Avoid concomitant use of allopurinol with capecitabine. Leucovorin The concentration of fluorouracil is increased and its toxicity may be enhanced by leucovorin, folic acid, or folate analog products. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
Instruct patients not to take products containing folic acid or folate analog products unless directed to do so by their healthcare provider.
7.2Effect of Capecitabine on Other Drugs CYP2C9 Substrates
Capecitabine increased exposure of CYP2C9 substrates [see Clinical Pharmacology ( 12.3 )], which may increase the risk of adverse reactions related to these substrates. Closely monitor for adverse reactions of CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions when used concomitantly with capecitabine (e.g., anticoagulants, antidiabetic drugs). Vitamin K Antagonists Capecitabine increases exposure of vitamin K antagonist [see Clinical Pharmacology ( 12.3 )], which may alter coagulation parameters and/or bleeding and could result in death [see Warning and Precautions ( 5.1 )] .
These events may occur within days of treatment initiation and up to 1 month after discontinuation of capecitabine. Monitor INR more frequently and refer to the prescribing information of oral vitamin K antagonist for dosage adjustment, as appropriate, when capecitabine is used concomitantly with vitamin K antagonist. Phenytoin Capecitabine may increases exposure of phenytoin, which may increase the risk of adverse reactions related to phenytoin.
Closely monitor phenytoin levels and refer to the prescribing information of phenytoin for dosage adjustment, as appropriate, when capecitabine is used concomitantly with phenytoin.
7.3 Nephrotoxic Drugs Due of the additive pharmacologic effect, concomitant use of capecitabine with other drugs known to cause renal toxicity may increase the risk of renal toxicity [see Warnings and Precautions ( 5.6 )]. Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates). For full Taxotere prescribing information, please refer to Taxotere Package Insert.
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Pregnancy and breastfeeding
5.6Renal 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 )].
8.1Pregnancy Risk Summary Based
on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )], capecitabine can cause fetal harm when administered to a pregnant woman. Available human data with capecitabine use in pregnant women is not sufficient to inform the 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 exposure (AUC) in patients receiving the recommended dose of 1,250 mg/m2 twice daily, respectively (see Data).
Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Animal Data Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC 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.
Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling:
Cardiotoxicity [see Warnings and Precautions ( 5.3 )]
Diarrhea [see Warnings and Precautions ( 5.4 )]
Dehydration [see Warnings and Precautions ( 5.5 )]
Renal Toxicity [see Warnings and Precautions ( 5.6 )]
Serious Skin Toxicities [see Warnings and Precautions ( 5.7 )]
Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions ( 5.8 )]
Myelosuppression [see Warnings and Precautions ( 5.9 )]
Hyperbilirubinemia [see Warnings and Precautions ( 5.10 )] ● Most common adverse reactions in patients who received capecitabine as a single agent for the adjuvant treatment for colon cancer (≥30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. ( 6.1 ) ● Most common adverse reactions (≥30%) in patients with metastatic colorectal cancer who received capecitabine as a single agent were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. ( 6.1 ) ● Most common adverse reactions (≥30%) in patients with metastatic breast cancer who received capecitabine with docetaxel were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. ( 6.1 ) ● Most common adverse reactions (≥30%) in patients with metastatic breast cancer who received capecitabine as a single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea,fatigue, vomiting, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Treatment of Colon Cancer Single Agent The safety of capecitabine as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies ( 14.1 )].
Patients received capecitabine 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle (N=995) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=974). Among patients who received capecitabine, the median duration of treatment was 5.4 months. Deaths due to all causes occurred in 0.8% of patients who received capecitabine on study or within 28 days of receiving study drug.
Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received capecitabine. Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities in X-ACT. Table 2 Adverse Reactions (≥ 10%) in Patients Who Received Capecitabine for Adjuvant Treatment of Colon Cancer in X-ACT Adverse Reaction Capecitabine (N=995) Fluorouracil + Leucovorin (N=974) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade3 or 4 (%) Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 60 17 9 <1 Gastrointestinal Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal Pain 14 3 16 2 General Fatigue 16 <1 16 1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Clinically relevant adverse reactions in <10% of patients are presented below: Eye: conjunctivitis Gastrointestinal: constipation, upper abdominal pain, dyspepsia General: pyrexia Metabolism and Nutrition: anorexia Nervous System: dizziness, dysgeusia, headache Skin & Subcutaneous Tissue: rash, alopecia, erythema Table 3 Grade 3 or 4 Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine as a Single Agent for Adjuvant Treatment of Colon Cancer in X- ACT Laboratory Abnormality Capecitabine (n=995) Grade 3 or 4 % Fluorouracil + Leucovorin (n=974) Grade 3 or 4 % Bilirubin increased 20 6 Lymphocytes decreased 13 13 Neutrophils/granulocytes decreased 2.4 26 Calcium decreased 2.3
2.2 Neutrophils decreased 2.2 26 ALT increased 1.6
0.6 Calcium increased 1.1
0.7 Hemoglobin decreased 1
1.2 Platelets decreased 1
0.7In Combination with Oxaliplatin-Containing Regimens
The safety of capecitabine for the perioperative treatment of adults with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies ( 14.1 )]. The safety of capecitabine for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine as a single agent, with the exception of an increased incidence of neurosensory toxicity.
Perioperative Treatment of Rectal Cancer The safety of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from published literature [seeClinical Studies ( 14.1 )] . The safety of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was similar to those in patients treated with capecitabine as a single agent, with the exception of an increased incidence of diarrhea.
Metastatic Colorectal C ance r Single Agent The safety of capecitabine as a single agent was evaluated in a pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [see Clinical Studies ( 14.1 )] . Patients received capecitabine 1,250 mg/m 2 orally twice a day for the first 14 days of a 21-day cycle (N=596) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=593).
Among the patients who received capecitabine, the median duration of treatment was 4.6 months. Deaths due to all causes occurred in 8% of patients who received capecitabine on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 13% of patients who received capecitabine. Most common adverse reactions (>30%) were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain.
Table 4 shows the adverse reactions occurring in this pooled colorectal cancer population. Table 4 Adverse Reactions (>10%) in Patients Who Received Capecitabine in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796) – Not observed *Includes weakness NA = Not Applicable Clinically relevant adverse reactions in <10% of patients are presented below: Eye: abnormal vision Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus General: chest pain Infections: viral Metabolism and Nutrition: dehydration Musculoskeletal: arthralgia Nervous System: dizziness (excluding vertigo), insomnia, taste disturbance Psychiatric: mood alteration, depression Respiratory, Thoracic, and Mediastinal: cough, pharyngeal disorder Skin and Subcutaneous Tissue: skin discoloration, alopecia Vascular: venous thrombosis In Combination with Oxaliplatin The safety of capecitabine for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies ( 14.1 )].
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
CAPECITABINE 150MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
The safety of capecitabine for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine as a single agent, with the
