Capecitabine (capecitabine)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Capecitabine, a prodrug that has little pharmacologic activity until it is converted to fluorouracil (an antimetabolite) in tumor tissue, is an antineoplastic agent.
Capecitabine, a fluoropyrimidine carbamate, is an antineoplastic agent. Capecitabine is a prodrug of 5'-deoxy-5-fluorouridine (doxifuridine, 5'-DFUR) and has little pharmacologic activity until it is converted to fluorouracil, a fluorinated pyrimidine antagonist, in tumor tissue. Because capecitabine is converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjacent normal tissues or plasma, it is thought that high tumor concentrations of the active drug may be achieved with less systemic toxicity.
Fluorouracil is metabolized in both normal and tumor cells to 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). The main mechanism of fluorouracil is via the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor (N5-10-methylenetetrahydrofolate) to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from 2'-deoxyuridylate, thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.
Capecitabine has been shown to be active in xenograft tumors that are resistant to fluorouracil indicating incomplete cross-resistance between the drugs.
Over a dosage range of 500-3500 mg/m2 daily, the pharmacokinetics of capecitabine and its metabolite, 5'-deoxy-5-fluorocytidine (5'-DFCR), were dose proportional and did not change over time. However, the manufacturer reports that increases in area under the concentration-time curves (AUCs) of metabolites 5'-DFUR and fluorouracil were greater than proportional to the increase in dose. Considerable interindividual variations (i.e., exceeding 85%) in peak plasma concentrations and AUCs have been reported following oral administration of capecitabine.
According to the manufacturer, peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil, its active metabolite, occur at 2 hours.
Administration of capecitabine after a breakfast that is medium-rich in fat and carbohydrates resulted in decreases in the peak plasma concentration and AUC of capecitabine by 60 and 34%, respectively. The peak plasma concentration and AUC of fluorouracil were also decreased by 37 and 12%, respectively. The time to maximum concentration of both capecitabine and fluorouracil were delayed by 1.5 hours.
Plasma protein binding (mainly to albumin) of capecitabine and its metabolites is less than 60% and is not concentration dependent. Capecitabine is extensively metabolized in the liver and tumors. The plasma elimination half-life of capecitabine and fluorouracil is about 45 minutes.
In the liver, capecitabine is largely hydrolyzed to 5'-DFCR by carboxylesterase. 5'-DFCR subsequently is converted to another noncytotoxic intermediate, 5'-deoxy-5-fluorouridine (5'-DFUR), by cytidine deaminase. Hydrolysis of 5'-DFUR to the active drug fluorouracil is catalyzed by thymidine phosphorylase.
Once capecitabine is converted to the active drug fluorouracil, mainly in tumor tissue, fluorouracil is anabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), the active metabolites of the drug. Fluorouracil is catabolized to dihydrofluorouracil (FUH2), by dihydropyrimidine dehydrogenase. Dihydropyrimidinase cleaves the pyrimidine ring of FUH2, yielding 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by beta-ureido-propionase to form alpha-fluoro-beta-alanine (FBAL).
Capecitabine and its metabolites are excreted predominantly in urine (96%); fecal excretion is minimal (2.6%). Most of the capecitabine dose is excreted in urine as metabolites, principally FBAL, a catabolite of fluorouracil (57% of an administered dose); about 3% of an administered dose is excreted in urine as unchanged drug.
Following therapeutic doses of capecitabine, no clinically meaningful differences in the pharmacokinetics of 5'-DFUR, fluorouracil, or FBAL were observed based on sex and race; additionally, no clinically meaningful differences of 5'-DFUR and fluorouracil were observed based on age (range, 27--86 years). The exposure to FBAL increased by 15% following a 20% increase in age. Data from a study in Japanese and white patients receiving capecitabine 825 mg/m2 twice daily for 14 days showed differences in the pharmacokinetic disposition of capecitabine and its catabolite, FBAL.
Peak plasma concentration and the AUC of capecitabine were reduced by about 36 and 24%, respectively, and peak plasma concentration and AUC of FBAL were about 25 and 34% lower, respectively, in the Japanese patients than in the white patients. The clinical importance of these differences is not known. No clinically significant differences in the pharmacokinetics of 5'-DFCR, 5'-DFUR, or fluorouracil were observed.
USES: Capecitabine is used to treat certain types of cancer (such as breast, colon, rectal, stomach, esophageal, pancreatic cancer). It works by slowing or stopping the growth of cancer cells.
Generic name: capecitabine
Pronunciation: (KAP-e-SYE-ta-been)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Capecitabine
Indications
The following indications are listed for Capecitabine:
- Adenocarcinoma Of Pancreas
- Gastric Cancer
- Her2-Positive Adenocarcinoma Of Gastroesophageal Junction
- Lymph Node Positive Colorectal Carcinoma
- Malignant Esophageal Neoplasm
- Metastatic Breast Carcinoma
- Metastatic Colorectal Cancer
- Metastatic Her2-Positive Carcinoma Of Breast
Also known as: Advanced Breast Carcinoma, Esophageal Cancer, Esophagus Cancer, Gastric Malignancy, Her-2 Overexpressing Adenocarcinoma Of Gastroesophageal Junction, Her-2 Overexpressing Gastroesophageal Junction Adenocarcinoma, Her2-Positive Gastroesophageal Junction Adenocarcinoma, Malignancy Of Esophagus, Malignant Neoplasm Of Esophagus, Malignant Neoplasm Of Stomach, Malignant Tumor Of Esophagus, Malignant Tumor Of Stomach, Metastatic Breast Cancer, Metastatic Malignancy Of Breast, Metastatic Malignant Neoplasm Of Breast, Metastatic Malignant Tumor Of Breast, Pancreatic Adenocarcinoma, Stage Iii Colon Cancer.
Dosing
Monitor patients for adverse reactions during treatment with capecitabine and modify dosages as indicated in Table 1 below. When capecitabine is administered in combination with docetaxel, withhold both capecitabine and docetaxel until the requirements for resuming both agents are met. Refer to the prescribing information for docetaxel for additional dosing information.
Table 1. Recommended Capecitabine Dosage Modifications for Adverse Reactions
Severity Dosage Modification Resume at Same or Reduce Dose (Percent of Current Dose) Grade 2 toxicity First appearance Withhold therapy until 100% resolved to grade 0 or 1 Second appearance Withhold therapy until 75% resolved to grade 0 or 1 Third appearance Withhold therapy until 50% resolved to grade 0 or 1 Fourth appearance Permanently discontinue capecitabine Grade 3 toxicity First appearance Withhold therapy until 75% resolved to grade 0 or 1 Second appearance Withhold therapy until 50% resolved to grade 0 or 1 Third appearance Permanently discontinue capecitabine Grade 4 toxicity First appearance Permanently discontinue 50% capecitabine OR withhold until resolved to grade 0 or 1
If patients develop grade 3 or 4 hyperbilirubinemia during treatment with capecitabine, withhold treatment and resume once the event is grade 2 or less (i.e., bilirubin level below 3 times the upper limit of normal); use the percent of current dose column of Table 1 to determine the appropriate dose of capecitabine to resume therapy.
Capecitabine is administered orally. Capecitabine tablets should be swallowed whole with water within 30 minutes after the end of a meal. The recommended dose should be rounded to the nearest 150-mg dose so that whole tablets are administered. Capecitabine tablets should not be chewed, cut, or crushed. If a dose is missed or vomited, skip the missed/vomited dose and continue with the next scheduled dose.
Capecitabine tablets should be stored in tightly closed containers at 20-25degreesC; excursions are permitted to 15-30degreesC.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Capecitabine is not metabolized by cytochrome P-450 (CYP) isoenzymes. In vitro studies indicate that capecitabine and its metabolites do not inhibit CYP isoenzymes 1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or CYP2E1.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*History of severe hypersensitivity reactions to fluorouracil or capecitabine.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >=30% of patients receiving capecitabine monotherapy for adjuvant treatment of colon cancer include palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.
Adverse effects reported in >=30% of patients receiving capecitabine monotherapy for metastatic colorectal cancer include anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain.
Adverse effects reported in >=30% of patients receiving capecitabine monotherapy for metastatic breast cancer include lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis.
Adverse effects reported in >=30% of patients receiving capecitabine in combination with docetaxel for metastatic breast cancer include lymphocytopenia, leukopenia, neutropenia, anemia, diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, thrombocytopenia, vomiting, edema, and abdominal pain.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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The manufacturer states that safety and efficacy of capecitabine in children younger than 18 years of age have not been established.
Based on its mechanism of action and animal findings, capecitabine can cause fetal harm when administered to a pregnant patient. (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Advise pregnant patients of the potential risk to a fetus.
In lactating mice receiving a single dose of capecitabine, significant amounts of capecitabine metabolites were distributed into milk. It is not known whether capecitabine or its metabolites are distributed into human milk. The effects of the drug on nursing infants or on milk production are unknown. Because of the potential for serious adverse reactions to capecitabine in nursing infants, women should be advised to discontinue nursing during capecitabine therapy and for 1 week after discontinuance of therapy.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In clinical trials of patients with colorectal cancer (N=7938), metastatic breast cancer (N=4536), gastric, esophageal, or gastrointestinal junction cancer (N=1951), or pancreatic cancer (N=364) who were treated with capecitabine, 33, 18, 26, and 47% of patients, respectively, were >=65 years of age. No differences in efficacy were noted in geriatric patients compared to younger patients in these trials. However, geriatric patients experienced increased GI toxicity from capecitabine. Deaths have been reported from severe enterocolitis, diarrhea, and dehydration in geriatric patients treated with weekly leucovorin and fluorouracil.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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