카페시타빈

0.4

0.4

White to off-white crystalline powder

Crystals from ethyl acetate

26

In water, 26 mg/mL at 20 °C

2.48e-01 g/L

110-121 °C

110-121 °C

110 - 121 °C

Danger

H315 (13.7%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (13.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H341 (84.3%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]；H350 (90.2%): May cause cancer [Danger Carcinogenicity]；H360 (96.1%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P264, P264+P265, P280, P302+P352, P305+P351+P338, P318, P321, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 51 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl capecitabine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

Ocular irritation occurred in 5-15% of patients receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer. Abnormal vision occurred in 5% of patients receiving capecitabine monotherapy for metastatic colorectal cancer. Severe ocular irritation and corneal deposits were reported in 2 patients with a history of keratoconjunctivitis sicca who received higher doses of capecitabine for metastatic breast cancer or metastatic colon cancer. Ophthalmic examination is recommended for patients receiving capecitabine who experience severe ocular symptoms or decreased visual acuity. Increased lacrimation was reported in 12% of patients receiving capecitabine and docetaxel and in 7% of those receiving docetaxel alone for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, conjunctivitis occurred in 5% of patients. Conjunctivitis and lacrimal duct stenosis each occurred in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated contain

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/

For more Disposal Methods (Complete) data for CAPECITABINE (8 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/

For more Preventive Measures (Complete) data for CAPECITABINE (19 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

Concomitant use of folic acid may affect the metabolism of capecitabine.

In 4 patients receiving chronic administration of capecitabine 1250 mg/sq m twice daily with a single dose of warfarin 20 mg, the mean area under the concentration-time curve (AUC) of S-warfarin was increased by 57% and clearance was decreased by 37%. The baseline corrected AUC of INR in these patients increased by 2.8-fold, and the maximum observed mean INR increased by 91%. The mechanism for this interaction probably involves inhibition of cytochrome P-450 (CYP) 2C9 isoenzyme by capecitabine and/or its metabolites. Because the decreased rate of anticoagulant metabolism may increase patient response to coumarin and indandione derivatives, capecitabine and these agents should be used concomitantly with great caution.

Leucovorin potentiates the antineoplastic activity of fluorouracil (the active drug of capecitabine) and also may increase its toxicity. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving a weekly regimen of combination therapy with leucovorin and fluorouracil.

Concomitant use of phenytoin and capecitabine may result in toxicity from increased serum phenytoin concentrations. The mechanism of interaction is presumed to be inhibition of the metabolism of phenytoin by capecitabine and/or its metabolites through inhibition of the cytochrome P-450 (CYP) 2C9 isoenzyme. In patients receiving capecitabine, serum concentrations of phenytoin must be monitored carefully, and reduction in the phenytoin dosage may be necessary.

For more Interactions (Complete) data for CAPECITABINE (6 total), please visit the HSDB record page.

Serum aminotransferase elevations occur in a proportion of patients on conventional doses of capecitabine therapy, but elevations above 5 times the upper limit of normal are uncommon, occurring in；Likelihood score: E* (Unproven but suspected cause of clinically apparent liver injury).

Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. FdUMP inhibits DNA synthesis by reducing normal thymidine production, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate.3 The active moiety of capecitabine, fluorouracil, is cell cycle phase-specific (Sphase). Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/HUMAN EXPOSURE STUDIES/ .../Investigators/ performed a retrospective evaluation of hypokalemia in 77 patients, who received capecitabine for gastrointestinal malignancies between April 2002 and November 2004. Hypokalemia was defined as K(+) level <3.2 mEq/L. Patients with documented >/=grade 2 vomiting or diarrhea, diuretics, hypomagnesemia, hypokalemia, renal insufficiency, endocrine dysfunction (thyroid, adrenal, diabetic) were excluded. Hypokalemic patients were graded as: mild (grade 1: 3.0-3.2 mEq/L), moderate (grade 3: 2.5-2.9 mEq/L) and severe (grade 4: <2.5 mEq/L). /Investigators/ also reviewed the literature. Fifty-four patients met the above criteria. The most common cause of exclusion was >/= grade 2 diarrhea (23 patients; 30%). Overall, hypokalemia was encountered in 11 patients (20.4%). Among hypokalemic patients, 8 patients (73%) presented with mild/grade 1 hypokalemia (3.0-3.2 mEq/L), 2 patients (18.18%) with moderate/grade 3 hypokalemia (2.5-2.9 mEq/L) and 1 patient (9.09%) with severe/grade 4 hypokalemia (<2.5 mEq/L) 8 (73%). Dose of capecitabine ranged between 1000-2000 mg/sq m. Hypokalemia occurred after an average of 83.7 days of capecitabine administration. No cardiac or neuromuscular complications were noticed. Replacement of K(+) was required in 6 patients (2 intravenous and 4 oral), while 2 patients (3.7%) required oral supplements >4 weeks. No patient had to stop capecitabine due to hypokalemia. One patient had persistent hypokalemia even after stopping capecitabine. Normalization of K(+) levels was achieved in 91% of patients. Four patients were on K(+) sparing diuretics for ascites and never presented with hypokalemia. Mean urine K(+) was 28 mEq/L. Only 5.5% patients had >/=grade 3 hypokalemia in our study compared with 2% and 14% in two other studies. ...

/HUMAN EXPOSURE STUDIES/ Macrocytosis has not been previously reported in association with capecitabine therapy. /Investigators/ performed a retrospective review of consecutive metastatic breast cancer (MBC) patients receiving standard 21-day cycles of oral capecitabine therapy at a single center during the year 2000. Patients were assessed prior to each cycle with clinical examinations and complete blood counts. Seventy-six women (median age 52 years, median follow-up 273 days) met inclusion criteria for the study. Prior to treatment, the average mean corpuscular volume (MCV) was 91.6 fl (normal range 80-100 fl). During chemotherapy, MCV increased in a dose-dependent and time-dependent manner. Fifty-seven percent of study patients developed macrocytosis (MCV > 100 fl) while on capecitabine therapy; 85% of women who received at least nine cycles of therapy exhibited macrocytosis. Development of macrocytosis was independent of anemia, thrombocytopenia, neutropenia, liver metastasis, and hepatic dysfunction; however, increases in MCV were more pronounced in 5-FU-naive patients. Alternative causes of macrocytosis were not identified in patients without coexisting anemia. /The authors/ conclude that capecitabine therapy produces time-dependent and dose-dependent macrocytosis in MBC patients. However, macrocytosis was not associated with anemia or overt myelosuppression. ...

/SIGNS AND SYMPTOMS/ Overdosage of capecitabine would be expected to cause nausea, vomiting, diarrhea, GI irritation and bleeding, and bone marrow depression. Patients receiving capecitabine 1657 mg/sq m daily (as 2 divided doses) in a continuous daily regimen for at least 6 weeks experienced severe palmar-plantar erythrodysesthesia, mucositis, and diarrhea.

/CASE REPORTS/ ... A 65-year-old white woman with stage IV colorectal cancer with liver metastasis was started on a chemotherapy regimen of capecitabine, oxaliplatin, and bevacizumab, given every three weeks. She tolerated the first two treatment cycles fairly well without major toxicities. The capecitabine dosage was started at 2000 mg daily for 14 days during the first cycle and increased to 2500 and 3000 mg daily during the second and the third cycles, respectively. On day 5 of the third cycle, the patient reported increased nausea, fatigue, and sleepiness, and the dosage of capecitabine was subsequently reduced to 2500 mg daily. On day 12 of the fourth treatment cycle, she reported ongoing lightheadedness and progressive gait disturbance with worsening ataxia over the past 3 days. Her capecitabine dosage was further reduced to 2000 mg daily, and the time between treatment intervals was increased to four weeks. The patient continued to experience intermittent, but less severe, ataxia during the fifth treatment cycle. On the day before the seventh cycle was to begin, she had ataxic gait and could not walk without assistance. Subsequent magnetic resonance imaging of the brain revealed no evidence of brain metastasis or cerebellar abnormality. The chemotherapy was postponed for a total of six weeks until the ataxia completely resolved. Her chemotherapy was ultimately discontinued due to disease progression. Her neurologic symptoms did not recur. ...

For more Human Toxicity Excerpts (Complete) data for CAPECITABINE (25 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Capecitabine

vLess-DILI-concern

2

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In an experimental model of transplant rejection, renal transplants were performed on 6 mixed-breed dogs. Capecitabine (CPC) was administered as an oral immunosuppressive agent. All recipients received systemic CPC, cyclosporine (CSA), prednisolone, and famotidine throughout the study. Two dogs developed superficial keratitis, which was characterized by multifocal geographic erosions, superficial corneal epithelial pigmentation, and corneal neovascularization. These clinical signs correlated with the dose of CPC given, whereas other drug doses remained unchanged. After euthanasia (14 weeks after surgery), routine histologic sections were stained with hematoxylin and eosin and with alcian blue periodic acid-Schiff for light microscopic evaluation. Ocular histopathologic abnormalities were limited to neovascularization and inflammatory infiltrate of the anterior corneal stroma and abnormal basal cell morphology, disorganization, thinning, and pigmentation of the corneal epithelium. ...

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Capecitabine has been shown to be embryotoxic and teratogenic in animal studies. Fetal death was observed in monkeys receiving capecitabine 90 mg/kg daily (a dosage producing an AUC value for capecitabine metabolite 5'-deoxy-5-fluorouridine [5'-DFUR] in monkeys about 0.6 times the corresponding value in humans receiving the recommended daily dosage) during organogenesis.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Embryocidal and teratogenic effects, including cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles, were observed in the offspring of mice receiving capecitabine doses of 198 mg/kg daily (a dosage producing an AUC value for capecitabine metabolite 5'-DFUR in mice about 0.2 times the corresponding value in humans receiving the recommended daily dosage) during organogenesis.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In reproduction studies in mice, oral capecitabine dosages of 760 mg/kg daily (a dosage producing an AUC value for capecitabine metabolite 5'-DFUR in mice about 0.7 times the corresponding value in humans receiving the recommended daily dosage) caused a reversible disturbance in estrus and a consequent decrease in fertility; no fetuses survived in mice that became pregnant. Administration of the same dosage of capecitabine to male mice resulted in degenerative changes in the testes, including a decrease in the number of spermatocytes and spermatids.

/GENOTOXICITY/ Capecitabine ... was not clastogenic to mouse bone marrow (micronucleus test) in vivo. Capecitabine was not mutagenic in the Ames test or the Chinese hamster V79/HPRT gene mutation assay. Fluorouracil, the biologically active form of capecitabine, has been shown to be mutagenic in some bacteria and yeast. Fluorouracil also causes chromosomal aberrations in the micronucleus test in mice in vivo.

Capecitabine is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. In rare instances, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia, neurotoxicity) associated with fluorouracil has been attributed to a deficiency of DPD activity. A causal relationship between decreased DPD activity and increased, potentially fatal, fluorouracil toxicity (and thus capecitabine toxicity) cannot be ruled out.

.../Investigators/ performed a retrospective evaluation of hypokalemia in 77 patients, who received capecitabine for gastrointestinal malignancies between April 2002 and November 2004. Hypokalemia was defined as K(+) level <3.2 mEq/L. Patients with documented >/=grade 2 vomiting or diarrhea, diuretics, hypomagnesemia, hypokalemia, renal insufficiency, endocrine dysfunction (thyroid, adrenal, diabetic) were excluded. Hypokalemic patients were graded as: mild (grade 1: 3.0-3.2 mEq/L), moderate (grade 3: 2.5-2.9 mEq/L) and severe (grade 4: <2.5 mEq/L). /Investigators/ also reviewed the literature. Fifty-four patients met the above criteria. The most common cause of exclusion was >/= grade 2 diarrhea (23 patients; 30%). Overall, hypokalemia was encountered in 11 patients (20.4%). Among hypokalemic patients, 8 patients (73%) presented with mild/grade 1 hypokalemia (3.0-3.2 mEq/L), 2 patients (18.18%) with moderate/grade 3 hypokalemia (2.5-2.9 mEq/L) and 1 patient (9.09%) with severe/grade 4 hypokalemia (<2.5 mEq/L) 8 (73%). Dose of capecitabine ranged between 1000-2000 mg/sq m. Hypokalemia occurred after an average of 83.7 days of capecitabine administration. No cardiac or neuromuscular complications were noticed. Replacement of K(+) was required in 6 patients (2 intravenous and 4 oral), while 2 patients (3.7%) required oral supplements >4 weeks. No patient had to stop capecitabine due to hypokalemia. One patient had persistent hypokalemia even after stopping capecitabine. Normalization of K(+) levels was achieved in 91% of patients. Four patients were on K(+) sparing diuretics for ascites and never presented with hypokalemia. Mean urine K(+) was 28 mEq/L. Only 5.5% patients had >/=grade 3 hypokalemia in our study compared with 2% and 14% in two other studies. ...

Leucovorin potentiates the antineoplastic activity of fluorouracil (the active drug of capecitabine) and also may increase its toxicity. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving a weekly regimen of combination therapy with leucovorin and fluorouracil.

Although the safety and efficacy of capecitabine in geriatric patients have not been specifically studied to date, the manufacturer reports that elderly individuals may experience increased frequency and severity of the toxic effects of capecitabine and its metabolites. Among 21 patients aged 80 years or older receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer in clinical trials, 62% experienced a grade 3 or 4 adverse effect. In particular, severe adverse GI effects (grade 3 or 4 diarrhea, nausea, or vomiting) or severe hand-foot syndrome associated with capecitabine may occur more frequently in such patients. ... Geriatric patients should be monitored closely for the occurrence of capecitabine-induced adverse effects.

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. ... /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective.

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

◉ Summary of Use during Lactation；Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence. some have suggested a period of 24 hours before resuming nursing, although the manufacturer recommends an abstinence period of 2 weeks. Capecitabine is metabolized to fluorouracil. Limited information indicates that a maternal continuous intravenous fluorouracil infusion at a dose of 200 mg/square meter daily produces undetectable levels in milk. If capecitabine use is undertaken, monitoring of the infant's complete blood count and differential is advisable. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl capecitabine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

L01BC06

L - Antineoplastic and immunomodulating agents；L01 - Antineoplastic agents；L01B - Antimetabolites；L01BC - Pyrimidine analogues；L01BC06 - Capecitabine

QL - Antineoplastic and immunomodulating agents；QL01 - Antineoplastic agents；QL01B - Antimetabolites；QL01BC - Pyrimidine analogues；QL01BC06 - Capecitabine

L01BC06

Capecitabine is a fluoropyrimidine carbamate belonging to a group of antineoplastic agents called antimetabolites, which kill cancerous cells by interfering with DNA synthesis. It is an orally administered systemic prodrug that has little pharmacologic activity until it is converted to 5-fluorouracil (5-FU) by enzymes that are expressed in higher concentrations in many tumors. Capecitabine was designed specifically to overcome the disadvantages of 5-FU and to mimic the infusional pharmacokinetics of 5-FU without the associated complexity and complications of central venous access and infusion pumps. Particularly, since the enzymes converting 5-FU into active metabolites exist in the gastrointestinal tract, infusion of 5-FU can have gastrointestinal toxicity while also losing efficacy. Since capecitabine can be transported intact across the intestinal mucosa, it can be selectively delivered 5-FU to tumor tissues through enzymatic conversion preferentially inside tumor cells. 5-FU exerts its pharmacological action through the inhibition and interference of 3 main targets: thymidylate synthase, DNA, and RNA, leading through protein synthesis disruption and apoptosis. Population-based exposure-effect analyses demonstrated a positive association between AUC of 5-FU and grade 3-4 hyperbilirubinemia.

Capecitabine is metabolized to 5-fluorouracil in vivo by carboxylesterases, cytidine deaminase, and thymidine phosphorylase/uridine phosphorylase sequentially. 5-fluorouracil is further metabolized through a series of enzymatic reactions into 3 main active metabolites: 5-fluorouridine triphosphate (5-FUTP), 5-fluoro-2’-deoxyuridine monophosphate (5-FdUMP), and 5-fluorodeoxyuridine triphosphate (5-FdUTP).. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate (CH₂THF), bind to thymidylate synthase (TS) to form a covalently bound ternary complex. TS is an enzyme that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Under normal physiological conditions, dUMP binds to TS first before CH₂THF, followed by a 1,4 or Michael addition from the pyrimidine C (6)atom to the Cys146 nucleophile. If correctly positioned, dUMP, CH₂THF, and TS would form a ternary complex to facilitate the donation of the methyl group from CH₂THF to dUMP. However, the substitution of dUMP with FdUMP results in a new time-dependent TS–FdUMP–CH2THF complex. Since the fluorine group prevents dissociation of FdUMP from the pyrimidine ring, the whole complex is rendered irreversibly deactivated, terming this reaction "suicide inhibition". TS inhibition prevents the conversion of dUMP to dTMP, depleting the pool of dTMP that could be phosphorylated into dTTP to be incorporated as DNA nucleotides. This disrupts the nucleotides balance, particularly the the ATP/dTTP ratio, thus impairing DNA synthesis and repair and causing apoptosis. 5-FdUMP can also be phosphorylated into 5-FdUTP, further increasing the pool of dUTP base to potentially overwhelm the activity of dUTPase. Coupled with the decrease in dTTP, 5-FdUMP, and 5-FdUTP increase the probability of mistakenly incorporating a uracil base into DNA strands in place of thymine.

Capecitabine is a prodrug and has little pharmacologic activity until it is converted to fluorouracil, an antimetabolite. 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). Although the precise mechanisms of action of fluorouracil have not been fully elucidated, the main mechanism is thought to be 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.

In this report, /the authors/ investigated whether apoptosis induced by capecitabine was mediated by the Fas/FasL system. To achieve this goal, a specific in vitro coculture model mixing hepatoma and human colorectal cell line was used. A bystander effect was observed between HepG2 and LS174T cells treated with capecitabine. Besides this, Xeloda showed a 7-fold higher cytotoxicity and markedly stronger apoptotic potential in thymidine phosphorylase (TP)-transfected LS174T-c2 cells. The striking enhancement of thymidylate synthase inhibition that we observed in cells with high TP activity was most probably at the origin of the potentiation of capecitabine antiproliferative efficacy. In addition, this increase of sensitivity was accompanied by a strong overexpression of the CD95-Fas receptor on the cell surface. Both Fas and FasL mRNA expression were triggered after exposing TP+ cells to the drug. This implication of Fas in Xeloda-induced apoptosis was next confirmed by using antagonistic anti-Fas and anti-FasL antibodies that proved to reverse capecitabine antiproliferative activity, thus highlighting the key role that Fas could play in the optimization of an antitumor response to fluoropyrimidine drugs. /The/ data, therefore, show that TP plays a key role in the capecitabine activity and that the Fas/FasL system could be considered as a new determinant for Xeloda efficacy.

The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour.

The plasma elimination half-life of capecitabine and its metabolites, including the active drug, fluorouracil, is about 45-60 minutes, except for alpha-fluoro-beta-alanine (FBAL), a catabolite of fluorouracil, which has an initial half-life of about 3 hours.

Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’-DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolyzed by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL).

Capecitabine, an anticancer prodrug, is thought to be biotransformed into active 5-fluorouracil (5-FU) by three enzymes. After oral administration, capecitabine is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase (CES), then 5'-DFCR is converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase. 5'-DFUR is activated to 5-FU by thymidine phosphorylase. Although high activities of drug metabolizing enzymes are expressed in human liver, the involvement of the liver in capecitabine metabolism is not fully understood. In this study, the metabolism of capecitabine in human liver was investigated in vitro. 5'-DFCR, 5'-DFUR, and 5-FU formation from capecitabine were investigated in human liver S9, microsomes, and cytosol in the presence of the inhibitor of dihydropyrimidine dehydrogenase, 5-chloro-2,4-dihydroxypyridine. 5'-DFCR, 5'-DFUR, and 5-FU were formed from capecitabine in cytosol and in the combination of microsomes and cytosol. Only 5'-DFCR formation was detected in microsomes. The apparent K(m) and V(max) values of 5-FU formation catalyzed by cytosol alone and in combination with microsomes were 8.1 mM and 106.5 pmol/min/mg protein, and 4.0 mM and 64.0 pmol/min/mg protein, respectively. The interindividual variability in 5'-DFCR formation in microsomes and cytosol among 14 human liver samples was 8.3- and 12.3-fold, respectively. Capecitabine seems to be metabolized to 5-FU in human liver. 5'-DFCR formation was exhibited in cytosol with large interindividual variability, although CES is located in microsomes in human liver. In the present study, it has been clarified that the cytosolic enzyme would be important in 5'-DFCR formation, as is CES.

Capecitabine (Xeloda; CAP) is a recently developed oral antineoplastic prodrug of 5-fluorouracil (5-FU) with enhanced tumor selectivity. Previous studies have shown that CAP activation follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-FU preferentially in tumor tissues. In the present work, all fluorinated compounds present in liver, bile, and perfusate medium of isolated perfused rat liver (IPRL) and in liver, plasma, kidneys, bile, and urine of healthy rats /were investigated/. Moreover, data obtained from rat urine were compared with those from mice and human urine. According to a low cytidine deaminase activity in rats, 5'-DFCR was by far the main product in perfusate medium from IPRL and plasma and urine from rats. Liver and circulating 5'-DFCR in perfusate and plasma equilibrated at the same concentration value in the range 25 to 400 microM, which supports the involvement of es-type nucleoside transporter in the liver. 5'-DFUR and alpha-fluoro-beta-ureidopropionic acid (FUPA) + alpha-fluoro-beta-alanine (FBAL) were the main products in urine of mice, making up 23 to 30% of the administered dose versus 3 to 4% in rat. In human urine, FUPA + FBAL represented 50% of the administered dose, 5'-DFCR 10%, and 5'-DFUR 7%. Since fluorine-19 nuclear magnetic resonance spectroscopy gives an overview of all the fluorinated compounds present in a sample, we observed the following unreported metabolites of CAP: 1) 5-fluorocytosine and its hydroxylated metabolite, 5-fluoro-6-hydroxycytosine, 2) fluoride ion, 3) 2-fluoro-3-hydroxypropionic acid and fluoroacetate, and 4) a glucuroconjugate of 5'-DFCR.

Fluorouracil is catabolized to dihydrofluorouracil (FUH2), a much less toxic metabolite, by dihydropyrimidine dehydrogenase. Dihydropyrimidinase cleaves the pyrimidine ring of dihydrofluorouracil, yielding 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by beta-ureido-propionase to form alpha-fluoro-beta-alanine (FBAL).

Metabolized by thymidine phosphorylase to fluoruracil. Route of Elimination: Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose.About 3% of the administered dose is excreted in urine as unchanged drug. Half Life: 45-60 minutes for capecitabine and its metabolites.

6804DJ8Z9U

CAPECITABINE

Mechanisms of Action [MoA] - Nucleic Acid Synthesis Inhibitors

Established Pharmacologic Class [EPC] - Nucleoside Metabolic Inhibitor

Capecitabine is a Nucleoside Metabolic Inhibitor. The mechanism of action of capecitabine is as a Nucleic Acid Synthesis Inhibitor.

CAPECITABINE

The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%. Following oral administration of capecitabine 1,255 mg/m2 orally twice daily (the recommended dosage when used as a single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively.

Following administration of radiolabeled capecitabine, 96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces.

In colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1, the volume of distribution is calculated to be 186 ± 28 L.

In colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1, the clearance of capecitabine is calculated to be 775 ± 213 mL/min.

Capecitabine is readily absorbed from the GI tract; on average, at least 70% of an oral dose of the drug is absorbed. Although in vitro studies have shown that capecitabine is unstable under highly acidic conditions, the drug appears to be absorbed intact immediately upon dissolution without degradation secondary to the acidic pH of the stomach.

According to the manufacturer, peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil, its active drug, occur slightly later at 2 hours.

Antineoplastic ... colorectal cancer ... breast cancer

Use (kg) in Switzerland (2009): >500；Use (kg; approx.) in Germany (2009): >5000；Use (kg; exact) in Germany (2009): 5502；Consumption (g per capita) in Switzerland (2009): 0.064；Consumption (g per capita; approx.) in Germany (2009): 0.061；Consumption (g per capita; exact) in Germany (2009): 0.067；Excretion rate: 0.029；Calculated removal (%): 75.1

For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relasped during or following anthracycline-containing chemotherapy. Capecitabine is used alone as an adjuvant therapy following the complete resection of primary tumor in patients with stage III colon cancer when monotherapy with fluroprymidine is preferred. The use or capecitabine in combination regimens for advanced gastric cancer is currently being investigated.

2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine; 5'-deoxy-5-fluoro-N4-(2-methyl-1-butyloxycarbonyl)cytidine; 5'-deoxy-5-fluoro-N4-(3-methyl-1-butyloxycarbonyl)cytidine; [1-[5-deoxy-3-O-(5-deoxy-beta-D-ribofuranosyl)-beta-D-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester; [1-[5-deoxy-2-O-(5-deoxy-beta-D-ribofuranosyl)-beta-D-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester; [1-[5-deoxy-3-O-(5-deoxy-alpha-D-ribofuranosyl)-beta-D-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester; 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine