Description: Capecitabine is a unique antineoplastic agent. It is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which generates 5-fluorouracil (5-FU) selectively in tumor cells. Chemically, capecitabine is classified as a fluoropyrimidine carbamate. It is the first oral antineoplastic agent approved for the treatment of metastatic breast carcinoma and is also being studied in colorectal cancer. In patients with metastatic breast cancer who were resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen, a tumor response rate of about 25% has been observed. However, no results are available from controlled trials in patients with breast cancer that demonstrate improvement in disease-related symptoms, disease progression, or survival. Unlike many other antineoplastic agents, use of capecitabine has not been associated with alopecia, and myelosuppression is uncommon. Final FDA-approval of capecitabine for the treatment of breast cancer was granted in April 1998 following accelerated review. In September 1999, a supplemental NDA was filed for the use of capecitabine in the treatment of metastatic colorectal cancer. The basis of this application is the result of phase III trials which show a greater overall response rate (21% vs. 11%) and similar time to progression and survival as compared to 5-fluorouracil and leucovorin therapy in patients with metastatic colorectal cancer. Mechanism of Action: Capecitabine is converted into 5-fluorouracil (5-FU) by a series of 3 enzymes (see Pharmacokinetics). Two of the converting enzymes, cytidine deaminase and thymidine phosphorylase, are found in many tissues, including tumor cells. Some human carcinomas express thymidine phosphorylase in higher concentrations than surrounding tissues. Thus, the drug is preferentially "tumor-activated" meaning that high concentrations of the active metabolite are delivered right to the cancer cells. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP and the folate cofactor, 5,10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is the necessary precursor of thymidine triphosphate (dTTP), one of four deoxyribonucleotides required for synthesis of DNA. Thus, a deficiency of thymidylate leads to depletion of dTTP, which inhibits cell division. Also, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during synthesis of RNA. Thus, RNA processing and protein synthesis are disrupted. Pharmacokinetics: Capecitabine is administered orally. The drug is extensively absorbed from the GI tract. Peak blood concentrations are achieved about 1.5 hours after dosing. Food reduces both the rate and extent of absorption of capecitabine with mean Cmax and AUC decreased by 60% and 35%, respectively. In the liver, capecitabine is hydrolyzed by a carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-DFCR). Over a dosage range of 500—3500 mg/m2/day, the pharmacokinetics of capecitabine and 5'-DFCR are dose proportional and do not change over time. After hydrolysis of capecitabine to 5'DFCR in the liver, 5'-DFCR is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytadine deaminase, an enzyme found in most tissues, including tumors. The enzyme, thymidine phosphorylase (dThdPase) then hydrolyzes 5'-DFUR to 5-fluorouracil (5-FU) which is converted in tissues to nucleotides with antitumor activity (FdUMP, FUTP). Peak blood concentrations of 5-FU are achieved about 2 hours after administration of capecitabine. Administration of capecitabine with food decreases the Cmax and AUC of 5-FU by roughly 43% and 21%, respectively; in addition, Tmax of 5-FU is delayed by about 1.5 hours. In patients with mild to moderate hepatic dysfunction, the AUC and Cmax of 5-FU is similar to that of patients with normal hepatic function. Over a dosage range of 500—3500 mg/m2/day, increases in the AUC of 5'-DFUR and 5-FU are greater than proportional to the increase in dose, and the AUC of 5-FU increases over time (e.g., 34% higher on day 14 than on day 1 of dosing). The interpatient variability in Cmax and AUC of 5-FU is greater than 85%. Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range: 0.9—8). Plasma protein binding of capecitabine and its metabolites is < 60% and is not concentration-dependent. Capecitabine, 5'-DFCR, and 5'-DFUR are mostly bound to albumin. The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU to a much less toxic 5-fluoro-5,6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, beta-ureido-propionase cleaves FUPA to alpha-fluoro-beta-alanine (FBAL), which is cleared in the urine. Over 70% of an administered capecitabine dose is recovered in urine as drug-related species, about 50% of it as FBAL. The elimination half-life of both capecitabine and 5-FU ranges 0.5—1 h. In contrast to the parent compound, the intracellular nucleotides FdUMP and FUTP have prolonged half-lives. •Special Populations: Capecitabine requires dosage adjustment in patients with renal dysfunction due to an increased incidence of severe adverse reactions in this population. No formal studies have examined capecitabine pharmacokinetics in elderly patients. In patients with mild to moderate hepatic dysfunction due to liver metastasis, the AUC and Cmax of capecitabine increased by 60% compared to patients with normal hepatic function. The AUC and Cmax of 5-FU were not affected. The effect of severe hepatic dysfunction on capecitabine pharmacokinetics is not known.

ndications...Dosage For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalent): Oral dosage: Adults: 2500 mg/m2/day PO in 2 divided doses (approximately 12 hours apart) after a meal for 2 weeks, repeated every 3 weeks. In a phase II study, patients with refractory metastatic disease were randomized to capecitabine 2510 mg/m2/day PO in two divided doses on days 1—14 of a 3-week treatment cycle or CMF (cyclophosphamide, methotrexate, 5-FU). Responses were observed in 25% of capecitabine-treated patients and in 16% of CMF-treated patients.[1725] For the treatment of previously untreated advanced or metastatic colorectal cancer†: Oral dosage: Adults: 2500 mg/m2/day PO in 2 divided doses (approximately 12 hours apart) after a meal for 2 weeks, repeated every 3 weeks. This regimen is repeated in three-week cycles. In phase III trials, this regimen resulted in an overall response rate of 23—26% in patients with previously untreated advanced or metastatic colorectal carcinoma. As compared to 5-fluorouracil and leucovirin, capecitabine resulted in less grade 3 stomatitis and neutropenia but a higher incidence of grade 3 hand-foot syndrome. Dosage adjustments of capecitabine based on the most severe toxicity: Grade 1 toxicity: Maintain current dosage. Grade 2 toxicity (1st appearance): Interrupt therapy until toxicity is resolved to grade 0—1; begin the next cycle with 100% of the starting dose. Grade 2 toxicity (2nd appearance): Interrupt therapy until toxicity is resolved to grade 0—1; begin the next cycle with 75% of the starting dose. Grade 2 toxicity (3rd appearance): Interrupt therapy until toxicity is resolved to grade 0—1; begin the next cycle with 50% of the starting dose. Grade 2 toxicity (4th appearance): Discontinue treatment permanently. Grade 3 toxicity (1st appearance): Interrupt therapy until toxicity is resolved to grade 0—1; begin the next cycle with 75% of the starting dose. Grade 3 toxicity (2nd appearance): Interrupt therapy until toxicity is resolved to grade 0—1; begin the next cycle with 50% of the starting dose. Grade 3 toxicity (3rd appearance): Discontinue treatment permanently. Grade 4 toxicity (1st appearance): Discontinue treatment permanently, or interrupt therapy until toxicity is resolved to grade 0—1 and begin the next cycle with 50% of the starting dose. Patients with hepatic impairment: In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is necessary; however, patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied. Patients with renal impairment: CrCl >= 51 ml/min: No initial dosage adjustment is recommended. CrCl 30—50 ml/min: Reduce recommended starting dose by 25%. CrCl < 30 ml/min: Use is contraindicated. †non-FDA approved indication

Oral Administration •Capecitabine is administered orally with food. The daily dose is given in two divided doses approximately 12 hours apart at the end of a meal. Capecitabine tablets should be swallowed with water.

Contraindications Capecitabine is contraindicated in patients with severe renal impairment or renal failure (creatinine clearance < 30 ml/min). Patients with severe renal impairment had a higher rate of grade 3—4 adverse reactions and a shorter duration of treatment than patients with normal renal function. In patients with moderate renal impairment at baseline (creatinine clearance 30—50 ml/min), a reduction in the initial capecitabine dose is recomended (see Dosage). Moderate renal impairment was associated with a higher incidence of treatment-related grade 3—4 serious adverse reactions relative to patients with normal renal function. No dosage adjustment is recommended in patients with mild renal impairment (creatinine clearance 51—80 ml/min). Although patients with mild renal impairment did experience slightly more serious adverse events and withdrawals due to adverse events than patients with normal renal function, they maintained their overall benefit/risk ratio. Although relatively uncommon, patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy are at risk of increased bone marrow suppression during capecitabine treatment. Therefore, this drug should be used only by clinicians experienced in chemotherapy. The active form of capecitabine, fluorouracil, is a radiation sensitizer. Patients with an active infection should be treated prior to receiving capecitabine. Opportunistic infections including fungal infections may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, other herpes infections (e.g., herpes simplex), or other viral infections are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding. Capecitabine should be used with caution in patients with cardiac disease. Use of fluorinated pyrimidine therapy has been associated with adverse cardiac events, including myocardial infarction, dysrhythmias, and cardiogenic shock. These adverse reactions may be more common in patients with a prior history of coronary artery disease (e.g., angina) or cardiac arrhythmias. Patients should be monitored for diarrhea and given fluid and electrolyte replacement as necessary. In patients who develop diarrhea during therapy, dosage adjustments (see Dosage) and standard antidiarrheal treatments (e.g., loperamide) are recommended. Elderly patients >= 80 years of age may experience a greater incidence of severe grade 3—4 adverse GI reactions. Among patients 60—79 years old, the incidence of GI toxicity was similar to the overall population. Elderly patients may be more sensitive to the toxic effects of capecitabine. Patients with mild to moderate hepatic disease due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is unknown. Capecitabine is classified as FDA pregnancy risk category D. When capecitabine was given to pregnant mice or monkeys during organogenesis, teratogenesis and embryo death were observed. The dose used in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Teratogenic malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles. There are no adequate and well controlled studies in pregnant women. Females of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine. If the drug is used during pregnancy, or if a patient becomes pregnant while receiving the drug, she should be informed of the potential hazards to the fetus. It is not known whether capecitabine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that breast-feeding be discontinued during capecitabine therapy. The safety and effectiveness of capecitabine have not been established in children < 18 years of age. Vaccination during chemotherapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

Interactions Administration of capecitabine concomitantly with coumarin-derivative anticoagulants has resulted in prolonged coagulation parameters and/or bleeding. These events may occur within several days and up to several months after initiating capecitabine therapy and within a month of stopping capecitabine. Patients with or without liver metastasis may be affected. Patients taking warfarin or other coumarin-derivative anticoagulants with capecitabine should be closely monitored. When an aluminum hydroxide; magnesium hydroxide antacid was administered immediately after capecitabine (1250 mg/m 2 ) in 12 cancer patients, AUC and Cmax increased by 16% and 35%, respectively, for capecitabine, and by 18% and 22%, respectively, for the metabolite 5'-DFCR. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). Because the pharmacokinetics of 5-FU were not affected, the clinical relevance of this interaction may be minor. Concomitant administration of leucovorin and capecitabine may increase the serum concentration and toxicity of 5-fluorouracil (5-FU). Deaths from severe enterocolitis, diarrhea and dehydration have been reported in elderly patients receiving weekly administration of leucovorin and fluorouracil. In vitro studies indicate that capecitabine and 5'-DFUR (a metabolite of capecitabine) have no inhibitory effects on substrates of cytochrome P450 for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1. Thus, capecitabine is not likely to interact with drugs metabolized by cytochrome P450 enzymes. Food reduces both the rate and extent of absorption of capecitabine and its metabolites. Administration of capecitabine with food resulted in a mean decrease in Cmax and AUC of 60% and 35%, respectively. The Cmax and AUC of the active drug, 5-FU, were reduced by about 43% and 21%, respectively, in the presence of food. In addition, when capecitabine is administered with food, the Tmax of 5-FU is delayed by about 1.5 hours. Although food decreases Cmax and AUC of capecitabine and its metabolites, it is currently recommended that capecitabine be administered with food as this procedure was used in the clinical trials. Concurrent use of capecitabine with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects. The immune response of the immunocompromised patient to vaccines is decreased and higher doses or more frequent boosters may be required. Despite these dose increases, the immune response may still be suboptimal. Live virus vaccines are contraindicated during therapy with antineoplastic agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. Those undergoing antineoplastic therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Estimates for postponing vaccination vary from 3 months to 1 year following discontinuation of treatment depending of the type of antineoplastic agent used and the disease state of the patient. Due to the thrombocytopenic effects of capecitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. Large doses of salicylates (>= 6 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients should be monitored closely during concurrent therapy with capecitabine. Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, sargramostim, GM-CSF, and filgrastim, G-CSF, are contraindicated for use in patients within 24 hours of treatment with antineoplastic agents. Increased phenytoin plasma concentrations have been reported during concomitant use of capecitabine and phenytoin, suggesting a potential interaction. Patients taking phenytoin or fosphenytoin concurrently with capecitabine should be monitored for increased phenytoin plasma concentrations and associated clinical symptoms of phenytoin toxicity such as nystagmus, diplopia, ataxia, and confusion. Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; no significant change was seen with digoxin capsules, and the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin capsules (Lanoxicapsฎ) may be utilized to avoid this interaction in patients receiving antineoplastic agents and digoxin tablets. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.

Adverse Reactions Diarrhea is a dose-limiting toxicity of capecitabine and occurs in roughly 50—57% of patients. Grade 2 diarrhea is an increase of 4—6 stools/day or nocturnal stools, grade 3 diarrhea is an increase of 7—9 stools/day or incontinence and malabsorption, and grade 4 diarrhea is an increase of >= 10 stools/day or grossly bloody diarrhea or the need for parenteral support. Grade 3 or 4 diarrhea is observed in 11—12% and 2—3% of patients, respectively. Patients >= 80 years of age may experience a greater incidence of grade 3 or 4 adverse GI events. The median time to first occurrence of grade 2—4 diarrhea is about 31 days (range: 1—322 days). If grade 2, 3, or 4 diarrhea occurs, capecitabine administration should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased (see Dosage). Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrheal treatments (e.g., loperamide) are recommended. Other gastrointestinal side effects of capecitabine include nausea/vomiting (44—53%/26—37%), stomatitis (23—24%), abdominal pain (17—20%), constipation (9—15%), and dyspepsia (6—8%). In < 5% of patients the following GI adverse reactions have been reported: GI obstruction, rectal bleeding, GI bleeding, esophagitis, gastritis, colitis, duodenitis, hematemesis, and necrotizing enterocolitis (typhlitis). Neurologic reactions reported during use of capecitabine include paresthesias (12—21%), headache (7—9%), dizziness (5—8%), and insomnia (3—8%). Other neurological reactions occurring in < 5% of patients include ataxia, confusion, depressed level of consciousness, encephalopathy (e.g., impaired cognition), and loss of consciousness (e.g., coma). Palmar-plantar erythrodysesthesia (hand and foot syndrome) has been reported in roughly 45—57% of patients receiving capecitabine therapy. Hand and foot syndrome is characterized by numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering, and severe pain. Grade 2 hand and foot syndrome is defined as painful erythema and swelling of the hands and/or feet that results in discomfort affecting the patient's activities of daily living. Grade 3 hand and foot syndrome is defined as moist desquamation, ulceration, blistering and severe pain of the hands and feet that results in severe discomfort that causes the patient to be unable to work or perform activities of daily living. Grade 3 hand and foot syndrome has been reported in 11—13% of patients. Other dermatologic reactions observed in patients receiving capecitabine have included exfoliative dermatitis (31—37%) and nail disorder (4—7%). In < 5% of patients the following dermatologic adverse reactions have been reported: diaphoresis, photosensitivity, radiation recall reaction, and rash (unspecified). Grade 3 or 4 hyperbilirubinemia (jaundice) has been reported in about 17% of patients treated with capecitabine. Grade 3 hyperbilirubinemia is defined as 1.5—3 times normal and grade 4 as > 3 times normal. Of 339 patients who had hepatic metastases at baseline and 231 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 21.2% and 10.4%, respectively. Seventy-six percent of the patients with grade 3 or 4 hyperbilirubinemia also had concurrent elevations in alkaline phosphatase and/or elevated hepatic enzymes (i.e., AST/ALT). Only 4% of these patients had elevated hepatic transaminases without a concurrent elevation in alkaline phosphatase. Hepatic fibrosis, cholestatic hepatitis (cholestasis), and hepatitis have been reported in < 5% of patients receiving capecitabine. Bone marrow suppression including, anemia (3%), leukopenia, neutropenia (4%) thrombocytopenia (2%), or pancytopenia can occur during capecitabine therapy. Lymphopenia has been reported in 94% of patients. Infections reported in < 5% of patients receiving capectiabine include oral/GI tract candidiasis, upper respiratory tract infection, urinary tract infection, bronchitis, pneumonia, sepsis, gastroenteritis, and laryngitis. Other adverse reactions reported during use of capecitabine include fatigue (34—41%), fever (10—12%), limb pain (4—6%), anorexia (20—23%), dehydration (5—7%), ocular irritation (10—15%), myalgia (4—9%), and cardiogenic edema (6—9%). In < 5% of patients the following adverse reactions were reported: bone pain, bronchospasm, drug hypersensitivity, dyspnea, epistaxis, idiopathic thrombocytopenia purpura (ITP), lymphedema, nocturia, and respiratory distress. Cardiovascular events have been reported in < 5% of patients treated with capecitabine. Reported adverse cardiovascular reactions include angina, cardiomyopathy, cerebrovascular accident (stroke), chest pain (unspecified), deep venous thrombosis, hypertension, hypotension, pulmonary embolism, venous phlebitis, and thrombophlebitis. Clastogenesis was reported in vitro in human peripheral blood lymphocytes exposed to capecitabine but not clastogenic in vivo to mouse bone marrow. However, fluorouracil has been shown to cause mutations in bacteria and yeast, and chromosomal abnormalities in the mouse micronucleus test in vivo. Capecitabine may cause infertility. In reproductive studies performed in mice, capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in fertility. The disturbance in estrus was reversible. In male mice, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. The dose used in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

Capecitabine Xeloda™

1725. O'Shaughnessy J, Moiseyenko V, Bell D et al. A randomized phase II study of Xeloda(TM) (capecitabine) vs CMF as first line chemotherapy of breast cancer in women aged >= 55 years. Proc Am Soc Clin Oncol 1998;17:A398.