CAPTIB

Capecitabine is an

Oral-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers.

Capecitabine is a prodrug, that is enzymatically converted to fluorouracil (antimetabolite) in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue.

Capecitabine is indicated as treatment for a variety of cancer types.

For colorectal cancer, capecitabine is indicated as a single agent or a component of a combination chemotherapy regiment for the adjuvant treatment of stage III colon cancer and treatment unresectable or metastatic colorectal cancer.

It can also be used as a part of a combination chemotherapy perioperative treatment of adult locally advanced rectal cancer.

For breast cancer, capecitabine is indicated for advanced or metastatic breast cancer as a single agent if an anthracycline.

• or taxane-containing chemotherapy is not indicated or as a regimen with docetaxel after disease progression on prior anthracycline-containing chemotherapy.

For gastric, esophageal, or gastroesophageal junction (GEJ) cancer, capecitabine is indicated as a component of a combination chemotherapy treatment for the treatment of adult unresectable or metastatic gastric, esophageal, or GEJ cancer or adult HER2-overexpressing metastatic gastric or GEJ adenocarcinoma who have not received prior treatment for metastatic disease.

Finally, for pancreatic cancer, capecitabine is indicated as adjuvant treatment for adult pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

Capecitabine is a fluoropyrimidine carbamate belonging to a group of antineoplastic agents called antimetabolites, which kill cancerous cells by interfering with DNA synthesis. 39, 26 It is an Oral 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. 41 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. 26, 20 Population-based exposure-effect analyses demonstrated a positive association between AUC of 5-FU and grade 3-4 hyperbilirubinemia.

Incorporation into and destabilization Inhibition of synthesis RNA Incorporation into and destabilization Thymidylate synthase Inhibitor.

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 (0.2-1.4 times the approved recommended dosage).

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/m 2 Oral 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.

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.

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).

Hover over products below to view reaction partners Capecitabine 5'-Deoxy-5-fluorocytidine (5'-DFCR) 5'-Deoxy-5-fluorouridine (5'DFUR) 5-fluorouracil 5-fluouridine (5-FUR) 5-fluorouridine monophosphate (5-FUMP) 5-fluorouridine diphosphate (5-FUDP) 5-fluorouridine triphosphate (5-FUTP) 5-FUDP-hexose 5-fluorouridine monophosphate (5-FUMP) 5-fluorouridine diphosphate (5-FUDP) 5-fluorodeoxyuridine diphosphate (5-FdUDP) 5-fluorodeoxyuridine monophosphate (5-FdUMP) 5-fluorodeoxyuridine triphosphate (5-FdUTP) 5-fluorodeoxyuridine monophosphate (5-FdUMP) 5-fluorouridine triphosphate (5-FUTP) 5-FUDP-hexose 5-fluorodeoxyuridine (5-FUdR) 5-fluorodeoxyuridine monophosphate (5-FdUMP) 5-fluorodeoxyuridine diphosphate (5-FdUDP) 5-fluorodeoxyuridine triphosphate (5-FdUTP) 5-fluorodeoxyuridine monophosphate (5-FdUMP) dihydrofluorouracil (DHFU) β-ureidopropionic acid (FUPA) Urea + fluoro-β-alanine (FBAL).

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.

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

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.

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Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted.

Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay).

Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test).

Fluorouracil causes mutations in bacteria and yeast.

Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2,300 mg/m2/day) disturbed estrus and consequently caused a decrease in fertility.

In mice that became pregnant, no fetuses survived this dose.

The disturbance in estrus was reversible.

In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids.

In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

Based on findings in animal reproduction studies and its mechanism of action, XELODA can cause fetal harm when administered to a pregnant woman.

Available human data on

XELODA 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 embryo lethality and teratogenicity in mice and embryo lethality 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.

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.

Administer uridine triacetate within 96 hours for management of XELODA overdose.

Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low–molecular-weight metabolite of the parent compound.

Capecitabine tablets are contraindicated in patients with history of severe hypersensitivity reaction to fluorouracil or capecitabine.

History of severe hypersensitivity reactions to fluorouracil or capecitabine.

• Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles.

In combination with Oxaliplatin-Containing

Regimens: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day of each cycle.

• With Concomitant Radiation Therapy: 825 mg/m 2 orally twice daily.

• Without Radiation Therapy: 1,250 mg/m 2 orally twice daily Unresectable or Metastatic Colorectal Cancer:

• Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity.

• In Combination with Oxaliplatin: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day of each cycle.

• Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity.

• In combination with docetaxel: 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m 2 administered intravenously on day of each cycle Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer.

• 625 mg/m 2 orally twice daily on days to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy.

• 850 mg/m 2 or 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day of each cycle.

HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach.

• 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab.

Pancreatic cancer.

• 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle for maximum of 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and of each cycle.

Refer to

Sections 2.5 and 2.6 for information related to dosage modifications for adverse reactions and renal impairment. 2.1 Evaluation and Testing of DPD Deficiency Before Initiating Capecitabine Tablets Prior to initiating capecitabine tablets, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary.

An FDA-authorized test for the detection of the DPYD gene to identify patients at risk of serious adverse reactions with capecitabine tablets are 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).

Avoid use of capecitabine tablets in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

No capecitabine tablets dose has been proven safe for patients with complete DPD deficiency.

For patients with partial

DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment. 2.2 Recommended Dosage for Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The recommended dosage of capecitabine tablets is 1,250 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles.

In Combination with Oxaliplatin-Containing Regimens

The recommended dosage of capecitabine tablets is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day of each cycle.

Refer to the oxaliplatin prescribing information for additional dosing information as appropriate.

The recommended dosage of capecitabine is 825 mg/m 2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m 2 orally twice daily when administered without radiation therapy as part of a peri-operative combination regimen.

Unresectable or Metastatic Colorectal Cancer Single Agent The recommended dosage of capecitabine tablets is 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity.

The recommended dosage of capecitabine tablets is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day of each cycle.

Information for oxaliplatin for additional dosing information as appropriate. 2.3 Recommended Dosage for Breast Cancer Advanced or Metastatic Breast Cancer Single Agent The recommended dosage of capecitabine tablets is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity.

Individualize the dose and dosing schedule of capecitabine tablets based on patient risk factors and adverse reactions.

The recommended dosage of capecitabine tablets is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75 mg/m 2 administered intravenously on day of each cycle.

Information for docetaxel for additional dosing information as appropriate. 2.4 Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer The recommended dosage of capecitabine tablets for unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer is: 625 mg/m 2 orally twice daily on days to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy.

OR 850 mg/m 2 or 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day of each cycle.

The recommended dosage of capecitabine tablets for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab.

Information for agents used in combination for additional dosing information as appropriate. 2.5 Recommended Dosage for Pancreatic Cancer The recommended dosage of capecitabine tablets is 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression, unacceptable toxicity, or for a maximum 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and of each cycle.

Information for gemcitabine for additional dosing information as appropriate. 2.6 Dosage Modifications for Adverse Reactions Monitor patients for adverse reactions and modify dosages of capecitabine tablets as described in Table 1.

Do not replace missed doses of capecitabine tablets; instead resume capecitabine tablets with the next planned dosage.

When capecitabine tablets is administered with docetaxel, withhold capecitabine tablets and docetaxel until the requirements for resuming both capecitabine tablets and docetaxel are met.

Information for docetaxel for additional dosing information as appropriate.

Table 1 Recommended Dosage Modifications for Adverse Reactions Severity Dosage Modification Resume at Sameor Reduced Dose (Percentof Current Dose) Grade 2 1st appearance Withhold until resolved to grade 0-1. 100% 2nd appearance 75% 3rd appearance 50% 4th appearance Permanently discontinue.

• Grade 3 1st appearance Withholduntil resolved to grade 0-1. 75% 2nd appearance 50% 3rd appearance Permanently discontinue.

• Grade 4 1st appearance Permanently discontinue OR Withhold until resolved to grade 0-1. 50% Hyperbilirubinemia Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (less than three times the upper limit of normal), using the percent of current dose as shown in column of Table 1. 2.7 Dosage Modification For Renal Impairment Reduce the dose of capecitabine tablets by 25% for patients with creatinine clearance (CLcr) of to 50 mL/min as determined by Cockcroft-Gault equation.

A dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min) . 2.8 Administration Round the recommended dosage for patients to the nearest 150 mg dose to provide whole capecitabine tablets.

Swallow capecitabine tablets whole with water within 30 minutes after a meal.

Do not chew, cut, or crush capecitabine tablets.

Take capecitabine tablets at the same time each day approximately 12 hours apart.

Do not take an additional dose after vomiting and continue with the next scheduled dose.

Do not take a missed dose and continue with the next scheduled dose.

Capecitabine tablet is a hazardous drug.

Follow applicable special handling and disposal procedures.

mg Capecitabine tablets USP, 150 mg are light peach colored, biconvex, oblong film-coated tablets with “150” debossed on one side and “RDY” on other side and are supplied in bottles of 60’s and 500’s.

Bottles of 60’s NDC 55111-496-60 Bottles of 500’s NDC 55111-496-05 500 mg Capecitabine tablets USP, 500 mg are peach colored, biconvex, oblong tablets with “500” debossing on one side and “RDY” on other side and are supplied in bottles of 120’s and 500’s.

Bottles of 120 NDC 55111-497-04 Bottles of 500 NDC 55111-497-05 Storage and Handling Store at 20° to 25°C (68° to 77°F). .

Capecitabine tablets is a hazardous drug.

Follow applicable special handling and disposal procedures.

Based on findings in animal reproduction studies and its mechanism of action, capecitabine tablets can cause fetal harm when administered to a pregnant woman.

Available human data with capecitabine tablets 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/m 2 twice daily, respectively.

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.

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.

The safety and effectiveness of capecitabine tablets in pediatric patients have not been established.

Safety and effectiveness were assessed, but not established in two single arm studies in 56 pediatric patients aged 3 months to <17 years with newly diagnosed gliomas.

In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions).

The relative bioavailability of the investigational formulation to capecitabine tablets was similar.

The adverse reaction profile was consistent with that of adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients.

The most frequently reported laboratory abnormalities (per-patient incidence ≥ 40%) were increased ALT (75%), lymphocytopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

Of 7938 patients with colorectal cancer who were treated with capecitabine tablets, 33% were older than 65 years.

Of the 4536 patients with metastatic breast cancer who were treated with capecitabine tablets, 18% were older than 65 years.

Of 1951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treated with capecitabine tablets, 26% were older than 65 years.

Of 364 patients with pancreatic cancer who received adjuvant treatment with capecitabine tablets, 47% were 65 years or older.

No overall differences in efficacy were observed comparing older versus younger patients with colorectal cancer, gastric, esophageal or gastrointestinal junction cancer, or pancreatic cancer using the approved recommended dosages and treatment regimens.

Older patients experience increased gastrointestinal toxicity due to capecitabine tablets compared to younger patients.

Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.