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    Capecitabine

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    Mar.21.2024

    Capecitabine

    Indications/Dosage

    Labeled

    • breast cancer
    • colorectal cancer
    • esophageal cancer
    • gastric cancer
    • pancreatic cancer

    Off-Label

    • biliary tract cancer
    • ovarian cancer
    † Off-label indication

    For the treatment of breast cancer

    for the treatment of advanced or metastatic breast cancer if anthracycline- or taxane-containing chemotherapy is not indicated, as monotherapy

    Oral dosage

    Adults

    1,000 mg/m2 or 1,250 mg/m2 PO twice daily on days 1 to 14, repeated every 21 days until disease progression or unacceptable toxicity; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a subset of patients with stage IV breast cancer that was resistant to both paclitaxel and an anthracycline (n = 43) from an open-label, single-arm clinical trial (SO14697), treatment with capecitabine resulted in a partial response rate of 25.6% (no complete responses) for a median duration of 5.1 months; the median time to progression in these patients was 3.4 months and the median survival was 8.4 months. The objective response rate in the overall population of patients who were less resistant to chemotherapy (n = 135) was 18.5% (1 complete response) with a median time to progression of 3 months and median survival of 10.1 months.[44458]

    for the treatment of advanced or metastatic breast cancer after disease progression on prior anthracycline-containing chemotherapy, in combination with docetaxel

    Oral dosage

    Adults

    1,000 mg/m2 or 1,250 mg/m2 PO twice daily on days 1 to 14, in combination with docetaxel (75 mg/m2 IV on day 1), every 3 weeks until disease progression or unacceptable toxicity; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] In a multicenter, randomized, open-label, phase 3 trial (SO14999), treatment with capecitabine plus docetaxel significantly improved the time to disease progression (6.1 months vs. 4.2 months), overall survival (14.5 months vs. 11.6 months), and objective response rate (32% vs. 22%) compared to monotherapy with docetaxel in patients with metastatic breast cancer resistant to or recurring during/after anthracycline-based chemotherapy.[44575] [44458]

    for the treatment of patients with advanced or metastatic breast cancer whose tumor overexpresses the HER2 protein and who have received prior therapy including an anthracycline, a taxane, and trastuzumab, in combination with lapatinib†

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 through 14, in combination with lapatinib (1,250 mg PO once daily on days 1 to 21), repeated every 21 days until disease progression or unacceptable toxicity; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, phase 3 clinical trial of patients with progressive, locally advanced or metastatic breast cancer, treatment with lapatinib plus capecitabine significantly improved the median time to progression (TTP) by independent assessment compared with capecitabine alone (27.1 weeks vs. 18.6 weeks), with a response rate of 23.7% versus 13.9%; by investigator assessment, the median TTP was 23.9 weeks vs. 18.3 weeks with a response rate of 31.8% vs. 17.4%, respectively. Median progression-free survival (PFS) and overall survival (OS) were decreased in patients with HER2-positive metastatic breast cancer treated with lapatinib plus capecitabine compared with trastuzumab plus capecitabine in a randomized, open-label trial. Patients with HER2-positive metastatic breast cancer receiving first-line treatment with lapatinib plus taxane-based chemotherapy also had a shorter median PFS compared with trastuzumab plus taxane-based chemotherapy in another randomized, open-label trial. Patients should have progressed on trastuzumab and taxane-based therapy prior to treatment with lapatinib and capecitabine.[33192]

    for the treatment of metastatic or locally advanced breast cancer that is resistant to treatment with an anthracycline and a taxane, or that is taxane resistant and for whom further anthracycline therapy is contraindicated in combination with ixabepilone†

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14, in combination with ixabepilone (40 mg/m2 [maximum BSA, 2.2 m2] IV on day 1), every 3 weeks; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label clinical trial of patients with anthracycline- and taxane-resistant locally advanced or metastatic breast cancer, treatment with ixabepilone plus capecitabine significantly improved the median progression-free survival (PFS) (5.7 months vs. 4.1 months) and objective response rate (34.7% vs. 14.3%) compared with capecitabine alone; the median duration of response was 6.4 months versus 5.6 months, respectively. There was no significant difference in overall survival (12.9 months vs. 11.1 months).[33563]

    for the treatment of advanced or metastatic HER2-positive breast cancer in patients who have received 2 or more prior anti-HER2 based regimens in the metastatic setting, in combination with neratinib†

    Oral dosage

    Adults

    750 mg/m2 PO twice daily on days 1 to 14 every 21 days in combination with neratinib (240 mg PO once daily) until disease progression or unacceptable toxicity; alternatively, a 2-week neratinib dose escalation schedule may be given as follows: 120 mg PO once daily on days 1 to 7 (week 1), 160 mg PO once daily on days 8 to 14 (week 2), and 240 mg PO once daily starting on day 15 (week 3 and beyond).[62127] Round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[62127] [44458] Treatment with neratinib plus capecitabine significantly improved median progression-free survival (PFS) (5.6 months vs. 5.5 months) compared with lapatinib plus capecitabine in patients with metastatic HER2-positive breast cancer who had received at least 2 prior anti-HER2 based regimens in the metastatic setting in a randomized, open-label clinical trial (the NALA study). Rates of PFS were more durable in the neratinib plus capecitabine arm at 12 months (29% vs. 15%) and 24 months (12% vs. 3%). The objective response rate was 32.8 months in the neratinib arm for a median duration of 8.5 months compared with 26.7 months in the lapatinib arm for a median duration of 5.6 months. Overall survival was 21 months versus 18.7 months, respectively.[65929]

    for the treatment of advanced unresectable or metastatic HER2-positive breast cancer in patients who have received at least one prior anti-HER2-based regimen in the metastatic setting, in combination with trastuzumab and tucatinib†

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14 of each 21-day cycle in combination with tucatinib (300 mg PO twice daily) and trastuzumab (8 mg/kg IV over 90 minutes on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 21 days) until disease progression or unacceptable toxicity; tucatinib and capecitabine can be taken at the same time. Round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The addition of tucatinib to trastuzumab and capecitabine significantly improved median progression-free survival (PFS) (7.8 months vs. 5.6 months) and overall survival (21.9 months vs. 17.4 months) compared with placebo plus trastuzumab and capecitabine in patients with HER2-positive, unresectable locally advanced or metastatic breast cancer after prior HER2 treatment in a randomized, double-blind clinical trial (HER2CLIMB); all patients had received prior trastuzumab and ado-trastuzumab emtansine and all but 2 patients had prior pertuzumab. The confirmed objective response rate was also significantly improved with the addition of tucatinib (40.6% vs. 22.8%; complete response, 3% vs. 2%) for a median duration of 8.3 months versus 6.3 months, respectively. Patients with brain metastases were eligible for inclusion in the HER2CLIMB study as long as they were neurologically stable and did not require immediate radiation or surgery; patients with leptomeningeal disease were excluded. The median PFS in patients with brain metastases was similar to the overall population (7.6 months vs. 5.4 months).[65295] [65296]

    For the treatment of colorectal cancer

    for the perioperative treatment of locally advanced rectal cancer, as a component of chemoradiotherapy

    Oral dosage

    Adults

    825 mg/m2 PO twice daily with concomitant radiation therapy and 1,250 mg/m2 PO twice daily without radiation therapy when administered as part of a peri-operative combination regimen; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] In a multicenter, randomized, open-label clinical trial, patients with stage II to III locally advanced rectal cancer were randomized to adjuvant treatment with capecitabine-based chemoradiotherapy or fluorouracil-based chemoradiotherapy; patients in the capecitabine arm received 2 cycles of capecitabine (1,250 mg/m2 PO twice daily on days 1 to 14, every 21 days) followed by chemoradiotherapy (50.4 Gy plus capecitabine 825 mg/m2), followed by 3 cycles of capecitabine (1,250 mg/m2 PO twice daily on days 1 to 14, every 21 days). After 3 years, the protocol was amended to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50.4 Gy plus capecitabine 825 mg/m2 PO twice daily) followed by radical surgery and 5 cycles of capecitabine (1,250 mg/m2 PO twice daily on days 1 to 14, every 21 days). During chemoradiotherapy, radiation and the reduced dose of capecitabine were started on the same day and capecitabine was stopped on the last day of radiotherapy, including weekends. After a median follow-up of 52 months, the 5-year overall survival rate with capecitabine was noninferior to fluorouracil (76% vs. 67%); the 3-year disease-free survival rate was 75% versus 67%, respectively. The numbers of local recurrences were similar in each group (6% vs 7%), but fewer patients treated with capecitabine developed distant metastases (19% vs. 28%).[68392]

    for the adjuvant treatment of stage III colon cancer, as monotherapy

    Oral dosage

    Adults

    1,250 mg/m2 PO twice daily on days 1 to 14, repeated every 21 days for a maximum of 8 cycles. Dosages should be adjusted based on toxicity during treatment cycle; once a dosage is reduced, it should not be increased at a later time. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] After a median follow-up time of 6.9 years, adjuvant treatment with capecitabine was non-inferior to fluorouracil plus leucovorin in patients with previously untreated Dukes' stage C colon cancer in terms of 5-year disease-free survival (59% vs. 55%) and 5-year overall survival (71% vs. 68%).[31340]

    for the adjuvant treatment of stage III colon cancer in combination with oxaliplatin (XELOX or CapeOX)

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14 in combination with oxaliplatin (130 mg/m2 IV on day 1), repeated every 21 days for a maximum of 8 cycles; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] Treatment with capecitabine/oxaliplatin (XELOX) improved 7-year disease-free survival compared with fluorouracil/leucovorin in patients with stage III colon cancer in a multicenter, randomized, phase 3 clinical trial (63% vs. 56%; p = 0.004); 7-year overall survival rates were 73% and 67% respectively (p = 0.04). Because alpha levels were not prespecified for testing treatment differences in the final analysis, p values provide only a descriptive statistical measure of a possible difference. In a biomarker analysis, low tumor expression of dihydropyridine dehydrogenase (DPD) may be predictive for XELOX efficacy; no significant associations were observed in the fluorouracil group.[45258] [69445]

    for the first-line treatment of unresectable or metastatic colorectal cancer, as monotherapy

    Oral dosage

    Adults

    1,250 mg/m2 PO twice daily on days 1 to 14, repeated every 21 days until disease progression or unacceptable toxicity; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] Treatment with capecitabine significantly improved the overall response rate (21% vs. 11% to 14%) compared with fluorouracil plus leucovorin in 2 multicenter, randomized clinical trials (SO14695 and SO14796). The median time to progression was not significantly different in either study (4.2 to 4.5 months vs. 4.3 months), and treatment with capecitabine was noninferior to fluorouracil/leucovorin in terms of overall survival (12.5 to 13.3 months vs. 12.1 to 13.4 months).[69447] [46959]

    for the treatment of unresectable or metastatic colorectal cancer, in combination with oxaliplatin (XELOX or CapeOX)

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14, in combination with oxaliplatin (130 mg/m2 IV on day 1), every 21 days until disease progression or unacceptable toxicity; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] In a multicenter, randomized, phase 3 clinical trial, patients with metastatic colorectal cancer were randomized to treatment with XELOX or fluorouracil/leucovorin/oxaliplatin (FOLFOX4); the protocol was later amended to a 2 x 2 factorial design to allow further randomization to bevacizumab or placebo. Treatment with XELOX was noninferior to FOLFOX4 with regard to the primary outcome of progression-free survival (8 months vs. 8.5 months).[41607] In an exploratory overall survival analysis, the median overall survival was 19 months in the pooled capecitabine/capecitabine-placebo arms compared with 18.9 months in the pooled FOFOX4/FOLFOX4-placebo arms; the study was not powered for formal noninferiority testing for overall survival.[68390]

    for the treatment of unresectable or metastatic colorectal cancer, in combination with oxaliplatin (XELOX or CapeOX) and bevacizumab

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14, in combination with bevacizumab (7.5 mg/kg IV on day 1) and oxaliplatin (130 mg/m2 IV on day 1), every 21 days until disease progression or unacceptable toxicity; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Bevacizumab was administered prior to oxaliplatin on day 1 in the randomized clinical trial. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, phase 3 clinical trial, patients with metastatic colorectal cancer were randomized to treatment with XELOX or fluorouracil/leucovorin/oxaliplatin (FOLFOX4); the protocol was later amended to a 2 x 2 factorial design to allow further randomization to bevacizumab or placebo. The primary endpoint of median progression-free survival was significantly improved in patients treated with either XELOX or FOLFOX4 plus bevacizumab compared with those who received XELOX or FOLFOX4 alone (9.4 months vs. 8 months), with a median duration of response of 8.45 months versus 7.4 months, respectively. Overall survival, a secondary endpoint, was improved in the bevacizumab arms but did not reach statistical significance (21.3 vs. 19.9 months).[41609] [44458]

    For the treatment of unresectable advanced or metastatic biliary tract cancer†

    Oral dosage

    Adults

    Multiple dosage regimens have been studied. Capecitabine 1,250 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with cisplatin 60 mg/m2 IV over 1 hour on day 1, repeated every 21 days until disease progression or unacceptable toxicity. In a phase II trial of 38 patients, capecitabine/cisplatin produced an overall response rate of 21.4%. Grade III or IV neutropenia occurred in 20% of patients.[36002] Another regimen is capecitabine 650 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1 and 8, repeated every 21 days. In phase II trials, this dosage produced an ORR of 29% to 31%.[36003] [36004] Another phase II trial of 43 patients studied capecitabine 1,000 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with cisplatin 60 mg/m2 IV on day 1 and epirubicin 50 mg/m2 IV on day 1, repeated every 21 days until disease progression or unacceptable toxicity.[36005]

    For the treatment of inoperable, recurrent, platinum- and taxane-resistant ovarian cancer†

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14, then a 7-day rest period has been given every 21 days. Treatment should be continued until the patient experiences unacceptable toxicity or disease progression. In a phase II study of 41 patients, a partial response was observed in 7.3% of patients and stable disease was achieved in 54% of patients. Grade 3 adverse effects included hand-foot syndrome (27%), abdominal pain (17%), and diarrhea (10%).[34432] In other phase II studies, a higher dose of 1,250 mg/m2 led to the overall response rate in heavily pretreated patients of 3% to 9%.[46087][46088]

    For the treatment of esophageal cancer, gastric cancer, and gastroesophageal junction (GEJ) cancer

    for the adjuvant treatment of stage II through IIIB gastric cancer† in combination with oxaliplatin

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14 in combination with oxaliplatin 130 mg/m2 IV on day 1, repeated every 3 weeks for 8 cycles. In a phase 3 clinical trial, 1,035 patients with stage II to IIIB gastric cancer were randomized to receive adjuvant capecitabine and oxaliplatin (XELOX) or observation after surgical (D2) resection. The primary endpoint, 3-year disease free survival (DFS), was significantly improved with XELOX (74% vs. 60%, HR 0.56, 95% CI 0.44 to 0.72, p less than 0.0001). At a median follow-up of 34.4 months, the difference in overall survival was not significantly different between the 2 treatment arms (HR 0.74, 95% CI 0.53 to 1.03, p = 0.0775).[45379]

    for the treatment of unresectable or metastatic gastric cancer, esophageal cancer, or gastroesophageal junction (GEJ) cancer as a component of a combination chemotherapy regimen

    Oral dosage

    Adults

    625 mg/m2 PO twice daily on days 1 to 21 of every 21-day cycle for a maximum of 8 cycles has been studied in combination with platinum-containing chemotherapy. Additionally, capecitabine 850 mg/m2 or 1,000 mg/m2 PO twice daily on days 1 to 14 of every 21-day cycle until disease progression or unacceptable toxicity has been studied in combination with oxaliplatin 130 mg/m2 IV on day 1 of each cycle. Round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] [34869] [69456] [69457] [40571]

    for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in patients who have not received prior treatment for metastatic disease, as a component of a combination chemotherapy regimen

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14, in combination with cisplatin (80 mg/m2 IV on day 1) and trastuzumab (8 mg/kg IV on day 1, then 6 mg/kg IV every 21 days thereafter), every 3 weeks until disease progression or unacceptable toxicity. Round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] In a phase 3 trial, patients with inoperable, locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive 6 cycles of cisplatin and fluorouracil or capecitabine, with or without trastuzumab which was continued until disease progression or unacceptable toxicity. Overall survival (13.5 months vs. 11 months), the primary endpoint, and objective response rate (47% vs. 35%) were significantly increased with the addition of trastuzumab. An updated survival analysis conducted 1 year after the final analysis showed a continued overall survival benefit in the trastuzumab arm (13.1 months vs. 11.7 months). A subgroup analysis revealed an even greater increase in overall survival (18 months vs. 13.2 months) for the trastuzumab arm in patients with high expression of the HER2 protein. Cardiac dysfunction (LVEF decrease of 10% or more from baseline to an absolute value less than 50%) occurred in 5% of patients who received trastuzumab vs. 1.1% of patients who did not receive trastuzumab.[41715] [28061]

    for the treatment of advanced or metastatic esophageal, gastric, or gastroesophageal junction (GEJ) cancer, in combination with oxaliplatin and nivolumab†

    Oral dosage

    Adults

    1,000 mg/m2 PO twice daily on days 1 to 14, in combination with oxaliplatin (130 mg/m2 IV on day 1) and nivolumab (360 mg IV on day 1), every 3 weeks until disease progression, unacceptable toxicity, or for nivolumab, up to 2 years in patients without disease progression. Round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[45258] [43412] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]

    For the treatment of pancreatic cancer

    for the adjuvant treatment of pancreatic adenocarcinoma, in combination with gemcitabine

    Oral dosage

    Adults

    830 mg/m2 PO twice daily on days 1 to 21 in combination with gemcitabine (1,000 mg/m2 IV on days 1, 8, and 15), repeated every 28 days until disease progression, unacceptable toxicity, or for a maximum of 6 cycles; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] After a median follow-up of 60 months, patients with ductal adenocarcinoma of the pancreas treated with gemcitabine plus capecitabine after an R0 or R1 resection had significantly prolonged median overall survival compared with those treated with gemcitabine alone in a multicenter, randomized, open-label phase 3 clinical trial (27.7 months vs. 26 months); 5-year survival rates were 20% and 28%, respectively.[69450] In a subgroup analysis after , the magnitude of effect on median overall survival in patients with R0 resection (39.5 months vs. 27.9 months) was significantly greater than in patients with R1 resection (23.7 months vs. 23 months).[62255]

    Therapeutic Drug Monitoring

    Dosage Adjustments for Treatment-Related Toxicities:

     

    Monotherapy or in Combination with Docetaxel:

    NOTE: At the beginning of a treatment cycle, if the patient is receiving capecitabine in combination with docetaxel and a treatment delay is indicated, delay administration of both agents until the requirements for restarting both drugs are met.

    Other Nonhematologic Adverse Reactions

    • Grade 1: No dose adjustment needed.
    • Grade 2: Interrupt capecitabine therapy. For the first appearance, therapy may be resumed without a dose reduction when the toxicity has resolved to grade 1 or less. Resume therapy at a reduced dose when the toxicity has resolved to grade 1 or less for the second (75% of starting dose) or third (50% of starting dose) appearance. Once the dose of capecitabine has been reduced, it should not be increased at a later time. For the fourth appearance of a grade 2 toxicity, permanently discontinue therapy.
    • Grade 3: Interrupt capecitabine therapy. Treatment may be resumed at a reduced dose when the toxicity has resolved to grade 1 or less for the first (75% of starting dose) or second (50% of starting dose) appearance. Once the dose of capecitabine has been reduced, it should not be increased at a later time. For the third appearance of a grade 3 toxicity, permanently discontinue therapy.
    • Grade 4: Permanently discontinue capecitabine therapy. If the physician feels it is in the patient's best interest to continue therapy, interrupt capecitabine until the toxicity has resolved to grade 1 or less and resume therapy at a reduced dose (50% of starting dose).[44458]

    Severe Cutaneous Adverse Reactions (SCARs) including Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

    • Any grade: Permanently discontinue capecitabine therapy.[44458]

     

    Dosage Adjustments for Hematologic Toxicities when used in Combination with Ixabepilone:

    NOTE: Follow recommendations for treatment-related toxicity, above, for nonhematologic toxicity.

    • Platelets less than 25,000/mm3, or less than 50,000/mm3 with bleeding: Hold capecitabine therapy for concurrent diarrhea or stomatitis until platelet count greater than 50,000/mm3, then continue at same dose.
    • Neutrophils less than 500 cells/mm3 for 7 or more days, or febrile neutropenia: Hold capecitabine therapy for concurrent diarrhea or stomatitis until neutrophil count greater than 1,000 cells/mm3, then continue at same dose.[33563]

    Maximum Dosage Limits

    • Adults

      2,500 mg/m2 PO total daily dose (1,250 mg/m2 PO administered twice daily) on days 1 to 14, every 21 days.

    • Geriatric

      2,500 mg/m2 PO total daily dose (1,250 mg/m2 PO administered twice daily) on days 1 to 14, every 21 days.

    • Adolescents

      Safety and efficacy have not been established.

    • Children

      Safety and efficacy have not been established.

    Patients with Hepatic Impairment Dosing

    Baseline 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.[44458]

     

    Treatment-Related Hepatotoxicity:

    • Grade 3 hyperbilirubinemia: Interrupt capecitabine therapy. Treatment may be resumed at a reduced dose when the toxicity has resolved to grade 2 or less (i.e., less than 3 times the upper limit of normal [ULN]) for the first (75% of starting dose) or second (50% of starting dose) appearance. Once the dose of capecitabine has been reduced, it should not be increased at a later time. For the third appearance of a grade 3 toxicity, permanently discontinue therapy.
    • Grade 4 hyperbilirubinemia: Permanently discontinue capecitabine therapy. If the physician feels it is in the patient's best interest to continue therapy, interrupt capecitabine until the toxicity has resolved to grade 2 or less (i.e., less than 3 times ULN) and resume therapy at a reduced dose (50% of starting dose).[44458]

    Patients with Renal Impairment Dosing

    Baseline Renal Insufficiency:

    • Mild renal impairment (CrCl more than 51 mL/min): No dosage adjustment is recommended.
    • Moderate renal impairment (CrCl 30 to 50 mL/min): Reduce the dose of capecitabine by 25%.
    • Severe renal impairment (CrCl less than 30 mL/min): Dosage not established. If an alternative to capecitabine treatment is not available, capecitabine can be administered on an individual basis at a reduced starting dose and close monitoring of patient-specific clinical and biochemical data; adjust the dose as necessary for treatment-related toxicities.[44458]
    † Off-label indication
    Revision Date: 03/21/2024, 01:46:00 AM

    References

    28061 - Herceptin (trastuzumab) package insert. South San Francisco, CA: Genentech Inc.; 2021 Feb.31340 - Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-2704.33192 - Tykerb (lapatinib) tablet package insert. Research Triangle Park, NC: GlaxoSmithKline; 2022 March.33563 - Ixempra (ixabepilone) for injection package insert. Princeton, NJ: R-Pharm US LLC; 2023 Jan.34432 - Wolf JK, Bodurka DC, Verschraegen C, et al. A phase II trial of oral capecitabine in patients with platinum - and taxane - refractory ovarian, fallopian tube, or peritoneal cancer. Gynecol Oncol 2006;102:468-474.34869 - Kang YK, Kang WK, Shing DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 2009;20(4):666-73. Epub 2009 Jan 19.36002 - Kim TW, Chang HM, Kang HJ, et al. Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced biliary tract cancer. Ann Oncol 2003;14:1115-11120.36003 - Riechelmann RP, Townsley CA, Chin SN, et al. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer 2007;110:1307-1312.36004 - Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 2005;23:2332-2338.36005 - Park SH, Park YH, Lee JN, et al. Phase II study of epirubicin, cisplatin, and capecitabine for advanced biliary tract adenocarcinoma. Cancer 2006;106:361-365.40571 - Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36-46.41607 - Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006-2012.41609 - Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013-2019.41715 - Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697.43412 - Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 2007;25:102-109.44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.44575 - O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20:2812-2823.45258 - Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-1471.45379 - Bang Y, Kim YW, Yang H, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer: results of the Phase III CLASSIC trial. J Clin Oncol 2011;29. ASCO Abstract #LBA4002.46087 - Rischin D, Phillips KA, Friedlander M, et al. A phase II trial of capecitabine in heavily pre-treated platinum-resistant ovarian cancer. Gynecol Oncol 2004;93:417-42146088 - Pisano C, Morabito A, Sorio R, et al. A phase II study of capecitabine in the treatment of ovarian cancer resistant or refractory to platinum therapy: a muticentre Italian trial in ovarian cancer (MITO-6) trial. Cancer Chemother Pharmacol 2009;64:1021-102746959 - Van Custem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097-4106.58668 - Opdivo (nivolumab) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2024 Mar.62127 - Nerlynx (neratinib) package insert. Los Angeles, CA: Puma Biotechnology, Inc; 2021 June.62255 - Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011-1024.62658 - Ogivri (trastuzumab-dkst) package insert. Cambridge, MA: Biogen Biologics, Inc; 2023 July.63839 - Herzuma (trastuzumab-pkrb) package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2019 May.63887 - Ontruzant (trastuzumab-dttb) package insert. Jersey City, NJ: Organon LLC; 2021 June.64521 - Kanjinti (trastuzumab-anns) package insert. Thousand Oaks, CA: Amgen, Inc; 2022 Oct.64524 - Trazimera (trastuzumab-qyyp) package insert. New York, NY: Pfizer Labs; 2020 Nov.65295 - Tukysa (tucatinib) tablets package insert. Bothell, WA: Seattle Genetics, Inc.; 2023 Jan65296 - Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metatatic breast cancer. NEJM. 2020;382(7):597-609.65929 - Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with 2 or more HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-3149.66712 - Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastrooesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. The Lancet. 2021;398:27-40.68390 - Cassidy J, Clarke S, Diaz-Rubio E, et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. British Journal of Cancer. 2011;105:58-64.68392 - Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13:579-588.69445 - Schmoll H-J, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol. 2015;33(32):3733-3742.69447 - Hoff PM, Ansari R, Batist G, et al. Comparison of Oral Capecitabine Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Treatment in 605 Patients With Metastatic Colorectal Cancer: Results of a Randomized Phase III Study. J Clin Oncol. 2001;19(8):2282-2292.69450 - Neoptolemos JP, Palmer DH, Ghaneh P, et al. ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma: Five year follow-up. J Clin Oncol. 2020:38(15 suppl);abstract 4516.69456 - Kim GM, Jeung HC, Rha SY, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine–oxaliplatin in advanced gastric cancer. European J of Cancer. 2012;48:518-526.69457 - van Meerten E, Eskens FA, van Gameren EC, et al. First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study. British J of Cancer. 2007;95:1348-1352.

    How Supplied

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (16729-0072) (Accord Healthcare, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (65162-0843) (Amneal Pharmaceuticals LLC) (off market)

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (59923-0721) (Areva Pharmaceuticals Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (72485-0204) (Armas Pharmaceuticals, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (67877-0458) (Ascend Laboratories, LLC a Subsidiary of Alkem Laboratories Ltd) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (59651-0204) (Aurobindo Pharma Limited) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (42291-0190) (AvKARE, Inc.) (off market)

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (42291-0166) (AvKARE, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (68001-0487) (BluePoint Laboratories) nullCapecitabine 150mg Tablet package photo

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (72606-0554) (Celltrion USA, Inc.) (off market)

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (62135-0783) (Chartwell RX LLC) nullCapecitabine 150mg Tablet package photo

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (69097-0949) (Cipla USA, Inc) (off market)

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (55111-0496) (Dr. Reddy's Laboratories, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (51407-0095) (Golden State Medical Supply, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (51407-0639) (Golden State Medical Supply, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (00054-0271) (Hikma Pharmaceuticals USA Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (70756-0815) (Lifestar Pharma, LLC.) (off market)

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (70756-0815) (Lifestar Pharma, LLC.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (00378-2511) (Mylan Pharmaceuticals Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (16714-0467) (NorthStar Rx LLC) nullCapecitabine 150mg Tablet package photo

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (72205-0006) (Novadoz Pharmaceuticals LLC) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (64980-0276) (Rising Pharmaceuticals Inc) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (62756-0238) (Sun Pharmaceutical Industries, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 150mg Tablet (00093-7473) (Teva Pharmaceuticals USA) null

    Capecitabine Oral tablet

    Xeloda 150mg Tablet (00004-1100) (Genentech Inc) null

    Capecitabine Oral tablet

    Xeloda 150mg Tablet (61269-0470) (H2-Pharma, LLC) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (16729-0073) (Accord Healthcare, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (60687-0149) (American Health Packaging) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (65162-0844) (Amneal Pharmaceuticals LLC) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (72485-0205) (Armas Pharmaceuticals, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (67877-0459) (Ascend Laboratories, LLC a Subsidiary of Alkem Laboratories Ltd) nullCapecitabine 500mg Tablet package photo

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (59651-0205) (Aurobindo Pharma Limited) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (42291-0191) (AvKARE, Inc.) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (42291-0167) (AvKARE, Inc.) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (50268-0154) (AvPAK; a Division of AvKARE Inc) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (68001-0488) (BluePoint Laboratories) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (72606-0555) (Celltrion USA, Inc.) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (62135-0784) (Chartwell RX LLC) nullCapecitabine 500mg Tablet package photo

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (69097-0948) (Cipla USA, Inc) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (55111-0497) (Dr. Reddy's Laboratories, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (51407-0096) (Golden State Medical Supply, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (51407-0640) (Golden State Medical Supply, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (00054-0272) (Hikma Pharmaceuticals USA Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (70756-0816) (Lifestar Pharma, LLC.) (off market)

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (70756-0816) (Lifestar Pharma, LLC.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (51079-0510) (Mylan Institutional LLC) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (00378-2512) (Mylan Pharmaceuticals Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (16714-0468) (NorthStar Rx LLC) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (72205-0007) (Novadoz Pharmaceuticals LLC) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (82009-0112) (Quallent Pharmaceuticals Health LLC) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (64980-0277) (Rising Pharmaceuticals Inc) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (62756-0239) (Sun Pharmaceutical Industries, Inc.) null

    Capecitabine Oral tablet

    Capecitabine 500mg Tablet (00093-7474) (Teva Pharmaceuticals USA) null

    Capecitabine Oral tablet

    Xeloda 500mg Tablet (00004-1101) (Genentech Inc) null

    Capecitabine Oral tablet

    Xeloda 500mg Tablet (61269-0475) (H2-Pharma, LLC) null

    Description/Classification

    Description

    Capecitabine is a prodrug that is metabolized to fluorouracil, an antimetabolite nucleoside inhibitor. It is FDA approved as monotherapy for the adjuvant treatment of stage III colon cancer and for the treatment of unresectable or metastatic colorectal cancer or breast cancer; as a component of a combination chemotherapy regimen for the adjuvant treatment of colorectal cancer or pancreatic cancer and for unresectable or metastatic colorectal cancer, gastric cancer, esophageal cancer, gastroesophageal junction (GEJ) cancer; in combination with docetaxel in progressive advanced or metastatic breast cancer; and as a component of chemoradiotherapy for the perioperative treatment of locally advanced rectal cancer. Capecitabine carries a black box warning for an increased risk of bleeding with concomitant use of oral vitamin K antagonists such as warfarin.[44458]

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Antimetabolite Antineoplastic Agents
          • Pyrimidine Analogs
    Revision Date: 03/21/2024, 01:46:00 AM

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Hazardous Drugs Classification

    • NIOSH 2016 List:Group 1 [63664]
    • NIOSH (Draft) 2020 List: Table 1
    • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    • Use gloves. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.[63664] Exposure to crushed capecitabine tablets has resulted in eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and diarrhea.[44458]

     

    Emetic Risk

    • Minimal/Low
    • Administer prn antiemetics as necessary.[67389]

    Route-Specific Administration

    Oral Administration

    • Round the calculated dose of capecitabine to the nearest 150-mg tablet strength.
    • Capecitabine is administered orally twice daily within 30 minutes after a meal; take doses approximately 12 hours apart.
    • Do not cut, crush, or chew capecitabine tablets. The safety and effectiveness of crushed capecitabine tablets have not been established.
    • If vomiting occurs, do not take an additional dose; continue with the next scheduled dose.[44458]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 03/21/2024, 01:46:00 AMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616167389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.

    Adverse Reactions

    Mild

    • abdominal pain
    • anorexia
    • arthralgia
    • asthenia
    • back pain
    • cough
    • diarrhea
    • dizziness
    • dysgeusia
    • dyspepsia
    • epistaxis
    • fatigue
    • fever
    • flushing
    • headache
    • hyperhidrosis
    • hypoesthesia
    • infection
    • influenza
    • insomnia
    • lacrimation
    • lethargy
    • myalgia
    • nail discoloration
    • nausea
    • ocular irritation
    • onycholysis
    • paresthesias
    • photosensitivity
    • polydipsia
    • pruritus
    • rash
    • rhinorrhea
    • skin discoloration
    • syncope
    • tremor
    • vertigo
    • vomiting
    • weakness
    • weight loss
    • xerostomia

    Severe

    • abdominal pain
    • agranulocytosis
    • anemia
    • angioedema
    • anorexia
    • arrhythmia exacerbation
    • arthralgia
    • asthenia
    • atrial fibrillation
    • back pain
    • bradycardia
    • cardiac arrest
    • cardiomyopathy
    • cardiotoxicity
    • cholestasis
    • coagulopathy
    • constipation
    • cough
    • dehydration
    • diarrhea
    • dyspnea
    • edema
    • elevated hepatic enzymes
    • enterocolitis
    • esophageal ulceration
    • fatigue
    • fever
    • GI bleeding
    • headache
    • heart failure
    • hepatic failure
    • hepatitis
    • hepatotoxicity
    • hyperbilirubinemia
    • hypercalcemia
    • hypocalcemia
    • ileus
    • jaundice
    • keratitis
    • keratoconjunctivitis
    • lethargy
    • leukoencephalopathy
    • leukopenia
    • lupus-like symptoms
    • lymphopenia
    • myalgia
    • myocardial infarction
    • myocarditis
    • nausea
    • neutropenia
    • palmar-plantar erythrodysesthesia (hand and foot syndrome)
    • pancytopenia
    • paresthesias
    • peptic ulcer
    • pleural effusion
    • pulmonary embolism
    • renal failure
    • sinus tachycardia
    • Stevens-Johnson syndrome
    • stomatitis
    • supraventricular tachycardia (SVT)
    • thrombocytopenia
    • thrombosis
    • toxic epidermal necrolysis
    • typhlitis
    • visual impairment
    • vomiting

    Moderate

    • alopecia
    • anemia
    • angina
    • ataxia
    • bleeding
    • bone marrow suppression
    • bone pain
    • chest pain (unspecified)
    • confusion
    • conjunctivitis
    • constipation
    • dehydration
    • depression
    • dysarthria
    • dysphagia
    • dyspnea
    • edema
    • elevated hepatic enzymes
    • encephalopathy
    • erythema
    • hot flashes
    • hyperbilirubinemia
    • hypertension
    • hypertriglyceridemia
    • hypoalbuminemia
    • hypokalemia
    • hypomagnesemia
    • hyponatremia
    • hypophosphatemia
    • hypotension
    • lymphopenia
    • migraine
    • neurotoxicity
    • neutropenia
    • palmar-plantar erythrodysesthesia (hand and foot syndrome)
    • peripheral neuropathy
    • phlebitis
    • radiation recall reaction
    • skin ulcer
    • stomatitis
    • thrombocytopenia

    Insomnia, depression, and confusion were each reported in fewer than 10% of patients treated with capecitabine monotherapy in a pooled safety population. A general alteration in mood was also reported in less than 10% of patients who received capecitabine monotherapy in 1 randomized clinical trial.[44458]

    Palmar-plantar erythrodysesthesia (hand and foot syndrome) is a dose-limiting toxicity of capecitabine and occurred in 54% to 63% (grade 3 or 4, 11% to 24%) of patients treated with capecitabine as monotherapy or in combination with docetaxel across clinical trials; persistent or severe palmar-plantar erythrodysesthesia can eventually lead to the loss of fingerprints. In patients with metastatic breast or colorectal cancer who received capecitabine monotherapy, the median time to onset of grade 1 to 3 palmar-plantar erythrodysesthesia was 2.6 months (range, 11 days to 1 year). Dermatitis was additionally reported in 27% to 37%; grade 3, 1% of patients treated with capecitabine monotherapy in clinical trials. Additional dermatologic adverse reactions reported in less than 10% of patients treated with capecitabine monotherapy include alopecia, erythema, hyperhidrosis, nail disorder, photosensitivity reaction, pruritus, radiation recall reaction, rash, skin discoloration, and skin ulcer. Nail discoloration and onycholysis were each reported in less than 10% of patients treated with capecitabine and docetaxel in a clinical trial; the addition of capecitabine to docetaxel did not increase the incidence of alopecia (41% vs. 42%; grade 3, 6% vs. 7%) or nail disorders (14% vs. 15%; grade 3, 2% vs. 0%) compared with docetaxel alone. Cutaneous lupus erythematosus (lupus-like symptoms) and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported in postmarketing experience with capecitabine; permanently discontinue capecitabine for SCARs.[44458]

    Hyperbilirubinemia occurred in 48% of patients with metastatic colorectal cancer treated with capecitabine compared with 17% of those who received fluorouracil/leucovorin in a randomized clinical trial (grade 3 or 4, 23% vs. 6%); the incidence of grade 3 or 4 increases in bilirubin was similar (20%) in another clinical trial of patients with colorectal cancer receiving adjuvant treatment with capecitabine therapy. In a single-arm trial of patients with metastatic breast cancer, hyperbilirubinemia occurred in 22% of patients who received monotherapy (grade 3 or 4, 11%). Hyperbilirubinemia was more common in metastatic breast cancer patients treated with capecitabine plus docetaxel compared with docetaxel alone (20% vs. 6%; grade 3 or 4, 9% vs. 4%). In patients with metastatic breast or colorectal cancer, the incidence of patients who developed grade 3 or 4 hyperbilirubinemia was higher in those with hepatic metastases at baseline compared to those without (23% vs. 12%). The median total bilirubin increased from 8 micromol/liter at baseline to 13 micromol/liter during therapy; the median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days. Of patients with grade 3 or 4 hyperbilirubinemia, 58% (grade 3 or 4, 8%) had both pre- and postbaseline increases in alkaline phosphatase and 19% had only postbaseline increases in alkaline phosphatase; 35% (grade 3 or 4, 3%) had both pre- and postbaseline elevated hepatic enzymes and 28% only had postbaseline transaminitis. Grade 3 or 4 increases in ALT were reported in 1.6% of patients who received capecitabine monotherapy in one noncomparative trial. Hepatic fibrosis, hepatitis, cholestasis, and abnormal liver function tests were also each reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population, while jaundice, abnormal liver function tests, hepatic failure, hepatic coma, and hepatotoxicity were reported in less than 10% of patients treated with capecitabine plus docetaxel in 1 clinical trial. Hepatic failure was also reported in postmarketing experience with capecitabine. Increased ALT (75%) and hypoalbuminemia (55%) were more common in pediatric patients compared to adult patients. Monitor patients with hepatic disease more frequently for adverse reactions; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if hyperbilirubinemia occurs.[44458]

    Cardiotoxicity has been reported with capecitabine treatment, including myocardial infarction/ischemia, angina, dysrhythmias or arrhythmia exacerbation, cardiac arrest, heart failure, cardiomyopathy, ECG changes, and sudden death. Sinus tachycardia, bradycardia, atrial fibrillation, and myocarditis were each reported in less than 10% of patients who received capecitabine monotherapy in a pooled safety population; chest pain was additionally reported in less than 10% of capecitabine-treated patients in 1 randomized clinical trial. Fewer than 10% of breast cancer patients treated with capecitabine plus docetaxel experienced supraventricular tachycardia (SVT) in another randomized clinical trial. Use capecitabine with caution in patients with cardiac disease or a prior history of coronary artery disease. If cardiotoxicity occurs, interrupt therapy with capecitabine as clinically appropriate; the safety of resuming capecitabine therapy after cardiotoxicity has occurred has not been established.[44458]

    Bone marrow suppression can occur with capecitabine treatment. Lymphopenia (94%; grade 3 or 4, 59%), anemia (72%; grade 3 or 4, 4%), neutropenia (26%; grade 3 or 4, 4%), and thrombocytopenia (24%; grade 3 or 4, 4%) were reported in a single-arm clinical trial of patients treated with capecitabine. In pooled data from 2 randomized clinical trials, anemia occurred with a similar frequency in patients treated with capecitabine to those who received fluorouracil and leucovorin (80% vs. 79%; grade 3 or 4, 2% to 3% vs. 1% to 2%); however, neutropenia occurred in 13% of patients who received capecitabine compared with 46% of those in the fluorouracil/leucovorin arm (grade 3 or 4, 3% vs. 21%). In another trial, the incidence of grade 3 or 4 decreases from baseline in lymphocytes (13% vs. 13%), hemoglobin (1% vs. 1.2%), and platelets (1% vs. 0.7%) were similar in patients treated with capecitabine compared with fluorouracil/leucovorin; grade 3 or 4 decreases from baseline in neutrophils/granulocytes (2.4% vs. 26%) and neutrophils (2.2% vs. 26%) were again more common in the fluorouracil/leucovorin arm. In a pooled safety population, bone marrow depression, leukopenia, and pancytopenia each occurred in less than 10% of patients who received capecitabine monotherapy. The addition of capecitabine to docetaxel resulted in a similar incidence of lymphopenia (99% vs. 98%; grade 3 or 4, 89% vs. 84%), leukopenia (91% vs. 88%; grade 3 or 4, 61% vs. 75%), neutropenia (86% vs. 87%; grade 3 or 4, 69% vs. 76%), anemia (80% vs. 83%; grade 3 or 4, 10% vs. 5% to 6%), and febrile neutropenia (16% vs. 21%; grade 3 or 4, 16% vs. 21%) compared to those who received docetaxel alone in a randomized clinical trial; thrombocytopenia was reported in 41% versus 23% of patients, respectively (grade 3 or 4, 3% vs. 3%). Agranulocytosis and neutropenic sepsis were each reported in less than 10% of patients who received capecitabine and docetaxel. Lymphopenia (73%), thrombocytopenia (57%), neutropenia (50%), and low hematocrit (50%) were more common in the pediatric population compared to adults. Monitor complete blood counts at baseline and prior to each cycle. Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm3 or platelet counts below 100,000 cells/mm3. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary if grade 3 or 4 myelosuppression occurs during the course of treatment.[44458]

    Nausea (34% to 53%; grade 3 or higher, 2% to 4%), vomiting (15% to 37%; grade 3 or higher, 2% to less than 5%), abdominal pain (14% to 35%; grade 3 or higher, 3% to less than 10%), stomatitis (22% to 25%; grade 3 or higher, 2% to 7%), and constipation (15% or less; grade 3 or higher, less than 2%), were reported in patients treated with capecitabine monotherapy across clinical trials; grade 1 or 2 oral discomfort was also reported in capecitabine-treated patients in 1 trial. Less than 10% of patients who received capecitabine monotherapy in a pooled safety population reported abdominal distention, gastric ulcer (peptic ulcer), ileus, and proctalgia. The incidence of stomatitis was higher in a clinical trial of patients who received docetaxel plus capecitabine (67%; grade 3 or higher, 17% to 18%), but the incidence of nausea (45% (grade 3, 7%), vomiting (35%; grade 3 or higher, 5%), abdominal pain (30%; grade 3 or higher, 3% to 4%), constipation (20%; grade 3, 2%), and ileus (less than 10%) were similar to capecitabine monotherapy. Sore throat was additionally reported in 12% (grade 3, 2%) of those who received capecitabine and docetaxel, as well as esophageal ulceration (less than 10%). Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including mucositis.[44458]

    Diarrhea which can sometimes be severe is a dose-limiting toxicity of capecitabine and was reported in 47% to 67% (grade 3 or 4, 12% to 15%) of patients treated with capecitabine as monotherapy or in combination with docetaxel or oxaliplatin in clinical trials; the incidence of diarrhea was higher when used as a component of chemoradiotherapy. Gastroenteritis was reported in less than 10% of patients receiving capecitabine monotherapy in a pooled safety population. An upper GI inflammatory disorder (less than 10%) and a GI motility disorder (10%; grade 3, less than 1%) were reported in a clinical trial of patients with advanced colorectal cancer who received capecitabine monotherapy. Necrotizing enterocolitis (typhlitis) developed in less than 10% of metastatic breast cancer patients treated with capecitabine plus docetaxel; consider typhlitis in patients with fever, neutropenia, and abdominal pain. Monitor hydration status and renal function at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for grade 2 or higher diarrhea or dehydration.[64032] [44458]

    Anorexia or decreased appetite (26% or less; grade 3 or higher, 3% to 4%), dysgeusia (less than 10%), dysphagia (less than 10%), and dyspepsia (14% or less) were reported in patients treated with capecitabine as monotherapy or in combination with docetaxel across clinical trials. Dyspepsia and cachexia were each additionally reported in less than 10% of patients who received capecitabine monotherapy while weight loss and xerostomia were each reported in less than 10% of patients treated with capecitabine plus docetaxel.[44458]

    Dehydration was reported in 10% or fewer patients treated with capecitabine as monotherapy or in combination with docetaxel in clinical trials (grade 3, 2% or less). Deaths from severe dehydration have been reported in elderly patients treated with weekly fluorouracil and leucovorin. Renal impairment occurred in less than 10% of patients who received capecitabine in clinical trials, with acute renal failure secondary to dehydration (including fatal outcome) reported in postmarketing experience with capecitabine. Optimize hydration prior to starting therapy. Monitor renal function and hydration status at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if dehydration or renal impairment occur.[44458]

    Fever was reported in 18% or fewer patients treated with capecitabine monotherapy across clinical trials (grade 3 or 4, 1% or less). Various types of infection including bronchitis, fungal infections, influenza-like illnesses, pneumonia, sepsis, and other viral infections have each been reported in less than 10% of patients who received capecitabine monotherapy.[44458]

    Fatigue (16% to 42% vs. 16% to 46%; grade 3 or 4, 8% or less vs. 1% to 4%), asthenia (10% vs. 10%; less than 1% vs. 1%), and lethargy (10% vs. 9%; grade 3 or 4, less than 1% vs. less than 1%) occurred with a similar frequency in patients treated with capecitabine monotherapy versus fluorouracil/leucovorin in clinical trials. Muscle weakness was also reported in fewer than 10% of patients who received capecitabine monotherapy in a pooled safety population. The addition of capecitabine to docetaxel in patients with metastatic breast cancer did not increase the incidence of asthenia (26% vs. 25%; grade 3 or 4, 4% to 5% vs. 6%) or fatigue (22% vs. 27%; grade 3 or 4, 4% vs. 6%) compared with docetaxel alone. Weakness was reported in 16% of patients who received capecitabine plus docetaxel compared with 11% of those who received docetaxel alone (grade 3, 2% vs. 2%); lethargy was reported in less than 10% of patients in the capecitabine arm.[44458]

    Mild (grade 1 or 2) ocular irritation was reported in 13% to 15% of patients with metastatic breast or colorectal cancer treated with capecitabine monotherapy in 2 clinical trials. Additionally, abnormal vision/visual impairment, conjunctivitis, and keratoconjunctivitis have each been reported in fewer than 10% of patients receiving capecitabine monotherapy. Increased lacrimation was reported in 12% of patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel compared with 7% (grade 3, less than 1%) of those receiving docetaxel alone; conjunctivitis and eye irritation were also each reported in fewer than 10% of patients in the capecitabine arm. There have been reports of lacrimal duct stenosis and corneal disorders including keratitis in postmarketing experience with capecitabine.[44458]

    Hypercalcemia and hypocalcemia have been reported in patients with metastatic colorectal cancer treated with capecitabine monotherapy in a randomized clinical trial, including grade 3 or 4 decreases (2.3%) and increases (1.1%) from baseline in calcium levels. Hypokalemia, hypomagnesemia, and hypertriglyceridemia were also each reported in fewer than 10% of patients receiving capecitabine monotherapy in a pooled safety population. Hypokalemia (68%), hypocalcemia (48%), hypophosphatemia (45%), and hyponatremia (45%) were more common in pediatric patients compared to adult patients.[44458]

    Hemorrhage (bleeding), coagulopathy, and epistaxis were each reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population; GI bleeding was additionally reported in less than 10% of patients treated with capecitabine monotherapy in 1 randomized clinical trial. Hemorrhagic diarrhea, decreased prothrombin, and epistaxis were also reported in less than 10% of patients treated with capecitabine plus docetaxel in a randomized clinical trial.[44458]

    Musculoskeletal adverse reactions reported with capecitabine treatment when administered as monotherapy or in combination with docetaxel include arthralgia (15% or less; grade 3, 2% or less), arthritis (less than 10%), back pain (12% or less; grade 3, 2% or less), myalgia (15 or less%; grade 3, 2% or less), noncardiac chest pain (unspecified) (less than 10%), generalized pain (12% or less; grade 3, 1% or less), limb pain (13% or less; grade 3, less than 1%), and myalgia (less than 10%). Bone pain was reported in fewer than 10% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in 1 randomized clinical trial.[44458]

    Headache (15% or less; grade 3, 3% or less), dizziness (12% or less), and vertigo (less than 10%) have been reported in patients treated with capecitabine as monotherapy or in combination with docetaxel across clinical trials; migraine was additionally reported in fewer than 10% of patients treated with capecitabine plus docetaxel in 1 randomized clinical trial.[44458]

    Paresthesias (12% to 21%; grade 3, 1% or less), peripheral neuropathy (10% or less), hypoesthesia (less than 10%), and polyneuropathy (less than 10%) were reported in patients treated with capecitabine monotherapy across clinical trials. Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including neurotoxicity.[44458]

    Edema was reported in 15% or fewer patients treated with capecitabine monotherapy across clinical trials (grade 3, 1%). The addition of capecitabine to docetaxel did not increase the incidence of edema compared to docetaxel alone in 1 randomized clinical trial (33% vs. 34%; grade 3 or 4, less than 2% vs. less than 4%). Lymphedema was reported in less than 10% of patients treated with capecitabine as monotherapy or in combination with docetaxel in clinical trials.[44458]

    Dyspnea (14% or less; grade 3, less than 3%), cough (13% or less; grade 3, 1% or less), respiratory distress (less than 10%), and a nonspecific pharyngeal disorder (less than 10%) were reported in patients treated with capecitabine as monotherapy or in combination with docetaxel in clinical trials. Pleural effusion and rhinorrhea each occurred in fewer than 10% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in 1 clinical trial.[44458]

    Venous thrombosis and pulmonary embolism were each reported in less than 10% of patients treated with capecitabine monotherapy in clinical trials. Venous phlebitis and thrombophlebitis were each reported in less than 10% of metastatic breast cancer patients who received capecitabine plus docetaxel in 1 clinical trial.[44458]

    Hot flashes were reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population. Flushing was also reported in less than 10% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in 1 clinical trial.[44458]

    Ataxia, impaired balance, encephalopathy, syncope, and tremor were each reported in less than 10% of patients treated with capecitabine monotherapy across clinical trials. Toxic leukoencephalopathy was reported in postmarketing experience with capecitabine therapy.[44458]

    Hypotension and hypertension were each reported in less than 10% of patients treated with capecitabine monotherapy in a pooled safety population.[44458]

    Thirst (polydipsia) was reported in less than 10% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials.[44458]

    Dysarthria and dysphasia were each reported in less than 10% of patients receiving capecitabine monotherapy in a pooled safety population.[44458]

    Angioedema has been reported with capecitabine use in postmarketing experience.[44458]

    Revision Date: 03/21/2024, 01:46:00 AM

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.64032 - Walko CM and Lindley C. Capecitabine: A Review. Clinical Therapeutics. 2005;27(1):23-44.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • anticoagulant therapy
    • bone marrow suppression
    • breast-feeding
    • cardiac disease
    • cardiotoxicity
    • contraception requirements
    • coronary artery disease
    • dehydration
    • diarrhea
    • dihydropyrimidine dehydrogenase (DPD) deficiency
    • geriatric
    • hepatic disease
    • infertility
    • male-mediated teratogenicity
    • nausea/vomiting
    • pregnancy
    • pregnancy testing
    • renal failure
    • renal impairment
    • reproductive risk
    • serious rash
    • skin disease

    Optimize hydration prior to starting therapy with capecitabine. Diarrhea, sometimes severe, has been reported with capecitabine therapy. Carefully monitor patients with severe diarrhea and administer standard antidiarrheal treatments (e.g., loperamide) if necessary. Dehydration can occur with capecitabine therapy and patients with anorexia, asthenia, nausea/vomiting, or diarrhea may be at increased risk. Monitor hydration status and renal function at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for grade 2 or higher diarrhea or dehydration.[44458]

    Use capecitabine with caution in patients with renal impairment; a dose reduction is necessary for patients with creatinine clearance (CrCl) 30 to 50 mL/min, and capecitabine has not been studied in patients with CrCl less than 30 mL/min. Serious cases of renal failure, some fatal, can occur with capecitabine treatment. Optimize hydration prior to starting therapy. Monitor renal function at baseline and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if renal impairment or renal failure occurs.[44458]

     

    Capecitabine is not recommended for patients with certain homozygous or compound heterozygous variants in the DPYD gene that result in complete dihydropyrimidine dehydrogenase (DPD) deficiency due to an increased risk of acute early-onset toxicities and serious adverse reactions that can result in death (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity); patients with partial DPD deficiency may also have an increased risk of serious adverse reactions. Capecitabine has not been proven safe for patients with complete DPD deficiency at any dose, and there is insufficient data regarding capecitabine dosing in patients with partial DPD activity. Consider testing for DPD deficiency prior to starting therapy if clinically appropriate. There is not an FDA-approved test to detect DPYD mutations; currently available tests may vary in accuracy and design. Hold or permanently discontinue capecitabine in patients with acute early-onset or unusually severe toxicities, which may indicate near complete or total absence of DPD activity.[44458]

    Bone marrow suppression can occur with capecitabine treatment. Monitor complete blood counts at baseline and prior to each cycle. Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm3 or platelet counts below 100,000 cells/mm3. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary if grade 3 or 4 myelosuppression occurs during the course of treatment.[44458]

    Monitor the INR more frequently in patients receiving concomitant capecitabine and vitamin K antagonist anticoagulant therapy and adjust the anticoagulant dose as clinically appropriate. Clinically significant increases in PT and INR and/or bleeding events, including fatalities, have been reported in patients taking capecitabine concomitantly with oral vitamin K antagonists such as warfarin, occurring within several days and up to several months after initiating capecitabine therapy; patients included those with and without liver metastases, as well as those who were on stable doses of oral vitamin K antagonists at the time capecitabine was introduced.[44458]

    Use capecitabine with caution in patients with cardiac disease or a prior history of coronary artery disease. Capecitabine therapy has been associated with cardiotoxicity including myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, electrocardiogram changes, cardiomyopathy, and sudden death; patients with a history of coronary artery disease may be at increased risk. If cardiotoxicity occurs, interrupt therapy with capecitabine as clinically appropriate; the safety of resuming capecitabine therapy after cardiotoxicity has occurred has not been established.[44458]

    Monitor patients with hepatic disease more frequently for adverse reactions. Capecitabine exposure increases in patients with mild to moderate hepatic impairment, while the effect of severe hepatic impairment on the safety and pharmacokinetics of capecitabine is unknown. Hyperbilirubinemia has been reported with capecitabine treatment and is more common in patients with hepatic metastases at baseline; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if hyperbilirubinemia occurs.[44458]

    Monitor geriatric patients (65 years or older) for an increased incidence of capecitabine-related gastrointestinal adverse reactions compared to younger patients. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil in clinical trials.[44458]

    Severe cutaneous adverse reactions (SCARs) (serious rash and skin disease) have been reported with capecitabine therapy including toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS), which can be fatal. Palmar-plantar erythrodysesthesia (hand and foot syndrome) has also occurred with capecitabine treatment; persistent or severe hand and foot syndrome can lead to loss of fingerprints, which could impact patient identification. Monitor patients for new or worsening skin conditions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for skin toxicity, depending on the severity of the reaction. Permanently discontinue capecitabine for SCARs.[44458]

    Pregnancy should be avoided by females of reproductive potential during capecitabine treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, capecitabine can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving capecitabine should be apprised of the potential hazard to the fetus. When capecitabine was given to pregnant animals during organogenesis, teratogenesis and embryolethality were observed in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC), respectively, in patients receiving the recommended dose. Teratogenic malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles.[44458]

    Counsel patients about the reproductive risk and contraception requirements during capecitabine treatment. Capecitabine can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with capecitabine. Females of reproductive potential should undergo pregnancy testing prior to initiation of capecitabine. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose. Women who become pregnant while receiving capecitabine should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of capecitabine on human fertility, male and female infertility has been observed in animal studies.[44458]

    Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether capecitabine is present in human milk, although many drugs are excreted in human milk.[44458]

    Revision Date: 03/21/2024, 01:46:00 AM

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.

    Mechanism of Action

    Capecitabine is converted into fluorouracil by a series of enzymatic reactions. One of the enzymes involved in this activation process, thymidine phosphorylase is expressed in higher concentrations in some human carcinomas compared to normal tissues, which may result in higher intra-tumor concentrations of fluorouracil. Both normal and tumor cells metabolize fluorouracil 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 also disrupted.[44458]

    Revision Date: 03/21/2024, 01:46:00 AM

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.

    Pharmacokinetics

    Capecitabine is administered orally. Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent; the primary protein involved is human albumin (35%). The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hours. After administration of radiolabeled capecitabine, 96% of the administered dose was recovered in urine (3% as unchanged drug and 57% as the inactive metabolite alpha-fluoro-beta-alanine [FBAL]) and 2.6% in feces.[44458]

     

    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP2C9

    Capecitabine is a prodrug that is metabolized to fluorouracil. It is hydrolyzed by carboxylesterase and to 5'-deoxy-5-fluorocytidine (5'-DFCR), which is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase. 5'-DFUR is subsequently hydrolyzed by thymidine phosphorylase to fluorouracil. More than 80% of fluorouracil is metabolized by dihydropyrimidine dehydrogenase (DPD) to 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). The pyrimidine ring of FUH2 is then cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by beta-ureido-propionase to FBAL. Capecitabine is a weak inhibitor of CYP2C9.[44458]

    Route-Specific Pharmacokinetics

    Oral Route

    Peak blood concentrations (Tmax) of capecitabine are achieved at a median of 1.5 hours after dosing, with peak fluorouracil levels occurring at a median of 2 hours; food delayed the Tmax of both capecitabine and fluorouracil by 1.5 hours. Food also reduces the extent of absorption of capecitabine, with mean Cmax and AUC decreased by 60% and 34%, respectively; the mean Cmax and AUC of fluorouracil were also reduced by 37% and 12%, respectively. The AUC of capecitabine and its metabolite, 5'-DFCR, are dose-proportional over a dosage range of 500 to 3,500 mg/m2 per day. However, increases in the AUC of 5'-DFUR and fluorouracil are greater than proportional to the increase in dose. The interpatient variability in Cmax and AUC of fluorouracil is greater than 85%. Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of fluorouracil concentration in colorectal tumors to adjacent tissues was 2.9 (range, 0.9 to 8).[44458]

    Administration of an aluminum hydroxide- or magnesium hydroxide-containing antacid immediately after a dose of capecitabine increased the Cmax and AUC of capecitabine by 35% and 16%, respectively; the Cmax and AUC of 5'DRCR were increased by 22% and 18%, respectively. The antacids did not have an observable effect on the Cmax or AUC of 5'-DFUR, fluorouracil, or FBAL.[44458]

    Special Populations

    Hepatic Impairment

    The AUC and Cmax of capecitabine increased by 60% in patients with mild to moderate hepatic dysfunction compared to patients with normal hepatic function; the AUC and Cmax of fluorouracil were not affected. The effect of severe hepatic dysfunction on capecitabine pharmacokinetics is not known.[44458]

    Renal Impairment

    The AUC of capecitabine and its inactive metabolites 5'-DFUR and FBAL increased by 25%, 42%, and 85%, respectively, in patients with moderate renal impairment (CrCl 30 to 50 mL/min) compared to patients with a CrCl greater than 80 mL/min; there was no relevant change to the AUC of fluorouracil in these patients. The AUC of capecitabine and fluorouracil increased by 25% and 24%, respectively, in patients with severe renal impairment (CrCl less than 30 mL/min); the AUC of inactive metabolites 5'-DFUR and FBAL increased by 71% and 258% in these patients, respectively. Although no clinical experience using dialysis has been reported, dialysis may be of benefit in reducing circulating concentrations of the metabolite 5'-DFUR.[44458]

    Geriatric

    Age (range, 27 to 86 years) did not have a clinically meaningful effect on the pharmacokinetics of 5'-DFUR or fluorouracil; however, a 20% increase in age results in a 15% increase in the AUC of FBAL.[44458]

    Gender Differences

    Gender did not have a clinically meaningful effect on the pharmacokinetics of 5'-DFUR, fluorouracil, or FBAL.[44458]

    Ethnic Differences

    Race (White, Black, Other) did not have a clinically meaningful effect on the pharmacokinetics of 5'-DFUR, fluorouracil, or FBAL. However, in a separate study, Japanese patients (n = 18) had approximately a 36% lower Cmax and 24% lower AUC for capecitabine than White patients (n = 22); the Cmax and AUC for FBAL were also approximately 25% and 34% lower in Japanese patients compared with White patients, respectively. The clinical significance of these differences is unknown. There were no clinically significant differences in exposure to other metabolites (5'-DFCR, 5'-DFUR, and fluorouracil).[44458]

     

    Approximately 3% to 5% of White populations have a partial DPD deficiency and 0.2% of White populations have complete DPD deficiency; DPD deficiency is estimated to be more prevalent in Black populations. There is insufficient information available to estimate the prevalence of DPD deficiency in other populations. Partial or complete DPD deficiency is associated with an increased risk of acute early-onset toxicities and serious adverse reactions.[44458]

    Revision Date: 03/21/2024, 01:46:00 AM

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.

    Pregnancy/Breast-feeding

    pregnancy

    Pregnancy should be avoided by females of reproductive potential during capecitabine treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant women, capecitabine can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving capecitabine should be apprised of the potential hazard to the fetus. When capecitabine was given to pregnant animals during organogenesis, teratogenesis and embryolethality were observed in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC), respectively, in patients receiving the recommended dose. Teratogenic malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles.[44458]

    breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether capecitabine is present in human milk, although many drugs are excreted in human milk.[44458]

    Revision Date: 03/21/2024, 01:46:00 AM

    References

    44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.

    Interactions

    Level 2 (Major)

    • Aldesleukin, IL-2
    • Allopurinol
    • Decitabine; Cedazuridine
    • Lonafarnib

    Level 3 (Moderate)

    • Bosentan
    • Bupivacaine; Meloxicam
    • Cholera Vaccine
    • Dengue Tetravalent Vaccine, Live
    • Diclofenac
    • Diclofenac; Misoprostol
    • Drospirenone; Ethinyl Estradiol; Levomefolate
    • Folic Acid, Vitamin B9
    • Fosphenytoin
    • Leucovorin
    • Levoleucovorin
    • Levomefolate
    • Meloxicam
    • Methadone
    • Nateglinide
    • Phenytoin
    • SARS-CoV-2 (COVID-19) vaccines
    • SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine
    • SARS-CoV-2 Virus (COVID-19) mRNA Vaccine
    • SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine
    • Tuberculin Purified Protein Derivative, PPD
    • Vitamin B Complex Supplements
    • Warfarin

    Level 4 (Minor)

    • food
    Aldesleukin, IL-2: (Major) Avoid concomitant use of capecitabine and aldesleukin; coadministration may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required. [41853] [44458] Allopurinol: (Major) Avoid coadministration of allopurinol with capecitabine due to the risk of decreased exposure to the active metabolites of capecitabine, which may decrease capecitabine efficacy. Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites FdUMP and FUTP. [44458] Bosentan: (Moderate) Monitor for an increase in bosentan-related adverse reactions if concomitant use of capecitabine is necessary. Concomitant use may increase bosentan exposure. Bosentan is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. [28496] [44458] Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with capecitabine is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. [44458] [65019] Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. [60871] Decitabine; Cedazuridine: (Major) Avoid the concomitant use of decitabine; cedazuridine with drugs that are metabolized by the enzyme cytidine deaminase (CDA), such as capecitabine; the effectiveness of capecitabine may be reduced. Cedazuridine is a CDA inhibitor. Capecitabine is a prodrug that depends on CDA for get converted to the active therapeutic drug, 5-fluorouracil. [65678] [65704] Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine. [60092] [64100] [65107] Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with capecitabine is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. [44458] [45871] Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with capecitabine is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. [44458] [45871] Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with L-methylfolate is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. L-methylfolate is the biologically active form of folic acid, which is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. [26073] [28942] [29720] [44458] Folic Acid, Vitamin B9: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with folic acid is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Folic acid (vitamin B9) is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. [26073] [28942] [29720] [44473] [44474] Food: (Minor) 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. [4717] Fosphenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and capecitabine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. [28535] [44458] Leucovorin: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with leucovorin is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. [26073] [28942] [29720] [44458] [44473] [44474] Levoleucovorin: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with leucovorin is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. [26073] [28942] [29720] [44458] [44473] [44474] Levomefolate: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with L-methylfolate is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. L-methylfolate is the biologically active form of folic acid, which is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. [26073] [28942] [29720] [44458] Lonafarnib: (Major) Avoid coadministration of lonafarnib and capecitabine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. [44458] [66129] Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with capecitabine is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. [44458] [65019] Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of capecitabine is necessary. If capecitabine is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; capecitabine is a weak CYP2C9 inhibitor. Concomitant use with capecitabine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. [33136] [44458] Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with capecitabine is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. [44458] [45644] Phenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with capecitabine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. [41239] [44458] SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy. [43298] [43299] Vitamin B Complex Supplements: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with folic acid is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Folic acid (vitamin B9) is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. [26073] [28942] [29720] [44473] [44474] Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with capecitabine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Coadministration of warfarin and capecitabine has been reported to cause altered coagulation parameters and bleeding, including death. The effects of the interaction may occur within days to several months after starting or 1 month after stopping capecitabine therapy. Capecitabine is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. In 4 patients with cancer, chronic administration of capecitabine with a single dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these patients increased by 2.8-fold, and the maximum observed mean INR was increased by 91%. [28549] [44458] [65827] [65828] [65829]
    Revision Date: 03/21/2024, 01:46:00 AM

    References

    4717 - Xeloda® (capecitabine) package insert. Nutley, NJ: Roche Laboratories; 2003 Apr.26073 - Bleyer WA. New vistas for leucovorin in cancer chemotherapy. Cancer 1989;63:995-1007.28496 - Tracleer (bosentan) package insert. Titusville, NJ: Actelion Pharmaceuticals US, Inc.; 2024 Feb.28535 - Cerebyx (fosphenytoin sodium) package insert. New York, NY: Pfizer Labs; 2022 Apr.28549 - Coumadin (warfarin tablets) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2017 Aug.28942 - Leucovorin calcium injection package insert. Bedford, OH: Bedford Laboratories; 2008 Sep.29720 - Mini E, Trave F, Rustum YM, et al. Enhancement of the antitumor effects of 5-fluorouracil by folinic acid. Pharmacol Ther 1990;47:1-19.33136 - Methadone hydrochloride tablets package insert. Webster Groves, MO: SpecGx LLC; 2024 Jan.41239 - Dilantin (phenytoin sodium extended-release capsules) package insert. New York, NY: Parke-Davis Division of Pfizer Inc; 2021 Mar.41853 - Proleukin (aldesleukin) package insert. Malvern, PA: Clinigen, Inc.; 2023 Sept.43298 - Aplisol (tuberculin purified protein derivative, diluted) package insert. Chestnut Ridge, NY: Par Pharmaceuticals; 2016 Mar.43299 - Tubersol (tuberculin purified protein derivative, mantoux) package insert. Swiftwater, PA: Sanofi Pasteur, Inc.; 2020 Nov.44458 - Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Dec.44473 - Clippe C, Freyer G, Milano G, et al. Lethal toxicity of capecitabine due to abusive folic acid prescription? Clin Oncol 2003;15:299-300.44474 - Sharma R, Rivory L, Beale P, et al. A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer. Br J Cancer 2006;94:964-968.45644 - Starlix (nateglinide) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation.; 2021 Oct.45871 - Zipsor (diclofenac potassium capsule) package insert. Newark, CA: Depomed, Inc.; 2021 May.60092 - Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014; 58: e44-100.60871 - Vaxchora (Cholera Vaccine, live, oral) package insert. Redwood City, CA: Emergent Travel Health Inc.; 2022 Dec.64100 - Dengvaxia (dengue tetravalent vaccine, live) package insert. Swiftwater, PA: Sanofi Pasteur Inc.; 2023 August.65019 - Anjeso (meloxicam) injection package insert. Malvern, PA: Baudax Bio, Inc; 2021 Jul.65107 - Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). Accessed April 25, 2024. Available at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html.65678 - Inqovi (decitabine and cedazuridine) tablet package insert. Princeton, NJ: Taiho Oncology; 2022 Mar.65704 - Frances A, Cordelier P. The emerging role of cytidine deaminase in human: a new opportunity for therapy?. Mol Ther 2020;28(2):357-366.65827 - Hata T, Kudo T, Sakai D, et al. Impact of capecitabine and S-1 on anticoagulant activity of warfarin in patients with gastrointestinal cancer. Cancer Chemother Pharmacol 2016;78:389-396.65828 - Camidge R, Reigner B, Cassidy J, et al. Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer. J Clin Oncol 2005;23:4719-4725.65829 - Shah HR, Ledbetter L, Diasio R, et al. A retrospective study of coagulation abnormalities in patients receiving concomitant capecitabine and warfarin. Clin Colorectal Cancer 2006;5:354-358.66080 - Food and Drug Administration (FDA). Fact Sheet for Healthcare Providers Administering Vaccine: Emergency Use Authorization (EUA) of Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for 12 years and older. Purple cap and purple border. Retrieved November 22, 2022.66129 - Zokinvy (lonafarnib) capsules package insert. Palo Alto, CA: Eiger BioPharmaceuticals, Inc.; 2020 Nov.

    Monitoring Parameters

    • CBC with differential
    • LFTs
    • pregnancy testing
    • serum creatinine/BUN

    US Drug Names

    • Xeloda
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