English
1,250 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest, every 3 weeks. 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. 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, treatment with capecitabine resulted in a partial response rate of 25.6% 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 8.5 months.[44458]
1,250 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest; on day 1, give docetaxel 75 mg/m2 IV over 1 hour. Repeat every 3 weeks.[44458] Premedicate with dexamethasone 8 mg by mouth twice daily for 3 days, beginning 1 day prior to docetaxel administration, to reduce the incidence and severity of fluid retention and hypersensitivity reactions.[60484] Capecitabine doses 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. In a multicenter, randomized, open-label, phase 3 trial (n = 511), treatment with capecitabine plus docetaxel significantly improved the time to disease progression (6.2 months vs. 4.3 months), overall survival (14.7 months vs. 11.7 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. Docetaxel/capecitabine patients experienced more hand-foot syndrome, diarrhea, stomatitis, nausea, and vomiting. Neutropenic fever, myalgia, arthralgia, and fatigue occurred more frequently with single-agent docetaxel.[44575] [44458]
1,000 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 through 14, in combination with lapatinib (1,250 mg PO once daily on an empty stomach on days 1 to 21). Repeat every 21 days until disease progression or unacceptable toxicity. 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 (after anthracyclines, taxanes, and trastuzumab), locally advanced or metastatic breast cancer, treatment with lapatinib plus capecitabine (n = 198) significantly improved the median time to progression (TTP) by independent assessment compared with capecitabine alone (n = 201) (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 (n = 540). 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 (n = 652). Patients should have progressed on trastuzumab and taxane-based therapy prior to treatment with lapatinib and capecitabine.[33192]
1,000 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes of a meal on days 1 to 14, followed by 1 week of rest; on day 1, give ixabepilone 40 mg/m2 (maximum BSA, 2.2 m2) IV over 3 hours. Repeat every 3 weeks. One hour prior to ixabepilone administration on day 1, premedicate with diphenhydramine 50 mg by mouth (or equivalent) and ranitidine 150 mg to 300 mg by mouth (or equivalent) to reduce the risk of hypersensitivity; add dexamethasone 20 mg in patients who have previously had a reaction to ixabepilone. 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 (n = 752), 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]
750 mg/m2 PO twice daily within 30 minutes after a meal on days 1 to 14 every 21 days in combination with neratinib until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided; review drug interactions. The neratinib dosage is 240 mg PO once daily; 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). Patients starting neratinib at the maximum dosage of 240 mg/day should receive antidiarrheal prophylaxis with loperamide for at least the first 56 days of therapy.[62127] 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]
1,000 mg/m2 PO twice daily within 30 minutes after a meal on days 1 to 14 of each 21-day cycle in combination with tucatinib and trastuzumab until disease progression or unacceptable toxicity; tucatinib and capecitabine can be taken at the same time. 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]
1,250 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest, every 3 weeks for a total of 8 cycles (24 weeks). 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. In a multicenter, randomized, phase 3 trial (X-ACT trial), adjuvant treatment with capecitabine (n = 995) was non-inferior to fluorouracil plus leucovorin (n = 974) in the treatment of Dukes' C colon cancer. After a median follow-up of 83 months, the 5-year disease-free survival (DFS) rate was 59.1% in capecitabine-treated patients compared with 54.6% in those who received fluorouracil/leucovorin; 5-year overall survival was 71.4% vs. 68.4%, respectively. Prescribers should consider the results of combination chemotherapy trials, which have shown an improvement in DFS and OS, when prescribing single-agent capecitabine in the adjuvant treatment of colon cancer.[44458] [31340]
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 a total of 8 cycles. In a phase III clinical trial, 1,886 patients with resected stage III colon cancer were randomized to receive oxaliplatin/capecitabine (XELOX) or 5-fluorouracil/leucovorin. After a median follow-up of 57 months, the addition of oxaliplatin to capecitabine produced a significant improvement in the primary endpoint, disease-free survival (HR 0.8; p = 0.0045). Disease-free survival at 3 years was 70.9% with XELOX vs. 66.5% with 5-FU/leucovorin. Overall survival was not significantly different between the arms (HR 0.87; p = 0.1486).[45258] Grade 3 or 4 neurosensory toxicity, vomiting, hand-foot syndrome, and thrombocytopenia occurred more frequently in the XELOX arm (p < 0.05); neutropenia, febrile neutropenia, and stomatitis occurred more frequently with 5-FU/leucovorin (p < 0.05).[43412]
1,250 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest, every 3 weeks. 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. In a multicenter (North American and Brazil), randomized, open-label clinical trial, patients with previously untreated metastatic colorectal cancer who received capecitabine (n = 302) had a significantly improved overall response rate (ORR) compared with those who received fluorouracil plus leucovorin (n = 303) (21% vs. 11%); the median time to progression (TTP) was 4.3 months versus 4.4 months and the median overall survival (OS) was 12.7 months versus 13.6 months, respectively. Results were similar in an identical trial operated in Europe, Australia, New Zealand, and Taiwan (ORR, 21% vs. 14%; TTP, 4.6 months vs. 4.4 months; OS 13.5 months vs. 12.3 months). Of note, combination chemotherapy has shown a survival benefit as compared with fluorouracil/leucovorin monotherapy; the safety and survival effect of capecitabine use versus combination chemotherapy with fluorouracil/leucovorin has not been adequately studied.[44458]
1,000 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on the evening of day 1 through the morning of day 15 in combination with oxaliplatin (130 mg/m2 IV on day 1), repeated every 3 weeks. In a phase III trial of 2,034 patients, capecitabine/oxaliplatin (XELOX) with or without bevacizumab was compared with fluorouracil/leucovorin/oxaliplatin (FOLFOX4) with or without bevacizumab in a 2-by-2 factorial design. XELOX was found to be noninferior to FOLFOX4 for the first line treatment of metastatic colorectal cancer (8 months vs. 8.5 months, HR 1.04; 97.5% CI, 0.93 to 1.16). In the safety analysis of 1,304 patients, grade 3 or 4 adverse reactions observed more frequently with XELOX included diarrhea (grade 3, 19%; grade 4: 1%) and hand-foot syndrome (grade 3, 6%), while FOLFOX4 produced more neutropenia (grade 3, 27%; grade 4, 16%). A meta-analysis of this trial and 5 additional trials was performed concurrently with this study. No difference in progression-free survival or overall survival was observed between capecitabine/oxaliplatin combinations and fluorouracil/leucovorin/oxaliplatin combinations in patients with metastatic colorectal cancer.[33964] [41607] Additional trials have shown efficacy for XELOX in the treatment of both previously treated and previously untreated patients with advanced colorectal cancer.[41750] [28881] [27033]
1,000 mg/m2 PO twice daily on days 1 to 14, followed by 1 week of rest; on day 1 of each cycle, give bevacizumab 7.5 mg/kg IV followed by oxaliplatin 130 mg/m2 IV over 2 hours. Repeat every 3 weeks until progressive disease. In a randomized, phase III, clinical trial (n = 1,401), capecitabine/oxaliplatin (XELOX/CapeOx) with or without bevacizumab was compared with fluorouracil/leucovorin/oxaliplatin (FOLFOX4) with or without bevacizumab. The primary endpoint of median progression-free survival was 9.4 months in patients treated with either XELOX or FOLFOX4 plus bevacizumab, compared with 8 months in patients who received XELOX or FOLFOX4 alone (HR 0.83; p = 0.0023), with a median duration of response of 8.45 months versus 7.4 months, respectively (HR 0.82; p = 0.0307 (level of significance, p < 0.025)). Overall survival, a secondary endpoint, was improved in the bevacizumab arms but did not reach statistical significance (21.3 vs. 19.9 months; HR 0.89; p = 0.0769).[41609]
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]
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]
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]
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 over 90 minutes on day 1, then 6 mg/kg IV over 30 to 90 minutes every 21 days from day 22); repeat cycles every 3 weeks. Chemotherapy should be continued up to a maximum of 6 cycles; trastuzumab should be continued until disease progression or unacceptable toxicity. In a phase 3 trial, 594 patients with inoperable, locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive cisplatin and fluorouracil or capecitabine, with or without trastuzumab. Overall survival (13.5 months vs. 11 months, p = 0.0038), the primary endpoint, and objective response rate (47% vs. 35%, p = 0.0017) 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, HR 0.8, 95% CI 0.67 to 0.97). In addition, a subgroup analysis revealed an even greater increase in overall survival (18 months vs. 13.2 months, HR 0.66, 95% CI 0.5 to 0.87) for the trastuzumab arm in patients with high expression of the HER2 protein (FISH-negative and IHC3 +; or, FISH-positive). 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.[36110] [41715] [28061]
1,000 mg/m2 PO twice daily on days 1 to 14 every 3 weeks. Administer in combination with oxaliplatin (130 mg/m2 IV every 3 weeks for up to 6 to 8 cycles), pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), and trastuzumab (8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day. Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a duration of response of at least 6 months.[57889] [66655]
1,000 mg/m2 PO twice daily on days 1 to 14 in combination with cisplatin (80 mg/m2 IV on day 1), repeated every 3 weeks until disease progression or unacceptable toxicity. In a phase III clinical trial, 316 patients with advanced gastric cancer were randomized to receive capecitabine/cisplatin (XP) or 5-fluorouracil/cisplatin (FP). The primary objective of the study, which was to confirm noninferiority of XP compared with FP for progression-free survival (PFS), was met. In the per-protocol population, the median PFS was 5.6 months for XP and 5 months for FP (HR=0.81, 95% CI 0.63 to 1.04; p<0.001 versus noninferiority margin of 1.25). Once noninferiority was confirmed, a superiority test was performed. A trend for PFS was shown favoring patients who received XP; however, this difference was not statistically significant (p = 0.0801). Treatment-related adverse events were similar between the treatment arms. Hand-foot syndrome occurred more frequently with XP; vomiting and stomatitis were more frequent with FP.[34869]
625 mg/m2 PO twice daily on days 1 to 21 in combination with epirubicin (50 mg/m2 IV on day 1) and oxaliplatin (130 mg/m2 IV on day 1) or cisplatin (60 mg/m2 IV on day 1); repeated every 3 weeks up to a maximum of 8 cycles. In a phase III trial, 1,002 patients with previously untreated esophagogastric cancer were randomized in a 2:2 trial design to receive epirubicin and oxaliplatin with either capecitabine (EOX) or fluorouracil (EOF), or epirubicin and cisplatin with either capecitabine (ECX) or fluorouracil (ECF). The trial was designed to show noninferiority in overall survival for the treatment arms containing capecitabine as compared to the treatment arms containing fluorouracil. Noninferiority was met with a median overall survival of 10.9 months for capecitabine-containing arms vs. 9.6 months for fluorouracil-containing arms (HR 0.86, 95% CI 0.80 to 0.99 with a noninferiority margin of 1.23); toxicity was similar between the capecitabine and fluorouracil treatment arms.[40571]
1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle until disease progression or unacceptable toxicity. Administer in combination with oxaliplatin (130 mg/m2 IV on day 1, every 3 weeks until disease progression or unacceptable toxicity) and nivolumab (360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression).[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; n = 1,581). 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]
830 mg/m2 orally twice daily on days 1 to 21 followed by 7 days of rest, in combination with gemcitabine (1,000 mg/m2 IV on days 1, 8, and 15), repeated every 28 days for 6 cycles. After a median follow-up of 43.2 months, patients who underwent complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection) and were treated with gemcitabine plus capecitabine had significantly longer median overall survival compared with those receiving gemcitabine alone (28 months vs. 25.5 months; HR 0.82; p = 0.032) in a multicenter, randomized, open-label phase 3 clinical trial. In a subgroup analysis, the magnitude of effect on median overall survival in patients with R0 resection (39.5 months vs. 27.9 months) was greater than in patients with R1 resection (23.7 months vs. 23 months) (X2 14.83; p = 0.0001).[62255] [44458]
1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle until disease progression or unacceptable toxicity. Administer in combination with oxaliplatin (130 mg/m2 IV on day 1 every 3 weeks until disease progression or unacceptable toxicity) and nivolumab (360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression).[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; n = 1,581). 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]
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.
Dosage Adjustments for Hematologic Toxicities when used in Combination with Ixabepilone:
NOTE: Follow recommendations for treatment-related toxicity, above, for nonhematologic toxicity.
2,500 mg/m2 PO total daily dose (1,250 mg/m2 PO administered twice daily) on days 1 to 14, every 21 days.
2,500 mg/m2 PO total daily dose (1,250 mg/m2 PO administered twice daily) on days 1 to 14, every 21 days.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
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]
Baseline Renal Insufficiency:
Capecitabine is a unique antineoplastic agent. It is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which generates fluorouracil selectively in tumor cells. Chemically, capecitabine is classified as a fluoropyrimidine carbamate. It was the first oral antineoplastic agent approved for the treatment of metastatic breast carcinoma. In patients with metastatic breast cancer who were resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen, a tumor response rate of about 25% has been observed. However, no results are available from controlled trials in patients with breast cancer that demonstrate improvement in disease-related symptoms, disease progression, or survival. Unlike many other antineoplastic agents, use of capecitabine has not been associated with alopecia, and myelosuppression is uncommon. Capecitabine is FDA approved as monotherapy for the adjuvant treatment of colorectal cancer and for the treatment of metastatic colorectal cancer and metastatic breast cancer; it is FDA approved in combination with docetaxel for the treatment of metastatic breast cancer.[44458]
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Hazardous Drugs Classification
Emetic Risk
Mild (grade 1 or 2) insomnia was reported in 7% to 8% of patients with metastatic colorectal or breast cancer treated with capecitabine monotherapy (n = 758) or in combination with docetaxel (n = 251) in 3 clinical trials; mood alteration (5% or less) and depression (5%) were also reported. Irritability (less than 5%), sedation (less than 5%), and confusion (grade 3 or 4, 0.1%) were additionally reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials.[44458]
Palmar-plantar erythrodysesthesia (hand and foot syndrome) is a dose-limiting toxicity of capecitabine and has been reported more often in patients receiving capecitabine monotherapy (n = 1,753) or in combination with docetaxel (54% to 63%; grade 3, 11% to 24%) compared with fluorouracil/leucovorin (n = 1,567) (6% to 9%; grade 3, 1% or less) in clinical trials.[64032] [44458] The median time to onset of palmar-plantar erythrodysesthesia was 79 days. Alopecia was more common in patients treated with fluorouracil/leucovorin (6% vs. 21% to 22%; grade 3 or 4, 0% vs. less than 1%). Dermatitis (27% to 37%; grade 3, 1%), skin discoloration (7%; grade 3, less than 1%), rash (7%), nail disorder (7%; grade 3 or 4, 0.1%), erythema (6%; grade 3 or 4, 1%), skin ulcer (less than 5%), pruritus (less than 5%), radiation recall reaction (grade 3 or 4, 0.2%), hyperhidrosis (grade 3 or 4, 0.1%), and photosensitivity reaction (grade 3 or 4, 0.1%) were also reported in patients treated with capecitabine monotherapy in clinical trials. The addition of capecitabine to docetaxel (n = 251) in patients with metastatic breast cancer did not meaningfully increase the incidence of dermatologic adverse reactions compared with docetaxel alone (n = 255) in a randomized clinical trial, including alopecia (41% vs. 42%; grade 3, 6% vs. 7%), nail disorder (14% vs. 15%; grade 3, 2% vs. 0%), dermatitis (8% vs. 11%; grade 3, 0% vs. 1%), erythematous rash (9% vs. 5%; grade 3, less than 1% vs. 0%), nail discoloration (6% vs. 4%; grade 3, less than 1%), onycholysis (5% vs. 5%; grade 3, 1% vs. 1%), pruritus (4% vs. 5%). Grade 3 or 4 hypersensitivity reactions occurred in 0.1% of patients receiving capecitabine monotherapy and in 1.2% of patients receiving capecitabine in combination with docetaxel. Lupus-like symptoms (cutaneous lupus erythematosus) and severe skin reactions such as Stevens-Johnson Syndrome and toxic epidermal necrolysis have additionally been reported in postmarketing experience with capecitabine.[44458]
Hyperbilirubinemia has been reported in patients (48% or less; grade 3 or 4, 11% to 23%) treated with capecitabine monotherapy in clinical trials (n = 1,870) and is a dose-limiting toxicity. The incidence of hyperbilirubinemia in patients receiving treatment with fluorouracil/leucovorin (n = 1,567) was much lower (17% or less; grade 3 or 4, 6% to 6.3%). In patients with metastatic breast or colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was higher in patients with hepatic metastases at baseline (n = 566) compared to those without hepatic metastases at baseline (n = 309) (22.8% vs. 12.3%). Of the patients who developed grade 3 or 4 hyperbilirubinemia, 18.6% also had postbaseline elevations in alkaline phosphatase and 27.5% had elevated hepatic enzymes postbaseline; most of these patients (64.5% and 71.7%, respectively) had liver metastases at baseline. Also, 57.5% of patients who developed grade 3 or 4 hyperbilirubinemia had both pre- and postbaseline increases in alkaline phosphatase (grade 3 or 4, 7.8%) and 35.3% had both pre- and postbaseline increases in transaminases (grade 3 or 4, 3%). The median time to onset for grade 3 or 4 hyperbilirubinemia patients with colorectal cancer was 64 days. Abnormal liver function tests in general were reported in less than 5% of patients treated with capecitabine monotherapy, along with ascites (grade 3 or 4, 0.1%), hepatic fibrosis (grade 3 or 4, less than 0.1%), hepatitis (grade 3 or 4, 0.1%), and cholestasis/cholestatic hepatitis (grade 3 or 4, 0.1%). Hyperbilirubinemia was reported in 20% (grade 3 or 4, 9%) of patients with metastatic breast cancer treated with capecitabine plus docetaxel (n = 251); grade 3 or 4 hepatotoxicity (0.4%), jaundice (0.4%), abnormal liver function tests (0.4%), and hepatic failure (0.4%) were also reported in these patients. Increased ALT was reported in 75% and hypoalbuminemia in 55% of children treated with capecitabine.[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. Clinically relevant atrial fibrillation, bradycardia, extrasystoles, ventricular extrasystoles, and pericardial effusion were each reported in less than 5% of patients treated with capecitabine monotherapy in clinical trials; grade 3 or 4 sinus tachycardia (0.1%) and myocarditis (0.1%) were also reported. Supraventricular tachycardia (SVT) (grade 3 or 4, 0.4%) was reported in patients with metastatic breast cancer receiving capecitabine in combination with docetaxel.[44458]
Neutropenia has been reported across clinical trials of patients treated with capecitabine, although it is less common than with fluorouracil/leucovorin treatment in comparative trials. Neutropenia or decreased neutrophils/granulocytes was reported in 13% to 26% (grade 3 or 4, 2.2% to 4%) patients receiving capecitabine monotherapy as adjuvant or metastatic treatment for colorectal cancer or treatment for metastatic breast cancer (n = 1,753) compared with 46% or fewer (grade 3 or 4, 21% to 26.4%) patients receiving fluorouracil/leucovorin (n = 1,567). Anemia or decreased hemoglobin occurred with a similar frequency in patients with adjuvant or metastatic colorectal cancer or metastatic breast cancer receiving capecitabine versus fluorouracil/leucovorin (72% to 80%; grade 3 or 4, 4% or less). Lymphopenia occurred in 94% (grade 3 or 4, 59%) of patients with metastatic breast cancer receiving capecitabine monotherapy in a phase 2 clinical trial (n = 162) and thrombocytopenia was reported in 24% (grade 3 or 4, 4%). Grade 3 or 4 decreases in lymphocytes (13%) and platelets (1%) occurred less often in a large clinical trial of patients receiving adjuvant capecitabine monotherapy for colorectal cancer (n = 995). Additional hematologic adverse reactions reported with capecitabine monotherapy across adjuvant and metastatic indications include idiopathic thrombocytopenic purpura (grade 3 or 4, 1%), leukopenia (grade 3 or 4, 0.2%), bone marrow depression (grade 3 or 4, 0.1%), and pancytopenia (grade 3 or 4, 0.1%). In a randomized clinical trial of patients with metastatic breast cancer, the addition of capecitabine to docetaxel (n = 251) increased the incidence of thrombocytopenia compared with docetaxel alone (n = 255) (41% vs. 23%; grade 3 or 4, 3% vs. 3%), but other hematologic adverse reactions were similar between study arms including lymphopenia (99% vs. 98%; grade 3 or 4, 89% vs. 84%), leukopenia (91% vs. 88%; grade 3 or 4, 61% vs. 75%), neutropenia/granulocytopenia (86% vs. 87%; grade 3 or 4, 69% vs. 77%), and anemia (80% vs. 83%; grade 3 or 4, 10% vs. less than 6%). Grade 3 or 4 agranulocytosis was also reported in 0.4% of metastatic breast cancer patients who received capecitabine plus docetaxel. Laboratory abnormalities were more common in 2 clinical trials of pediatric patients receiving capecitabine with radiation therapy (n = 56), including lymphopenia (73%), leukopenia (73%), thrombocytopenia (57%), neutropenia (50%), and anemia (50%). 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 neutropenia.[44458]
Nausea (34% to 43% vs. 47% to 51%; grade 3 or 4, 2% to 4% vs. 2% or less), stomatitis (22% to 25% vs. 60% to 62%; grade 3 or 4, less than 3% vs. 14% to 15%) and vomiting (15% to 27% vs. 21% to 30%; grade 3 or 4, less than 5% vs. less than 5%) were less common in patients with colorectal cancer receiving adjuvant or metastatic treatment with capecitabine monotherapy (n = 1,591) compared to treatment with fluorouracil/leucovorin (n = 1,567). Nausea (53%; grade 3, 4%) and vomiting (37%; grade 3, 4%) were more common in patients with metastatic breast cancer receiving capecitabine monotherapy in a single-arm, phase 2 trial (n = 162); stomatitis occurred at a similar incidence as the colorectal trials (24%; grade 3, 7%). Abdominal pain (7% to 35%; grade 3 or 4, less than 10%), constipation (9% to 15%; grade 3 or 4, less than 2%), GI motility disorder (10%; grade 3, less than 1%), oral discomfort (10%), upper GI inflammatory disorders (8%; grade 3, less than 1%), GI bleeding (6%; grade 3 or 4, less than 2%), ileus (6%; grade 3 or 4, 0.3% to 5%), abdominal distension (less than 5%), proctalgia (less than 5%), toxic dilation of intestine (less than 5%), and peptic ulcer (grade 3 or 4, 0.1%) have also been reported with capecitabine monotherapy. Stomatitis (67% vs. 43%; grade 3 or 4, less than 18% vs. 5%), nausea (45% vs. 36%; grade 3, 7% vs. 2%), vomiting (35% vs. 24%; grade 3 or 4, 5% vs. 2%), constipation (20% vs. 18%; grade 3 or 4, 2% vs. 0%), and abdominal pain (30% vs. 24%; grade 3 or 4, less than 4% vs. 2%) occurred more often in patients with metastatic breast cancer treated with docetaxel plus capecitabine (n = 251) compared with docetaxel alone (n = 255) in a randomized clinical trial; grade 3 or 4 ileus (0.4%) and esophageal ulceration (0.4%) were also reported. Geriatric patients may be at an increased risk for some GI adverse reactions, with grade 3 or 4 nausea (1.3% to 13.1%), vomiting (1.5% to 9.5%), and stomatitis (3% to 30%) reported at an increased incidence in these patients (n = 429) in clinical trials of patients receiving capecitabine monotherapy or in combination with docetaxel. 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 occurs in 47% to 57% (grade 3 or 4, 12% to 15%) of patients with breast cancer or colorectal cancer who received capecitabine monotherapy in several clinical trials (n = 1,753), and in 67% (grade 3 or 4, less than 15%) of breast cancer patients treated with capecitabine plus docetaxel in another clinical trial (n = 251).[64032] [44458] Grade 3 or 4 gastroenteritis has also been reported in 0.1% of patients receiving capecitabine monotherapy in clinical trials. Grade 3 or 4 necrotizing enterocolitis (typhlitis) (0.4%) and hemorrhagic diarrhea (0.8%) have also been reported in patients with metastatic breast cancer treated with capecitabine in combination with docetaxel. Geriatric patients may be at an increased risk, with grade 3 or 4 diarrhea reported in 13.1% to 30% of these patients (n = 429) in clinical trials of patients receiving capecitabine monotherapy or in combination with docetaxel. 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 diarrhea. Carefully monitor patients with diarrhea and replace fluids and electrolytes if needed; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. In patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy (n = 875), the median time to first occurrence of grade 2 to 4 diarrhea was 34 days, with a median duration of grade 3 to 4 diarrhea of 5 days.[44458]
Anorexia or decreased appetite has been reported in 9% to 26% (grade 3 or 4, less than 4%) of patients treated with capecitabine monotherapy in clinical trials (n = 1,753); dyspepsia (8% or less; grade 3 or 4, less than 1%), dysgeusia or taste disturbance (6%; grade 3 or 4, 1% or less), dysphagia (less than 5%), and cachexia (grade 3 or 4, 0.4%) has also been reported in patients receiving capecitabine monotherapy. Taste disturbance (16% vs. 14%; grade 3, less than 1% vs. less than 1%), dyspepsia (14% vs. 8%; grade 3 or 4, 0% vs. 1%), anorexia (13% vs. 11%; grade 3, 1% vs. less than 1%), decreased appetite (10% vs. 5%), xerostomia (6% vs. 5%; grade 3, less than 1% vs. 0%), and weight loss (7% vs. 5%) were also reported more often in patients with metastatic breast cancer who received docetaxel in combination with capecitabine (n = 251) compared with docetaxel alone (n = 255).[44458]
Dehydration has been reported in patients treated with capecitabine (7% to 10%; grade 3 or 4, 5% or less), which may cause acute renal failure. Monitor patients to prevent dehydration and quickly correct it if it occurs; an interruption of therapy and intravenous fluids may be needed. Do not be restart therapy until the patient is rehydrated and any precipitating causes have been corrected or controlled.[44458]
Severe (grade 3 or 4) renal impairment (0.6%) and renal failure (unspecified) (0.4%) have been reported in patients treated with capecitabine as monotherapy or in combination with docetaxel during clinical trials. Acute renal failure secondary to dehydration (including fatal outcome) has been reported in postmarketing experience with capecitabine.[44458]
Fever was reported in 7% to 18% (grade 3 or 4, 1% or less) of patients with colorectal or breast cancer treated with capecitabine monotherapy in clinical trials (n = 1,753). Infection has also been reported in patients receiving capecitabine monotherapy, including viral infections (5%; grade 3, less than 1%) as well as grade 3 or 4 laryngitis (1%), sepsis (0.3%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), and fungal infections including candidiasis (0.2%). The incidence of infection was similar between treatment arms in patients with metastatic breast cancer randomized to treatment with capecitabine plus docetaxel (n = 251) vs. docetaxel alone (n = 255), including fever (28%; grade 3, 2%), neutropenic fever (16%; grade 3 or 4, 16%), influenza-line illness (5%), oral candidiasis (7%; grade 3, less than 1%), urinary tract infection (6%; grade 3, less than 1%), and upper respiratory tract infection (4%); grade 3 or 4 neutropenic sepsis (2.4%), sepsis (0.4%), and bronchopneumonia (0.4%) were also reported in these patients.[44458]
Fatigue, asthenia, and lethargy occurred with a similar frequency in patients treated with capecitabine versus fluorouracil/leucovorin in clinical trials. In a randomized clinical trial of patients receiving adjuvant treatment for colorectal cancer with either capecitabine (n = 995) or fluorouracil/leucovorin (n = 974), fatigue (16% vs. 16%; grade 3 or 4, less than 1% vs. 1%), asthenia (10% vs. 10%; grade 3 or 4, less than 1% vs. 1%), and lethargy (10% vs. 9%; grade 3 or 4, less than 1% vs. less than 1%) were reported with similar frequencies between arms. Fatigue/weakness occurred in 42% (grade 3, 4%) of patients with metastatic colorectal cancer receiving capecitabine monotherapy (n = 596) compared with 46% (grade 3, 4%) of those treated with fluorouracil/leucovorin (n = 593). Fatigue occurred in a similar percentage of patients with metastatic breast cancer receiving capecitabine monotherapy in a phase 2 clinical trial (n = 162) (41%; grade 3, 8%). Muscle weakness was reported in less than 5% of patients receiving capecitabine monotherapy in clinical trials. The addition of capecitabine to docetaxel in patients with metastatic breast cancer (n = 251) did not increase the incidence of these adverse reactions compared with docetaxel alone (n = 255) in a randomized clinical trial, including asthenia (26% vs. 25%; grade 3 or 4, 4% to 5% vs. 6%), fatigue (22% vs. 27%; grade 3, 4% vs. 6%), weakness (16% vs. 11%; grade 3, 2% vs. 2%), and lethargy (7% vs. 6%; grade 3, 0% vs. 2%).[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 (n = 758). Abnormal vision/visual impairment (5%), conjunctivitis (5%; grade 3 or 4, less than 1%), and keratoconjunctivitis (less than 5%) have been reported in patients receiving capecitabine monotherapy. Increased lacrimation (12%), conjunctivitis (5%), and eye irritation (5%) were reported in patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel (n = 251). There have been reports of lacrimal duct stenosis and corneal disorders including keratitis in postmarketing experience with capecitabine.[44458]
Hypercalcemia (1.1%; grade 3 or 4, 0.7%) and hypocalcemia (2.3%; grade 3 or 4, 2.2%) were reported in patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 995) in a randomized clinical trial. Hypokalemia (less than 5%), hypomagnesemia (less than 5%), and hypertriglyceridemia (grade 3 or 4, 0.1%) were additionally reported in patients receiving capecitabine monotherapy for the treatment of colorectal or breast cancer. The adverse reaction profile of capecitabine in pediatric patients (n = 56) was consistent with adult patients with the exception of laboratory abnormalities, which were more common in pediatric patients including hypokalemia (68%), hypocalcemia (48%), hypophosphatemia (45%), and hyponatremia (45%).[44458]
Generally mild epistaxis has been reported in clinical trials of patients receiving capecitabine monotherapy as adjuvant or metastatic treatment for colorectal cancer (n = 1,591) (2% to 3%; grade 3, less than 1%); the incidence was slightly higher when administered in combination with docetaxel (n = 251) to patients with metastatic breast cancer (7%; grade 3, less than 1%). Hemorrhage (bleeding) and hemoptysis were each reported in less than 5% of patients receiving capecitabine monotherapy; grade 3 or 4 coagulopathy (0.1%) was also reported. Grade 3 or 4 decreases in prothrombin time occurred in 0.4% of metastatic breast cancer patients receiving capecitabine plus docetaxel.[44458]
Musculoskeletal adverse reactions occurred with a similar frequency in patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 596) compared with fluorouracil/leucovorin (n = 593) in a randomized clinical trial, including pain (12% vs. 10%; grade 3, 1% vs. 1%), chest pain (unspecified) (6% vs. 6%; grade 3 or 4, 1% vs. less than 2%), back pain (10% vs. 9%; grade 3, 2% vs. less than 1%), and arthralgia (8% vs. 6%; grade 3, 1% vs. 1%). Limb pain 6%; grade 3, 1%) and myalgia (9%) were also reported in a phase 2 trial of capecitabine monotherapy for the treatment of metastatic breast cancer (n = 162). Grade 3 or 4 chest pain (0.2%) and pain (0.1%) were reported across clinical trials of patients with colorectal or breast cancer receiving capecitabine monotherapy in clinical trials. The incidence of musculoskeletal adverse reactions were similar when capecitabine was added to docetaxel in patients with metastatic breast cancer (n = 251), including limb pain (13%; grade 3, less than 1%), pain (7%; grade 3, less than 1%), non-cardiac chest pain (4%; grade 3, less than 1%), arthralgia (13%; grade 3, 2%), myalgia (13%; grade 3, 2%), back pain (12%; grade 3, less than 1%), and bone pain (8%; grade 3, less than 1%); bone pain (grade 3 or 4, 0.1%) and arthritis (grade 3 or 4, 0.1%) have also been reported.[44458]
Headache (5% to 10%; grade 3 or 4, 1% or less) and dizziness (6% to 8%; grade 3 or 4, less than 1%) of patients with colorectal or breast cancer receiving capecitabine monotherapy (n = 1,753); vertigo was reported in less than 5% of patients receiving capecitabine monotherapy. The occurrence of headache (15%; grade 3, 3%) and dizziness (12%) was slightly higher when capecitabine was administered with docetaxel (n = 251) to patients with metastatic breast cancer in a randomized clinical trial, although the incidences were similar to docetaxel monotherapy (n = 255); grade 3 or 4 migraine was reported in 0.4% of patients receiving combination therapy.[44458]
Mild (grade 1 or 2) peripheral neuropathy was reported in 10% of patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 596) compared with 4% of those receiving fluorouracil/leucovorin (n = 593) in a randomized clinical trial. In a phase 2 single-arm trial of patients with metastatic breast cancer (n = 162), paresthesias occurred in 21% (grade 3, 1%) of patients receiving capecitabine monotherapy. In a randomized clinical trial of patients with metastatic breast cancer, paresthesias (12% vs. 16%; grade 3, less than 1% vs. 1%), peripheral neuropathy (6% vs. 10%; grade 3, 0% vs. 1%), and hypoesthesia (4% vs. 8%; grade 3, less than 1% vs. less than 1%) occurred less often in patients receiving capecitabine plus docetaxel (n = 251) compared with docetaxel alone (n = 255); grade 3 or 4 polyneuropathy was reported in 0.4% of patients receiving combination therapy. 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 9% to 15% (grade 3, 1%) of patients with metastatic colorectal or breast cancer treated with capecitabine monotherapy in 2 clinical trials (n = 758). Edema (less than 5%), weight gain (less than 5%), and lymphedema (grade 3 or 4, 0.1%) have also been reported across clinical trials of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. In patients with metastatic breast cancer randomized to treatment with docetaxel plus capecitabine (n = 251) or docetaxel alone (n = 255), the incidence of edema was higher than with capecitabine monotherapy, but similar between treatment arms (33% vs. 34%; grade 3, less than 2% vs. less than 4%); lymphedema was reported in 3% (grade 3, less than 1%) versus 5% (grade 3, 1%) of these patients, respectively.[44458]
Respiratory adverse reactions including dyspnea (14%; grade 3, 1% to 3%), cough (7% to 13%; grade 3 or 4, less than 2%), pharyngeal disorder (5%), and sore throat (2% to 12%; grade 3, 2% or less) were reported in patients with metastatic colorectal cancer receiving capecitabine monotherapy (n = 596) or metastatic breast cancer receiving capecitabine plus docetaxel (n = 251); the incidence was similar to patients receiving fluorouracil/leucovorin alone (n = 593). Hoarseness (less than 5%), dyspnea (less than 5%), as well as grade 3 or 4 asthma (0.2%), cough (0.1%), and respiratory distress (0.1%) were also reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. In patients receiving combination therapy with capecitabine and docetaxel, rhinorrhea (5%) and pleural effusion (2%; grade 3, 1%) were reported.[44458]
Venous thrombosis was reported in 8% (grade 3 or 4, 3% to 4%) of patients with metastatic colorectal cancer treated with capecitabine monotherapy (n = 596) compared with 6% (grade 3, 2%) of those treated with fluorouracil/leucovorin (n = 593). Pulmonary embolism (grade 3 or 4, 0.2%) and cerebrovascular accident/stroke (grade 3 or 4, 0.1%) were also reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. Grade 3 or 4 venous phlebitis and thrombophlebitis were additionally reported in 0.4% of patients with metastatic breast cancer treated with capecitabine plus docetaxel in a randomized clinical trial.[44458]
Hot flashes were reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials. Flushing was also reported in 5% of patients with metastatic breast cancer treated with capecitabine plus docetaxel; the incidence was similar to patients receiving docetaxel alone.[44458]
Difficulty walking, abnormal coordination, impaired balance, and tremor were each reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. Additionally, grade 3 or 4 ataxia (0.5%), loss of consciousness (0.2%), and encephalopathy (0.1%) were reported. Grade 3 or 4 syncope (1.2%) and ataxia (0.4%) were also reported in patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel. Toxic leukoencephalopathy was reported in postmarketing experience with capecitabine therapy.[44458]
Hypotension (grade 3 or 4, 0.2%) and hypertension (grade 3 or 4, 0.1%) were reported in patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials. Additionally, grade 3 or 4 hypotension (1.2%) and postural hypotension (0.8%) occurred in patients with metastatic breast cancer who received combination therapy with capecitabine plus docetaxel.[44458]
Polydipsia was reported in less than 5% 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 5% of patients receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials.[44458]
Angioedema has been reported with capecitabine use in postmarketing experience.[44458]
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; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Administer fluid and electrolyte replacement if patients become dehydrated; dehydration may cause acute renal insufficiency or failure which can be fatal. Patients with anorexia, asthenia, nausea/vomiting, or diarrhea may rapidly become dehydrated. Monitor patients to prevent and correct the causes of dehydration. If grade 2 or higher dehydration occurs, interrupt capecitabine therapy until dehydration is corrected and precipitating causes are corrected or controlled.[44458]
Capecitabine is contraindicated in patients with severe renal impairment or renal failure (creatinine clearance (CrCL) less than 30 mL/min). Patients with moderate renal impairment (CrCL 30 to 50 mL/min) require a reduced starting dose of capecitabine. Patients with pre-existing renal impairment or who are receiving concomitant nephrotoxic agents are at an increased risk of renal failure which has been reported in conjunction with dehydration. Closely monitor patients with mild and moderate renal impairment at baseline for adverse reactions; promptly interrupt therapy and reduce the dose of capecitabine as recommended if grade 2 to 4 adverse reactions occur.[44458]
Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or with fluorouracil hypersensitivity. Capecitabine has not been proven safe for patients with dihydropyrimidine dehydrogenase (DPD) deficiency at any dose, and there is insufficient data regarding capecitabine dosing in patients with partial DPD activity. Dihydropyrimidine dehydrogenase (DPD) is responsible for the metabolism of fluorouracil, the active metabolite of capecitabine, and deficiency of this enzyme leads to elevated concentrations of fluorouracil due to decreased clearance. Administration of capecitabine to individuals with DPD deficiency can lead to enhanced early-onset toxicity and severe, life-threatening or fatal adverse reactions including mucositis, neutropenia, neutropenic fever, neurotoxicity, abdominal pain, diarrhea, vomiting, and chills. 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]
Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm3 or platelet counts below 100,000 cells/mm3; patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy are at increased risk of bone marrow suppression during capecitabine treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be needed if myelosuppression occurs during the course of treatment. Patients with an active infection should be treated prior to receiving capecitabine. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.[44458]
Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or PT) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Post-marketing reports have shown clinically significant increases in PT and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within one month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.[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 prior history of coronary artery disease may be at increased risk.[44458]
Patients with mild to moderate hepatic disease due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is unknown. Serious elevations in bilirubin, resulting in jaundice, have been reported with capecitabine therapy. Monitor liver function tests; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.[44458]
Closely monitor geriatric patients for an increased incidence of adverse reactions, as they may experience more grade 3 or 4 adverse reactions compared with younger patients; insufficient data are available to provide a dosage recommendation. In a study of capecitabine monotherapy, 62% of patients aged 80 years and older (n = 21) experienced a treatment-related grade 3 or 4 adverse event including diarrhea (28.6%), nausea (14.3%), hand-and-foot syndrome (14.3%), and vomiting (9.5%). In patients age 70 and older receiving capecitabine plus docetaxel (n = 10), 30% experienced grade 3 or 4 diarrhea and stomatitis, and 40% experienced grade 3 hand-and-foot syndrome. The incidence of grade 3 or 4 treatment-related adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions, and treatment discontinuations within the first 2 treatment cycles was higher in patients age 60 and older who received capecitabine plus docetaxel (n = 67) compared to patients younger than 60 years of age. Of 398 patients age 65 or older receiving adjuvant capecitabine for Dukes' C colon cancer, 41% experienced a treatment-related grade 3 or 4 adverse event, including hand-and-foot syndrome (18.8%), diarrhea (13.1%), stomatitis (3%), neutropenia/granulocytopenia (2.8%), vomiting (1.5%), and nausea (1.3%).[44458]
Serious mucocutaneous reactions and skin disease, some with fatal outcome, have been reported with capecitabine therapy including toxic epidermal necrolysis and Stevens-Johnson syndrome. 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. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for skin toxicity. Permanently discontinue capecitabine in patients who develop a severe mucocutaneous reaction possibly associated with capecitabine therapy.[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. 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. In addition, capecitabine reversibly disturbed estrus in female mice and caused degenerative changes in the testes of male mice (including decreases in the number of spermatocytes and spermatids), resulting in impaired fertility or infertility.[44458]
Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether capecitabine is present in human milk, although many drugs are excreted in human milk.[44458]
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: 04/05/2019, 01:38:26 PMCapecitabine is administered orally. Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent, indicating a low potential for drug interactions related to protein binding; the primary protein involved is human albumin (35%).[44458]
Capecitabine is a prodrug that is metabolized to fluorouracil in the liver. Initially, it is hydrolyzed by a carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-DFCR), which is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase. Cytidine deaminase is found in both normal and tumor cells. Thymidine phosphorylase (dThdPase), an enzyme found in many tissues but in higher concentrations in some human carcinomas compared to surrounding normal tissues, then hydrolyzes 5'-DFUR to the active drug, fluorouracil. A small portion of fluorouracil is converted to active metabolites (FdUMP, FUTP) in the tissues; the rest (85%) is catabolized via dihydropyrimidine dehydrogenase (DPD), the initial rate-limiting step, and other enzymes to the less toxic dihydropyrimidine form (5-fluoro-5, 6-dihydro-fluorouracil, FUH2).[44458] [29028] Individuals with low or nonexistent DPD activity experience severe toxicity.[29028] [61019] Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, beta-ureido-propionase cleaves FUPA to alpha-fluoro-beta-alanine (FBAL), which is cleared in the urine. Of an administered dose, 95.5% is recovered in the urine, with 57% of the dose as FBAL; fecal excretion is minimal (2.6%). About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both capecitabine and fluorouracil is approximately 0.75 hour.[44458] In contrast to the parent compound, the intracellular nucleotides FdUMP and FUTP have prolonged half-lives.[29028]
Affected cytochrome P450 (CYP) isoenzymes: CYP2C9
Capecitabine and/or its metabolites are thought to be CYP2C9 inhibitors. Formal interaction studies have not been conducted with drugs other than warfarin; however, elevated phenytoin levels have also been observed with capecitabine coadministration. Caution is recommended if concomitant use with CYP2C9 substrates is necessary. In vitro studies have indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of CYP1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.[44458]
Peak blood concentrations of capecitabine are achieved about 1.5 hours after dosing, with peak fluorouracil levels occurring at approximately 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 35%, respectively; the mean Cmax and AUC of fluorouracil were also reduced by 43% and 21%, respectively.[44458]
Over a dosage range of 500 to 3,500 mg/m2 per day, the pharmacokinetics of capecitabine and its metabolite, 5'DFCR, are dose proportional and do not change over time. However, increases in the AUC of 5'-DFUR and fluorouracil are greater than proportional to the increase in dose, and the AUC of fluorouracil increases over time (e.g., 34% higher on day 14 than on day 1 of dosing). 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); these ratios have not been evaluated in breast cancer patients or compared to fluorouracil infusion.[44458]
In patients with mild to moderate hepatic dysfunction due to liver metastasis (n = 13), the AUC and Cmax of capecitabine increased by 60% compared to patients with normal hepatic function (n = 14); the AUC and Cmax of fluorouracil were not affected. The effect of severe hepatic dysfunction on capecitabine pharmacokinetics is not known.[44458]
Patients with moderate (CrCL 30 to 50 mL/min) and severe (CrCL less than 30 mL/min) renal impairment showed 85% and 258% higher exposure to the capecitabine metabolite, FBAL, on day 1 compared to patients with normal renal function (CrCL greater than 80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in patients with moderate and severe renal impairment, respectively, compared to normal patients. Systemic exposure to capecitabine was approximately 25% higher in patients with both moderate and severe renal impairment. Although no clinical experience using dialysis has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low-molecular-weight metabolite of the parent compound.[44458]
Based on a population analysis of pooled data from two large controlled studies in patients with metastatic colorectal cancer (n = 505), age (range, 27 to 86 years) does not significantly influence the pharmacokinetics of 5'-DFUR and fluorouracil; however, a 20% increase in age results in a 15% increase in the AUC of FBAL.[44458]
Based on a population analysis of pooled data from two large controlled studies in patients with metastatic colorectal cancer (n = 505), gender does not influence the pharmacokinetics of 5'-DFUR, fluorouracil, and FBAL.[44458]
Based on a population analysis of pooled data from two large controlled studies in patients with metastatic colorectal cancer (n = 505), ethnicity (Caucasian, n = 455; Black, n = 22; Other, n = 28) does not influence the pharmacokinetics of 5'-DFUR, fluorouracil, and FBAL. However, in a separate study, Japanese patients (n = 18) had approximately a 36% lower Cmax and 24% lower AUC for capecitabine than Caucasian patients (n = 22); the Cmax and AUC for FBAL were also approximately 25% and 34% lower in Japanese patients compared with Caucasian patients, respectively. The clinical significance of these differences is unknown. There were no significant differences in exposure to other metabolites (5'-DFCR, 5'DFUR, and fluorouracil).[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]
Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether capecitabine is present in human milk, although many drugs are excreted in human milk.[44458]