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  • CLASSES

    Pyrimidine Analogs

    BOXED WARNING

    Anticoagulant therapy

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Antimetabolite antineoplastic agent; oral prodrug of fluorouracil
    Used for the treatment of colorectal cancer and breast cancer
    Has not been associated with alopecia, and myelosuppression is uncommon; hand-foot syndrome is dose-limiting

    COMMON BRAND NAMES

    Xeloda

    HOW SUPPLIED

    Capecitabine/Xeloda Oral Tab: 150mg, 500mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic breast cancer.
    For the treatment of metastatic breast cancer that is resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen, or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalent), as monotherapy.
    NOTE: Resistance is defined as progressive disease while on treatment regardless of an initial response or relapse within 6 months of treatment completion with an anthracycline-containing adjuvant regimen.
    Oral dosage
    Adults

    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.

    For the treatment of metastatic breast cancer after failure of prior anthracycline-containing chemotherapy, in combination with docetaxel.
    Oral dosage
    Adults

    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. 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. 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.

    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†.
    NOTE: Lapatinib is FDA-approved in combination with capecitabine for this indication.
    Oral dosage
    Adults

    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.

    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†.
    NOTE: Ixabepilone is FDA approved in combination with capecitabine for this indication. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.
    Oral dosage
    Adults

    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]

    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†.
    NOTE: Neratinib is FDA approved in combination with capecitabine for this indication.
    Oral dosage
    Adults

    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. 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.

    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†.
    NOTE: Tucatinib is FDA-approved for this indication in combination with trastuzumab and capecitabine.
    Oral dosage
    Adults

    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).

    For the treatment of colorectal cancer.
    For the adjuvant treatment of Dukes' C colorectal cancer in patients who have undergone complete resection of the primary tumor, as monotherapy, when fluoropyrimidine therapy alone is preferred.
    Oral dosage
    Adults

    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]

    For the first-line treatment of metastatic colorectal cancer as monotherapy, when fluoropyrimidine therapy alone is preferred.
    Oral dosage
    Adults

    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.

    For the first- and second-line treatment of advanced colorectal cancer in combination with oxaliplatin (XELOX or CapeOX)†.
    Oral dosage
    Adults

    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. Additional trials have shown efficacy for XELOX in the treatment of both previously treated and previously untreated patients with advanced colorectal cancer.

    For the first line treatment of metastatic colorectal cancer in combination with oxaliplatin and bevacizumab (XELOX or CapeOx, with or without bevacizumab)†.
    Oral dosage
    Adults

    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).

    For the adjuvant treatment of stage III (Dukes C) 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 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). 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).]

    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. 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%. 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.

    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%). 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%.

    For the treatment of gastric cancer†.
    For the treatment of advanced gastric cancer in combination with cisplatin†.
    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), 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.

    For the treatment of advanced gastric cancer in combination with epirubicin and cisplatin or oxaliplatin†.
    Oral dosage
    Adults

    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.

    For the treatment of previously untreated patients with metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and trastuzumab†.
    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 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.

    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).

    For the treatment of advanced or metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) cancer, in combination with oxaliplatin (XELOX/CapeOx) and nivolumab†.
    NOTE: Nivolumab is FDA approved in combination with XELOX/CapeOx for this indication.
    Oral dosage
    Adults

    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).  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.

    For the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in combination with oxaliplatin (XELOX; CapeOx), trastuzumab, and pembrolizumab†.
    NOTE: Pembrolizumab is FDA-approved for this indication in combination with trastuzumab, oxaliplatin, and capecitabine.
    Oral dosage
    Adults

    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. 

    For the adjuvant treatment of pancreatic cancer (ductal adenocarcinoma), in combination with gemcitabine†.
    Oral dosage
    Adults

    1,660 mg/m2 orally 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).

    For the treatment of esophageal cancer†.
    For the treatment of advanced or metastatic esophageal adenocarcinoma or gastroesophageal junction (GEJ) cancer, in combination with capecitabine (XELOX/CapeOx) and nivolumab†.
    NOTE: Nivolumab is FDA approved in combination with XELOX/CapeOx for this indication.
    Oral dosage
    Adults

    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).   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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    Baseline Renal Insufficiency:
    Mild renal impairment (CrCL 51 mL/min or more): No initial dosage adjustment is recommended.
    Moderate renal impairment (CrCL 30 to 50 mL/min): Reduce the starting dose of capecitabine by 25% (from 1,250 mg/m2 to 950 mg/m2) when used either as monotherapy or in combination with docetaxel.
    Severe renal impairment (CrCL less than 30 mL/min): Use of capecitabine is contraindicated.

    ADMINISTRATION

    Oral Administration

    Capecitabine is administered orally within 30 minutes after a meal.
    Capecitabine is a cytotoxic drug. If capecitabine tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Exposure to crushed capecitabine tablets has resulted in eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and diarrhea.
    Do not replace doses of capecitabine that are omitted for toxicity; when toxicity resolves, the patient should resume planned treatment cycles.

    STORAGE

    Xeloda:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Dehydration, diarrhea, nausea/vomiting

    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.

    Renal failure, renal impairment

    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.
     

    Dihydropyrimidine dehydrogenase (DPD) deficiency

    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]

    Bone marrow suppression, chemotherapy, fungal infection, herpes infection, infection, radiation therapy, varicella, viral infection

    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]

    Anticoagulant therapy

    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.

    Cardiac disease, cardiotoxicity, coronary artery disease

    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.

    Hepatic disease

    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.

    Geriatric

    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]

    Skin disease

    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

    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.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    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.

    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 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.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 13.0-59.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 11.0-24.0
    hyperbilirubinemia / Delayed / 9.0-23.0
    diarrhea / Early / 12.0-15.0
    abdominal pain / Early / 0-10.0
    fatigue / Early / 0-8.0
    thrombosis / Delayed / 8.0-8.0
    stomatitis / Delayed / 0-7.0
    bradycardia / Rapid / 0-5.0
    atrial fibrillation / Early / 0-5.0
    pericardial effusion / Delayed / 0-5.0
    vomiting / Early / 0-5.0
    ileus / Delayed / 0.3-5.0
    dehydration / Delayed / 0-5.0
    keratoconjunctivitis / Early / 0-5.0
    visual impairment / Early / 0-5.0
    thrombocytopenia / Delayed / 1.0-4.0
    anemia / Delayed / 0-4.0
    neutropenia / Delayed / 2.2-4.0
    nausea / Early / 2.0-4.0
    anorexia / Delayed / 0-4.0
    weakness / Early / 0-4.0
    elevated hepatic enzymes / Delayed / 1.6-3.0
    dyspnea / Early / 1.0-3.0
    hypocalcemia / Delayed / 2.2-2.2
    GI bleeding / Delayed / 0-2.0
    constipation / Delayed / 0-2.0
    myalgia / Early / 0-2.0
    back pain / Delayed / 0-2.0
    pleural effusion / Delayed / 2.0-2.0
    erythema / Early / 0-1.0
    skin discoloration / Delayed / 0-1.0
    purpura / Delayed / 1.0-1.0
    dysgeusia / Early / 0-1.0
    dyspepsia / Early / 0-1.0
    infection / Delayed / 0-1.0
    fever / Early / 0-1.0
    lethargy / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    bone pain / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    dizziness / Early / 0-1.0
    headache / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    hypoesthesia / Delayed / 0-1.0
    edema / Delayed / 1.0-1.0
    cough / Delayed / 0-1.0
    hypercalcemia / Delayed / 0.7-0.7
    renal failure (unspecified) / Delayed / 0.4-0.6
    hepatotoxicity / Delayed / 0-0.4
    jaundice / Delayed / 0-0.4
    hepatic failure / Delayed / 0-0.4
    supraventricular tachycardia (SVT) / Early / 0-0.4
    agranulocytosis / Delayed / 0-0.4
    esophageal ulceration / Delayed / 0.4-0.4
    enterocolitis / Delayed / 0-0.4
    typhlitis / Delayed / 0-0.4
    leukopenia / Delayed / 0.2-0.2
    pulmonary embolism / Delayed / 0.2-0.2
    loss of consciousness / Rapid / 0.2-0.2
    cholestasis / Delayed / 0.1-0.1
    hepatitis / Delayed / 0.1-0.1
    myocarditis / Delayed / 0.1-0.1
    sinus tachycardia / Rapid / 0.1-0.1
    pancytopenia / Delayed / 0.1-0.1
    peptic ulcer / Delayed / 0.1-0.1
    coagulopathy / Delayed / 0.1-0.1
    stroke / Early / 0.1-0.1
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    cardiotoxicity / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    keratitis / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hypoalbuminemia / Delayed / 0-55.0
    peripheral neuropathy / Delayed / 0-10.0
    alopecia / Delayed / 6.0-6.0
    depression / Delayed / 5.0-5.0
    skin ulcer / Delayed / 0-5.0
    dysphagia / Delayed / 0-5.0
    hemoptysis / Delayed / 0-5.0
    bleeding / Early / 0-5.0
    hot flashes / Early / 0-5.0
    dysarthria / Delayed / 0-5.0
    ataxia / Delayed / 0.5-0.5
    migraine / Early / 0-0.4
    phlebitis / Rapid / 0-0.4
    radiation recall reaction / Delayed / 0.2-0.2
    candidiasis / Delayed / 0.2-0.2
    hypotension / Rapid / 0.2-0.2
    confusion / Early / 0.1-0.1
    ascites / Delayed / 0.1-0.1
    encephalopathy / Delayed / 0.1-0.1
    hypertension / Early / 0.1-0.1
    angina / Early / Incidence not known
    neurotoxicity / Early / Incidence not known

    Mild

    ocular irritation / Rapid / 13.0-15.0
    lacrimation / Early / 0-12.0
    insomnia / Early / 7.0-8.0
    rash / Early / 0-7.0
    irritability / Delayed / 0-5.0
    pruritus / Rapid / 0-5.0
    influenza / Delayed / 0-5.0
    vertigo / Early / 0-5.0
    weight gain / Delayed / 0-5.0
    hoarseness / Early / 0-5.0
    rhinorrhea / Early / 0-5.0
    flushing / Rapid / 0-5.0
    tremor / Early / 0-5.0
    polydipsia / Early / 0-5.0
    syncope / Early / 0-1.2
    laryngitis / Delayed / 1.0-1.0
    hyperhidrosis / Delayed / 0.1-0.1
    photosensitivity / Delayed / 0.1-0.1
    onycholysis / Delayed / Incidence not known
    nail discoloration / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    xerostomia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Diphenhydramine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    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. Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites FdUMP and FUTP; however, the clinical significance was not fully characterized.
    Aluminum Hydroxide: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL).
    Aluminum Hydroxide; Magnesium Carbonate: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL).
    Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with magnesium hydroxide is necessary. When a magnesium hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL).
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with magnesium hydroxide is necessary. When a magnesium hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL).
    Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL).
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Aspirin, ASA; Omeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    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.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    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.
    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.
    Dexlansoprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Diclofenac: (Moderate) The dose of diclofenac may need to be reduced if coadministration with capecitabine is necessary; monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Diclofenac; Misoprostol: (Moderate) The dose of diclofenac may need to be reduced if coadministration with capecitabine is necessary; monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Diphenhydramine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Diphenhydramine; Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Diphenhydramine; Naproxen: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    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.
    Esomeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (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. (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.
    Famotidine; Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    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.
    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.
    Fosphenytoin: (Moderate) Carefully monitor phenytoin levels if coadministration of fosphenytoin with capecitabine is necessary; a dose reduction of fosphenytoin may be necessary. Fosphenytoin is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug interaction studies of capecitabine with phenytoin have not been conducted.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Ibuprofen; Oxycodone: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Ibuprofen; Pseudoephedrine: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Lansoprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Lansoprazole; Naproxen: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Lesinurad; 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. Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites FdUMP and FUTP; however, the clinical significance was not fully characterized.
    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.
    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.
    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.
    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.
    Magnesium Hydroxide: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration with magnesium hydroxide is necessary. When a magnesium hydroxide-containing antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL).
    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.
    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, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2C9 substrate, and coadministration with weak CYP2C9 inhibitors like 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. If capecitabine is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Naproxen; Esomeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Nateglinide: (Moderate) Monitor for hypoglycemia if coadministration of nateglinide with capecitabine is necessary; a dose reduction of nateglinide and increased frequency of blood glucose monitoring may be necessary. Nateglinide is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor.
    Omeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Omeprazole; Sodium Bicarbonate: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pantoprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenytoin: (Moderate) Carefully monitor phenytoin levels if coadministration with capecitabine is necessary; a dose reduction of phenytoin may be necessary. Phenytoin is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug interaction studies of capecitabine with phenytoin have not been conducted.
    Proton pump inhibitors: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Rabeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    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.
    Torsemide: (Moderate) Monitor diuretic effect and blood pressure if coadministration of torsemide with capecitabine is necessary; adjust the dose of torsemide if clinically appropriate. Torsemide is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. Concomitant use can decrease torsemide clearance and increase torsemide plasma concentrations.
    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.
    Warfarin: (Major) 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. Additionally, age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

    PREGNANCY AND LACTATION

    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.

    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.

    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]

    PHARMACOKINETICS

    Capecitabine 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]

    Oral Route

    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.
     
    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.