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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 5-fluorouracil (5-FU) 
    FDA approved 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
    Adult females

    1,250 mg/m2 by mouth twice daily (approximately 12 hours apart), within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest. Repeat 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. 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% (95% CI, 13.5% to 41.2%) for a median duration of 5 months (range, 2.1 months to 7.6 months). The median time to progression in these patients was 3.3 months and the median survival was 8.4 months.

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

    1,250 mg/m2 by mouth 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. Dosages should be adjusted based on toxicity during treatment cycle; once a dosage is reduced, it should not be increased at a later time. In a multicenter, randomized, open-label, phase III trial of 511 patients randomized to docetaxel/capecitabine or docetaxel alone, overall response rate (32% vs. 23%, p = 0.009), time-to-progression (6.1 months vs. 4.2 months, HR 0.643, p = 0.0001), and overall survival (14.5 months vs. 11.5 months, HR 0.775, p = 0.0126) were improved in the combination arm. 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. Patients should exhibit disease progression on trastuzumab prior to initiating combination therapy with lapatinib and capecitabine. In a randomized, open-label study of HER2-positive metastatic breast cancer patients (n = 540), median progression free survival (PFS) and overall survival (OS) for lapatinib plus capecitabine was less than for patients treated with trastuzumab plus capecitabine (PFS: 6.6 months vs. 8 months, HR 1.3, 95% CI, 1.04 to 1.64; OS: HR 1.34, 95% CI, 0.95 to 1.92). In another randomized, open-label study of women with HER2-positive metastatic breast cancer, first-line treatment with lapatinib plus taxane-based chemotherapy also had a shorter median PFS compared with trastuzumab plus taxane-based chemotherapy (9 months vs. 11.3 months; HR 1.37; 95% CI, 1.13 to 1.65)
    Oral dosage
    Adult females

    1,000 mg/m2 by mouth 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. In a randomized, phase III clinical trial of patients with progressive (after anthracyclines, taxanes, and trastuzumab), locally advanced or metastatic breast cancer, treatment with lapatinib plus capecitabine (n = 198) improved the median time to progression (TTP) by independent assessment compared with capecitabine alone (n = 201) (27.1 months vs. 18.6 months; HR 0.57; p = 0.00013), with a response rate of 23.7% vs. 13.9%. By investigator assessment, the median TTP was 23.9 months vs. 18.3 months (HR 0.72; p = 0.00762) with a response rate of 31.8% vs. 17.4%, respectively.

    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
    Adult females

    1,000 mg/m2 by mouth twice daily, approximately 12 hours apart, within 30 minutes of a meal, on days 1 to 14, followed by 1 week of rest, plus ixabepilone 40 mg/m2 IV (maximum BSA, 2.2 m2) over 3 hours on day 1; 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. 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 median progression-free survival (PFS) compared with capecitabine alone (5.7 months vs. 4.1 months; HR 0.69; p < 0.0001), with an objective response of 34.7% for patients receiving combination therapy and 14.3% for those treated with capecitabine monotherapy (p < 0.0001). The median duration of response was 6.4 months versus 5.6 months, respectively. There was no significant difference in overall survival (combination therapy, 12.9 months; capecitabine monotherapy, 11.1 months; HR 0.9; p = 0.12).

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

    1,250 mg/m2 orally twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest. Repeat 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. In a multicenter, randomized, phase III trial (X-ACT trial), adjuvant treatment with capecitabine (n = 1,004) was non-inferior to 5-fluorouracil plus leucovorin (5-FU/LV) (n = 983) in the treatment of Dukes' C colon cancer. After a median follow-up of 83 months, the 5-year disease-free survival (DFS) was 59.1% in capecitabine-treated patients compared with 54.6% in those who received 5-FU/LV (HR 0.88; p = 0.068); 5-year overall survival was 71.4% vs. 68.4%, respectively (HR 0.86; 95% CI, 0.74 to 1.01). 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.

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

    1,250 mg/m2 orally twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed by 1 week of rest. Repeat 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. 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 an overall response rate (ORR) of 21%, compared with 11% in patients treated with 5-fluorouracil plus leucovorin (5-FU/LV) (n = 303) (p = 0.0014); the median time to progression (TTP) was 4.3 months vs. 4.4 months (HR 0.99; 95% CI, 0.84 to 1.17), and the median overall survival (OS) was 12.7 months vs. 13.6 months, respectively (HR 1; 95% CI, 0.84 to 1.18). Results were similar in an identical trial operated in Europe, Australia, New Zealand, and Taiwan (ORR, 21% vs. 14%, p = 0.027; TTP, 4.6 months vs. 4.4 months, HR 0.97, 95% CI 0.82 to 1.14; OS 13.5 months vs. 12.3 months, HR 0.92, 95% CI, 0.78 to 1.09). Of note, combination chemotherapy has shown a survival benefit as compared with 5-FU/LV monotherapy. The safety and survival effect of capecitabine use versus 5-FU/LV in combinations 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 III 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 III 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 < 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).

    †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.
    Treatment-Related Hepatotoxicity:
    Grade 2 (AST/ALT 3.1 to 5 times the upper limit of normal (ULN) or bilirubin 1.6 to 3 times ULN): For the first, second, or third occurrences, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment (1st occurrence, no dosage adjustment; 2nd occurrence, 75% of the starting dose; 3rd occurrence, 50% of the starting dose). For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine therapy. Do not replace missed doses. Do not rechallenge patient with a higher dose after a dose reduction.
    Grade 3 elevations in AST/ALT (AST/ALT 5.1 to 20 times ULN or bilirubin 3.1 to 10 times ULN): For the first and second occurrence, hold capecitabine therapy. After resolution of AST/ALT to grade 1 or less or bilirubin to grade 2 or less (AST/ALT/bilirubin less than or equal to 3 times ULN), resume treatment at a reduced dose (1st occurrence, 75% of the starting dose; 2nd occurrence, 50% of the starting dose). For the third occurrence of a grade 3 toxicity, discontinue capecitabine therapy. Do not replace missed doses. Do not rechallenge patient with a higher dose after a dose reduction.
    Grade 4 elevations in AST/ALT (AST/ALT more than 20 times ULN or bilirubin more than 10 times ULN): Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy. Begin next treatment at 50% of the starting dose when AST/ALT resolves to grade 1 or less or bilirubin to grade 2 or less (AST/ALT/bilirubin less than or equal to 3 times ULN); do not replace missed doses. Do not rechallenge patient with a higher dose.

    Renal Impairment

    Baseline Renal Insufficiency:
    Mild renal impairment (CrCL greater than or equal to 51 mL/min: 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.
    Treatment-Related Nephrotoxicity:
    Grade 2 (SCr more than 1.5 to 3 times baseline or upper limit of normal (ULN)): For the first, second, or third occurrences, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment (1st occurrence, no dosage adjustment; 2nd occurrence, 75% of the starting dose; 3rd occurrence, 50% of the starting dose). For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine therapy. Do not replace missed doses. Do not rechallenge patient with a higher dose after a dose reduction.
    Grade 3 (SCr more than 3 times baseline, or 3.1 to 6 times ULN): For the first and second occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment at a reduced dose (1st occurrence, 75% of the starting dose; 2nd occurrence, 50% of the starting dose). For the third occurrence of a grade 3 toxicity, discontinue capecitabine therapy. Do not replace missed doses. Do not rechallenge patient with a higher dose after a dose reduction.
    Grade 4 (SCr more than 6 times ULN): Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy. Begin next treatment at 50% of the starting dose when toxicity resolves to grade 1 or less do not replace missed doses. Do not rechallenge patient with a higher dose. Although no clinical experience using dialysis has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low-molecular weight metabolite of the parent compound.

    ADMINISTRATION

    Oral Administration

    Capecitabine is administered orally within 30 minutes after a meal.
    Swallow tablet whole with water. 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.
    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

    Diarrhea, sometimes severe, has been reported with capecitabine therapy. The occurrence of severe diarrhea may contribute to renal dysfunction due to dehydration. Hold capecitabine therapy for grade 2 or higher diarrhea or dehydration; if the patient has diarrhea, treat with standard antidiarrheal therapy (e.g., loperamide). Treatment with capecitabine may be resumed after resolution to grade 1 or less and correction of any precipitating causes; a dose reduction may be necessary. Carefully monitor patients with diarrhea and give electrolyte and fluid replacement as needed. In clinical trials of capecitabine monotherapy (n = 875), the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range, 1 to 369 days) and the median duration was 5 days.

    Nausea/vomiting, 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 severe renal impairment had a higher rate of grade 3 or 4 adverse reactions and a shorter duration of treatment than patients with normal renal function. Moderate renal impairment (CrCL 30 to 50 mL/min) was associated with a higher incidence of grade 3 or 4 serious adverse reactions relative to patients with normal renal function; monitor these patients closely. A reduction in the initial capecitabine dose is recommended. Although patients with mild renal impairment (CrCL 51 to 80 mL/min) did experience slightly more serious adverse events and withdrawals due to adverse events than patients with normal renal function, they maintained their overall benefit/risk ratio. Patients with pre-existing renal dysfunction, anorexia, asthenia, nausea/vomiting, diarrhea, or who are receiving concomitant nephrotoxic agents may rapidly become dehydrated. Dehydration has occurred with capecitabine treatment, and may cause acute renal failure that can be fatal. 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.

    Dihydropyrimidine dehydrogenase (DPD) deficiency

    Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or with 5-fluorouracil hypersensitivity. Capecitabine has not been proven safe for patients with dihydropyrimidine dehydrogenase (DPD) deficiency (familial pyrimidinemia) 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 5-fluorouracil (5-FU), the active metabolite of capecitabine, and deficiency of this enzyme leads to elevated concentrations of 5-FU 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.

    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. Although relatively uncommon, patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy are at risk of increased bone marrow suppression during capecitabine treatment. Therefore, this drug should be used only by clinicians experienced in chemotherapy. The active form of capecitabine, 5-fluorouracil, is a radiation sensitizer. 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.

    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.

    Angina, cardiac arrhythmias, cardiac disease, coronary artery disease

    Capecitabine should be used with caution in patients with cardiac disease. Use of capecitabine therapy has been associated with cardiotoxicity, including myocardial infarction, dysrhythmias, electrocardiogram changes, cardiogenic shock, and sudden death. These adverse reactions may be more common in patients with a prior history of coronary artery disease (e.g., angina) or cardiac arrhythmias.

    Hepatic disease, jaundice

    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. If grade 2 to 4 elevations in bilirubin occur, administration of capecitabine should be discontinued until serum bilirubin falls to 3 times the upper limit of normal or less.

    Geriatric

    Monitor geriatric patients (>= 60 years) for an increased incidence of adverse reactions, as they may experience more grade 3 or 4 adverse reactions compared with younger patients. Age greater than 60 years also predisposes patients to an increased risk of coagulopathy. In a study of capecitabine monotherapy, 62% of the 21 patients aged 80 years and older experienced a treatment-related grade 3 or 4 adverse event such as diarrhea (n = 6), nausea (n = 3), hand-and-foot syndrome (n = 3), or vomiting (n = 2). Further, of 398 patients at least 65 years of age who received capecitabine as adjuvant therapy for Dukes' C colon cancer after primary tumor resection, 41% had a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome (n = 75), diarrhea (n = 52), stomatitis (n = 12), neutropenia/granulocytopenia (n = 11), vomiting (n = 6), and nausea (n = 5). Elderly patients may be more sensitive to the toxic effects of capecitabine.

    Skin disease

    Serious mucocutaneous reactions and skin disease, some with fatal outcome, have been reported with capecitabine therapy including toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS). Permanently discontinue capecitabine in patients who develop a severe mucocutaneous reaction possibly associated with capecitabine therapy. Palmar-plantar erythrodysesthesia (hand and foot syndrome) has also occurred with capecitabine treatment; persistent or severe hand and foot syndrome (grade >= 2) can lead to loss of fingerprints, which could impact patient identification. The median time to onset of hand and foot syndrome in the metastatic setting was 79 days (range, 11 to 360 days). Hold capecitabine for grade 2 or 3 hand and foot syndrome until resolution to grade 1 or less, and resume therapy with a dose reduction if appropriate.

    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

    neutropenia / Delayed / 0-68.0
    lymphopenia / Delayed / 15.0-48.0
    leukopenia / Delayed / 24.0-37.0
    hyperbilirubinemia / Delayed / 3.9-22.8
    diarrhea / Early / 0-13.0
    anemia / Delayed / 0-9.6
    thrombosis / Delayed / 8.0-8.0
    ileus / Delayed / 0.3-6.0
    GI bleeding / Delayed / 6.0-6.0
    GI obstruction / Delayed / 0.3-6.0
    atrial fibrillation / Early / 0-5.0
    pericardial effusion / Delayed / 0-5.0
    bradycardia / Rapid / 0-5.0
    visual impairment / Early / 5.0-5.0
    keratoconjunctivitis / Early / 0-5.0
    thrombocytopenia / Delayed / 1.0-3.0
    pleural effusion / Delayed / 2.0-2.0
    hepatic failure / Delayed / 0.4-0.4
    agranulocytosis / Delayed / 0.4-0.4
    typhlitis / Delayed / 0.4-0.4
    enterocolitis / Delayed / 0.4-0.4
    esophageal ulceration / Delayed / 0.4-0.4
    renal failure (unspecified) / Delayed / 0.4-0.4
    pulmonary embolism / Delayed / 0.2-0.2
    stroke / Early / 0.1-0.1
    myocarditis / Delayed / 0.1-0.1
    pancytopenia / Delayed / 0.1-0.1
    coagulopathy / Delayed / 0.1-0.1
    peptic ulcer / Delayed / 0.1-0.1
    Stevens-Johnson syndrome / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    keratitis / Delayed / Incidence not known

    Moderate

    stomatitis / Delayed / 22.0-67.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 54.0-63.0
    hypoalbuminemia / Delayed / 55.0-55.0
    edema / Delayed / 0-33.0
    elevated hepatic enzymes / Delayed / 0.4-27.5
    constipation / Delayed / 9.0-20.0
    dyspnea / Early / 0-14.0
    peripheral neuropathy / Delayed / 6.0-10.0
    dehydration / Delayed / 7.0-10.0
    bone pain / Delayed / 0.1-8.0
    candidiasis / Delayed / 0.2-7.0
    erythema / Early / 6.0-6.0
    chest pain (unspecified) / Early / 0.2-6.0
    depression / Delayed / 0-5.0
    dysarthria / Delayed / 0-5.0
    hot flashes / Early / 0-5.0
    skin ulcer / Delayed / 0-5.0
    hemoptysis / Delayed / 0-5.0
    bleeding / Early / 0-5.0
    dysphagia / Delayed / 0-5.0
    conjunctivitis / Delayed / 0-5.0
    hypotension / Rapid / 0.2-1.2
    orthostatic hypotension / Delayed / 0.8-0.8
    ataxia / Delayed / 0.5-0.5
    migraine / Early / 0.4-0.4
    jaundice / Delayed / 0.4-0.4
    phlebitis / Rapid / 0.4-0.4
    radiation recall reaction / Delayed / 0.2-0.2
    encephalopathy / Delayed / 0.1-0.1
    confusion / Early / 0.1-0.1
    cholestasis / Delayed / 0.1-0.1
    hepatitis / Delayed / 0.1-0.1
    ascites / Delayed / 0.1-0.1
    hypertension / Early / 0.1-0.1
    sinus tachycardia / Rapid / 0.1-0.1
    angina / Early / Incidence not known
    clastogenesis / Delayed / Incidence not known

    Mild

    nausea / Early / 34.0-53.0
    fatigue / Early / 16.0-42.0
    weakness / Early / 0-42.0
    alopecia / Delayed / 6.0-41.0
    vomiting / Early / 15.0-37.0
    abdominal pain / Early / 7.0-35.0
    fever / Early / 7.0-28.0
    anorexia / Delayed / 9.0-26.0
    asthenia / Delayed / 10.0-26.0
    paresthesias / Delayed / 12.0-21.0
    dysgeusia / Early / 6.0-16.0
    headache / Early / 5.0-15.0
    arthralgia / Delayed / 8.0-15.0
    myalgia / Early / 0-15.0
    ocular irritation / Rapid / 5.0-15.0
    dyspepsia / Early / 6.0-14.0
    cough / Delayed / 0.1-13.0
    dizziness / Early / 6.0-12.0
    throat irritation / Early / 2.0-12.0
    back pain / Delayed / 10.0-12.0
    lacrimation / Early / 12.0-12.0
    lethargy / Early / 7.0-10.0
    rash (unspecified) / Early / 7.0-9.0
    insomnia / Early / 0-8.0
    skin discoloration / Delayed / 7.0-7.0
    epistaxis / Delayed / 0.1-7.0
    weight loss / Delayed / 7.0-7.0
    infection / Delayed / 0.2-7.0
    nail discoloration / Delayed / 6.0-6.0
    xerostomia / Early / 6.0-6.0
    irritability / Delayed / 0-5.0
    vertigo / Early / 0-5.0
    tremor / Early / 0-5.0
    onycholysis / Delayed / 5.0-5.0
    flushing / Rapid / 5.0-5.0
    weight gain / Delayed / 0-5.0
    polydipsia / Early / 0-5.0
    influenza / Delayed / 0-5.0
    rhinorrhea / Early / 5.0-5.0
    hoarseness / Early / 0-5.0
    hypoesthesia / Delayed / 4.0-4.0
    pruritus / Rapid / 4.0-4.0
    syncope / Early / 1.2-1.2
    purpura / Delayed / 1.0-1.0
    laryngitis / Delayed / 1.0-1.0
    photosensitivity / Delayed / 0.1-0.1

    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%.
    Aliskiren; Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    Aluminum Hydroxide: (Minor) When an aluminum hydroxide containing antacid was administered immediately after capecitabine, AUC and Cmax increased for capecitabine and for the metabolite 5'-DFCR. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). Because the pharmacokinetic parameters of 5-FU were not affected, the clinical relevance of this interaction may be minor.
    Aluminum Hydroxide; Magnesium Carbonate: (Minor) When an aluminum hydroxide containing antacid was administered immediately after capecitabine, AUC and Cmax increased for capecitabine and for the metabolite 5'-DFCR. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). Because the pharmacokinetic parameters of 5-FU were not affected, the clinical relevance of this interaction may be minor.
    Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Use caution if coadministration of capecitabine with magnesium hydroxide is necessary, and monitor for an increase in capecitabine-related adverse reactions. When an aluminum hydroxide; magnesium hydroxide containing antacid was administered immediately after capecitabine (1,250 mg/m2) in 12 cancer patients, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively, and the respective AUC and Cmax for 5'-DFCR increased by 18% and 22%. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). The clinical relevance of this interaction is unknown. (Minor) When an aluminum hydroxide containing antacid was administered immediately after capecitabine, AUC and Cmax increased for capecitabine and for the metabolite 5'-DFCR. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). Because the pharmacokinetic parameters of 5-FU were not affected, the clinical relevance of this interaction may be minor.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Use caution if coadministration of capecitabine with magnesium hydroxide is necessary, and monitor for an increase in capecitabine-related adverse reactions. When an aluminum hydroxide; magnesium hydroxide containing antacid was administered immediately after capecitabine (1,250 mg/m2) in 12 cancer patients, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively, and the respective AUC and Cmax for 5'-DFCR increased by 18% and 22%. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). The clinical relevance of this interaction is unknown. (Minor) When an aluminum hydroxide containing antacid was administered immediately after capecitabine, AUC and Cmax increased for capecitabine and for the metabolite 5'-DFCR. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). Because the pharmacokinetic parameters of 5-FU were not affected, the clinical relevance of this interaction may be minor.
    Aluminum Hydroxide; Magnesium Trisilicate: (Minor) When an aluminum hydroxide containing antacid was administered immediately after capecitabine, AUC and Cmax increased for capecitabine and for the metabolite 5'-DFCR. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). Because the pharmacokinetic parameters of 5-FU were not affected, the clinical relevance of this interaction may be minor.
    Amitriptyline: (Moderate) Use caution if coadministration of capecitabine with amitriptyline is necessary, and monitor for an increase in amitriptyline-related adverse reactions such as nausea, dizziness, hypotension, syncope, and QT prolongation. Amitriptyline is a primarily a CYP2D6 and 2C19 substrate, with lesser contributions from CYP2C9, 1A2, and 3A4. 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%.
    Amitriptyline; Chlordiazepoxide: (Moderate) Use caution if coadministration of capecitabine with amitriptyline is necessary, and monitor for an increase in amitriptyline-related adverse reactions such as nausea, dizziness, hypotension, syncope, and QT prolongation. Amitriptyline is a primarily a CYP2D6 and 2C19 substrate, with lesser contributions from CYP2C9, 1A2, and 3A4. 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%.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    Amlodipine; Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    Amoxicillin; Clarithromycin; 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.
    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.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Artemether; Lumefantrine: (Minor) Use caution if coadministration of capecitabine with artemether is necessary, and monitor for an increase in artemether-related adverse reactions. Artemether is a minor substrate of CYP2C9; 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%.
    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.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Use caution if coadministration of capecitabine with phenobarbital is necessary, and monitor for an increase in phenobarbital-related adverse reactions. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. 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%.
    Azathioprine: (Minor) Additive immunosuppressant affects may be seen when azathioprine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Major) Capecitabine is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which generates 5-fluorouracil (5-FU) selectively in tumor cells. Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. Adverse GI effects, especially stomatitis and diarrhea, are more common and prolonged in patients treated with the combination of leucovorin plus 5-FU than with 5-FU alone. Severe enterocolitis, dehydration, and diarrhea have been fatal in geriatric patients receiving weekly leucovorin and 5-FU concomitantly. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. Ask patients about any vitamins they take, as folic acid, vitamin B9 is converted to folinic acid in vivo, and leucovorin is the calcium salt of folinic acid. Carefully consider the risks and benefits of multivitamin supplements containing folic acid when used concurrently with capecitabine. A woman who was taking oral folic acid 15 mg/day developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after starting capecitabine 2500 mg/m2/day. Although both folic acid and capecitabine were stopped, she developed necrotic colitis and died from septic shock. Among patients who received capecitabine for colon cancer, pretreatment serum folate concentrations of at least 17.96 nmol/L were statistically significantly associated with an increased incidence of grade 2 or 3 adverse effects. Specific grade 2 or 3 adverse events that were significantly more frequent included diarrhea, nausea, and vomiting. (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since capecitabine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of capecitabine and L-methylfolate. Although no interaction between L-methylfolate and capecitabine has been reported, caution still should be exercised with the coadministration of these agents.
    Azilsartan: (Moderate) Use caution if coadministration of capecitabine with azilsartan is necessary, and monitor for an increase in azilsartan-related adverse reactions. Azilsartan is a major 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%.
    Azilsartan; Chlorthalidone: (Moderate) Use caution if coadministration of capecitabine with azilsartan is necessary, and monitor for an increase in azilsartan-related adverse reactions. Azilsartan is a major 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%.
    Basiliximab: (Minor) Additive immunosuppressant affects may be seen when basiliximab is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Use caution if coadministration of capecitabine with phenobarbital is necessary, and monitor for an increase in phenobarbital-related adverse reactions. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. 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%.
    Bosentan: (Moderate) Use caution if coadministration of capecitabine with bosentan is necessary, and monitor for an increase in bosentan-related adverse reactions. If also administering a moderate or strong CYP3A4 inhibitor, the use of capecitabine and bosentan is not recommended. Bosentan is a CYP2C9 and 3A4 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%. According to the manufacturer of bosentan, concomitant administration of a CYP2C9 inhibitor and a moderate or strong CYP3A4 inhibitor will likely lead to large increases in plasma concentrations of bosentan.
    Calcium Carbonate; Magnesium Hydroxide: (Minor) Use caution if coadministration of capecitabine with magnesium hydroxide is necessary, and monitor for an increase in capecitabine-related adverse reactions. When an aluminum hydroxide; magnesium hydroxide containing antacid was administered immediately after capecitabine (1,250 mg/m2) in 12 cancer patients, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively, and the respective AUC and Cmax for 5'-DFCR increased by 18% and 22%. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). The clinical relevance of this interaction is unknown.
    Candesartan: (Moderate) Use caution if coadministration of capecitabine with candesartan is necessary, and monitor for an increase in candesartan-related adverse reactions. Candesartan 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%.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if coadministration of capecitabine with candesartan is necessary, and monitor for an increase in candesartan-related adverse reactions. Candesartan 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%.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    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%.
    Carvedilol: (Moderate) Use caution if coadministration of capecitabine with carvedilol is necessary, and monitor for an increase in carvedilol-related adverse reactions, including bradycardia or heart block. Carvedilol 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%.
    Celecoxib: (Moderate) Use caution if coadministration of capecitabine with celecoxib is necessary, and monitor for an increase in celecoxib-related adverse reactions. Celecoxib 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%.
    Chlorpropamide: (Moderate) Use caution if coadministration of capecitabine with chlorpropamide is necessary, and monitor for an increase in chlorpropamide-related adverse reactions such as hypoglycemia. Chlorpropamide 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%.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cyclosporine: (Minor) Additive immunosuppressant affects may be seen when cyclosporine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    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%.
    Diazepam: (Moderate) Use caution if coadministration of capecitabine with diazepam is necessary, and monitor for an increase in diazepam-related adverse reactions. Diazepam 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) Use caution if coadministration of capecitabine with diclofenac is necessary, and monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a 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%. When diclofenac was coadministered with voriconazole (an inhibitor of CYP2C9, 2C19, and 3A4), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively.
    Diclofenac; Misoprostol: (Moderate) Use caution if coadministration of capecitabine with diclofenac is necessary, and monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a 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%. When diclofenac was coadministered with voriconazole (an inhibitor of CYP2C9, 2C19, and 3A4), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    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) Use caution if coadministration of capecitabine with ibuprofen is necessary, and monitor for an increase in ibuprofen-related adverse reactions. Ibuprofen 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%. (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: (Moderate) Use caution if coadministration of capecitabine with naproxen is necessary, and monitor for an increase in naproxen-related adverse reactions. Naproxen is a CYP2C9 substrate in vitro; 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%. (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%.
    Doxepin: (Moderate) Use caution if coadministration of capecitabine with doxepin is necessary, and monitor for an increase in doxepin-related adverse reactions. Doxepin 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%.
    Dronabinol, THC: (Moderate) Use caution if coadministration of capecitabine with dronabinol, THC is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 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: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since capecitabine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of capecitabine and L-methylfolate. Although no interaction between L-methylfolate and capecitabine has been reported, caution still should be exercised with the coadministration of these agents. (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efalizumab: (Minor) Concurrent use of efalizumab with other agents which cause bone marrow or immune suppression such as antineoplastic agents may result in additive effects. Dosage reductions may be required.
    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.
    Esomeprazole; Naproxen: (Moderate) Use caution if coadministration of capecitabine with naproxen is necessary, and monitor for an increase in naproxen-related adverse reactions. Naproxen is a CYP2C9 substrate in vitro; 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%. (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: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Desogestrel: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Etonogestrel: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Capecitabine is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which generates 5-fluorouracil (5-FU) selectively in tumor cells. Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. Adverse GI effects, especially stomatitis and diarrhea, are more common and prolonged in patients treated with the combination of leucovorin plus 5-FU than with 5-FU alone. Severe enterocolitis, dehydration, and diarrhea have been fatal in geriatric patients receiving weekly leucovorin and 5-FU concomitantly. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. Ask patients about any vitamins they take, as folic acid, vitamin B9 is converted to folinic acid in vivo, and leucovorin is the calcium salt of folinic acid. Carefully consider the risks and benefits of multivitamin supplements containing folic acid when used concurrently with capecitabine. A woman who was taking oral folic acid 15 mg/day developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after starting capecitabine 2500 mg/m2/day. Although both folic acid and capecitabine were stopped, she developed necrotic colitis and died from septic shock. Among patients who received capecitabine for colon cancer, pretreatment serum folate concentrations of at least 17.96 nmol/L were statistically significantly associated with an increased incidence of grade 2 or 3 adverse effects. Specific grade 2 or 3 adverse events that were significantly more frequent included diarrhea, nausea, and vomiting. (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since capecitabine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of capecitabine and L-methylfolate. Although no interaction between L-methylfolate and capecitabine has been reported, caution still should be exercised with the coadministration of these agents. (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norelgestromin: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norethindrone: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norgestimate: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Ethinyl Estradiol; Norgestrel: (Minor) Use caution if coadministration of capecitabine with ethinyl estradiol is necessary, and monitor for an increase in ethinyl estradiol-related adverse reactions. Ethinyl estradiol is a CYP2C9 substrate in vitro; 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%.
    Etravirine: (Moderate) Use caution if coadministration of capecitabine with etravirine is necessary, and monitor for an increase in etravirine-related adverse reactions. Etravirine 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%.
    Famotidine; Ibuprofen: (Moderate) Use caution if coadministration of capecitabine with ibuprofen is necessary, and monitor for an increase in ibuprofen-related adverse reactions. Ibuprofen 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%.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fluoxetine: (Moderate) Use caution if coadministration of capecitabine with fluoxetine is necessary, and monitor for an increase in fluoxetine-related adverse reactions. Fluoxetine 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%.
    Fluoxetine; Olanzapine: (Moderate) Use caution if coadministration of capecitabine with fluoxetine is necessary, and monitor for an increase in fluoxetine-related adverse reactions. Fluoxetine 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%.
    Flurbiprofen: (Moderate) Use caution if coadministration of capecitabine with flurbiprofen is necessary, and monitor for an increase in flurbiprofen-related adverse reactions. Flurbiprofen 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%.
    Fluvastatin: (Moderate) Use caution if coadministration of capecitabine with fluvastatin is necessary, and monitor for an increase in fluvastatin-related adverse reactions (e.g., myopathy, rhabdomyolysis). Fluvastatin is primarily (75%) 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%.
    Folic Acid, Vitamin B9: (Major) Capecitabine is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which generates 5-fluorouracil (5-FU) selectively in tumor cells. Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. Adverse GI effects, especially stomatitis and diarrhea, are more common and prolonged in patients treated with the combination of leucovorin plus 5-FU than with 5-FU alone. Severe enterocolitis, dehydration, and diarrhea have been fatal in geriatric patients receiving weekly leucovorin and 5-FU concomitantly. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. Ask patients about any vitamins they take, as folic acid, vitamin B9 is converted to folinic acid in vivo, and leucovorin is the calcium salt of folinic acid. Carefully consider the risks and benefits of multivitamin supplements containing folic acid when used concurrently with capecitabine. A woman who was taking oral folic acid 15 mg/day developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after starting capecitabine 2500 mg/m2/day. Although both folic acid and capecitabine were stopped, she developed necrotic colitis and died from septic shock. Among patients who received capecitabine for colon cancer, pretreatment serum folate concentrations of at least 17.96 nmol/L were statistically significantly associated with an increased incidence of grade 2 or 3 adverse effects. Specific grade 2 or 3 adverse events that were significantly more frequent included diarrhea, nausea, and vomiting. (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since capecitabine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of capecitabine and L-methylfolate. Although no interaction between L-methylfolate and capecitabine has been reported, caution still should be exercised with the coadministration of these agents.
    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.
    Fosamprenavir: (Moderate) Use caution if coadministration of capecitabine with fosamprenavir is necessary, and monitor for an increase in fosamprenavir-related adverse reactions. Fosamprenavir 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%.
    Fosphenytoin: (Moderate) Use caution if coadministration of capecitabine with fosphenytoin is necessary, monitoring phenytoin levels and watching for phenytoin-related adverse reactions (e.g., nystagmus, diplopia, ataxia, and confusion); adjust the dose of phenytoin as necessary. Phenytoin 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%. Postmarketing reports indicate that some patients receiving both phenytoin and capecitabine have had toxicity associated with elevated phenytoin levels.
    Glimepiride: (Moderate) Use caution if coadministration of capecitabine with glimepiride is necessary, and monitor for an increase in glimepiride-related adverse reactions such as hypoglycemia. Glimepiride 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%.
    Glimepiride; Pioglitazone: (Moderate) Use caution if coadministration of capecitabine with glimepiride is necessary, and monitor for an increase in glimepiride-related adverse reactions such as hypoglycemia. Glimepiride 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%.
    Glimepiride; Rosiglitazone: (Moderate) Use caution if coadministration of capecitabine with glimepiride is necessary, and monitor for an increase in glimepiride-related adverse reactions such as hypoglycemia. Glimepiride 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%. (Moderate) Use caution if coadministration of capecitabine with rosiglitazone is necessary, and monitor for an increase in rosiglitazone-related adverse reactions including hypoglycemia. Rosiglitazone is primarily a CYP2C8 substrate in vitro, with a lesser contribution from CYP2C9; 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%.
    Glipizide: (Moderate) Use caution if coadministration of capecitabine with glipizide is necessary, and monitor for an increase in glipizide-related adverse reactions such as hypoglycemia. Glipizide 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%.
    Glipizide; Metformin: (Moderate) Use caution if coadministration of capecitabine with glipizide is necessary, and monitor for an increase in glipizide-related adverse reactions such as hypoglycemia. Glipizide 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%.
    Glyburide: (Moderate) Use caution if coadministration of capecitabine with glyburide is necessary, and monitor for an increase in glyburide-related adverse reactions such as hypoglycemia. Glyburide is primarily 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%.
    Glyburide; Metformin: (Moderate) Use caution if coadministration of capecitabine with glyburide is necessary, and monitor for an increase in glyburide-related adverse reactions such as hypoglycemia. Glyburide is primarily 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%.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Use caution if coadministration of capecitabine with losartan is necessary, and monitor for an increase in losartan-related adverse reactions. Losartan 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%.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    Hydrocodone; Ibuprofen: (Moderate) Use caution if coadministration of capecitabine with ibuprofen is necessary, and monitor for an increase in ibuprofen-related adverse reactions. Ibuprofen 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%.
    Ibuprofen: (Moderate) Use caution if coadministration of capecitabine with ibuprofen is necessary, and monitor for an increase in ibuprofen-related adverse reactions. Ibuprofen 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%.
    Ibuprofen; Oxycodone: (Moderate) Use caution if coadministration of capecitabine with ibuprofen is necessary, and monitor for an increase in ibuprofen-related adverse reactions. Ibuprofen 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%.
    Ibuprofen; Pseudoephedrine: (Moderate) Use caution if coadministration of capecitabine with ibuprofen is necessary, and monitor for an increase in ibuprofen-related adverse reactions. Ibuprofen 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%.
    Imatinib: (Moderate) Use caution if coadministration of capecitabine with imatinib, STI-571 is necessary, and monitor for an increase in imatinib-related adverse reactions. Imatinib is primarily a CYP3A4 substrate, with a lesser contribution by CYP2C9, 1A2, 2D6, and 2C19. 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%.
    Indomethacin: (Moderate) Use caution if coadministration of capecitabine with indomethacin is necessary, and monitor for an increase in indomethacin-related adverse reactions. Indomethacin is a CYP2C9 substrate in vitro; 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%.
    Iron Salts: (Major) Capecitabine is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which generates 5-fluorouracil (5-FU) selectively in tumor cells. Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. Adverse GI effects, especially stomatitis and diarrhea, are more common and prolonged in patients treated with the combination of leucovorin plus 5-FU than with 5-FU alone. Severe enterocolitis, dehydration, and diarrhea have been fatal in geriatric patients receiving weekly leucovorin and 5-FU concomitantly. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. Ask patients about any vitamins they take, as folic acid, vitamin B9 is converted to folinic acid in vivo, and leucovorin is the calcium salt of folinic acid. Carefully consider the risks and benefits of multivitamin supplements containing folic acid when used concurrently with capecitabine. A woman who was taking oral folic acid 15 mg/day developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after starting capecitabine 2500 mg/m2/day. Although both folic acid and capecitabine were stopped, she developed necrotic colitis and died from septic shock. Among patients who received capecitabine for colon cancer, pretreatment serum folate concentrations of at least 17.96 nmol/L were statistically significantly associated with an increased incidence of grade 2 or 3 adverse effects. Specific grade 2 or 3 adverse events that were significantly more frequent included diarrhea, nausea, and vomiting.
    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; Naproxen: (Moderate) Use caution if coadministration of capecitabine with naproxen is necessary, and monitor for an increase in naproxen-related adverse reactions. Naproxen is a CYP2C9 substrate in vitro; 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%. (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: (Moderate) Use caution if coadministration of capecitabine with lesinurad is necessary, and monitor for an increase in lesinurad-related adverse reactions. Lesinurad 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%.
    Lesinurad; Allopurinol: (Moderate) Use caution if coadministration of capecitabine with lesinurad is necessary, and monitor for an increase in lesinurad-related adverse reactions. Lesinurad 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%.
    Leucovorin: (Major) Use caution if coadministration of capecitabine with leucovorin or levoleucovorin is necessary, and monitor for an increase in capecitabine-related adverse reactions. Capecitabine is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which generates 5-fluorouracil (5-FU). Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. Adverse GI effects, especially stomatitis and diarrhea, are more common and prolonged in patients treated with the combination of leucovorin plus 5-FU than with 5-FU alone. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. Ask patients about any vitamins they take, as folic acid, vitamin B9 is converted to folinic acid in vivo, and leucovorin is the calcium salt of folinic acid. Carefully consider the risks and benefits of multivitamin supplements containing folic acid when used concurrently with capecitabine. A woman who was taking oral folic acid 15 mg/day developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after starting capecitabine 2,500 mg/m2 per day. Although both folic acid and capecitabine were stopped, she developed necrotic colitis and died from septic shock. Among patients who received capecitabine for colon cancer, pretreatment serum folate concentrations of at least 17.96 nmol/L were statistically significantly associated with an increased incidence of grade 2 or 3 adverse effects. Specific grade 2 or 3 adverse events that were significantly more frequent included diarrhea, nausea, and vomiting.
    Levoleucovorin: (Major) Use caution if coadministration of capecitabine with leucovorin or levoleucovorin is necessary, and monitor for an increase in capecitabine-related adverse reactions. Capecitabine is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which generates 5-fluorouracil (5-FU). Leucovorin enhances the binding of fluorouracil, 5-FU, to thymidylate synthase. Administration of leucovorin concurrently with 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy. Adverse GI effects, especially stomatitis and diarrhea, are more common and prolonged in patients treated with the combination of leucovorin plus 5-FU than with 5-FU alone. In addition, concomitant administration of 5-FU and leucovorin increases the risk of myelosuppression including leukopenia and thrombocytopenia. Ask patients about any vitamins they take, as folic acid, vitamin B9 is converted to folinic acid in vivo, and leucovorin is the calcium salt of folinic acid. Carefully consider the risks and benefits of multivitamin supplements containing folic acid when used concurrently with capecitabine. A woman who was taking oral folic acid 15 mg/day developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after starting capecitabine 2,500 mg/m2 per day. Although both folic acid and capecitabine were stopped, she developed necrotic colitis and died from septic shock. Among patients who received capecitabine for colon cancer, pretreatment serum folate concentrations of at least 17.96 nmol/L were statistically significantly associated with an increased incidence of grade 2 or 3 adverse effects. Specific grade 2 or 3 adverse events that were significantly more frequent included diarrhea, nausea, and vomiting.
    Levomefolate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since capecitabine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of capecitabine and L-methylfolate. Although no interaction between L-methylfolate and capecitabine has been reported, caution still should be exercised with the coadministration of these agents.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since capecitabine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of capecitabine and L-methylfolate. Although no interaction between L-methylfolate and capecitabine has been reported, caution still should be exercised with the coadministration of these agents.
    Losartan: (Moderate) Use caution if coadministration of capecitabine with losartan is necessary, and monitor for an increase in losartan-related adverse reactions. Losartan 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%.
    Magnesium Hydroxide: (Minor) Use caution if coadministration of capecitabine with magnesium hydroxide is necessary, and monitor for an increase in capecitabine-related adverse reactions. When an aluminum hydroxide; magnesium hydroxide containing antacid was administered immediately after capecitabine (1,250 mg/m2) in 12 cancer patients, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively, and the respective AUC and Cmax for 5'-DFCR increased by 18% and 22%. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR, 5-FU, FBAL). The clinical relevance of this interaction is unknown.
    Meloxicam: (Moderate) Use caution if coadministration of capecitabine with meloxicam is necessary, and monitor for an increase in meloxicam-related adverse reactions. Meloxicam 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%.
    Mephobarbital: (Moderate) Use caution if coadministration of capecitabine with mephobarbital is necessary, and monitor for an increase in mephobarbital- or phenobarbital-related adverse reactions. Mephobarbital is converted to phenobarbital in the liver; therefore, drug interactions occurring with phenobarbital must be considered when mephobarbital is prescribed. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. Capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9, and therefore, may inhibit the inactivation of phenobarbital by CYP2C9.
    Metformin; Rosiglitazone: (Moderate) Use caution if coadministration of capecitabine with rosiglitazone is necessary, and monitor for an increase in rosiglitazone-related adverse reactions including hypoglycemia. Rosiglitazone is primarily a CYP2C8 substrate in vitro, with a lesser contribution from CYP2C9; 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%.
    Methadone: (Moderate) Use caution if coadministration of capecitabine with methadone is necessary, especially if a concomitant CYP3A4 inhibitor is used, according to the manufacturer of methadone. Monitor for an increase in methadone-related adverse reactions including respiratory depression and sedation. Methadone undergoes hepatic N-demethylation primarily by CYP3A4, CYP2B6, and CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. 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%.
    Methotrexate: (Minor) Capecitabine may cause leukopenia or other hematologic effects and result in side effects that may be additive to other agents which cause bone marrow or immune suppression such as other antineoplastic agents.
    Montelukast: (Moderate) Use caution if coadministration of capecitabine with montelukast is necessary, and monitor for an increase in montelukast-related adverse reactions. Montelukast 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%.
    Naproxen: (Moderate) Use caution if coadministration of capecitabine with naproxen is necessary, and monitor for an increase in naproxen-related adverse reactions. Naproxen is a CYP2C9 substrate in vitro; 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%.
    Naproxen; Pseudoephedrine: (Moderate) Use caution if coadministration of capecitabine with naproxen is necessary, and monitor for an increase in naproxen-related adverse reactions. Naproxen is a CYP2C9 substrate in vitro; 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%.
    Naproxen; Sumatriptan: (Moderate) Use caution if coadministration of capecitabine with naproxen is necessary, and monitor for an increase in naproxen-related adverse reactions. Naproxen is a CYP2C9 substrate in vitro; 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%.
    Nateglinide: (Moderate) Use caution if coadministration of capecitabine with nateglinide is necessary, and monitor for an increase in nateglinide-related adverse reactions. Nateglinide is primarily (70%) a CYP2C9 substrate in vitro; 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%.
    Nebivolol; Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    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; 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.
    Perphenazine; Amitriptyline: (Moderate) Use caution if coadministration of capecitabine with amitriptyline is necessary, and monitor for an increase in amitriptyline-related adverse reactions such as nausea, dizziness, hypotension, syncope, and QT prolongation. Amitriptyline is a primarily a CYP2D6 and 2C19 substrate, with lesser contributions from CYP2C9, 1A2, and 3A4. 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%.
    Phenobarbital: (Moderate) Use caution if coadministration of capecitabine with phenobarbital is necessary, and monitor for an increase in phenobarbital-related adverse reactions. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. 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%.
    Phenytoin: (Moderate) Use caution if coadministration of capecitabine with phenytoin is necessary, monitoring phenytoin levels and watching for phenytoin-related adverse reactions (e.g., nystagmus, diplopia, ataxia, and confusion); adjust the dose of phenytoin as necessary. Phenytoin is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. Postmarketing reports indicate that some patients receiving both phenytoin and capecitabine have had toxicity associated with elevated phenytoin levels.
    Pirfenidone: (Moderate) Use caution if coadministration of capecitabine with pirfenidone is necessary, and monitor for an increase in pirfenidone-related adverse reactions; do not use pirfenidone in combination with both capecitabine and a CYP1A2 inhibitor. Pirfenidone is primarily (70 to 80%) a CYP1A2 substrate, with minor contributions from CYP2C9, 2C19, 2D6 and 2E1. 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%.
    Piroxicam: (Moderate) Use caution if coadministration of capecitabine with piroxicam is necessary, and monitor for an increase in piroxicam-related adverse reactions. Piroxicam 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%.
    Pitavastatin: (Moderate) Use caution if coadministration of capecitabine with pitavastatin is necessary, and monitor for an increase in pitavastatin-related adverse reactions. Pitavastatin 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%.
    Primidone: (Moderate) Use caution if coadministration of capecitabine with primidone is necessary, and monitor for an increase in primidone- or phenobarbital-related adverse reactions. Primidone is converted to two active metabolites, one being phenobarbital. Because primidone is metabolized to phenobarbital, drug interactions occurring with phenobarbital must be considered when primidone is prescribed. Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. 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%.
    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.
    Quazepam: (Moderate) Use caution if coadministration of capecitabine with quazepam is necessary, and monitor for an increase in quazepam-related adverse reactions. Quazepam is primarily metabolized by CYP3A4, but is also a substrate of CYP2C9 and CYP2C19; 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%.
    Quinine: (Moderate) Use caution if coadministration of capecitabine with quinine is necessary, and monitor for an increase in quinine-related adverse reactions. CYP3A4 is the major enzyme responsible for quinine metabolism; other isoenzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 have some role in the metabolism of quinine; however, the extent of involvement of each of these differs depending on methodology used in the studies. 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%.
    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.
    Ramelteon: (Moderate) Use caution if coadministration of capecitabine with ramelteon is necessary, and monitor for an increase in ramelteon-related adverse reactions. Ramelteon is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. The AUC of ramelteon (single dose, 16 mg) was elevated > 150% when administered with a strong CYP2C9 inhibitor, fluconazole; similar increases were seen in regard to the active metabolite, M-II. Patients should be monitored closely for ramelteon side effects even though ramelteon has a wide therapeutic index.
    Rosiglitazone: (Moderate) Use caution if coadministration of capecitabine with rosiglitazone is necessary, and monitor for an increase in rosiglitazone-related adverse reactions including hypoglycemia. Rosiglitazone is primarily a CYP2C8 substrate in vitro, with a lesser contribution from CYP2C9; 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%.
    Rosuvastatin: (Minor) Use caution if coadministration of capecitabine with rosuvastatin is necessary, and monitor for an increase in rosuvastatin-related adverse reactions. Capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In human hepatocytes, the in vitro formation of the N-desmethyl metabolite of rosuvastatin is inhibited by sulphaphenazole, and to a lower extent by omeprazole, which suggests some metabolism by CYP2C9 and CYP2C19 isoenzymes. 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%. However, hepatic metabolism is a minor pathway for elimination for rosuvastatin, which suggests that clinically significant drug interactions with rosuvastatin via inhibition of the drug's metabolism may be limited.
    Ruxolitinib: (Moderate) Use caution if coadministration of capecitabine with ruxolitinib is necessary, and monitor for an increase in ruxolitinib-related adverse reactions. Ruxolitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP2C9; 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%.
    Sacubitril; Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    Selegiline: (Moderate) Use caution if coadministration of capecitabine with selegiline is necessary, and monitor for an increase in selegiline-related adverse reactions. Selegiline is a CYP2C9 substrate in vitro; 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%.
    Sertraline: (Moderate) Use caution if coadministration of capecitabine with sertraline is necessary, and monitor for an increase in sertraline-related adverse reactions. Sertraline is a CYP2C9 substrate in vitro; 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%.
    Sildenafil: (Minor) Use caution if coadministration of capecitabine with sildenafil is necessary, and monitor for an increase in sildenafil-related adverse reactions. Sildenafil is metabolized principally CYP3A4 (major route) and 2C9 (minor route); 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%.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Use caution if coadministration of capecitabine with sulfamethoxazole is necessary, and monitor for an increase in sulfamethoxazole-related adverse reactions. Sulfamethoxazole 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%.
    Tamoxifen: (Minor) Use caution if coadministration of capecitabine with tamoxifen is necessary, and monitor for a possible decrease in the efficacy of tamoxifen. Tamoxifen is metabolized in by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. Capecitabine may inhibit the CYP2C9 metabolism of tamoxifen to its active metabolites, potentially decreasing its efficacy.
    Terbinafine: (Moderate) Use caution if coadministration of capecitabine with terbinafine is necessary, and monitor for an increase in terbinafine-related adverse reactions. Terbinafine is metabolized by at least 7 CYP isoenzymes, with major contributions coming from CYP2C9 and CYP3A4; 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%.
    Torsemide: (Moderate) Use caution if coadministration of capecitabine with torsemide is necessary, and monitor for an increase in torsemide-related adverse reactions. Torsemide 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%.
    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.
    Valproic Acid, Divalproex Sodium: (Moderate) Use caution if coadministration of capecitabine with valproic acid, divalproex sodium is necessary, and monitor for an increase in valproic acid-related adverse reactions. Valproic acid 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%.
    Valsartan: (Moderate) Use caution if coadministration of capecitabine with valsartan is necessary, and monitor for an increase in valsartan-related adverse reactions. Valsartan 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%.
    Voriconazole: (Moderate) Use caution if coadministration of capecitabine with voriconazole is necessary, and monitor for an increase in voriconazole-related adverse reactions. Capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9; the affinity of voriconazole appears to be highest for 2C19, followed by 2C9 and is appreciably lower for 3A4. 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%.
    Warfarin: (Major) Use caution and frequently monitor the PT/INR of patients receiving concomitant therapy with capecitabine and warfarin; adjust the dose of warfarin as appropriate. The manufacturer of capecitabine includes a black box warning for this interaction. Capecitabine and/or its metabolites are CYP2C9 inhibitors; S-warfarin is a CYP2C9 substrate. In a drug interaction study (n = 4), the mean AUC of S-warfarin (20 mg, single dose) was increased by 57% after administration with capecitabine (1,250 mg/m2 twice daily), and the clearance decreased by 37%; baseline corrected AUC of INR increased by 2.8-fold, and the maximum observed INR value increased by 91%. In a clinical pharmacology trial, altered coagulation parameters and/or bleeding, including death, were reported in patients taking capecitabine with either warfarin or another coumarin-derivative anticoagulant, phenprocoumon. Postmarketing reports have also shown clinically significant increases in the PT/INR within several days to months of initiating capecitabine therapy; in a few cases, these events occurred within 1 month of stopping capecitabine therapy. Alterations in bleeding time occurred in patients with and without liver metastases.
    Zafirlukast: (Minor) Use caution if coadministration of capecitabine with zafirlukast is necessary, and monitor for an increase in zafirlukast-related adverse reactions. Zafirlukast is a CYP2C9 substrate in vitro; 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%.
    Zileuton: (Minor) Use caution if coadministration of capecitabine with zileuton is necessary, and monitor for an increase in zileuton-related adverse reactions. Zileuton 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%.

    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 5-fluorouracil (5-FU) 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 5-FU. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP and the folate cofactor, 5,10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is the necessary precursor of thymidine triphosphate (dTTP), one of four deoxyribonucleotides required for synthesis of DNA. Thus, a deficiency of thymidylate leads to depletion of dTTP, which inhibits cell division. Also, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during synthesis of RNA. Thus, RNA processing and protein synthesis are also disrupted.

    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%).
     
    Capecitabine is a prodrug that is metabolized to 5-fluorouracil (5-FU) 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 cytadine deaminase. Cytadine 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, 5-FU. A small portion of fluorouracil is converted to active metabolites (FdUMP, FUTP) in the tissues; the rest (85%) is catabolized via dihydropryrimidine dehydrogenase (DPD), the initial rate-limiting step, and other enzymes to the less toxic dihydropyrimidine form (5-fluoro-5, 6-dihydrofluorouracil, FUH2). Individuals with low or nonexistent DPD activity experience severe toxicity. 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%). The elimination half-life of both capecitabine and 5-FU is approximately 0.75 hour. In contrast to the parent compound, the intracellular nucleotides FdUMP and FUTP have prolonged half-lives.
     
    Affected cytochrome P450 (CYP) isoenzymes: CYP2C9
    Capecitabine and/or its metabolites are thought to be CYP2C9 inhibitors. Formal interaction studies have not been conduced 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.

    Oral Route

    Capecitabine is extensively absorbed from the GI tract. Peak blood concentrations of capecitabine are achieved about 1.5 hours after dosing, with peak 5-FU levels occurring at approximately 2 hours; food delayed the Tmax of both capecitabine and 5-FU 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 5-FU 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 metabolites are dose proportional and do not change over time. However, increases in the AUC of 5'-DFUR and 5-FU are greater than proportional to the increase in dose, and the AUC of 5-FU increases over time (e.g., 34% higher on day 14 than on day 1 of dosing). The interpatient variability in Cmax and AUC of 5-FU is greater than 85%. Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range, 0.9 to 8); these ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.