Capecitabine - ClinicalKey

7/8/2021 Capecitabine - ClinicalKey
DRUG MONOGRAPH
Capecitabine
Xeloda
Drug Information Provided By Gold Standard
Description
Capecitabine is a unique antineoplastic agent. It is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-
DFUR) which generates fluorouracil selectively in tumor cells. Chemically, capecitabine is classified as a
fluoropyrimidine carbamate. It was the first oral antineoplastic agent approved for the treatment of metastatic breast
carcinoma. In patients with metastatic breast cancer who were resistant to both paclitaxel and an anthracycline-
containing chemotherapy regimen, a tumor response rate of about 25% has been observed. However, no results are
available from controlled trials in patients with breast cancer that demonstrate improvement in disease-related
symptoms, disease progression, or survival. Unlike many other antineoplastic agents, use of capecitabine has not been
associated with alopecia, and myelosuppression is uncommon. Capecitabine is FDA approved as monotherapy for the
adjuvant treatment of colorectal cancer and for the treatment of metastatic colorectal cancer and metastatic breast
cancer; it is FDA approved in combination with docetaxel for the treatment of metastatic breast cancer.
(_WPS/RefShow.aspx?rid=44458)44458
Mechanism of Action
Capecitabine is converted into fluorouracil by a series of enzymatic reactions. One of the enzymes involved in this
activation process, thymidine phosphorylase is expressed in higher concentrations in some human carcinomas
compared to normal tissues, which may result in higher intra-tumor concentrations of fluorouracil. Both normal and
tumor cells metabolize fluorouracil to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine
triphosphate (FUTP). FdUMP and the folate cofactor, 5,10-methylenetetrahydrofolate, bind to thymidylate synthase
(TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from uracil.
Thymidylate is the necessary precursor of thymidine triphosphate (dTTP), one of four deoxyribonucleotides required
for synthesis of DNA. Thus, a deficiency of thymidylate leads to depletion of dTTP, which inhibits cell division. Also,
nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during
synthesis of RNA. Thus, RNA processing and protein synthesis are also disrupted. (_WPS/RefShow.aspx?rid=44458)44458
Pharmacokinetics
Capecitabine is administered orally. Plasma protein binding of capecitabine and its metabolites is less than 60% and is
not concentration-dependent, indicating a low potential for drug interactions related to protein binding; the primary
protein involved is human albumin (35%). (_WPS/RefShow.aspx?rid=44458)44458
Capecitabine is a prodrug that is metabolized to fluorouracil in the liver. Initially, it is hydrolyzed by a carboxylesterase
to 5'-deoxy-5-fluorocytidine (5'-DFCR), which is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine
deaminase. Cytidine deaminase is found in both normal and tumor cells. Thymidine phosphorylase (dThdPase), an
enzyme found in many tissues but in higher concentrations in some human carcinomas compared to surrounding
normal tissues, then hydrolyzes 5'-DFUR to the active drug, fluorouracil. A small portion of fluorouracil is converted to
active metabolites (FdUMP, FUTP) in the tissues; the rest (85%) is catabolized via dihydropyrimidine dehydrogenase
(DPD), the initial rate-limiting step, and other enzymes to the less toxic dihydropyrimidine form (5-fluoro-5, 6-
dihydro-fluorouracil, FUH2). (_WPS/RefShow.aspx?rid=44458)44458 (_WPS/RefShow.aspx?rid=29028)29028 Individuals
with low or nonexistent DPD activity experience severe toxicity. (_WPS/RefShow.aspx?rid=29028)29028
(_WPS/RefShow.aspx?rid=61019)61019 Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-
https://0810fu9os-1106-y-https-www-clinicalkey-com.mplbci.ekb.eg/#!/content/drug_monograph/6-s2.0-2279 1/47
propionic acid (FUPA). Finally, beta-ureido-propionase cleaves FUPA to alpha-fluoro-beta-alanine (FBAL), which is
cleared in the urine. Of an administered dose, 95.5% is recovered in the urine, with 57% of the dose as FBAL; fecal
excretion is minimal (2.6%). About 3% of the administered dose is excreted in urine as unchanged drug. The
elimination half-life of both capecitabine and fluorouracil is approximately 0.75 hour. (_WPS/RefShow.aspx?
rid=44458)44458 In contrast to the parent compound, the intracellular nucleotides FdUMP and FUTP have prolonged
half-lives. (_WPS/RefShow.aspx?rid=29028)29028
Affected cytochrome P450 (CYP) isoenzymes: CYP2C9
Capecitabine and/or its metabolites are thought to be CYP2C9 inhibitors. Formal interaction studies have not been
conducted with drugs other than warfarin; however, elevated phenytoin levels have also been observed with
capecitabine coadministration. Caution is recommended if concomitant use with CYP2C9 substrates is necessary. In
vitro studies have indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit
the metabolism of CYP1A2, 2A6, 3A4, 2C19, 2D6, and 2E1. (_WPS/RefShow.aspx?rid=44458)44458
•Route-Specific Pharmacokinetics
Oral Route
Peak blood concentrations of capecitabine are achieved about 1.5 hours after dosing, with peak fluorouracil levels
occurring at approximately 2 hours; food delayed the Tmax of both capecitabine and fluorouracil by 1.5 hours. Food
also reduces the extent of absorption of capecitabine, with mean Cmax and AUC decreased by 60% and 35%,
respectively; the mean Cmax and AUC of fluorouracil were also reduced by 43% and 21%, respectively.44458
Over a dosage range of 500 to 3,500 mg/m2 per day, the pharmacokinetics of capecitabine and its metabolite, 5'DFCR,
are dose proportional and do not change over time. However, increases in the AUC of 5'-DFUR and fluorouracil are
greater than proportional to the increase in dose, and the AUC of fluorouracil increases over time (e.g., 34% higher on
day 14 than on day 1 of dosing). The interpatient variability in Cmax and AUC of fluorouracil is greater than 85%.
Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio
of fluorouracil concentration in colorectal tumors to adjacent tissues was 2.9 (range, 0.9 to 8); these ratios have not
been evaluated in breast cancer patients or compared to fluorouracil infusion.44458
•Special Populations
Hepatic Impairment
In patients with mild to moderate hepatic dysfunction due to liver metastasis (n = 13), the AUC and Cmax of
capecitabine increased by 60% compared to patients with normal hepatic function (n = 14); the AUC and Cmax of
fluorouracil were not affected. The effect of severe hepatic dysfunction on capecitabine pharmacokinetics is not
known.44458
Renal Impairment
Patients with moderate (CrCL 30 to 50 mL/min) and severe (CrCL less than 30 mL/min) renal impairment showed
85% and 258% higher exposure to the capecitabine metabolite, FBAL, on day 1 compared to patients with normal renal
function (CrCL greater than 80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in patients with
moderate and severe renal impairment, respectively, compared to normal patients. Systemic exposure to capecitabine
was approximately 25% higher in patients with both moderate and severe renal impairment. Although no clinical
experience using dialysis has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-
DFUR, a low-molecular-weight metabolite of the parent compound. (_WPS/RefShow.aspx?rid=44458)44458
Geriatric
Based on a population analysis of pooled data from two large controlled studies in patients with metastatic colorectal
cancer (n = 505), age (range, 27 to 86 years) does not significantly influence the pharmacokinetics of 5'-DFUR and
fluorouracil; however, a 20% increase in age results in a 15% increase in the AUC of FBAL.44458
Gender Differences
cancer (n = 505), gender does not influence the pharmacokinetics of 5'-DFUR, fluorouracil, and FBAL.44458
Ethnic Differences
cancer (n = 505), ethnicity (Caucasian, n = 455; Black, n = 22; Other, n = 28) does not influence the pharmacokinetics
of 5'-DFUR, fluorouracil, and FBAL. However, in a separate study, Japanese patients (n = 18) had approximately a 36%
lower Cmax and 24% lower AUC for capecitabine than Caucasian patients (n = 22); the Cmax and AUC for FBAL were
also approximately 25% and 34% lower in Japanese patients compared with Caucasian patients, respectively. The
clinical significance of these differences is unknown. There were no significant differences in exposure to other
metabolites (5'-DFCR, 5'DFUR, and fluorouracil).44458
Last revised: April 5, 2019
Indications & Dosage

biliary tract cancer
breast cancer
colorectal cancer
esophageal cancer
gastric cancer
ovarian cancer
pancreatic cancer
For the treatment of metastatic breast cancer
for the treatment of metastatic breast cancer that is resistant to both paclitaxel and an anthracycline-
containing chemotherapy regimen, or resistant to paclitaxel and for whom further anthracycline
therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of
doxorubicin or doxorubicin equivalent), as monotherapy
NOTE: Resistance is defined as progressive disease while on treatment regardless of an initial response or relapse
within 6 months of treatment completion with an anthracycline-containing adjuvant regimen.
Oral dosage
Adults:
1,250 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 to 14, followed
by 1 week of rest, every 3 weeks. Dosages should be adjusted based on toxicity during treatment cycle; once a dosage is
reduced, it should not be increased at a later time. Coadministration of certain drugs may need to be avoided or dosage
adjustments may be necessary; review drug interactions. In a subset of patients with stage IV breast cancer that was
resistant to both paclitaxel and an anthracycline (n = 43) from an open-label, single-arm clinical trial, treatment with
capecitabine resulted in a partial response rate of 25.6% for a median duration of 5.1 months. The median time to
progression in these patients was 3.4 months and the median survival was 8.5 months.44458
for the treatment of metastatic breast cancer after failure of prior anthracycline-containing
chemotherapy, in combination with docetaxel
Oral dosage
Adults:
by 1 week of rest; on day 1, give docetaxel 75 mg/m2 IV over 1 hour. Repeat every 3 weeks.44458 Premedicate with
dexamethasone 8 mg by mouth twice daily for 3 days, beginning 1 day prior to docetaxel administration, to reduce the
incidence and severity of fluid retention and hypersensitivity reactions.60484 Capecitabine doses should be adjusted
based on toxicity during treatment cycle; once a dosage is reduced, it should not be increased at a later time.
Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug
interactions. In a multicenter, randomized, open-label, phase 3 trial (n = 511), treatment with capecitabine plus
docetaxel significantly improved the time to disease progression (6.2 months vs. 4.3 months), overall survival (14.7
months vs. 11.7 months), and objective response rate (32% vs. 22%) compared to monotherapy with docetaxel in
patients with metastatic breast cancer resistant to or recurring during/after anthracycline-based chemotherapy.
Docetaxel/capecitabine patients experienced more hand-foot syndrome, diarrhea, stomatitis, nausea, and vomiting.
Neutropenic fever, myalgia, arthralgia, and fatigue occurred more frequently with single-agent docetaxel.44575 44458
for the treatment of patients with advanced or metastatic breast cancer whose tumor overexpresses
the HER2 protein and who have received prior therapy including an anthracycline, a taxane, and
trastuzumab, in combination with lapatinib†
NOTE: Lapatinib is FDA-approved in combination with capecitabine for this indication.
Oral dosage
Adults:
1,000 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on days 1 through 14, in
combination with lapatinib (1,250 mg PO once daily on an empty stomach on days 1 to 21). Repeat every 21 days until
disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage
adjustments may be necessary; review drug interactions. In a randomized, phase 3 clinical trial of patients with
progressive (after anthracyclines, taxanes, and trastuzumab), locally advanced or metastatic breast cancer, treatment
with lapatinib plus capecitabine (n = 198) significantly improved the median time to progression (TTP) by independent
assessment compared with capecitabine alone (n = 201) (27.1 weeks vs. 18.6 weeks), with a response rate of 23.7%
versus 13.9%; by investigator assessment, the median TTP was 23.9 weeks vs. 18.3 weeks with a response rate of 31.8%
vs. 17.4%, respectively. Median progression-free survival (PFS) and overall survival (OS) were decreased in patients
with HER2-positive metastatic breast cancer treated with lapatinib plus capecitabine compared with trastuzumab plus
capecitabine in a randomized, open-label trial (n = 540). Patients with HER2-positive metastatic breast cancer
receiving first-line treatment with lapatinib plus taxane-based chemotherapy also had a shorter median PFS compared
with trastuzumab plus taxane-based chemotherapy in another randomized, open-label trial (n = 652). Patients should
have progressed on trastuzumab and taxane-based therapy prior to treatment with lapatinib and capecitabine.33192
for the treatment of metastatic or locally advanced breast cancer that is resistant to treatment with an
anthracycline and a taxane, or that is taxane resistant and for whom further anthracycline therapy is
contraindicated in combination with ixabepilone†
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.33563
Oral dosage
Adults:
1,000 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes of a meal on days 1 to 14, followed by 1
week of rest; on day 1, give ixabepilone 40 mg/m2 (maximum BSA, 2.2 m2 ) IV over 3 hours. Repeat every 3 weeks.
One hour prior to ixabepilone administration on day 1, premedicate with diphenhydramine 50 mg by mouth (or
equivalent) and ranitidine 150 mg to 300 mg by mouth (or equivalent) to reduce the risk of hypersensitivity; add
dexamethasone 20 mg in patients who have previously had a reaction to ixabepilone. Coadministration of certain drugs
may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter,
randomized, open-label clinical trial of patients with anthracycline- and taxane-resistant locally advanced or metastatic
breast cancer (n = 752), treatment with ixabepilone plus capecitabine significantly improved the median progression-
free survival (PFS) (5.7 months vs. 4.1 months) and objective response rate (34.7% vs. 14.3%) compared with
capecitabine alone; the median duration of response was 6.4 months versus 5.6 months, respectively. There was no
significant difference in overall survival (12.9 months vs. 11.1 months). (_WPS/RefShow.aspx?rid=33563)33563
for the treatment of advanced or metastatic HER2-positive breast cancer in patients who have
received 2 or more prior anti-HER2 based regimens in the metastatic setting, in combination with
neratinib†
NOTE: Neratinib is FDA approved in combination with capecitabine for this indication.62127
Oral dosage
Adults:
750 mg/m2 PO twice daily within 30 minutes after a meal on days 1 to 14 every 21 days in combination with neratinib
until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided; review
drug interactions. The neratinib dosage is 240 mg PO once daily; alternatively, a 2-week neratinib dose escalation
schedule may be given as follows: 120 mg PO once daily on days 1 to 7 (week 1), 160 mg PO once daily on days 8 to 14
(week 2), and 240 mg PO once daily starting on day 15 (week 3 and beyond). Patients starting neratinib at the
maximum dosage of 240 mg/day should receive antidiarrheal prophylaxis with loperamide for at least the first 56 days
of therapy.62127 Treatment with neratinib plus capecitabine significantly improved median progression-free survival
(PFS) (5.6 months vs. 5.5 months) compared with lapatinib plus capecitabine in patients with metastatic HER2-
positive breast cancer who had received at least 2 prior anti-HER2 based regimens in the metastatic setting in a
randomized, open-label clinical trial (the NALA study). Rates of PFS were more durable in the neratinib plus
capecitabine arm at 12 months (29% vs. 15%) and 24 months (12% vs. 3%). The objective response rate was 32.8
months in the neratinib arm for a median duration of 8.5 months compared with 26.7 months in the lapatinib arm for
a median duration of 5.6 months. Overall survival was 21 months versus 18.7 months, respectively.65929
for the treatment of advanced unresectable or metastatic HER2-positive breast cancer in patients who
have received at least one prior anti-HER2-based regimen in the metastatic setting, in combination
with trastuzumab and tucatinib†
NOTE: Tucatinib is FDA-approved for this indication in combination with trastuzumab and capecitabine.
Oral dosage
Adults:
1,000 mg/m2 PO twice daily within 30 minutes after a meal on days 1 to 14 of each 21-day cycle in combination with
tucatinib and trastuzumab until disease progression or unacceptable toxicity; tucatinib and capecitabine can be taken
at the same time. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary;
review drug interactions. The addition of tucatinib to trastuzumab and capecitabine significantly improved median
progression-free survival (PFS) (7.8 months vs. 5.6 months) and overall survival (21.9 months vs. 17.4 months)
compared with placebo plus trastuzumab and capecitabine in patients with HER2-positive, unresectable locally
advanced or metastatic breast cancer after prior HER2 treatment in a randomized, double-blind clinical trial
(HER2CLIMB); all patients had received prior trastuzumab and ado-trastuzumab emtansine and all but 2 patients had
prior pertuzumab. The confirmed objective response rate was also significantly improved with the addition of tucatinib
(40.6% vs. 22.8%; complete response, 3% vs. 2%) for a median duration of 8.3 months versus 6.3 months, respectively.
Patients with brain metastases were eligible for inclusion in the HER2CLIMB study as long as they were neurologically
stable and did not require immediate radiation or surgery; patients with leptomeningeal disease were excluded. The
median PFS in patients with brain metastases was similar to the overall population (7.6 months vs. 5.4 months).65295
65296
For the treatment of colorectal cancer
for the adjuvant treatment of Dukes' C colorectal cancer in patients who have undergone complete
resection of the primary tumor, as monotherapy, when fluoropyrimidine therapy alone is preferred
Oral dosage
Adults:
by 1 week of rest, every 3 weeks for a total of 8 cycles (24 weeks). Dosages should be adjusted based on toxicity during
treatment cycle; once a dosage is reduced, it should not be increased at a later time. Coadministration of certain drugs
may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter,
randomized, phase 3 trial (X-ACT trial), adjuvant treatment with capecitabine (n = 995) was non-inferior to
fluorouracil plus leucovorin (n = 974) in the treatment of Dukes' C colon cancer. After a median follow-up of 83
months, the 5-year disease-free survival (DFS) rate was 59.1% in capecitabine-treated patients compared with 54.6% in
those who received fluorouracil/leucovorin; 5-year overall survival was 71.4% vs. 68.4%, respectively. Prescribers
should consider the results of combination chemotherapy trials, which have shown an improvement in DFS and OS,
when prescribing single-agent capecitabine in the adjuvant treatment of colon cancer. (_WPS/RefShow.aspx?
rid=44458)44458 (_WPS/RefShow.aspx?rid=31340)31340
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).45258 Grade 3
or 4 neurosensory toxicity, vomiting, hand-foot syndrome, and thrombocytopenia occurred more frequently in the
XELOX arm (p < 0.05); neutropenia, febrile neutropenia, and stomatitis occurred more frequently with 5-
FU/leucovorin (p < 0.05).43412
for the first-line treatment of metastatic colorectal cancer as monotherapy, when fluoropyrimidine
therapy alone is preferred
Oral dosage
Adults:
by 1 week of rest, every 3 weeks. Dosages should be adjusted based on toxicity during treatment cycle; once a dosage is
reduced, it should not be increased at a later time. Coadministration of certain drugs may need to be avoided or dosage
adjustments may be necessary; review drug interactions. In a multicenter (North American and Brazil), randomized,
open-label clinical trial, patients with previously untreated metastatic colorectal cancer who received capecitabine (n =
302) had a significantly improved overall response rate (ORR) compared with those who received fluorouracil plus
leucovorin (n = 303) (21% vs. 11%); the median time to progression (TTP) was 4.3 months versus 4.4 months and the
median overall survival (OS) was 12.7 months versus 13.6 months, respectively. Results were similar in an identical
trial operated in Europe, Australia, New Zealand, and Taiwan (ORR, 21% vs. 14%; TTP, 4.6 months vs. 4.4 months; OS
13.5 months vs. 12.3 months). Of note, combination chemotherapy has shown a survival benefit as compared with
fluorouracil/leucovorin monotherapy; the safety and survival effect of capecitabine use versus combination
chemotherapy with fluorouracil/leucovorin has not been adequately studied.44458
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.33964 41607
Additional trials have shown efficacy for XELOX
in the treatment of both previously treated and previously untreated patients with advanced colorectal cancer.41750
28881 27033
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).41609
For the treatment of unresectable advanced or metastatic biliary tract cancer†
Oral dosage
Adults:
Multiple dosage regimens have been studied. Capecitabine 1,250 mg/m2 PO twice daily on days 1 to 14, followed by a
7-day rest period, given in combination with cisplatin 60 mg/m2 IV over 1 hour on day 1, repeated every 21 days until
disease progression or unacceptable toxicity. In a phase II trial of 38 patients, capecitabine/cisplatin produced an
overall response rate of 21.4%. Grade III or IV neutropenia occurred in 20% of patients.36002 Another regimen is
capecitabine 650 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with
gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1 and 8, repeated every 21 days. In phase II trials, this dosage
produced an ORR of 29% to 31%.36003 36004
Another phase II trial of 43 patients studied capecitabine 1,000 mg/m2
PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with cisplatin 60 mg/m2 IV on
day 1 and epirubicin 50 mg/m2 IV on day 1, repeated every 21 days until disease progression or unacceptable
toxicity.36005
For the treatment of inoperable, recurrent, platinum- and taxane-resistant ovarian cancer†
Oral dosage
Adults:
1,000 mg/m2 PO twice daily on days 1 to 14, then a 7-day rest period has been given every 21 days. Treatment should
be continued until the patient experiences unacceptable toxicity or disease progression. In a phase II study of 41
patients, a partial response was observed in 7.3% of patients and stable disease was achieved in 54% of patients. Grade
3 adverse effects included hand-foot syndrome (27%), abdominal pain (17%), and diarrhea (10%).34432 In other phase
II studies, a higher dose of 1,250 mg/m2 led to the overall response rate in heavily pretreated patients of 3% to
9%.46087 46088
For the treatment of gastric cancer†
for the adjuvant treatment of stage II through IIIB gastric cancer† in combination with oxaliplatin
Oral dosage
Adults:
1,000 mg/m2 PO twice daily on days 1 to 14 in combination with oxaliplatin 130 mg/m2 IV on day 1, repeated every 3
weeks for 8 cycles. In a phase 3 clinical trial, 1,035 patients with stage II to IIIB gastric cancer were randomized to
receive adjuvant capecitabine and oxaliplatin (XELOX) or observation after surgical (D2) resection. The primary
endpoint, 3-year disease free survival (DFS), was significantly improved with XELOX (74% vs. 60%, HR 0.56, 95% CI
0.44 to 0.72, p less than 0.0001). At a median follow-up of 34.4 months, the difference in overall survival was not
significantly different between the 2 treatment arms (HR 0.74, 95% CI 0.53 to 1.03, p = 0.0775).45379
for the treatment of previously untreated patients with metastatic gastric or gastroesophageal
junction adenocarcinoma in combination with cisplatin and trastuzumab†
Oral dosage
Adults:
1,000 mg/m2 PO twice daily on days 1 to 14 in combination with cisplatin (80 mg/m2 IV on day 1) and trastuzumab
(8 mg/kg IV over 90 minutes on day 1, then 6 mg/kg IV over 30 to 90 minutes every 21 days from day 22); repeat
cycles every 3 weeks. Chemotherapy should be continued up to a maximum of 6 cycles; trastuzumab should be
continued until disease progression or unacceptable toxicity. In a phase 3 trial, 594 patients with inoperable, locally
advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction were randomized to
receive cisplatin and fluorouracil or capecitabine, with or without trastuzumab. Overall survival (13.5 months vs. 11
months, p = 0.0038), the primary endpoint, and objective response rate (47% vs. 35%, p = 0.0017) were significantly
increased with the addition of trastuzumab. An updated survival analysis conducted 1 year after the final analysis
showed a continued overall survival benefit in the trastuzumab arm (13.1 months vs. 11.7 months, HR 0.8, 95% CI
0.67 to 0.97). In addition, a subgroup analysis revealed an even greater increase in overall survival (18 months vs. 13.2
months, HR 0.66, 95% CI 0.5 to 0.87) for the trastuzumab arm in patients with high expression of the HER2 protein
(FISH-negative and IHC3 +; or, FISH-positive). Cardiac dysfunction (LVEF decrease of 10% or more from baseline to
an absolute value less than 50%) occurred in 5% of patients who received trastuzumab vs. 1.1% of patients who did not
receive trastuzumab.36110 41715 28061
for the first-line treatment of HER2-positive locally advanced unresectable or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma, in combination with oxaliplatin (XELOX; CapeOx),
trastuzumab, and pembrolizumab†
NOTE: Pembrolizumab is FDA-approved for this indication in combination with trastuzumab, oxaliplatin, and
capecitabine.57889
Oral dosage
Adults:
1,000 mg/m2 PO twice daily on days 1 to 14 every 3 weeks. Administer in combination with oxaliplatin (130 mg/m2
IV every 3 weeks for up to 6 to 8 cycles), pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until
disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression), and
trastuzumab (8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV every 3 weeks in subsequent cycles).
Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug
interactions. Administer pembrolizumab prior to trastuzumab and chemotherapy when given on the same day.
Treatment with pembrolizumab plus trastuzumab and investigator's choice of chemotherapy (cisplatin plus
fluorouracil, or capecitabine plus oxaliplatin) significantly improved objective response rate (74% vs. 52%; complete
response, 11% vs. 3.1%) compared with placebo plus trastuzumab and chemotherapy in patients with previously
untreated HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at an interim analysis
of a multicenter, randomized phase 3 trial (KEYNOTE-811). The median duration of response was 10.6 months in the
pembrolizumab arm compared with 9.5 months in the placebo arm; 65% versus 53% of patients, respectively, had a
duration of response of at least 6 months.57889 66655
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.34869
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.40571
for the treatment of advanced or metastatic gastric adenocarcinoma or gastroesophageal junction

(GEJ) cancer, in combination with oxaliplatin (XELOX/CapeOx) and nivolumab†
NOTE: Nivolumab is FDA approved in combination with XELOX/CapeOx for this indication.58668
Oral dosage
Adults:
1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle until disease progression or unacceptable toxicity.
Administer in combination with oxaliplatin (130 mg/m2 IV on day 1, every 3 weeks until disease progression or
unacceptable toxicity) and nivolumab (360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for
up to 2 years in patients without disease progression).45258 43412 58668
Administer nivolumab prior to chemotherapy
when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be
necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ
cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with
mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same
chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival
was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8
months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher
and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received
nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively
(complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.58668 66712
For the adjuvant treatment of pancreatic cancer (ductal adenocarcinoma), in combination with
gemcitabine†
Oral dosage
Adults:
1,660 mg/m2 orally daily on days 1 to 21 followed by 7 days of rest, in combination with gemcitabine (1,000 mg/m2
IV on days 1, 8, and 15), repeated every 28 days for 6 cycles. After a median follow-up of 43.2 months, patients who
underwent complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection) and were
treated with gemcitabine plus capecitabine had significantly longer median overall survival compared with those
receiving gemcitabine alone (28 months vs. 25.5 months; HR 0.82; p = 0.032) in a multicenter, randomized, open-label
phase 3 clinical trial. In a subgroup analysis, the magnitude of effect on median overall survival in patients with R0
resection (39.5 months vs. 27.9 months) was greater than in patients with R1 resection (23.7 months vs. 23 months)
(X2 14.83; p = 0.0001).62255
For the treatment of esophageal cancer†
for the treatment of advanced or metastatic esophageal adenocarcinoma or gastroesophageal junction

(GEJ) cancer, in combination with capecitabine (XELOX/CapeOx) and nivolumab†
NOTE: Nivolumab is FDA approved in combination with XELOX/CapeOx for this indication.58668
Oral dosage
Adults:
1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle until disease progression or unacceptable toxicity.
Administer in combination with oxaliplatin (130 mg/m2 IV on day 1 every 3 weeks until disease progression or
unacceptable toxicity) and nivolumab (360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for
up to 2 years in patients without disease progression).45258 43412 58668 Administer nivolumab prior to chemotherapy
when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be
necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ
cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with
mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same
chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival
was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8
months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher
and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received
nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively
(complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.58668
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Monotherapy or in Combination with Docetaxel:
NOTE: At the beginning of a treatment cycle, if the patient is receiving capecitabine in combination with docetaxel and
a treatment delay is indicated, delay administration of both agents until the requirements for restarting both drugs are
met.
Grade 1: No dose adjustment needed.
Grade 2: Interrupt capecitabine therapy. For the first appearance, therapy may be resumed without a dose reduction
when the toxicity has resolved to grade 1 or less. Resume therapy at a reduced dose when the toxicity has resolved to
grade 1 or less for the second (75% of starting dose) or third (50% of starting dose) appearance. Once the dose of
capecitabine has been reduced, it should not be increased at a later time. For the fourth appearance of a grade 2
toxicity, permanently discontinue therapy.
Grade 3: Interrupt capecitabine therapy. Treatment may be resumed at a reduced dose when the toxicity has
resolved to grade 1 or less for the first (75% of starting dose) or second (50% of starting dose) appearance. Once the
dose of capecitabine has been reduced, it should not be increased at a later time. For the third appearance of a grade
3 toxicity, permanently discontinue therapy.
Grade 4: Permanently discontinue capecitabine therapy. If the physician feels it is in the patient's best interest to
continue therapy, interrupt capecitabine until the toxicity has resolved to grade 1 or less and resume therapy at a
reduced dose (50% of starting dose).44458
Dosage Adjustments for Hematologic Toxicities when used in Combination with Ixabepilone:
NOTE: Follow recommendations for treatment-related toxicity, above, for nonhematologic toxicity.
Platelets less than 25,000/mm3 , or less than 50,000/mm3 with bleeding: Hold capecitabine therapy for concurrent
diarrhea or stomatitis until platelet count greater than 50,000/mm3 , then continue at same dose.
Neutrophils less than 500 cells/mm3 for 7 or more days, or febrile neutropenia: Hold capecitabine therapy for
concurrent diarrhea or stomatitis until neutrophil count greater than 1,000 cells/mm3 , then continue at same dose.
Maximum Dosage Limits:
•Adults
2,500 mg/m2 PO total daily dose (1,250 mg/m2 PO administered twice daily) on days 1 to 14, every 21 days.
•Geriatric
2,500 mg/m2 PO total daily dose (1,250 mg/m2 PO administered twice daily) on days 1 to 14, every 21 days.
•Adolescents
Safety and efficacy have not been established.
•Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment:
In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is
necessary; however, patients should be carefully monitored. Patients with severe hepatic dysfunction have not been
studied.44458
Patients with Renal Impairment Dosing
Baseline Renal Insufficiency:
Mild renal impairment (CrCL 51 mL/min or more): No initial dosage adjustment is recommended.
Moderate renal impairment (CrCL 30 to 50 mL/min): Reduce the starting dose of capecitabine by 25% (from 1,250
mg/m2 to 950 mg/m2 ) when used either as monotherapy or in combination with docetaxel.
Severe renal impairment (CrCL less than 30 mL/min): Use of capecitabine is contraindicated.44458
Last revised: July 2, 2021
Administration
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Capecitabine is administered orally within 30 minutes after a meal.
Capecitabine is a cytotoxic drug. If capecitabine tablets must be cut or crushed, this should be done by a professional
trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Exposure to crushed
capecitabine tablets has resulted in eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric
irritation, vomiting, and diarrhea.
Do not replace doses of capecitabine that are omitted for toxicity; when toxicity resolves, the patient should resume
planned treatment cycles.44458
Monitoring Parameters
CBC with differential
LFTs
pregnancy testing
serum creatinine/BUN
Contraindications
anticoagulant therapy
bone marrow suppression
breast-feeding
cardiac disease
cardiotoxicity
chemotherapy
contraception requirements
coronary artery disease
dehydration
diarrhea
dihydropyrimidine dehydrogenase (DPD) deficiency
fungal infection
geriatric
hepatic disease
herpes infection
infection
infertility
nausea/vomiting
pregnancy
pregnancy testing
radiation therapy
renal failure
renal impairment
reproductive risk
skin disease
varicella
viral infection
Diarrhea, sometimes severe, has been reported with capecitabine therapy. Carefully monitor patients with severe
diarrhea and administer standard antidiarrheal treatments (e.g., loperamide) if necessary; an interruption of therapy,
dose reduction, or discontinuation of therapy may be necessary. Administer fluid and electrolyte replacement if
patients become dehydrated; dehydration may cause acute renal insufficiency or failure which can be fatal. Patients
with anorexia, asthenia, nausea/vomiting, or diarrhea may rapidly become dehydrated. Monitor patients to prevent
and correct the causes of dehydration. If grade 2 or higher dehydration occurs, interrupt capecitabine therapy until
dehydration is corrected and precipitating causes are corrected or controlled.44458
Capecitabine is contraindicated in patients with severe renal impairment or renal failure (creatinine clearance (CrCL)
less than 30 mL/min). Patients with moderate renal impairment (CrCL 30 to 50 mL/min) require a reduced starting
dose of capecitabine. Patients with pre-existing renal impairment or who are receiving concomitant nephrotoxic agents
are at an increased risk of renal failure which has been reported in conjunction with dehydration. Closely monitor
patients with mild and moderate renal impairment at baseline for adverse reactions; promptly interrupt therapy and
reduce the dose of capecitabine as recommended if grade 2 to 4 adverse reactions occur.44458
Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or
with fluorouracil hypersensitivity. Capecitabine has not been proven safe for patients with dihydropyrimidine
dehydrogenase (DPD) deficiency at any dose, and there is insufficient data regarding capecitabine dosing in patients
with partial DPD activity. Dihydropyrimidine dehydrogenase (DPD) is responsible for the metabolism of fluorouracil,
the active metabolite of capecitabine, and deficiency of this enzyme leads to elevated concentrations of fluorouracil due
to decreased clearance. Administration of capecitabine to individuals with DPD deficiency can lead to enhanced early-
onset toxicity and severe, life-threatening or fatal adverse reactions including mucositis, neutropenia, neutropenic
fever, neurotoxicity, abdominal pain, diarrhea, vomiting, and chills. Hold or permanently discontinue capecitabine in
patients with acute early-onset or unusually severe toxicities, which may indicate near complete or total absence of
DPD activity. (_WPS/RefShow.aspx?rid=44458)44458
Do not administer capecitabine to patients with neutrophil counts less than 1,500 cells/mm3 or platelet counts below
100,000 cells/mm3 ; patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic
radiation therapy are at increased risk of bone marrow suppression during capecitabine treatment. An interruption of
therapy, dose reduction, or discontinuation of therapy may be needed if myelosuppression occurs during the course of
treatment. Patients with an active infection should be treated prior to receiving capecitabine. Opportunistic infections,
including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of
varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the
infection when treated with chemotherapy. Patients should immediately report any symptoms of severe
myelosuppression such as fever, sore throat, or abnormal bleeding. (_WPS/RefShow.aspx?rid=44458)44458
Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their
anticoagulant response (INR or PT) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered
coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine
concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Post-marketing reports
have shown clinically significant increases in PT and INR in patients who were stabilized on anticoagulants at the time
capecitabine was introduced. These events occurred within several days and up to several months after initiating
capecitabine therapy and, in a few cases, within one month after stopping capecitabine. These events occurred in
patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose
patients to an increased risk of coagulopathy.44458
Use capecitabine with caution in patients with cardiac disease or a prior history of coronary artery disease.
Capecitabine therapy has been associated with cardiotoxicity including myocardial infarction, angina, dysrhythmias,
cardiac arrest, cardiac failure, electrocardiogram changes, cardiomyopathy, and sudden death; patients with a prior
history of coronary artery disease may be at increased risk.44458
Patients with mild to moderate hepatic disease due to liver metastases should be carefully monitored when
capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is unknown.
Serious elevations in bilirubin, resulting in jaundice, have been reported with capecitabine therapy. Monitor liver
function tests; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.44458
Closely monitor geriatric patients for an increased incidence of adverse reactions, as they may experience more grade 3
or 4 adverse reactions compared with younger patients; insufficient data are available to provide a dosage
recommendation. In a study of capecitabine monotherapy, 62% of patients aged 80 years and older (n = 21)
experienced a treatment-related grade 3 or 4 adverse event including diarrhea (28.6%), nausea (14.3%), hand-and-foot
syndrome (14.3%), and vomiting (9.5%). In patients age 70 and older receiving capecitabine plus docetaxel (n = 10),
30% experienced grade 3 or 4 diarrhea and stomatitis, and 40% experienced grade 3 hand-and-foot syndrome. The
incidence of grade 3 or 4 treatment-related adverse reactions, withdrawals due to adverse reactions, treatment
discontinuations due to adverse reactions, and treatment discontinuations within the first 2 treatment cycles was
higher in patients age 60 and older who received capecitabine plus docetaxel (n = 67) compared to patients younger
than 60 years of age. Of 398 patients age 65 or older receiving adjuvant capecitabine for Dukes' C colon cancer, 41%
experienced a treatment-related grade 3 or 4 adverse event, including hand-and-foot syndrome (18.8%), diarrhea
(13.1%), stomatitis (3%), neutropenia/granulocytopenia (2.8%), vomiting (1.5%), and nausea (1.3%).
Serious mucocutaneous reactions and skin disease, some with fatal outcome, have been reported with capecitabine
therapy including toxic epidermal necrolysis and Stevens-Johnson syndrome. Palmar-plantar erythrodysesthesia (hand
and foot syndrome) has also occurred with capecitabine treatment; persistent or severe hand and foot syndrome can
lead to loss of fingerprints, which could impact patient identification. An interruption of therapy, dose reduction, or
discontinuation of therapy may be necessary for skin toxicity. Permanently discontinue capecitabine in patients who
develop a severe mucocutaneous reaction possibly associated with capecitabine therapy. (_WPS/RefShow.aspx?
rid=44458)44458
Pregnancy should be avoided by females of reproductive potential during capecitabine treatment and for at least 6
months after the last dose. Although there are no adequately controlled studies in pregnant women, capecitabine can
cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies.
Women who are pregnant or who become pregnant while receiving capecitabine should be apprised of the potential
hazard to the fetus. When capecitabine was given to pregnant animals during organogenesis, teratogenesis and
embryolethality were observed in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC),
respectively, in patients receiving the recommended dose. Teratogenic malformations in mice included cleft palate,
anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles.44458
Counsel patients about the reproductive risk and contraception requirements during capecitabine treatment.
Capecitabine can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use
effective contraception during and for at least 6 months after treatment with capecitabine. Females of reproductive
potential should undergo pregnancy testing prior to initiation of capecitabine. Males with female partners of
reproductive potential should use effective contraception during treatment and for 3 months after the last dose.
Women who become pregnant while receiving capecitabine should be apprised of the potential hazard to the fetus. In
addition, capecitabine reversibly disturbed estrus in female mice and caused degenerative changes in the testes of male
mice (including decreases in the number of spermatocytes and spermatids), resulting in impaired fertility or
infertility.44458
Due to the potential for serious adverse reactions in nursing infants from capecitabine, advise women to discontinue
breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether capecitabine is present in
human milk, although many drugs are excreted in human milk.44458
Last revised: April 11, 2019
Interactions
Acetaminophen; Diphenhydramine
Allopurinol
Aluminum Hydroxide
Aluminum Hydroxide; Magnesium Carbonate
Aluminum Hydroxide; Magnesium Hydroxide
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone
Aluminum Hydroxide; Magnesium Trisilicate
Amoxicillin; Clarithromycin; Lansoprazole
Amoxicillin; Clarithromycin; Omeprazole
Aspirin, ASA; Omeprazole
Bupivacaine; Meloxicam
Carbetapentane; Diphenhydramine; Phenylephrine
Cholera Vaccine
Decitabine; Cedazuridine
Dexlansoprazole
Dextromethorphan; Diphenhydramine; Phenylephrine
Diclofenac
Diclofenac; Misoprostol
Diphenhydramine
Diphenhydramine; Hydrocodone; Phenylephrine
Diphenhydramine; Ibuprofen
Diphenhydramine; Naproxen
Diphenhydramine; Phenylephrine
Drospirenone; Ethinyl Estradiol; Levomefolate
Esomeprazole
Esomeprazole; Naproxen
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate
Famotidine; Ibuprofen
Folic Acid, Vitamin B9
food
Fosphenytoin
Hydrocodone; Ibuprofen
Ibuprofen
Ibuprofen; Oxycodone
Ibuprofen; Pseudoephedrine
Lansoprazole
Lansoprazole; Naproxen
Lesinurad; Allopurinol
Leucovorin
Levoleucovorin
Levomefolate
Lonafarnib
Magnesium Hydroxide
Meloxicam
Methadone
Nateglinide
Omeprazole
Omeprazole; Amoxicillin; Rifabutin
Omeprazole; Sodium Bicarbonate
Palifermin
Pantoprazole
Penicillamine
Phenytoin
Proton pump inhibitors
Rabeprazole
SARS-CoV-2 (COVID-19) vaccines
Torsemide
Tuberculin Purified Protein Derivative, PPD
Warfarin
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%. 34522 34523 44458
Allopurinol: (Major) Avoid coadministration of allopurinol with capecitabine due to the risk of decreased exposure to
the active metabolites of capecitabine, which may decrease capecitabine efficacy. Published literature reported that
concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites FdUMP and FUTP;
however, the clinical significance was not fully characterized. 44458
Aluminum Hydroxide: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration
with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid was administered
immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC
and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three
major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). 44458
Aluminum Hydroxide; Magnesium Carbonate: (Minor) Monitor for an increase in capecitabine-related adverse
reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing antacid
was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%,
respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was
observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). 44458
Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Monitor for an increase in capecitabine-related adverse
observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). 44458 (Minor) Monitor
for an increase in capecitabine-related adverse reactions if coadministration with magnesium hydroxide is necessary.
When a magnesium hydroxide-containing antacid was administered immediately after capecitabine, the AUC and
Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by
18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR,
fluorouracil, FBAL). 44458
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Monitor for an increase in capecitabine-related
adverse reactions if coadministration with aluminum hydroxide is necessary. When an aluminum hydroxide-containing
antacid was administered immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and
35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was
observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). 44458 (Minor) Monitor
for an increase in capecitabine-related adverse reactions if coadministration with magnesium hydroxide is necessary.
When a magnesium hydroxide-containing antacid was administered immediately after capecitabine, the AUC and
Cmax of capecitabine increased by 16% and 35%, respectively; the AUC and Cmax of metabolite 5'-DFCR increased by
18% and 22%, respectively. No effect was observed on the other three major metabolites of capecitabine (5'-DFUR,
fluorouracil, FBAL). 44458
Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Monitor for an increase in capecitabine-related adverse
observed on the other three major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). 44458
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. 44458 62436 62438 62440 62443 62444 62446 62447
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is
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. 44458 62436 62438 62440 62443 62444 62446 62447
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if
coadministration with capecitabine is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a
CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. 44458 65019
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%. 34522
34523 44458
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to
the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant
medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine
response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. 60871
Decitabine; Cedazuridine: (Major) Avoid the concomitant use of decitabine; cedazuridine with drugs that are
metabolized by the enzyme cytidine deaminase (CDA), such as capecitabine; the effectiveness of capecitabine may be
reduced. Cedazuridine is a CDA inhibitor. Capecitabine is a prodrug that depends on CDA for get converted to the
active therapeutic drug, 5-fluorouracil. 65678 65704
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
available. 44458 62436 62438 62440 62443 62444 62446 62447
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with

34523 44458
Diclofenac: (Moderate) The dose of diclofenac may need to be reduced if coadministration with capecitabine is
necessary; monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a CYP2C9 substrate and
capecitabine is a weak CYP2C9 inhibitor. 40916 44458
Diclofenac; Misoprostol: (Moderate) The dose of diclofenac may need to be reduced if coadministration with
capecitabine is necessary; monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a CYP2C9
substrate and capecitabine is a weak CYP2C9 inhibitor. 40916 44458
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%. 34522 34523 44458
Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with

34523 44458
Diphenhydramine; Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid
retention, GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of
ibuprofen if necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. 34453 34454
34462 44458 (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%. 34522 34523 44458
Diphenhydramine; Naproxen: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is

Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is

Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in capecitabine-related adverse
reactions if coadministration with L-methylfolate is necessary. Capecitabine is an orally administered prodrug of
fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to
fluorouracil. L-methylfolate is the biologically active form of folic acid, which is converted to folinic acid in vivo;
leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been
reported in elderly patients receiving weekly leucovorin and fluorouracil. 26073 28942 29720 44458
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
available. 44458 62436 62438 62440 62443 62444 62446 62447
Esomeprazole; Naproxen: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in
available. 44458 62436 62438 62440 62443 62444 62446 62447
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for an increase in capecitabine-
related adverse reactions if coadministration with folic acid is necessary. Capecitabine is an orally administered
prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure
to fluorouracil. Folic acid (vitamin B9) is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid.
Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly
leucovorin and fluorouracil. 26073 28942 29720 44473 44474 (Moderate) Monitor for an increase in capecitabine-related
adverse reactions if coadministration with L-methylfolate is necessary. Capecitabine is an orally administered prodrug
of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to
fluorouracil. L-methylfolate is the biologically active form of folic acid, which is converted to folinic acid in vivo;
leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been
reported in elderly patients receiving weekly leucovorin and fluorouracil. 26073 28942 29720 44458
Famotidine; Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid
34462 44458
Folic Acid, Vitamin B9: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if
coadministration with folic acid is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin
enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Folic acid (vitamin
B9) is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis,
diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. 26073
28942 29720 44473 44474
Food: (Minor) Although food decreases Cmax and AUC of capecitabine and its metabolites, it is currently
recommended that capecitabine be administered with food as this procedure was used in the clinical trials. 4717
Fosphenytoin: (Moderate) Carefully monitor phenytoin levels if coadministration of fosphenytoin with capecitabine is
necessary; a dose reduction of fosphenytoin may be necessary. Fosphenytoin is a CYP2C9 substrate and capecitabine is
a weak CYP2C9 inhibitor. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had
toxicity associated with elevated phenytoin levels. Formal drug interaction studies of capecitabine with phenytoin have
not been conducted. 44458 56579
Hydrocodone; Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid
34462 44458
Ibuprofen: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention, GI
irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if
necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. 34453 34454 34462 44458
Ibuprofen; Oxycodone: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid retention,
GI irritation, renal dysfunction) if coadministration with capecitabine is necessary; adjust the dose of ibuprofen if
necessasry. Ibuprofen is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. 34453 34454 34462 44458
Ibuprofen; Pseudoephedrine: (Moderate) Monitor for an increase in ibuprofen-related adverse reactions (e.g., fluid
34462 44458
Lansoprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking
available. 44458 62436 62438 62440 62443 62444 62446 62447
Lansoprazole; Naproxen: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in
available. 44458 62436 62438 62440 62443 62444 62446 62447
Lesinurad; Allopurinol: (Major) Avoid coadministration of allopurinol with capecitabine due to the risk of decreased
exposure to the active metabolites of capecitabine, which may decrease capecitabine efficacy. Published literature
reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites
FdUMP and FUTP; however, the clinical significance was not fully characterized. 44458
Leucovorin: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with
leucovorin is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the
binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Deaths from severe enterocolitis,
28942 29720 44458 44473 44474
Levoleucovorin: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with
leucovorin is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the
binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Deaths from severe enterocolitis,
28942 29720 44458 44473 44474
Levomefolate: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with L-
methylfolate is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the
binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. L-methylfolate is the biologically
active form of folic acid, which is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths
from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin
and fluorouracil. 26073 28942 29720 44458
Lonafarnib: (Major) Avoid coadministration of lonafarnib and capecitabine; concurrent use may increase the exposure
of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-
related adverse reactions. Lonafarnib is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor. 44458 66129
Magnesium Hydroxide: (Minor) Monitor for an increase in capecitabine-related adverse reactions if coadministration
with magnesium hydroxide is necessary. When a magnesium hydroxide-containing antacid was administered
immediately after capecitabine, the AUC and Cmax of capecitabine increased by 16% and 35%, respectively; the AUC
and Cmax of metabolite 5'-DFCR increased by 18% and 22%, respectively. No effect was observed on the other three
major metabolites of capecitabine (5'-DFUR, fluorouracil, FBAL). 44458
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration
with capecitabine is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate
and capecitabine is a weak CYP2C9 inhibitor. 44458 65019
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression
and sedation if concurrent use of capecitabine is necessary. If capecitabine is discontinued, consider increasing the
methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a
CYP2C9 substrate, and coadministration with weak CYP2C9 inhibitors like capecitabine can increase methadone
exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an
inhibitor is added to a stable dose of methadone. If capecitabine is discontinued, methadone plasma concentrations
will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has
developed physical dependence to methadone. 31280 32532 44458
Nateglinide: (Moderate) Monitor for hypoglycemia if coadministration of nateglinide with capecitabine is necessary; a
dose reduction of nateglinide and increased frequency of blood glucose monitoring may be necessary. Nateglinide is a
CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. 44458 45644
Omeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking
available. 44458 62436 62438 62440 62443 62444 62446 62447
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is
Omeprazole; Sodium Bicarbonate: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is
Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24
hours after administration of antineoplastic agents. 54912
Pantoprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking
available. 44458 62436 62438 62440 62443 62444 62446 62447
Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing
severe hematologic and renal toxicity. 28834
Phenytoin: (Moderate) Carefully monitor phenytoin levels if coadministration with capecitabine is necessary; a dose
reduction of phenytoin may be necessary. Phenytoin is a CYP2C9 substrate and capecitabine is a weak CYP2C9
inhibitor. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had toxicity
associated with elevated phenytoin levels. Formal drug interaction studies of capecitabine with phenytoin have not
been conducted. 44458
Proton pump inhibitors: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in
available. 44458 62436 62438 62440 62443 62444 62446 62447
Rabeprazole: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking
available. 44458 62436 62438 62440 62443 62444 62446 62447
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a
diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating
immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of
a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after
receiving the vaccine. 65107 66080
Torsemide: (Moderate) Monitor diuretic effect and blood pressure if coadministration of torsemide with capecitabine is
necessary; adjust the dose of torsemide if clinically appropriate. Torsemide is a CYP2C9 substrate and capecitabine is a
weak CYP2C9 inhibitor. Concomitant use can decrease torsemide clearance and increase torsemide plasma
concentrations. 44458 61986
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological
response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after
treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy. 43298
43299
Warfarin: (Major) Closely monitor the INR if coadministration of warfarin with capecitabine is necessary as concurrent
use may increase the exposure of warfarin leading to increased bleeding risk. Coadministration of warfarin and
capecitabine has been reported to cause altered coagulation parameters and bleeding, including death. The effects of
the interaction may occur within days to several months after starting or 1 month after stopping capecitabine therapy.
Capecitabine is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9
substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but
the R-enantiomer generally has a slower clearance. Additionally, age greater than 60 and a diagnosis of cancer
independently predispose patients to an increased risk of coagulopathy. 28549 44458 65827 65828 65829
Last revised: May 25, 2021
Adverse Reactions
abdominal pain
abdominal pain
agranulocytosis
alopecia
anemia
anemia
angina
angioedema
anorexia
anorexia
arrhythmia exacerbation
arthralgia
arthralgia
ascites
asthenia
asthenia
ataxia
atrial fibrillation
back pain
back pain
bleeding
bone pain
bone pain
bradycardia
candidiasis
cardiac arrest
cardiomyopathy
cardiotoxicity
chest pain (unspecified)
chest pain (unspecified)
cholestasis
coagulopathy
confusion
conjunctivitis
conjunctivitis
constipation
constipation
cough
cough
dehydration
dehydration
depression
diarrhea
diarrhea
dizziness
dizziness
dysarthria
dysgeusia
dysgeusia
dyspepsia
dyspepsia
dysphagia
dyspnea
dyspnea
edema
edema
elevated hepatic enzymes
elevated hepatic enzymes
encephalopathy
enterocolitis
epistaxis
epistaxis
erythema
erythema
esophageal ulceration
fatigue
fatigue
fever
fever
flushing
GI bleeding
GI bleeding
headache
headache
heart failure
hemoptysis
hepatic failure
hepatitis
hepatotoxicity
hoarseness
hot flashes
hyperbilirubinemia
hyperbilirubinemia
hypercalcemia
hypercalcemia
hyperhidrosis
hypertension
hypertriglyceridemia
hypoalbuminemia
hypocalcemia
hypocalcemia
hypoesthesia
hypoesthesia
hypokalemia
hypomagnesemia
hyponatremia
hypophosphatemia
hypotension
ileus
ileus
infection
infection
influenza
insomnia
irritability
jaundice
keratitis
keratoconjunctivitis
lacrimation
laryngitis
lethargy
lethargy
leukoencephalopathy
leukopenia
loss of consciousness
lupus-like symptoms
lymphopenia
lymphopenia
migraine
myalgia
myalgia
myocardial infarction
myocarditis
nail discoloration
nausea
nausea
neurotoxicity
neutropenia
neutropenia
ocular irritation
onycholysis
palmar-plantar erythrodysesthesia (hand and foot syndrome)
palmar-plantar erythrodysesthesia (hand and foot syndrome)
pancytopenia
paresthesias
paresthesias
peptic ulcer
pericardial effusion
peripheral neuropathy
phlebitis
photosensitivity
pleural effusion
polydipsia
pruritus
pulmonary embolism
purpura
radiation recall reaction
rash
renal failure (unspecified)
rhinorrhea
sinus tachycardia
skin discoloration
skin discoloration
skin ulcer
Stevens-Johnson syndrome
stomatitis
stomatitis
stroke
supraventricular tachycardia (SVT)
syncope
thrombocytopenia
thrombocytopenia
thrombosis
toxic epidermal necrolysis
tremor
typhlitis
vertigo
visual impairment
vomiting
vomiting
weakness
weakness
weight gain
weight loss
xerostomia
Mild (grade 1 or 2) insomnia was reported in 7% to 8% of patients with metastatic colorectal or breast cancer treated
with capecitabine monotherapy (n = 758) or in combination with docetaxel (n = 251) in 3 clinical trials; mood
alteration (5% or less) and depression (5%) were also reported. Irritability (less than 5%), sedation (less than 5%), and
confusion (grade 3 or 4, 0.1%) were additionally reported in patients receiving capecitabine monotherapy for the
treatment of colorectal cancer or breast cancer in clinical trials.44458
Palmar-plantar erythrodysesthesia (hand and foot syndrome) is a dose-limiting toxicity of capecitabine and has been
reported more often in patients receiving capecitabine monotherapy (n = 1,753) or in combination with docetaxel (54%
to 63%; grade 3, 11% to 24%) compared with fluorouracil/leucovorin (n = 1,567) (6% to 9%; grade 3, 1% or less) in
clinical trials.64032 44458 The median time to onset of palmar-plantar erythrodysesthesia was 79 days. Alopecia was
more common in patients treated with fluorouracil/leucovorin (6% vs. 21% to 22%; grade 3 or 4, 0% vs. less than 1%).
Dermatitis (27% to 37%; grade 3, 1%), skin discoloration (7%; grade 3, less than 1%), rash (7%), nail disorder (7%;
grade 3 or 4, 0.1%), erythema (6%; grade 3 or 4, 1%), skin ulcer (less than 5%), pruritus (less than 5%), radiation recall
reaction (grade 3 or 4, 0.2%), hyperhidrosis (grade 3 or 4, 0.1%), and photosensitivity reaction (grade 3 or 4, 0.1%)
were also reported in patients treated with capecitabine monotherapy in clinical trials. The addition of capecitabine to
docetaxel (n = 251) in patients with metastatic breast cancer did not meaningfully increase the incidence of
dermatologic adverse reactions compared with docetaxel alone (n = 255) in a randomized clinical trial, including
alopecia (41% vs. 42%; grade 3, 6% vs. 7%), nail disorder (14% vs. 15%; grade 3, 2% vs. 0%), dermatitis (8% vs. 11%;
grade 3, 0% vs. 1%), erythematous rash (9% vs. 5%; grade 3, less than 1% vs. 0%), nail discoloration (6% vs. 4%; grade
3, less than 1%), onycholysis (5% vs. 5%; grade 3, 1% vs. 1%), pruritus (4% vs. 5%). Grade 3 or 4 hypersensitivity
reactions occurred in 0.1% of patients receiving capecitabine monotherapy and in 1.2% of patients receiving
capecitabine in combination with docetaxel. Lupus-like symptoms (cutaneous lupus erythematosus) and severe skin
reactions such as Stevens-Johnson Syndrome and toxic epidermal necrolysis have additionally been reported in
postmarketing experience with capecitabine.44458
Hyperbilirubinemia has been reported in patients (48% or less; grade 3 or 4, 11% to 23%) treated with capecitabine
monotherapy in clinical trials (n = 1,870) and is a dose-limiting toxicity. The incidence of hyperbilirubinemia in
patients receiving treatment with fluorouracil/leucovorin (n = 1,567) was much lower (17% or less; grade 3 or 4, 6% to
6.3%). In patients with metastatic breast or colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was
higher in patients with hepatic metastases at baseline (n = 566) compared to those without hepatic metastases at
baseline (n = 309) (22.8% vs. 12.3%). Of the patients who developed grade 3 or 4 hyperbilirubinemia, 18.6% also had
postbaseline elevations in alkaline phosphatase and 27.5% had elevated hepatic enzymes postbaseline; most of these
patients (64.5% and 71.7%, respectively) had liver metastases at baseline. Also, 57.5% of patients who developed grade
3 or 4 hyperbilirubinemia had both pre- and postbaseline increases in alkaline phosphatase (grade 3 or 4, 7.8%) and
35.3% had both pre- and postbaseline increases in transaminases (grade 3 or 4, 3%). The median time to onset for
grade 3 or 4 hyperbilirubinemia patients with colorectal cancer was 64 days. Abnormal liver function tests in general
were reported in less than 5% of patients treated with capecitabine monotherapy, along with ascites (grade 3 or 4,
0.1%), hepatic fibrosis (grade 3 or 4, less than 0.1%), hepatitis (grade 3 or 4, 0.1%), and cholestasis/cholestatic
hepatitis (grade 3 or 4, 0.1%). Hyperbilirubinemia was reported in 20% (grade 3 or 4, 9%) of patients with metastatic
breast cancer treated with capecitabine plus docetaxel (n = 251); grade 3 or 4 hepatotoxicity (0.4%), jaundice (0.4%),
abnormal liver function tests (0.4%), and hepatic failure (0.4%) were also reported in these patients. Increased ALT
was reported in 75% and hypoalbuminemia in 55% of children treated with capecitabine. (_WPS/RefShow.aspx?
rid=44458)44458
Cardiotoxicity has been reported with capecitabine treatment, including myocardial infarction/ischemia, angina,
dysrhythmias or arrhythmia exacerbation, cardiac arrest, heart failure, cardiomyopathy, ECG changes, and sudden
death. Clinically relevant atrial fibrillation, bradycardia, extrasystoles, ventricular extrasystoles, and pericardial
effusion were each reported in less than 5% of patients treated with capecitabine monotherapy in clinical trials; grade 3
or 4 sinus tachycardia (0.1%) and myocarditis (0.1%) were also reported. Supraventricular tachycardia (SVT) (grade 3
or 4, 0.4%) was reported in patients with metastatic breast cancer receiving capecitabine in combination with
docetaxel.44458
Neutropenia has been reported across clinical trials of patients treated with capecitabine, although it is less common
than with fluorouracil/leucovorin treatment in comparative trials. Neutropenia or decreased neutrophils/granulocytes
was reported in 13% to 26% (grade 3 or 4, 2.2% to 4%) patients receiving capecitabine monotherapy as adjuvant or
metastatic treatment for colorectal cancer or treatment for metastatic breast cancer (n = 1,753) compared with 46% or
fewer (grade 3 or 4, 21% to 26.4%) patients receiving fluorouracil/leucovorin (n = 1,567). Anemia or decreased
hemoglobin occurred with a similar frequency in patients with adjuvant or metastatic colorectal cancer or metastatic
breast cancer receiving capecitabine versus fluorouracil/leucovorin (72% to 80%; grade 3 or 4, 4% or less).
Lymphopenia occurred in 94% (grade 3 or 4, 59%) of patients with metastatic breast cancer receiving capecitabine
monotherapy in a phase 2 clinical trial (n = 162) and thrombocytopenia was reported in 24% (grade 3 or 4, 4%). Grade
3 or 4 decreases in lymphocytes (13%) and platelets (1%) occurred less often in a large clinical trial of patients
receiving adjuvant capecitabine monotherapy for colorectal cancer (n = 995). Additional hematologic adverse reactions
reported with capecitabine monotherapy across adjuvant and metastatic indications include idiopathic
thrombocytopenic purpura (grade 3 or 4, 1%), leukopenia (grade 3 or 4, 0.2%), bone marrow depression (grade 3 or 4,
0.1%), and pancytopenia (grade 3 or 4, 0.1%). In a randomized clinical trial of patients with metastatic breast cancer,
the addition of capecitabine to docetaxel (n = 251) increased the incidence of thrombocytopenia compared with
docetaxel alone (n = 255) (41% vs. 23%; grade 3 or 4, 3% vs. 3%), but other hematologic adverse reactions were similar
between study arms including lymphopenia (99% vs. 98%; grade 3 or 4, 89% vs. 84%), leukopenia (91% vs. 88%; grade
3 or 4, 61% vs. 75%), neutropenia/granulocytopenia (86% vs. 87%; grade 3 or 4, 69% vs. 77%), and anemia (80% vs.
83%; grade 3 or 4, 10% vs. less than 6%). Grade 3 or 4 agranulocytosis was also reported in 0.4% of metastatic breast
cancer patients who received capecitabine plus docetaxel. Laboratory abnormalities were more common in 2 clinical
trials of pediatric patients receiving capecitabine with radiation therapy (n = 56), including lymphopenia (73%),
leukopenia (73%), thrombocytopenia (57%), neutropenia (50%), and anemia (50%). Based on postmarketing reports,
patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at
increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including
neutropenia. (_WPS/RefShow.aspx?rid=44458)44458
Nausea (34% to 43% vs. 47% to 51%; grade 3 or 4, 2% to 4% vs. 2% or less), stomatitis (22% to 25% vs. 60% to 62%;
grade 3 or 4, less than 3% vs. 14% to 15%) and vomiting (15% to 27% vs. 21% to 30%; grade 3 or 4, less than 5% vs.
less than 5%) were less common in patients with colorectal cancer receiving adjuvant or metastatic treatment with
capecitabine monotherapy (n = 1,591) compared to treatment with fluorouracil/leucovorin (n = 1,567). Nausea (53%;
grade 3, 4%) and vomiting (37%; grade 3, 4%) were more common in patients with metastatic breast cancer receiving
capecitabine monotherapy in a single-arm, phase 2 trial (n = 162); stomatitis occurred at a similar incidence as the
colorectal trials (24%; grade 3, 7%). Abdominal pain (7% to 35%; grade 3 or 4, less than 10%), constipation (9% to
15%; grade 3 or 4, less than 2%), GI motility disorder (10%; grade 3, less than 1%), oral discomfort (10%), upper GI
inflammatory disorders (8%; grade 3, less than 1%), GI bleeding (6%; grade 3 or 4, less than 2%), ileus (6%; grade 3 or
4, 0.3% to 5%), abdominal distension (less than 5%), proctalgia (less than 5%), toxic dilation of intestine (less than
5%), and peptic ulcer (grade 3 or 4, 0.1%) have also been reported with capecitabine monotherapy. Stomatitis (67% vs.
43%; grade 3 or 4, less than 18% vs. 5%), nausea (45% vs. 36%; grade 3, 7% vs. 2%), vomiting (35% vs. 24%; grade 3 or
4, 5% vs. 2%), constipation (20% vs. 18%; grade 3 or 4, 2% vs. 0%), and abdominal pain (30% vs. 24%; grade 3 or 4,
less than 4% vs. 2%) occurred more often in patients with metastatic breast cancer treated with docetaxel plus
capecitabine (n = 251) compared with docetaxel alone (n = 255) in a randomized clinical trial; grade 3 or 4 ileus (0.4%)
and esophageal ulceration (0.4%) were also reported. Geriatric patients may be at an increased risk for some GI adverse
reactions, with grade 3 or 4 nausea (1.3% to 13.1%), vomiting (1.5% to 9.5%), and stomatitis (3% to 30%) reported at
an increased incidence in these patients (n = 429) in clinical trials of patients receiving capecitabine monotherapy or in
combination with docetaxel. Based on postmarketing reports, patients with complete or near complete absence of
dihydropyrimidine dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe,
life-threatening, or fatal adverse reactions including mucositis.44458
Diarrhea which can sometimes be severe is a dose-limiting toxicity of capecitabine and occurs in 47% to 57% (grade 3
or 4, 12% to 15%) of patients with breast cancer or colorectal cancer who received capecitabine monotherapy in several
clinical trials (n = 1,753), and in 67% (grade 3 or 4, less than 15%) of breast cancer patients treated with capecitabine
plus docetaxel in another clinical trial (n = 251). (_WPS/RefShow.aspx?rid=64032)64032 (_WPS/RefShow.aspx?
rid=44458)44458 Grade 3 or 4 gastroenteritis has also been reported in 0.1% of patients receiving capecitabine
monotherapy in clinical trials. Grade 3 or 4 necrotizing enterocolitis (typhlitis) (0.4%) and hemorrhagic diarrhea
(0.8%) have also been reported in patients with metastatic breast cancer treated with capecitabine in combination with
docetaxel. Geriatric patients may be at an increased risk, with grade 3 or 4 diarrhea reported in 13.1% to 30% of these
patients (n = 429) in clinical trials of patients receiving capecitabine monotherapy or in combination with docetaxel.
Based on postmarketing reports, patients with complete or near complete absence of dihydropyrimidine
dehydrogenase (DPD) activity are also at increased risk for acute early-onset of toxicity and severe, life-threatening, or
fatal adverse reactions including diarrhea. Carefully monitor patients with diarrhea and replace fluids and electrolytes
if needed; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. In patients with
either metastatic breast or colorectal cancer who received capecitabine monotherapy (n = 875), the median time to first
occurrence of grade 2 to 4 diarrhea was 34 days, with a median duration of grade 3 to 4 diarrhea of 5 days.
Anorexia or decreased appetite has been reported in 9% to 26% (grade 3 or 4, less than 4%) of patients treated with
capecitabine monotherapy in clinical trials (n = 1,753); dyspepsia (8% or less; grade 3 or 4, less than 1%), dysgeusia or
taste disturbance (6%; grade 3 or 4, 1% or less), dysphagia (less than 5%), and cachexia (grade 3 or 4, 0.4%) has also
been reported in patients receiving capecitabine monotherapy. Taste disturbance (16% vs. 14%; grade 3, less than 1%
vs. less than 1%), dyspepsia (14% vs. 8%; grade 3 or 4, 0% vs. 1%), anorexia (13% vs. 11%; grade 3, 1% vs. less than
1%), decreased appetite (10% vs. 5%), xerostomia (6% vs. 5%; grade 3, less than 1% vs. 0%), and weight loss (7% vs.
5%) were also reported more often in patients with metastatic breast cancer who received docetaxel in combination
with capecitabine (n = 251) compared with docetaxel alone (n = 255).44458
Dehydration has been reported in patients treated with capecitabine (7% to 10%; grade 3 or 4, 5% or less), which may
cause acute renal failure. Monitor patients to prevent dehydration and quickly correct it if it occurs; an interruption of
therapy and intravenous fluids may be needed. Do not be restart therapy until the patient is rehydrated and any
precipitating causes have been corrected or controlled.44458
Severe (grade 3 or 4) renal impairment (0.6%) and renal failure (unspecified) (0.4%) have been reported in patients
treated with capecitabine as monotherapy or in combination with docetaxel during clinical trials. Acute renal failure
secondary to dehydration (including fatal outcome) has been reported in postmarketing experience with
capecitabine.44458
Fever was reported in 7% to 18% (grade 3 or 4, 1% or less) of patients with colorectal or breast cancer treated with
capecitabine monotherapy in clinical trials (n = 1,753). Infection has also been reported in patients receiving
capecitabine monotherapy, including viral infections (5%; grade 3, less than 1%) as well as grade 3 or 4 laryngitis (1%),
sepsis (0.3%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), and fungal infections including
candidiasis (0.2%). The incidence of infection was similar between treatment arms in patients with metastatic breast
cancer randomized to treatment with capecitabine plus docetaxel (n = 251) vs. docetaxel alone (n = 255), including
fever (28%; grade 3, 2%), neutropenic fever (16%; grade 3 or 4, 16%), influenza-line illness (5%), oral candidiasis (7%;
grade 3, less than 1%), urinary tract infection (6%; grade 3, less than 1%), and upper respiratory tract infection (4%);
grade 3 or 4 neutropenic sepsis (2.4%), sepsis (0.4%), and bronchopneumonia (0.4%) were also reported in these
patients.44458
Fatigue, asthenia, and lethargy occurred with a similar frequency in patients treated with capecitabine versus
fluorouracil/leucovorin in clinical trials. In a randomized clinical trial of patients receiving adjuvant treatment for
colorectal cancer with either capecitabine (n = 995) or fluorouracil/leucovorin (n = 974), fatigue (16% vs. 16%; grade 3
or 4, less than 1% vs. 1%), asthenia (10% vs. 10%; grade 3 or 4, less than 1% vs. 1%), and lethargy (10% vs. 9%; grade 3
or 4, less than 1% vs. less than 1%) were reported with similar frequencies between arms. Fatigue/weakness occurred
in 42% (grade 3, 4%) of patients with metastatic colorectal cancer receiving capecitabine monotherapy (n = 596)
compared with 46% (grade 3, 4%) of those treated with fluorouracil/leucovorin (n = 593). Fatigue occurred in a similar
percentage of patients with metastatic breast cancer receiving capecitabine monotherapy in a phase 2 clinical trial (n =
162) (41%; grade 3, 8%). Muscle weakness was reported in less than 5% of patients receiving capecitabine
monotherapy in clinical trials. The addition of capecitabine to docetaxel in patients with metastatic breast cancer (n =
251) did not increase the incidence of these adverse reactions compared with docetaxel alone (n = 255) in a
randomized clinical trial, including asthenia (26% vs. 25%; grade 3 or 4, 4% to 5% vs. 6%), fatigue (22% vs. 27%; grade
3, 4% vs. 6%), weakness (16% vs. 11%; grade 3, 2% vs. 2%), and lethargy (7% vs. 6%; grade 3, 0% vs. 2%).
Mild (grade 1 or 2) ocular irritation was reported in 13% to 15% of patients with metastatic breast or colorectal cancer
treated with capecitabine monotherapy in 2 clinical trials (n = 758). Abnormal vision/visual impairment (5%),
conjunctivitis (5%; grade 3 or 4, less than 1%), and keratoconjunctivitis (less than 5%) have been reported in patients
receiving capecitabine monotherapy. Increased lacrimation (12%), conjunctivitis (5%), and eye irritation (5%) were
reported in patients with metastatic breast cancer receiving treatment with capecitabine plus docetaxel (n = 251).
There have been reports of lacrimal duct stenosis and corneal disorders including keratitis in postmarketing experience
with capecitabine.44458
Hypercalcemia (1.1%; grade 3 or 4, 0.7%) and hypocalcemia (2.3%; grade 3 or 4, 2.2%) were reported in patients with
metastatic colorectal cancer treated with capecitabine monotherapy (n = 995) in a randomized clinical trial.
Hypokalemia (less than 5%), hypomagnesemia (less than 5%), and hypertriglyceridemia (grade 3 or 4, 0.1%) were
additionally reported in patients receiving capecitabine monotherapy for the treatment of colorectal or breast cancer.
The adverse reaction profile of capecitabine in pediatric patients (n = 56) was consistent with adult patients with the
exception of laboratory abnormalities, which were more common in pediatric patients including hypokalemia (68%),
hypocalcemia (48%), hypophosphatemia (45%), and hyponatremia (45%).44458
Generally mild epistaxis has been reported in clinical trials of patients receiving capecitabine monotherapy as adjuvant
or metastatic treatment for colorectal cancer (n = 1,591) (2% to 3%; grade 3, less than 1%); the incidence was slightly
higher when administered in combination with docetaxel (n = 251) to patients with metastatic breast cancer (7%;
grade 3, less than 1%). Hemorrhage (bleeding) and hemoptysis were each reported in less than 5% of patients receiving
capecitabine monotherapy; grade 3 or 4 coagulopathy (0.1%) was also reported. Grade 3 or 4 decreases in prothrombin
time occurred in 0.4% of metastatic breast cancer patients receiving capecitabine plus docetaxel.44458
Musculoskeletal adverse reactions occurred with a similar frequency in patients with metastatic colorectal cancer
treated with capecitabine monotherapy (n = 596) compared with fluorouracil/leucovorin (n = 593) in a randomized
clinical trial, including pain (12% vs. 10%; grade 3, 1% vs. 1%), chest pain (unspecified) (6% vs. 6%; grade 3 or 4, 1%
vs. less than 2%), back pain (10% vs. 9%; grade 3, 2% vs. less than 1%), and arthralgia (8% vs. 6%; grade 3, 1% vs. 1%).
Limb pain 6%; grade 3, 1%) and myalgia (9%) were also reported in a phase 2 trial of capecitabine monotherapy for the
treatment of metastatic breast cancer (n = 162). Grade 3 or 4 chest pain (0.2%) and pain (0.1%) were reported across
clinical trials of patients with colorectal or breast cancer receiving capecitabine monotherapy in clinical trials. The
incidence of musculoskeletal adverse reactions were similar when capecitabine was added to docetaxel in patients with
metastatic breast cancer (n = 251), including limb pain (13%; grade 3, less than 1%), pain (7%; grade 3, less than 1%),
non-cardiac chest pain (4%; grade 3, less than 1%), arthralgia (13%; grade 3, 2%), myalgia (13%; grade 3, 2%), back
pain (12%; grade 3, less than 1%), and bone pain (8%; grade 3, less than 1%); bone pain (grade 3 or 4, 0.1%) and
arthritis (grade 3 or 4, 0.1%) have also been reported.44458
Headache (5% to 10%; grade 3 or 4, 1% or less) and dizziness (6% to 8%; grade 3 or 4, less than 1%) of patients with
colorectal or breast cancer receiving capecitabine monotherapy (n = 1,753); vertigo was reported in less than 5% of
patients receiving capecitabine monotherapy. The occurrence of headache (15%; grade 3, 3%) and dizziness (12%) was
slightly higher when capecitabine was administered with docetaxel (n = 251) to patients with metastatic breast cancer
in a randomized clinical trial, although the incidences were similar to docetaxel monotherapy (n = 255); grade 3 or 4
migraine was reported in 0.4% of patients receiving combination therapy.44458
Mild (grade 1 or 2) peripheral neuropathy was reported in 10% of patients with metastatic colorectal cancer treated
with capecitabine monotherapy (n = 596) compared with 4% of those receiving fluorouracil/leucovorin (n = 593) in a
randomized clinical trial. In a phase 2 single-arm trial of patients with metastatic breast cancer (n = 162), paresthesias
occurred in 21% (grade 3, 1%) of patients receiving capecitabine monotherapy. In a randomized clinical trial of patients
with metastatic breast cancer, paresthesias (12% vs. 16%; grade 3, less than 1% vs. 1%), peripheral neuropathy (6% vs.
10%; grade 3, 0% vs. 1%), and hypoesthesia (4% vs. 8%; grade 3, less than 1% vs. less than 1%) occurred less often in
patients receiving capecitabine plus docetaxel (n = 251) compared with docetaxel alone (n = 255); grade 3 or 4
polyneuropathy was reported in 0.4% of patients receiving combination therapy. Based on postmarketing reports,
patients with complete or near complete absence of dihydropyrimidine dehydrogenase (DPD) activity are also at
increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions including
neurotoxicity. (_WPS/RefShow.aspx?rid=44458)44458
Edema was reported in 9% to 15% (grade 3, 1%) of patients with metastatic colorectal or breast cancer treated with
capecitabine monotherapy in 2 clinical trials (n = 758). Edema (less than 5%), weight gain (less than 5%), and
lymphedema (grade 3 or 4, 0.1%) have also been reported across clinical trials of patients receiving capecitabine
monotherapy for the treatment of colorectal cancer or breast cancer. In patients with metastatic breast cancer
randomized to treatment with docetaxel plus capecitabine (n = 251) or docetaxel alone (n = 255), the incidence of
edema was higher than with capecitabine monotherapy, but similar between treatment arms (33% vs. 34%; grade 3,
less than 2% vs. less than 4%); lymphedema was reported in 3% (grade 3, less than 1%) versus 5% (grade 3, 1%) of
these patients, respectively.44458
Respiratory adverse reactions including dyspnea (14%; grade 3, 1% to 3%), cough (7% to 13%; grade 3 or 4, less than
2%), pharyngeal disorder (5%), and sore throat (2% to 12%; grade 3, 2% or less) were reported in patients with
metastatic colorectal cancer receiving capecitabine monotherapy (n = 596) or metastatic breast cancer receiving
capecitabine plus docetaxel (n = 251); the incidence was similar to patients receiving fluorouracil/leucovorin alone (n =
593). Hoarseness (less than 5%), dyspnea (less than 5%), as well as grade 3 or 4 asthma (0.2%), cough (0.1%), and
respiratory distress (0.1%) were also reported in patients receiving capecitabine monotherapy for the treatment of
colorectal cancer or breast cancer. In patients receiving combination therapy with capecitabine and docetaxel,
rhinorrhea (5%) and pleural effusion (2%; grade 3, 1%) were reported.44458
Venous thrombosis was reported in 8% (grade 3 or 4, 3% to 4%) of patients with metastatic colorectal cancer treated
with capecitabine monotherapy (n = 596) compared with 6% (grade 3, 2%) of those treated with
fluorouracil/leucovorin (n = 593). Pulmonary embolism (grade 3 or 4, 0.2%) and cerebrovascular accident/stroke
(grade 3 or 4, 0.1%) were also reported in patients receiving capecitabine monotherapy for the treatment of colorectal
cancer or breast cancer. Grade 3 or 4 venous phlebitis and thrombophlebitis were additionally reported in 0.4% of
patients with metastatic breast cancer treated with capecitabine plus docetaxel in a randomized clinical trial.
Hot flashes were reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of
colorectal cancer or breast cancer in clinical trials. Flushing was also reported in 5% of patients with metastatic breast
cancer treated with capecitabine plus docetaxel; the incidence was similar to patients receiving docetaxel alone.44458
Difficulty walking, abnormal coordination, impaired balance, and tremor were each reported in less than 5% of patients
receiving capecitabine monotherapy for the treatment of colorectal cancer or breast cancer. Additionally, grade 3 or 4
ataxia (0.5%), loss of consciousness (0.2%), and encephalopathy (0.1%) were reported. Grade 3 or 4 syncope (1.2%)
and ataxia (0.4%) were also reported in patients with metastatic breast cancer receiving treatment with capecitabine
plus docetaxel. Toxic leukoencephalopathy was reported in postmarketing experience with capecitabine therapy.
Hypotension (grade 3 or 4, 0.2%) and hypertension (grade 3 or 4, 0.1%) were reported in patients receiving
capecitabine monotherapy for the treatment of colorectal cancer or breast cancer in clinical trials. Additionally, grade 3
or 4 hypotension (1.2%) and postural hypotension (0.8%) occurred in patients with metastatic breast cancer who
received combination therapy with capecitabine plus docetaxel.44458
Polydipsia was reported in less than 5% of patients receiving capecitabine monotherapy for the treatment of colorectal
cancer or breast cancer in clinical trials.44458
Dysarthria and dysphasia were each reported in less than 5% of patients receiving capecitabine monotherapy for the
treatment of colorectal cancer or breast cancer in clinical trials.44458
Angioedema has been reported with capecitabine use in postmarketing experience.44458
Last revised: May 24, 2021
Classifications
Antimetabolite Antineoplastic Agents
Antineoplastic and Immunomodulating Agents
Antineoplastics
Pyrimidine Analogs
† - Off-Label Indication
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Global Drug Names

Argentina
Apecitab - (Dosa)
Capebina - (LKM)
Capecinova - (Gobbi)
Capecit - (Richmond)
Capectan - (Microsules)
Capefas - (Raffo)
Captech - (Biotechno)
Categor - (Sandoz)
Catepen - (Aspen)
Derebel - (Tuteur)
Vibacine - (Lafedar)
Xeloda - (Roche)
Xitabin - (Bioprofarma)
Australia
Capex - (Accord)
Xelabine - (Aspen)
Xelocitabine - (Reddy)
Xeloda - (Roche)
Austria
Capecel - (GL Pharma)
Xeloda - (Roche)
Belgium
Xeloda - (Roche)
Brazil Xeloda - (Roche)
Canada
Xeloda - (Roche)
Chile
Capefas - (Tecnofarma)
Categor - (Recalcine)
Xeloda - (Roche)
China
Ai Bin - (Hengrui)
Xeloda - (Roche)
Czech Republic
Coloxet - (Egis)
Ecansya - (KRKA)
Xalvobin - (Alvogen)
Xeloda - (Roche)
Denmark
Xeloda - (Roche)
Finland
Xeloda - (Roche)
France
Xeloda - (Roche)
Germany
Xeloda - (Roche)
Greece
Capibine - (Aphth)
Preveloda - (Farmazak)
Xelazor - (Vocate)
Xeloda - (Roche)
Hong Kong
Xeloda - (Roche)
Xitabin - (Health Alliance)
Hungary
Coloxet - (Egis)
Xeloda - (Roche)
India
Capecite - (Abbott)
Capiibine - (Reddy)
Captabin - (Shantha)
Capxcel - (Khandelwal)
Caxeta - (Sun)
Naprocap - (Miracalus)
Indonesia
Taceral - (Kalbe)
Xeloda - (Roche)
Ireland
Ecansya - (KRKA)
Xeloda - (Roche)
Israel
Xeloda - (Roche)
Italy
Capeoda - (Tiefenbacher)
Tificape - (Tiefenbacher)
Xeloda - (Roche)
Japan
Xeloda - (Chugai)
Malaysia
Xeloda - (Roche)
Mexico
Skemca - (Accord)
Skemka - (Accord)
Xeloda - (Roche)
Netherlands
Capecitastad - (Stada)
Coloxet - (Egis)
Ecansya - (KRKA)
Vopecidex - (PharmaSwiss)
Xelcip - (Cipla)
Xeloda - (Roche)
New Zealand
Brinov - (Rex)
Xeloda - (Roche)
Norway
Xeloda - (Roche)
Philippines
Capvex - (Vexxa)
Catacibin - (Hetero)
Caxeta - (Sun)
Naprocap - (Naprod)
Xeloda - (Roche)
Xeltabine - (Korea United)
Poland
Actabi - (Adamed)
Binoda - (GSK)
Capecitalox - (Mylan)
Capestri - (Strides Arcolab)
Coloxet - (Egis)
Symloda - (SymPhar)
Vopecidex - (PharmaSwiss)
Xeloda - (Roche)
Portugal
Xeloda - (Roche)
Russian Federation
Cabecin - (Sintez)
Capametin - (Nativa)
Capecitover - (Veropharm)
Tutabin - (Tuteur)
Xeloda - (Roche)
Singapore
Capetero - (Hetero)
Xeloda - (Roche)
South Africa
Capexa - (Ingwe)
Pecaset - (Eurolab)
Xeloda - (Roche)
Spain
Xelcip - (Cipla)
Xeloda - (Roche)
Zapecine - (Normon)
Sweden
Xalvobin - (Hospira)
Xeloda - (Roche)
Switzerland
Xeloda - (Roche)
Thailand
Intacape - (Intas)
Xeloda - (Roche)
Turkey
Kapeda - (Kocak)
Xeloda - (Roche)
Xeltabin - (Teva)
Ukraine
Apsibin - (Reddy)
Xeloda - (Roche)
United Kingdom
Xeloda - (Roche)
Venezuela
Xeloda - (Roche)
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7/8/2021 Capecitabine - ClinicalKey

Drug Information Provided By Gold Standard

Affected cytochrome P450 (CYP) isoenzymes: CYP2C9

Last revised: April 5, 2019

Indications & Dosage

For the treatment of metastatic breast cancer

NOTE: Lapatinib is FDA-approved in combination with capecitabine for this indication.

For the treatment of colorectal cancer

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

For the treatment of gastric cancer†

for the treatment of advanced gastric cancer in combination with cisplatin†

for the treatment of advanced or metastatic gastric adenocarcinoma or gastroesophageal junction

For the treatment of esophageal cancer†

for the treatment of advanced or metastatic esophageal adenocarcinoma or gastroesophageal junction

Therapeutic Drug Monitoring:

Dosage Adjustments for Treatment-Related Toxicities:

Monotherapy or in Combination with Docetaxel:

Grade 1: No dose adjustment needed.

Maximum Dosage Limits:

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

Baseline Hepatic Impairment:

Patients with Renal Impairment Dosing

Baseline Renal Insufficiency:

Last revised: July 2, 2021

Capecitabine is administered orally within 30 minutes after a meal.

bone marrow suppression

coronary artery disease

dihydropyrimidine dehydrogenase (DPD) deficiency

Last revised: April 11, 2019

Aluminum Hydroxide; Magnesium Carbonate

Aluminum Hydroxide; Magnesium Hydroxide

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone

Aluminum Hydroxide; Magnesium Trisilicate

Amoxicillin; Clarithromycin; Lansoprazole

Amoxicillin; Clarithromycin; Omeprazole

Aspirin, ASA; Omeprazole

Carbetapentane; Diphenhydramine; Phenylephrine

Dextromethorphan; Diphenhydramine; Phenylephrine

Diphenhydramine; Hydrocodone; Phenylephrine

Drospirenone; Ethinyl Estradiol; Levomefolate

Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate

Folic Acid, Vitamin B9

Omeprazole; Amoxicillin; Rifabutin

Omeprazole; Sodium Bicarbonate

Proton pump inhibitors

SARS-CoV-2 (COVID-19) vaccines

Tuberculin Purified Protein Derivative, PPD

Acetaminophen; Diphenhydramine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is

Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with

Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with

Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with

Diphenhydramine; Naproxen: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is

Diphenhydramine; Phenylephrine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is

Last revised: May 25, 2021

chest pain (unspecified)

chest pain (unspecified)

elevated hepatic enzymes