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capecitabine 150 mg tablet (generic xeloda)

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Uses

Breast Cancer

Combination Therapy

Capecitabine is used in combination with docetaxel for the treatment of metastatic breast cancer in patients with disease that failed to respond to, or recurred or relapsed during or following, anthracycline-containing chemotherapy. In addition to their individual antineoplastic effects, combination therapy with these agents appears to have a synergistic effect because docetaxel acts to increase the expression of an enzyme found at higher concentrations in many tumor cells that is involved in converting capecitabine to its active drug, fluorouracil.

The current indication for capecitabine as a component of combination chemotherapy is based principally on the results of an open-label, multicenter, randomized trial involving 511 patients with metastatic breast cancer resistant to or recurring during or following anthracycline-containing therapy, or relapsing during or recurring within 2 years of completion of anthracycline-containing adjuvant therapy. Patients received either combination therapy with capecitabine 1250 mg/m twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m as a 1-hour IV infusion administered on the first day of each 3-week cycle or monotherapy with docetaxel 100 mg/m as a 1-hour IV infusion administered on the first day of each 3-week cycle. Patients receiving combination therapy with capecitabine and docetaxel had increased overall median survival (442 versus 352 days), longer median time to disease progression (186 versus 128 days), and higher objective response rate (32 versus 22%) than those receiving docetaxel alone.

Adverse GI effects and hand-foot syndrome occurred more frequently in patients receiving capecitabine and docetaxel whereas myalgia and arthralgia were more common in those receiving docetaxel alone. Dose reduction (typically involving both drugs) for adverse effects was frequently required in patients receiving combination therapy with capecitabine and docetaxel.

Monotherapy

Capecitabine is used as monotherapy for the palliative treatment of metastatic breast cancer in patients with disease resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or in patients with disease resistant to paclitaxel who are not candidates for further anthracycline therapy (e.g., those who have received cumulative doses of 400 mg/m of doxorubicin or doxorubicin equivalents). Resistance to paclitaxel or an anthracycline agent is defined as progressive disease during treatment (regardless of initial response) with the respective agent or relapse within 6 months of completing adjuvant therapy with a regimen containing the respective agent. Capecitabine became commercially available in the US under the principles and procedures of the accelerated review policy of the US Food and Drug Administration (FDA), which allows approval based on analysis of surrogate markers of response (e.g., tumor shrinkage) rather than clinical end points such as improvement in disease-related symptoms, disease progression, or survival. The principal goal of therapy in patients with metastatic breast cancer generally has been palliative with an emphasis on extension of survival and improvement in the quality of life.

The current indication for capecitabine monotherapy is based principally on the results of a multicenter, open-label, single-arm phase 2 trial in 162 patients (135 patients with measurable disease) with previously treated stage IV breast cancer. Patients in the trial received 3-week treatment cycles of capecitabine 1255 mg/m twice daily for 2 weeks followed by a 1-week rest period. Most patients in the study had 3 or more sites of metastatic disease and predominantly visceral metastases (i.e., lung, pleura, liver, peritoneum). All patients had received prior paclitaxel treatment, and almost all (i.e., greater than 80%) patients also had previous treatment with anthracyclines and fluorouracil; 77% of patients in the study had disease that was resistant to paclitaxel, 41% had disease that was resistant to an anthracycline, and 31% had disease that was resistant to both paclitaxel and an anthracycline.

For the subgroup of 43 patients whose disease was resistant to both paclitaxel and an anthracycline, objective response rate was 25.6% (all partial responses), median time to progression was 102 days (3.4 months), and median survival was 255 days (8.5 months). For the 135 patients with measurable disease, objective response rate was 18.5% (0.7% complete responses, 17.8% partial responses), median time to progression was 90 days (3 months), and median survival was 306 days (10.2 months). Among patients with disease that responded to the drug, onset of response typically occurred within 6-12 weeks of capecitabine therapy.

Comparative studies are under way to confirm the clinical efficacy of capecitabine in patients with metastatic breast cancer. The role of capecitabine in the initial treatment of advanced breast cancer also is being studied.

Colorectal Cancer

Adjuvant Therapy for Colon Cancer

Capecitabine is used alone as adjuvant therapy following the complete resection of primary tumor in patients with stage III (Dukes' C) colon cancer when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine also has been used in combination with oxaliplatin as adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer.

Monotherapy

The current indication for use of capecitabine alone as adjuvant therapy in patients with stage III (Dukes' C) colon cancer is based principally on the results of a multicenter, randomized, controlled, phase 3 clinical study (X-ACT) in patients with stage III colon cancer who received capecitabine or IV fluorouracil and leucovorin following complete resection of the primary tumor.

In this study, 1987 patients were randomized to receive either capecitabine 1250 mg/m orally twice daily for 2 weeks followed by a 1-week rest period, administered in 3-week cycles for a total of 8 cycles (24 weeks), or rapid IV injection (''bolus'') fluorouracil 425 mg/m and IV leucovorin 20 mg/m on days 1-5, administered as 4-week cycles for a total of 6 cycles (24 weeks). The starting dose of capecitabine was reduced in patients with moderate renal impairment (i.e., creatinine clearance 30-50 mL/minute calculated with the formula of Cockroft-Gault) at baseline. For all patients, doses were reduced or interrupted according to toxicity. The median age of patients in this study was 62-63 years.

At a median follow-up of 83 months, the 5-year disease-free (59 versus 55%, respectively; hazard ratio 0.88) and overall (71 versus 68%, respectively; hazard ratio 0.86) survival rates in patients receiving capecitabine were at least equivalent to those in patients receiving fluorouracil and leucovorin as adjuvant therapy for colon cancer. These results indicate that capecitabine is noninferior to fluorouracil and leucovorin as adjuvant therapy for stage III colon cancer. While patients receiving either capecitabine or fluorouracil and leucovorin frequently required dose reductions (42 versus 44%, respectively), delay of treatment cycles (46 versus 29%) and treatment interruption (15 versus 5%) occurred more frequently in patients receiving capecitabine. Subgroup analysis based on prognostic factors (e.g., age, regional lymph node involvement, baseline carcinoembryonic antigen [CEA] concentration) suggested that capecitabine's effect on disease-free and overall survival was consistent across the subgroups, including those 70 years of age or older.

The onset of grade 3 or 4 adverse events was delayed in patients receiving capecitabine compared with those receiving fluorouracil and leucovorin. Hand-foot syndrome (all grades: 60 versus 9%, severe: 17 versus <1%) and grade 3 or 4 hyperbilirubinemia (defined as 1.5 or more times the upper limit of normal) occurred more frequently in patients receiving capecitabine (20 versus 6%), while diarrhea (65 versus 47%), stomatitis (60 versus 22%), nausea (47 versus 34%), alopecia (22 versus 6%), and neutropenia (8 versus 2%) occurred more frequently in patients receiving fluorouracil and leucovorin.

Combination Therapy

Capecitabine has been used in combination with oxaliplatin (CapeOx) as adjuvant therapy in patients with stage III colon cancer who have undergone complete resection of the primary tumor.

Adjuvant therapy with oxaliplatin in combination with IV fluorouracil and leucovorin has been shown to increase disease-free and overall survival in patients with stage III colon cancer who have undergone complete resection of the primary tumor. Therefore, efficacy and safety of oxaliplatin in combination with capecitabine as adjuvant therapy in patients with stage III colon cancer have been evaluated in an open-label, randomized phase 3 study (NO16968; XELOXA).

In this study, 1886 patients were randomized to receive either combination therapy with oxaliplatin (130 mg/m administered by IV infusion over 2 hours on day 1) and capecitabine (1 g/m administered orally twice daily on days 1-14) on a 3-week cycle for 8 cycles or combination therapy with IV fluorouracil and leucovorin (Mayo Clinic or Roswell Park regimen). The Mayo Clinic regimen consisted of fluorouracil 425 mg/m administered by rapid IV injection (''bolus'') and leucovorin 20 mg/m administered by rapid IV infusion on days 1-5 of each 4-week cycle for a total of 6 cycles (24 weeks), and the Roswell Park regimen consisted of fluorouracil 500 mg/m administered by rapid IV injection (''bolus'') and leucovorin 500 mg/m administered as a 2-hour IV infusion on day 1 of weeks 1-6 of each 8-week cycle for a total of 4 cycles (32 weeks). Patients were enrolled no more than 8 weeks following surgery with curative intent, by which time full recovery from surgery was required. The median age of patients was 61-62 years. Most patients (99%) enrolled in the study had a baseline ECOG performance status of 0 or 1. The primary measure of efficacy was disease-free survival. At a median follow-up of 74 months, patients who received capecitabine in combination with oxaliplatin had higher disease-free (66.1 versus 59.8%; hazard ratio: 0.8) and relapse-free (69.3 versus 62.2%; hazard ratio: 0.78) survival rates compared with patients who received fluorouracil and leucovorin.

At a median follow-up of 83 months, patients who received capecitabine in combination with oxaliplatin also had a higher overall survival rate (74.4 versus 69.6%; hazard ratio: 0.83) compared with those who received fluorouracil and leucovorin. Subgroup analysis based on prognostic factors (e.g., age, regional lymph node involvement, baseline CEA concentration) suggested that the effect of capecitabine in combination with oxaliplatin on disease-free and overall survival was consistent across the subgroups, including those 70 years of age or older; however, the effect size appeared to be reduced in patients 70 years of age or older compared with younger patients. Neurosensory toxicity (any grade: 78 versus 8%; grade 3 or 4: 11 versus less than 1%), grade 3 or 4 hand-foot syndrome (5 versus less than 1%), and grade 3 or 4 thrombocytopenia (5% versus less than 1%) occurred more frequently in patients receiving capecitabine in combination with oxaliplatin, while grade 3 or 4 neutropenia (9 versus 16%), febrile neutropenia (less than 1 versus 4%), and stomatitis (less than 1 versus 9%) occurred more frequently in those receiving fluorouracil and leucovorin.

Use of combination therapy with oxaliplatin and capecitabine also was investigated in a randomized, multicenter, phase 3 study in patients with high-risk stage II or stage III colorectal cancer who had undergone complete resection of the primary tumor; however, interpretation of the results is limited by the failure to meet the planned accrual of 800 patients in the study to demonstrate superiority. In this study, 408 patients were randomized to receive either combination therapy with oxaliplatin (130 mg/m on day 1) and capecitabine (1 g/m twice daily on days 1-14) on a 3-week cycle for 8 cycles or combination therapy with an oxaliplatin, fluorouracil, and leucovorin (modified FOLFOX6) regimen on a 2-week cycle for 12 cycles. At a median follow-up of 74.7 months, median disease-free and overall survival had not been reached; however, 3-year disease-free and overall survival rates were similar between patients receiving capecitabine in combination with oxaliplatin (79.5 and 86.9%, respectively) compared with patients receiving modified FOLFOX6 (79.8 and 87.2%, respectively).

Based on current evidence, combination therapy with oxaliplatin and capecitabine is a reasonable choice (accepted, treatment option) for use as adjuvant therapy in patients with stage III colon cancer who have undergone complete resection of the primary tumor.

First-line Therapy for Metastatic Colorectal Cancer

Capecitabine is used for the first-line treatment of metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred. Analysis of data from two phase 3 randomized trials indicates that higher response rates but similar duration of progression-free survival are observed for capecitabine compared with fluorouracil and leucovorin (IV loading ''bolus'' schedule) in previously untreated advanced or metastatic colorectal cancer; no difference in overall survival between the groups was demonstrated.

In 2 randomized trials involving a total of 1207 patients with previously untreated advanced or metastatic colorectal cancer, those receiving capecitabine 1250 mg/m twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles had higher overall objective response rates (21 versus 11% and 21 versus 14%) than those receiving fluorouracil and leucovorin (20 mg/m IV leucovorin followed by 425 mg/m rapid IV injection [''bolus''] fluorouracil, on days 1-5, every 28 days). Median time to progression (128 versus 131 days and 137 versus 131 days) and median survival (380 versus 407 days and 404 versus 369 days) were similar for patients receiving capecitabine versus fluorouracil and leucovorin. Pooled data from the two studies is consistent with capecitabine showing retention of at least 50% of the survival effect of fluorouracil and leucovorin; these results do not exclude the possibility of true equivalence of capecitabine to this schedule of fluorouracil and leucovorin.

Hand-foot syndrome and hyperbilirubinemia were more common and greater in severity in those receiving capecitabine, whereas stomatitis and neutropenia occurred more frequently and with greater severity in patients receiving fluorouracil and leucovorin. In both randomized trials, data analysis showed later onset of serious adverse reactions and longer median time to dose reduction in patients receiving capecitabine compared with those receiving fluorouracil and leucovorin as the IV loading rapid IV (''bolus'') schedule. The comparative efficacy and toxicity of capecitabine compared with other parenteral fluorouracil regimens (e.g., weekly ''bolus'' fluorouracil and leucovorin, continuous IV infusion fluorouracil) is not known. In addition to its equivalent efficacy and differing toxicity profile from the schedule of parenteral fluorouracil used in these randomized trials, the convenience of capecitabine, a prodrug of fluorouracil that is administered orally, may be a factor in choice of drug therapy.

A survival benefit has been demonstrated for the use of fluorouracil and leucovorin in combination with other agents compared with fluorouracil and leucovorin alone for advanced colorectal cancer. A survival benefit for the use of capecitabine alone versus fluorouracil and leucovorin has not been demonstrated. The comparative safety and efficacy of combination regimens using capecitabine as a substitute for fluorouracil and leucovorin is being investigated.

Other Uses

Capecitabine also has been used for treatment of gastric cancer. Interim results of phase 3 randomized trials suggest that capecitabine is noninferior with regard to progression-free survival or overall survival when used in place of fluorouracil in combination regimens for advanced gastric cancer.

Dosage and Administration

Administration

Capecitabine is administered orally. Capecitabine tablets should be swallowed whole with water within 30 minutes after the end of a meal; the tablets should not be cut or crushed. Although some clinicians state that capecitabine may be administered concomitantly with antacids containing aluminum and magnesium hydroxide, other clinicians advise delay of administration of antacids for at least 2 hours following induction of capecitabine therapy.

Individual adjustment of capecitabine dosage may be necessary for optimal management.

Dosage

Breast Cancer

Combination Therapy

When used in combination therapy with docetaxel for the treatment of metastatic breast cancer in patients with disease that failed to respond to or recurred following anthracycline-containing chemotherapy, the recommended initial dosage of capecitabine is 1250 mg/m twice daily (morning and evening), equivalent to a total daily dose of 2500 mg/m, for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. Docetaxel 75 mg/m is administered as a 1-hour IV infusion on the first day of each 3-week cycle. Patients should be premedicated prior to docetaxel administration . Treatment with the combination regimen was continued for at least 6 weeks in the randomized trial.

Treatment interruptions and dosage reductions because of adverse effects were required in 79 and 65%, respectively, of patients receiving capecitabine and docetaxel for metastatic breast cancer.

Monotherapy

For the palliative treatment of metastatic breast cancer in patients with disease resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or in patients with disease resistant to paclitaxel who are not candidates for further anthracycline therapy (e.g., those who have received cumulative doses of 400 mg/m of doxorubicin or doxorubicin equivalents), the recommended initial dosage of capecitabine is 1250 mg/m twice daily (morning and evening), equivalent to 2500 mg/m total daily dose, for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. Some experts suggest that a trial of 2 cycles (i.e., 6 weeks) of capecitabine therapy is adequate to assess response to the drug. During a clinical trial of patients with metastatic breast cancer, onset of response typically occurred within 6-12 weeks of capecitabine therapy.

Colorectal Cancer

Adjuvant Therapy for Colon Cancer

For adjuvant therapy following the complete resection of primary tumor in patients with stage III (Dukes' C) colon cancer when treatment with fluoropyrimidine therapy alone is preferred, the recommended dosage of capecitabine is 1250 mg/m twice daily (morning and evening) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles for a total of 8 cycles and a treatment period of 6 months.

When capecitabine has been used in combination with oxaliplatin (CapeOx) as adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer, capecitabine 1 g/m has been administered orally twice daily on days 1-14 and oxaliplatin 130 mg/m has been administered by IV infusion over 2 hours on day 1 of each 3-week cycle. Treatment has been continued for 8 cycles of therapy.

First-line Therapy for Metastatic Colorectal Cancer

For the first-line treatment of metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred, the recommended initial dosage of capecitabine is 1250 mg/m twice daily (morning and evening), equivalent to 2500 mg/m total daily dose, for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles.

Other Dosage Considerations

The following Recommended Initial Dosage table indicates the recommended initial dosage of capecitabine according to body surface area.

Table 1. Recommended Initial Dosage of Capecitabine: 1250 mg/m2 twice daily
Body Surface Area (m2) Total Daily Dose (mg)
<=1.25 3000
1.26-1.37 3300
1.38-1.51 3600
1.52-1.65 4000
1.66-1.77 4300
1.78-1.91 4600
1.92-2.05 5000
2.06-2.17 5300
>=2.18 5600

divide into 2 equal doses given morning and evening

Therapy with capecitabine should not be initiated in patients with baseline neutrophil counts of less than 1500/mm and/or baseline platelet counts of less than 100,000/mm.

Dosage Modification for Age-related Effects

Some clinicians recommend that capecitabine dosage be reduced (e.g., initial dosage reduced by up to 20%) in patients older than 80 years of age receiving capecitabine monotherapy. Because of decreased tolerance of the combination regimen of capecitabine and docetaxel for advanced breast cancer in patients 60 years of age or older, a 25% reduction of the initial capecitabine dose (to 950 mg/m) should be considered.(See Cautions: Geriatric Precautions.)

Dosage Modification for Toxicity

After the initial dose of capecitabine, subsequent doses should be modified as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Cautions and the following table on Criteria for Selected Toxicities Commonly Associated with Capecitabine Therapy for information on specific adverse effects of capecitabine.) The dose-limiting toxicities of capecitabine include diarrhea, nausea, vomiting, abdominal pain, palmar-plantar erythrodysesthesia (hand-foot syndrome), and leukopenia.

If a patient experiences a grade 4 toxicity, the drug should be discontinued or therapy interrupted until the toxicity resolves or decreases in intensity to grade 1; if capecitabine therapy is resumed, the dose should be decreased to 50% of the original dose. If a patient experiences a grade 2 or 3 toxicity, capecitabine therapy should be interrupted until the toxicity resolves or decreases in severity to grade 1.

At the start of the next treatment cycle, subsequent doses should be reduced according to the severity and number of appearances of the toxicity as shown in the following table on Recommended Dosage Modifications for Toxicity of Capecitabine. The manufacturer states that once the capecitabine dosage has been reduced, the dosage should not be increased at a later time.

When capecitabine therapy is interrupted because of toxicity, therapy should be resumed according to planned treatment cycles; doses of the drug omitted because of toxicity should not be replaced.

If a patient experiences either no toxicity or NCIC grade 1 toxicity within a course of treatment, the current capecitabine dose level may be maintained for subsequent courses of therapy until more serious toxicity occurs.

In patients receiving capecitabine in combination with docetaxel, modification of the docetaxel dosage also may be required, as shown in the table on Recommended Dosage Modifications for Docetaxel During Capecitabine and Docetaxel Combination Therapy. If initiation of a treatment cycle must be delayed because of toxicity associated with either capecitabine or docetaxel, administration of both drugs should be delayed until the criteria for reinitiating therapy with both drugs are met.

Table 2. Criteria for Selected Toxicities Commonly Associated with Capecitabine Therapy
Toxicity Grade Criteria
Diarrhea 1 2-3 stools daily > pretreatment
2 4-6 stools daily > pretreatment or nocturnal stools
3 7-9 stools daily > pretreatment or incontinence and malabsorption
4 >10 stools daily > pretreatment, grossly bloody diarrhea, or need for parenteral support
Nausea 1 able to eat reasonable intake of food
2 significant decrease in intake of food but able to eat intermittently
3 no significant intake of food
Vomiting 1 1 episode in 24 hours
2 2-5 episodes in 24 hours
3 6-10 episodes in 24 hours
4 >10 episodes in 24 hours, dehydration, or need for parenteral support
Abdominal pain 1 pain but no treatment required
2 pain controlled with nonopiates
3 pain controlled with opiates
4 uncontrollable pain
Palmar-plantar erythrodysesthesia (hand-foot syndrome) 1 numbness, dysesthesia/paresthesia, tingling, painless swelling, or erythema of the hands and/or feet that causes discomfort but does not disrupt normal activities of daily living
2 painful erythema and swelling of the hands and/or feet that results in discomfort affecting the normal activities of daily living
3 moist desquamation, ulceration, blistering, and severe pain of the hands and/or feet and/or severe discomfort that causes inability to work or perform activities of daily living
Lymphopenia 1 lymphocyte count 1500-1999/mm
2 lymphocyte count 1000-1499/mm
3 lymphocyte count 500-999/mm
4 lymphocyte count <500/mm

NCIC Common Toxicity Criteria except for hand-foot syndrome, which is defined according to a grading system incorporated by Roche and accepted by the FDA;[1 ][25 ] consult NCIC Common Toxicity Criteria for grading of other toxicities.

Table 3. Recommended Dosage Modifications for Toxicity of Capecitabine
NCIC Grade of Toxicity Number of Appearances During a Course of Therapy Dose Adjustment for Next Cycle (% of Initial Dose)
No toxicity Maintain dose level Maintain dose level
Grade 1 Any appearance Maintain dose level Maintain dose level
Grade 2 1 appearance Interrupt therapy until resolved to grade 0-1 100%
2 appearance Interrupt therapy until resolved to grade 0-1 75%
3 appearance Interrupt therapy until resolved to grade 0-1 50%
4 appearance Discontinue drug permanently
Grade 3 1 appearance Interrupt therapy until resolved to grade 0-1 75%
2 appearance Interrupt therapy until resolved to grade 0-1 50%
3 appearance Discontinue drug permanently
Grade 4 1 appearance Discontinue drug permanentlyor
If deemed in best interest of patient to continue therapy, interrupt therapy until resolved to grade 0-1 50%

NCIC Common Toxicity Criteria except for hand-foot syndrome, which is defined according to a grading system incorporated by Roche and accepted by the FDA.[1 ][25 ]

All dose modifications should be based on the worst preceding toxicity.

Table 4. Recommended Dosage Modifications for Docetaxel During Capecitabine and Docetaxel Combination Therapy
NCIC Grade of Toxicity Number of Appearances Dosage Modification
Grade 2 1 appearance Interrupt therapy until resolved to grade 0-1, then resume therapy at 100% of the original dose of docetaxel (75 mg/m)
2 appearance Interrupt therapy until resolved to grade 0-1, then resume therapy with docetaxel 55 mg/m
3 appearance Discontinue docetaxel therapy
Grade 3 1 appearance Interrupt therapy until resolved to grade 0-1, then resume therapy with docetaxel 55 mg/m
2 appearance Discontinue docetaxel therapy
Grade 4 1 appearance Discontinue docetaxel therapy

Prophylaxis for toxicity should be instituted whenever possible; all dosage modifications should be based on the worst preceding toxicity.

NCIC Common Toxicity Criteria except for hand-foot syndrome, which is defined according to a grading system incorporated by Roche and accepted by the FDA.[1 ][25 ]

Dosage in Renal and Hepatic Impairment

Capecitabine is contraindicated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute calculated with the formula of Cockroft-Gault). In patients with moderate renal impairment (i.e., creatinine clearance 30-50 mL/minute calculated with the formula of Cockroft-Gault), a dosage reduction to 75% of the initial capecitabine dose when used as monotherapy or in combination with docetaxel (i.e., from 1250 to 950 mg/m twice daily) is recommended. No adjustment in starting dose is recommended in patients with mild renal impairment. Careful monitoring is required in patients with mild or moderate renal impairment receiving capecitabine because the frequency and/or severity of adverse effects of capecitabine may be increased. If the patient develops a grade 2, 3, or 4 adverse effect, treatment with capecitabine should be discontinued promptly, and subsequent dose modification for toxicity should be made.(See table on Recommended Dosage Modifications for Toxicity of Capecitabine in Dosage and Administration: Dosage.)

The effects of hepatic impairment on the pharmacokinetics of capecitabine have not been fully evaluated. The manufacturer states that no adjustment in initial dosage of capecitabine is necessary in patients with mild to moderate hepatic dysfunction secondary to liver metastases. However, caution is advised and patients with mild to moderate hepatic dysfunction should be monitored carefully during capecitabine therapy. The safety and efficacy of capecitabine in patients with severe hepatic impairment have not been evaluated.

Cautions

Most adverse effects associated with capecitabine are reversible and do not necessitate discontinuance of the drug; however, depending on the severity and recurrence of the adverse effect, capecitabine doses may need to be withheld or reduced.

The incidence of adverse effects associated with capecitabine therapy for metastatic disease is derived principally from data for patients receiving the drug as a single agent in clinical trials for metastatic breast cancer (162 patients, mean duration of treatment of 114 days) or metastatic colorectal cancer (596 patients, median duration of treatment of 139 days) or in combination with docetaxel for metastatic breast cancer (251 patients, mean duration of treatment of 129 days). Unless otherwise specified, the incidence of adverse effects in patients with metastatic disease reflects the use of capecitabine alone or in combination with docetaxel. Information on adverse effects occurring in fewer than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer is derived from a clinical trial safety database reporting on 875 patients. The severity of adverse effects was graded according to toxicity criteria established by the National Cancer Institute of Canada (NCIC). Among patients receiving capecitabine in clinical trials, 8-13% or 26% of patients receiving the drug as a single agent for metastatic breast cancer or metastatic colorectal cancer, or in combination therapy for metastatic breast cancer, respectively, discontinued treatment because of adverse effects or intercurrent illness. Abdominal pain, diarrhea, and hand-foot syndrome were among the most common adverse events leading to withdrawal from the study among patients receiving capecitabine for metastatic breast cancer in clinical trials. Among patients with metastatic colorectal cancer, death due to all causes occurred during the study or within 28 days of receiving the study drug in 50 patients (8.4%) randomized to receive capecitabine compared with 32 patients (5.4%) randomized to receive 5-fluorouracil and leucovorin.

The incidence of adverse effects associated with capecitabine as adjuvant therapy for colon cancer is derived principally from data for patients receiving the drug as a single agent in a phase 3 study for stage III colon cancer (995 patients, median duration of treatment of 164 days). Among patients receiving capecitabine as adjuvant therapy for stage III colon cancer in a clinical trial, 11% discontinued treatment because of adverse effects and 0.8% died during the study or within 28 days of receiving the study drug.

GI Effects

Diarrhea, a dose-limiting and common adverse effect of capecitabine, occurs in 55-67% of patients receiving the drug for metastatic breast cancer or metastatic colorectal cancer, and is severe or life-threatening in 15% of patients. Nausea and vomiting occur in 43-53% and 27-37%, respectively, of patients receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer. Among patients with metastatic breast cancer who developed severe nausea and/or vomiting associated with capecitabine monotherapy, onset of these adverse GI effects was early, usually occurring during the first month of treatment.

Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, diarrhea occurred in 47% of patients and was severe or life-threatening (grade 3 or 4) in 12%; nausea occurred in 34%, and vomiting in 15%, of patients.

Severe adverse GI effects associated with capecitabine may occur more frequently in geriatric patients. Among 21 patients aged 80 years or older receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials, severe or life-threatening (grade 3 or 4) diarrhea, nausea, or vomiting occurred in 29, 14, or 10%, respectively. Among 10 patients aged 70-80 years receiving capecitabine in combination with docetaxel for metastatic breast cancer, grade 3 or 4 diarrhea and stomatitis each occurred in 30%.

The median time to onset of grade 2 to 4 diarrhea was 34 days (range: 1-369 days) following initiation of capecitabine therapy for metastatic breast cancer or metastatic colorectal cancer, and the median duration of grade 3 to 4 diarrhea was 5 days. According to NCIC toxicity criteria, grade 1 diarrhea is defined as an increase of 2-3 stools daily; grade 2 diarrhea, an increase of 4-6 stools daily or nocturnal stools; grade 3 diarrhea, an increase of 7-9 stools daily or incontinence and malabsorption; and grade 4 diarrhea, an increase of 10 or more stools daily, grossly bloody diarrhea, or the need for parenteral support. If grade 2, 3, or 4 diarrhea occurs, administration of capecitabine should be discontinued immediately until the diarrhea resolves or decreases in intensity to grade 1. The manufacturer recommends use of standard antidiarrheal therapy (e.g., loperamide) in patients experiencing diarrhea. Patients with severe diarrhea should be closely monitored and given fluid and electrolyte replacement for dehydration as indicated. Subsequent doses of capecitabine should be decreased in patients who have experienced grade 3 or 4 diarrhea or recurring episodes of grade 2 diarrhea.(See table on Recommended Dosage Modifications for Toxicity of Capecitabine in Dosage and Administration: Dosage.)

Abdominal pain has been reported in 20-35% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer or capecitabine and docetaxel for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, abdominal pain occurred in 14%, and upper abdominal pain in 7%, of patients. Stomatitis has occurred in about 25% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer; a higher incidence of stomatitis (67%), including severe or life-threatening stomatitis (approximately 20%), was reported in patients receiving capecitabine and docetaxel for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, stomatitis occurred in 22% of patients. Constipation has been reported in 14-20% of patients receiving the drug for metastatic breast cancer or metastatic colorectal cancer and in 9% of patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer. Among patients receiving capecitabine for metastatic colorectal cancer, GI motility disorder or oral discomfort each occurred in 10%, upper GI inflammatory disorders in 8%, and GI hemorrhage in 6%. Taste disturbance, which was reported in 6% of patients receiving capecitabine alone for metastatic colorectal cancer, occurred in about 15% of patients receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer.

Among patients receiving capecitabine for metastatic breast cancer, dyspepsia was reported in 8-14% of those receiving the drug alone or in combination therapy; dry mouth was reported in 6% of those receiving the drug in combination therapy. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, dyspepsia occurred in 6% of patients.

Adverse GI effects occurring in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials include abdominal distention, dysphagia, proctalgia, ascites, gastric ulcer, ileus, toxic dilation of the intestine, and gastroenteritis. Ileus, necrotizing enterocolitis, esophageal ulcer, and hemorrhagic diarrhea have been reported in less than 5% of patients receiving capecitabine and docetaxel for metastatic breast cancer; intestinal obstruction, rectal bleeding, esophagitis, gastritis, colitis, duodenitis, and hematemesis also have been reported in patients receiving capecitabine.

Hematologic Effects and Infectious Complications

Among those receiving capecitabine as a single agent or in combination therapy for metastatic breast cancer, lymphopenia is a common adverse effect, occurring in 94-99% of patients; grade 3 or grade 4 lymphopenia has been reported in approximately 60-90% of such patients. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, grade 3 or 4 decreased lymphocyte concentrations occurred in 13% of patients. Leukopenia, which was reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer, occurred in about 90% of patients receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer and was often severe or life-threatening. Thrombocytopenia has been reported in 41% of patients receiving capecitabine and docetaxel for metastatic breast cancer, and in 24% of patients receiving capecitabine alone, for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, grade 3 or 4 decreased platelet concentrations occurred in 1% of patients.

Anemia occurred in 72-80% of patients receiving capecitabine alone for metastatic breast cancer or metastatic colorectal cancer. Anemia occurred in 80% of patients receiving capecitabine and docetaxel for metastatic breast cancer and was severe or life-threatening in 10%. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, grade 3 or 4 decreased hemoglobin concentrations occurred in 1% of patients.

Neutropenia has been reported in 13-26% of patients receiving capecitabine as a single agent for metastatic breast cancer or metastatic colorectal cancer; neutropenia/granulocytopenia, often severe or life-threatening, occurred frequently in patients receiving either capecitabine and docetaxel (86%) or docetaxel alone (87%) for metastatic breast cancer. Severe or life-threatening neutropenic fever was reported in 16% of patients receiving capecitabine and docetaxel and in 21% of patients receiving docetaxel alone for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, neutropenia occurred in 2% of patients.

Adverse hematologic effects reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials include hemorrhage, coagulation disorder, idiopathic thrombocytopenic purpura, pancytopenia, and bone marrow depression. Agranulocytosis and decreased prothrombin time have been reported in less than 5% of patients receiving capecitabine and docetaxel for metastatic breast cancer.

Oral candidiasis (7%) or urinary tract infection (6%) occurred in patients receiving capecitabine and docetaxel for metastatic breast cancer; similar rates of such infections were observed in patients receiving docetaxel alone. Urinary tract infection also has been reported in patients receiving capecitabine as a single agent. Unspecified viral infection occurred in 5% of patients receiving capecitabine monotherapy for metastatic colorectal cancer. Infectious complications reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials include sepsis, gastroenteritis, bronchitis, pneumonia, bronchopneumonia, laryngitis, keratoconjunctivitis, influenza-like illness, and fungal infections (including candidiasis). Upper respiratory tract infection has been reported in patients receiving capecitabine as a single agent or in combination with docetaxel; neutropenic sepsis also has been reported in patients receiving capecitabine and docetaxel for metastatic breast cancer.

Dermatologic and Sensitivity Reactions

Palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema (commonly referred to as hand-foot syndrome) is a cutaneous toxicity ranging in severity from grade 1 to grade 3 that occurs in 54-63% of patients receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer and is severe (grade 3) in 11-24% of patients. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, hand-foot syndrome occurred in 60% of patients and was severe (grade 3 or 4) in 17% of patients. Grade 1 hand-foot syndrome is defined as numbness, dysesthesia/paresthesia, tingling, painless swelling, and/or erythema of the hands and/or feet that causes discomfort but does not disrupt the patient's normal activities of daily living; grade 2 hand-foot syndrome is defined as painful erythema and swelling of the hands and/or feet that results in discomfort affecting the patient's activities of daily living; grade 3 hand-foot syndrome is defined as moist desquamation, ulceration, blistering, or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. The median time to onset of hand-foot syndrome was 79 days (range: 11-360 days) in patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials.

Severe adverse dermatologic effects associated with capecitabine may occur more frequently in geriatric patients. Among 21 patients aged 80 years or older receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer in clinical trials, severe (grade 3) hand-foot syndrome occurred in 14%. Among 10 patients aged 70-80 years receiving capecitabine in combination with docetaxel for metastatic breast cancer, grade 3 hand-foot syndrome occurred in 40%.

If grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine should be interrupted until manifestations resolve or decrease in intensity to grade 1. Subsequent doses of capecitabine should be decreased in patients experiencing grade 3 hand-foot syndrome or recurring episodes of grade 2 hand-foot syndrome.(See table on Recommended Dosage Modifications for Toxicity of Capecitabine in Dosage and Administration: Dosage.) In addition to dose interruption and subsequent dose reductions, topical emollients (e.g., hand creams, udder balm) or oral pyridoxine therapy may ameliorate the manifestations of hand-foot syndrome in patients receiving capecitabine.

Severe, sometimes fatal, mucocutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis also can occur in patients receiving capecitabine. If such reactions occur and are potentially related to capecitabine, therapy with the drug should be permanently discontinued.

Capecitabine-induced dermatitis has been reported in 27-37% of patients receiving the drug alone for metastatic breast cancer or metastatic colorectal cancer and in 8% of patients receiving capecitabine and docetaxel for metastatic breast cancer. Alopecia, which was reported in 6% of patients receiving capecitabine alone for metastatic colorectal cancer or as adjuvant therapy for stage III colon cancer, occurred in about 40% of those receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer. Skin discoloration was reported in 7% of patients receiving capecitabine for metastatic colorectal cancer. Nail disorder, which was reported in less than 5% of patients receiving capecitabine alone for metastatic breast cancer or metastatic colorectal cancer, occurred in about 15% of patients receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer. Erythematous rash, nail discoloration, and onycholysis have been reported in 9, 6, and 5%, respectively, of patients receiving capecitabine and docetaxel for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, rash occurred in 7%, and erythema in 6%, of patients. Adverse dermatologic effects reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials include increased sweating, photosensitivity, skin ulceration, pruritus, and radiation recall syndrome.

Hypersensitivity reactions, including bronchospasm, have been reported in patients receiving capecitabine.

Nervous System Effects

Fatigue/weakness has been reported in about 40% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer and 16-22% of those receiving capecitabine and docetaxel for metastatic breast cancer in clinical trials. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, fatigue occurred in 16%, and lethargy in 10%, of patients. Asthenia was reported in about 25% of patients receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer and in 10% of patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer. The incidence of pain was higher in the subset of patients receiving capecitabine for metastatic colorectal cancer than in the overall database of patients receiving capecitabine monotherapy for metastatic colorectal cancer or metastatic breast cancer (12% versus less than 5%).

Paresthesia occurred in 12-21% of patients receiving capecitabine alone or in combination with docetaxel for metastatic breast cancer. Headache was reported in 9-15% of patients receiving capecitabine alone for metastatic breast cancer or metastatic colorectal cancer or in combination with docetaxel for metastatic breast cancer. Dizziness occurred in approximately 10% of patients receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer in clinical trials. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, dizziness occurred in 6%, dysgeusia in 6%, and headache in 5%, of patients. Peripheral neuropathy has occurred in patients receiving capecitabine as a single agent for metastatic colorectal cancer (10%) and in patients receiving capecitabine and docetaxel for metastatic breast cancer (6%). Mood alteration was reported in 5% of patients receiving capecitabine for metastatic colorectal cancer.

Insomnia, ataxia, tremor, dysphasia, encephalopathy, abnormal coordination, dysarthria, loss of consciousness, vertigo, impaired balance, irritability, sedation, mental depression, and confusion have been reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials. Depressed level of consciousness and syncope also have been reported in patients receiving capecitabine. Hypoesthesia, ataxia, syncope, taste loss, polyneuropathy, and migraine headache have been reported in less than 5% of patients receiving capecitabine and docetaxel for metastatic breast cancer. Lethargy also has been reported in patients receiving combined therapy with the drugs.

Hepatic Effects

Adverse hepatobiliary effects associated with capecitabine include elevations in serum concentrations of bilirubin, alkaline phosphatase, and hepatic aminotransferases (i.e., AST and/or ALT).

Hyperbilirubinemia was reported in 48% of patients receiving capecitabine as a single agent for metastatic colorectal cancer, and was severe or life-threatening in 18 or 5%, respectively. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, grade 3 or 4 hyperbilirubinemia occurred in 20% of patients. Hyperbilirubinemia occurred in about 20% of patients receiving capecitabine alone or in combination with docetaxel for metastatic breast cancer, and was severe or life-threatening in about 8 or 2%, respectively. According to the overall database of 875 patients with metastatic colorectal cancer or metastatic breast cancer receiving at least one twice-daily dose of capecitabine, severe (grade 3) or life-threatening (grade 4) hyperbilirubinemia occurred in 15 or 4%, respectively. In patients with metastatic colorectal cancer, the median time to onset of grade 3 or 4 hyperbilirubinemia was 64 days, and the median total serum bilirubin concentration increased from 8 mcm/L at baseline to 13 mcm/L during capecitabine therapy.

According to NCIC version 1 toxicity criteria, grade 2 hyperbilirubinemia is defined as an elevated serum bilirubin concentration of up to 1.5 times the normal value; grade 3 hyperbilirubinemia, 1.5-3 times the normal value; and grade 4 hyperbilirubinemia, greater than 3 times the normal value. If grade 2, 3, or 4 elevations in serum bilirubin concentration occur, administration of capecitabine should be discontinued until the hyperbilirubinemia resolves or decreases in intensity to grade 1.

Severe or life-threatening hyperbilirubinemia associated with capecitabine therapy occurs more frequently in patients with hepatic metastases; among 566 patients with hepatic metastases and 309 patients without hepatic metastases at baseline of a total of 875 patients with metastatic breast cancer or metastatic colorectal cancer, hyperbilirubinemia (grade 3 or 4) occurred in 23 and 12%, respectively. Liver function should be monitored carefully during capecitabine therapy in patients with mild to moderate hepatic impairment secondary to liver metastases.

Among patients with metastatic breast cancer or metastatic colorectal cancer who had grade 3 or 4 hyperbilirubinemia, both prebaseline and postbaseline elevations in serum concentrations of alkaline phosphatase or hepatic aminotransferase occurred in 58 or 35%, respectively. Among patients with metastatic breast cancer or metastatic colorectal cancer who had grade 3 or 4 hyperbilirubinemia, postbaseline only (but not necessarily concurrent) elevations in alkaline phosphatase or hepatic aminotransferase concentrations occurred in 19 or 28% and were severe/life-threatening in 8 or 3%, respectively; a majority of these patients had hepatic metastases.

Hepatic failure, hepatic fibrosis, cholestatic hepatitis, hepatitis, and abnormal liver function test results have been reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials. Jaundice, abnormal liver function test results, hepatic failure, hepatic coma, and hepatotoxicity have been reported in less than 5% of patients receiving capecitabine and docetaxel for metastatic breast cancer.

Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, grade 3 or 4 increased serum ALT concentrations occurred in 1.6% of patients.

Cardiovascular Effects

Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy have occurred in patients receiving capecitabine. The incidence of these adverse cardiovascular effects may be increased in patients with a history of coronary artery disease.

The incidence of edema was higher in the subsets of patients receiving capecitabine as a single agent for metastatic colorectal cancer (15%) or metastatic breast cancer (9%) than in the overall database of patients receiving capecitabine monotherapy for metastatic colorectal cancer or metastatic breast cancer (less than 5%); edema was reported in about 35% of those receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer. Venous thrombosis was reported in 8% of patients receiving capecitabine monotherapy for metastatic colorectal cancer. Other adverse cardiovascular effects, including tachycardia, bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis, pericardial effusion, hypotension, hypertension, lymphedema, pulmonary embolism, hot flushes, and cerebrovascular accident, have been reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials. Supraventricular tachycardia, venous phlebitis and thrombophlebitis, and postural hypotension have been reported in less than 5% of patients receiving capecitabine and docetaxel for metastatic breast cancer; flushing also has been reported in patients receiving combined therapy with the drugs. Deep-vein thrombosis also has been reported in patients receiving capecitabine.

Metabolic Effects

Decreased appetite was reported in 26% of patients receiving capecitabine alone for metastatic colorectal cancer and in 10% of patients receiving capecitabine and docetaxel for metastatic breast cancer. Anorexia occurred in 13-23% of patients receiving capecitabine alone or in combination with docetaxel for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, anorexia occurred in 9% of patients. Dehydration was reported in 7-10% of patients receiving capecitabine alone for metastatic breast cancer or metastatic colorectal cancer or in combination with docetaxel for metastatic breast cancer. Decreased weight occurred in 7% of patients receiving capecitabine and docetaxel for metastatic breast cancer. Increased weight, cachexia, hypertriglyceridemia, hypokalemia, and hypomagnesemia occurred in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials.

Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea. Acute renal failure secondary to dehydration, which can be fatal, can occur; patients with preexisting renal impairment and those receiving concomitant therapy with nephrotoxic agents are at increased risk. Dehydration should be corrected at its onset. In patients with grade 2 or greater dehydration, capecitabine therapy should interrupted immediately, and treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled; any necessary dosage modifications for the precipitating adverse event should be made.(See Dosage Modification for Toxicity under Dosage: Other Dosage Considerations, in Dosage and Administration.)

Ocular Effects

Ocular irritation occurred in 5-15% of patients receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer. Abnormal vision occurred in 5% of patients receiving capecitabine monotherapy for metastatic colorectal cancer. Severe ocular irritation and corneal deposits were reported in 2 patients with a history of keratoconjunctivitis sicca who received higher doses of capecitabine for metastatic breast cancer or metastatic colon cancer. Ophthalmic examination is recommended for patients receiving capecitabine who experience severe ocular symptoms or decreased visual acuity. Increased lacrimation was reported in 12% of patients receiving capecitabine and docetaxel and in 7% of those receiving docetaxel alone for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, conjunctivitis occurred in 5% of patients. Conjunctivitis and lacrimal duct stenosis each occurred in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials.

Musculoskeletal Effects

Back pain was reported in 10-12% and arthralgia was reported in 8-15% of patients receiving capecitabine as a single agent for metastatic colorectal cancer or in combination with docetaxel for metastatic breast cancer. The incidence of myalgia was higher in the subset of patients receiving capecitabine as a single agent for metastatic breast cancer (9%) than in the overall database of patients receiving capecitabine monotherapy for metastatic colorectal cancer or metastatic breast cancer (less than 5%); myalgia was reported in 15% of those receiving capecitabine and docetaxel, and in 25% of those receiving docetaxel alone, for metastatic breast cancer. Limb pain has been reported in 6-13% of patients receiving capecitabine alone or in combination with docetaxel for metastatic breast cancer. Adverse musculoskeletal effects reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials include bone pain, arthritis, and muscle weakness. Joint stiffness also has been reported in patients receiving capecitabine.

Respiratory Effects

The incidence of dyspnea was higher in the subset of patients receiving capecitabine as a single agent for metastatic colorectal cancer (14%) than in the overall database of patients receiving capecitabine monotherapy for metastatic colorectal cancer or metastatic breast cancer (less than 5%); dyspnea was reported in about 15% of those receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer. Cough was reported in 13% of patients receiving capecitabine and docetaxel for metastatic breast cancer and in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer. Sore throat was reported in 11-12% of patients receiving either capecitabine and docetaxel or docetaxel alone for metastatic breast cancer and in 2% of patients receiving capecitabine as a single agent for metastatic colorectal cancer. Other reported adverse respiratory effects include pharyngeal disorder (5%) in patients receiving capecitabine for metastatic colorectal cancer, and rhinorrhea (5%) and pleural effusion (2%) in patients receiving capecitabine and docetaxel for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, epistaxis occurred in 2% of patients. Epistaxis, asthma, hemoptysis, and respiratory distress each has been reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials. Bronchospasm also has been reported in patients receiving capecitabine as a single agent.

Renal Effects

Renal impairment has been reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials. Renal failure has been reported in less than 5% of patients receiving capecitabine and docetaxel for metastatic breast cancer. Nocturia also has been reported in patients receiving capecitabine.

Electrolyte Effects

Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, grade 3 or 4 decreased serum calcium concentrations occurred in about 2% of patients, and grade 3 or 4 increased serum calcium concentrations occurred in approximately 1% of patients.

Other Adverse Effects

Pyrexia (fever) occurred in 12-18% of patients receiving capecitabine alone for metastatic breast cancer or metastatic colorectal cancer and in 28% of patients receiving capecitabine and docetaxel for metastatic breast cancer. Among patients receiving capecitabine alone as adjuvant therapy for stage III colon cancer, pyrexia occurred in 7% of patients. Other adverse effects, including chest pain, hoarseness, difficulty in walking, thirst, chest mass, collapse, fibrosis, and drug hypersensitivity, have been reported in less than 5% of patients receiving capecitabine monotherapy for metastatic breast cancer or metastatic colorectal cancer in clinical trials.

Precautions and Contraindications

Capecitabine should be used under the supervision of a qualified clinician experienced in therapy with cytotoxic agents.

Patients and their caregivers should be informed of the expected adverse effects of capecitabine, particularly nausea, vomiting, diarrhea, and hand-foot syndrome; in addition, patients should understand that dosage adjustments during therapy are expected and necessary. Patients also should be instructed to recognize the common toxicities associated with capecitabine therapy and know when to discontinue the drug depending on the severity of symptoms. Patients experiencing any of the following adverse effects of capecitabine at the severity described should immediately discontinue capecitabine therapy and promptly notify their clinician: nocturnal stools or an increase of 4-6 stools daily or greatersevere bloody diarrhea with severe abdominal pain and fevergrade 2 or greater dehydrationnausea with a substantial decrease in food intakefrequent vomiting (i.e., 2-5 or more episodes of vomiting in a 24-hour period)painful erythema and swelling of the hands and/or feet that results in discomfort affecting activities of daily livingpainful erythema, edema, or ulcers of the mouth or tongue

Symptomatic treatment of such adverse effects (e.g., with antidiarrheals or antiemetics) is recommended. Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should promptly notify their clinician.

Patients receiving capecitabine should be monitored to prevent and promptly correct dehydration, which can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea, and can result in acute renal failure; patients with preexisting renal impairment and those receiving concomitant therapy with nephrotoxic agents are at increased risk.

Geriatric patients, particularly those 80 years of age and older, may be at increased risk for severe or life-threatening adverse effects of capecitabine and should be monitored closely.(See Cautions: Geriatric Precautions.)

In patients with mild to moderate hepatic impairment secondary to hepatic metastases, capecitabine should be used with caution and liver function should be monitored carefully during therapy; use of the drug in patients with severe hepatic impairment has not been studied.

Because the incidence of adverse cardiovascular effects associated with fluorinated pyrimidines (e.g., myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes) may be increased in patients with a history of coronary artery disease, such patients should be monitored carefully during capecitabine therapy (e.g., ECG for patients experiencing chest pain).

Patients who develop severe ocular symptoms or decreased visual acuity while receiving capecitabine should undergo ophthalmologic examination.

If capecitabine is used in patients receiving a coumarin-derivative anticoagulant, prothrombin time (PT) or international normalized ratio (INR) should be monitored frequently, and adjustment of the anticoagulant dose should be made accordingly.(See Drug Interactions: Anticoagulants.)

If capecitabine is used in patients receiving phenytoin, serum phenytoin concentrations must be monitored carefully, and reduction in the phenytoin dosage may be necessary.(See Drug Interactions: Phenytoin.)

In patients with moderate renal impairment (i.e., creatinine clearance 30-50 mL/minute calculated with the formula of Cockroft-Gault) at baseline, dosage reduction for capecitabine is required.(See: Dosage in Renal and Hepatic Impairment.) In patients with mild or moderate renal impairment receiving capecitabine, careful monitoring is necessary; prompt interruption of treatment is recommended if the patient develops a grade 2, 3, or 4 adverse effect, and subsequent dose adjustments should be made accordingly.(See table on Recommended Dosage Modifications for Toxicity of Capecitabine in Dosage and Administration: Dosage.).

Capecitabine is contraindicated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/min calculated with the formula of Cockroft-Gault).

Capecitabine should be withheld or permanently discontinued in patients experiencing acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dihydropyrimidine dehydrogenase (DPD) activity. Patients with certain homozygous or certain compound heterozygous mutations in the DPD gene resulting in complete or near complete absence of DPD activity are at increased risk for acute early-onset toxicity and severe, life-threatening, or fatal toxicity (e.g., mucositis, diarrhea, neutropenia, neurotoxicity); patients with partial DPD activity also may be at increased risk for severe, life-threatening, or fatal toxicity. No dosage of capecitabine has been proven safe for patients with complete absence of DPD activity, and there are insufficient data to support dosage recommendations for those with partial DPD activity. Patients should be advised to inform their clinician if they are known to have deficient DPD activity.

The use of capecitabine in combination with irinotecan has not been adequately studied.

Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine (including any component of the commercially available tablets) or fluorouracil.

Pediatric Precautions

The manufacturer states that safety and efficacy of capecitabine in children younger than 18 years of age have not been established.

Geriatric Precautions

Although the safety and efficacy of capecitabine in geriatric patients have not been specifically studied to date, the manufacturer reports that elderly individuals may experience increased frequency and severity of the toxic effects of capecitabine and its metabolites. Among 21 patients aged 80 years or older receiving capecitabine for metastatic breast cancer or metastatic colorectal cancer in clinical trials, 62% experienced a grade 3 or 4 adverse effect. In particular, severe adverse GI effects (grade 3 or 4 diarrhea, nausea, or vomiting) or severe hand-foot syndrome associated with capecitabine may occur more frequently in such patients.(See Cautions: GI Effects.)(See Cautions: Dermatologic and Sensitivity Reactions.) Among 67 patients aged 60 years or older receiving capecitabine in combination with docetaxel for metastatic breast cancer, a higher incidence of grade 3 or 4 adverse effects, serious adverse effects, withdrawals due to adverse effects, treatment discontinuations due to adverse effects, and treatment discontinuations within the first 2 treatment cycles was reported than in those less than 60 years of age.

Among 398 patients aged 65 years or older receiving capecitabine as adjuvant therapy for stage III colon cancer, 41% experienced a grade 3 or 4 adverse effect. Geriatric patients appeared to have similar or slightly higher rates of severe adverse effects, such as hand-foot syndrome, diarrhea, stomatitis, neutropenia/granulocytopenia, vomiting, and nausea, compared with the total patient population in this clinical trial. The hazard ratio for disease recurrence for capecitabine versus fluorouracil/leucovorin in patients 65 years of age or older was 1.01 compared with 0.87 for the total patient population.

According to the manufacturer, insufficient data are available to recommend adjustment of capecitabine dosage for age in geriatric patients; however, the greater frequency of decreased hepatic and/or renal function in the elderly should be considered, and some experts recommend dosage reduction for geriatric patients.(See Dosage Modification for Age-related Effects, under Dosage: Breast Cancer.) Geriatric patients should be monitored closely for the occurrence of capecitabine-induced adverse effects.

Mutagenicity and Carcinogenicity

Capecitabine was clastogenic to human peripheral blood lymphocytes in vitro but was not clastogenic to mouse bone marrow (micronucleus test) in vivo. Capecitabine was not mutagenic in the Ames test or the Chinese hamster V79/HPRT gene mutation assay. Fluorouracil, the biologically active form of capecitabine, has been shown to be mutagenic in some bacteria and yeast. Fluorouracil also causes chromosomal aberrations in the micronucleus test in mice in vivo.

Adequate studies evaluating the carcinogenic potential of capecitabine have not been performed to date.

Pregnancy, Fertility, and Lactation

Pregnancy

Capecitabine may cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.

Capecitabine has been shown to be embryotoxic and teratogenic in animal studies. Fetal death was observed in monkeys receiving capecitabine 90 mg/kg daily (a dosage producing an AUC value for capecitabine metabolite 5'-deoxy-5-fluorouridine [5'-DFUR] in monkeys about 0.6 times the corresponding value in humans receiving the recommended daily dosage) during organogenesis. Embryocidal and teratogenic effects, including cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles, were observed in the offspring of mice receiving capecitabine doses of 198 mg/kg daily (a dosage producing an AUC value for capecitabine metabolite 5'-DFUR in mice about 0.2 times the corresponding value in humans receiving the recommended daily dosage) during organogenesis. There are no adequate and well-controlled studies using capecitabine in pregnant women.

Capecitabine should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. If the drug is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with capecitabine.

Fertility

In reproduction studies in mice, oral capecitabine dosages of 760 mg/kg daily (a dosage producing an AUC value for capecitabine metabolite 5'-DFUR in mice about 0.7 times the corresponding value in humans receiving the recommended daily dosage) caused a reversible disturbance in estrus and a consequent decrease in fertility; no fetuses survived in mice that became pregnant. Administration of the same dosage of capecitabine to male mice resulted in degenerative changes in the testes, including a decrease in the number of spermatocytes and spermatids.

Lactation

In lactating mice receiving a single dose of capecitabine, significant amounts of capecitabine metabolites were distributed into milk. Because of the potential for serious adverse reactions to capecitabine in nursing infants, nursing should be discontinued during capecitabine therapy.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Capecitabine and/or its metabolites inhibit the metabolism of warfarin, probably through inhibition of the cytochrome P-450 (CYP) 2C9 isoenzyme.(See Drug Interactions: Anticoagulants.) No formal drug-drug interaction studies between capecitabine and CYP2C9 substrates other than warfarin have been performed. Caution is advised when capecitabine is administered concomitantly with other CYP2C9 substrates (e.g., phenytoin) (see Drug Interactions: Phenytoin), and the need for dosage adjustment should be considered.

Results of in vitro studies indicate that capecitabine and its metabolites do not inhibit the metabolism of substrates of the major cytochrome P-450 isoenzymes.

Antacids

In a small number of patients, administration of an antacid containing aluminum hydroxide and magnesium hydroxide (Maalox, 20 mL) immediately following capecitabine (1250 mg/m) resulted in an increased rate and extent of absorption of capecitabine; AUC and peak plasma concentration increased by 16 and 35%, respectively, for capecitabine and by 18 and 22%, respectively, for 5'-deoxy-5-fluorocytidine (5'-DFCR). Antacid administration had no effect on the other 3 major metabolites of capecitabine (i.e., 5'-deoxy-5-fluorouridine [5'-DFUR], fluorouracil, and α-fluoro-β-alanine [FBAL]).

Some experts state that the effects of concomitant administration of capecitabine with an antacid containing aluminum hydroxide and magnesium hydroxide are not clinically important, and adjustments in the dosage or timing of capecitabine are not necessary. In a clinical study of patients receiving capecitabine for metastatic breast cancer, administration of antacids was delayed for at least 2 hours following induction of capecitabine therapy.

Anticoagulants

Altered coagulation parameters and/or bleeding, sometimes fatal, have been reported in patients receiving capecitabine and concomitant therapy with coumarin anticoagulants (e.g., warfarin, phenprocoumon). In patients receiving coumarin anticoagulants, altered coagulation parameters (e.g., increased prothrombin time, increased international normalized ratio) and/or bleeding episodes have occurred within several days to months following initiation of capecitabine therapy; similar events have been reported in at least a few patients within 1 month following discontinuance of capecitabine therapy. Alterations in anticoagulant effect associated with capecitabine therapy have been reported in patients with or without liver metastases. Age exceeding 60 years and diagnosis of cancer are independent variables predisposing patients to an increased risk of coagulopathy.

In 4 patients receiving chronic administration of capecitabine 1250 mg/m twice daily with a single dose of warfarin 20 mg, the mean area under the concentration-time curve (AUC) of S-warfarin was increased by 57% and clearance was decreased by 37%. The baseline corrected AUC of INR in these patients increased by 2.8-fold, and the maximum observed mean INR increased by 91%. The mechanism for this interaction probably involves inhibition of cytochrome P-450 (CYP) 2C9 isoenzyme by capecitabine and/or its metabolites. Because the decreased rate of anticoagulant metabolism may increase patient response to coumarin and indandione derivatives, capecitabine and these agents should be used concomitantly with great caution. If capecitabine is used concomitantly with a coumarin anticoagulant, prothrombin time (PT) or international normalized ratio (INR) should be monitored frequently, and the anticoagulant dose should be adjusted accordingly.

Phenytoin

Concomitant use of phenytoin and capecitabine may result in toxicity from increased serum phenytoin concentrations. The mechanism of interaction is presumed to be inhibition of the metabolism of phenytoin by capecitabine and/or its metabolites through inhibition of the cytochrome P-450 (CYP) 2C9 isoenzyme. In patients receiving capecitabine, serum concentrations of phenytoin must be monitored carefully, and reduction in the phenytoin dosage may be necessary.

Leucovorin

Leucovorin potentiates the antineoplastic activity of fluorouracil (the active drug of capecitabine) and also may increase its toxicity. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving a weekly regimen of combination therapy with leucovorin and fluorouracil.

Leucovorin potentiated the antitumor activity of capecitabine in some xenograft tumors in mice but did not increase the toxicity of the drug; however, evidence from an open-label, randomized trial in patients with advanced colorectal cancer demonstrated comparable efficacy but greater toxicity for combination therapy with capecitabine and leucovorin compared with capecitabine alone.

Food

Food decreases the rate and extent of absorption of capecitabine.(See Pharmacokinetics: Absorption.) Administration with food causes decreases in peak plasma concentration and AUC and an increase in time to peak plasma concentration for capecitabine and its metabolites. According to data in 11 adult cancer patients, the magnitude of the effect of food on the pharmacokinetic parameters was most pronounced for capecitabine and decreased with the order of formation of its metabolites. Because food had only a minor effect on the AUC of the major metabolites of capecitabine, the investigators concluded that the effect of food on the pharmacokinetics of capecitabine probably is not clinically important. However, because current safety and efficacy data are based on administration with food (i.e., within 30 minutes following a meal), it is recommended that capecitabine be administered with food.

Pharmacokinetics

The pharmacokinetic behavior of capecitabine may be influenced by race or age. Limited evidence from population analysis of pooled data from 2 large controlled studies in 505 patients (303 males, 202 females; 455 white, 22 black, 28 other race) receiving capecitabine 1250 mg/m twice daily for metastatic colorectal cancer does not reveal any influence of gender or race on the pharmacokinetics of the intermediate metabolite of capecitabine, 5'-deoxy-5-fluorouridine (5'-DFUR), the active drug fluorouracil, or its catabolite, α-fluoro-β-alanine (FBAL). However, data from a study in 18 Japanese patients and 22 white patients receiving capecitabine 825 mg/m twice daily for 14 days shows differences in the pharmacokinetic disposition of capecitabine and its catabolite, FBAL. Peak plasma concentration and the area under the concentration-time curve (AUC) of capecitabine were reduced by about 36 and 24%, respectively, and peak plasma concentration and AUC of FBAL were about 25 and 34% lower, respectively, in the Japanese patients than in the white patients. The clinical importance of these differences is not known. Among patients aged 27 to 86 years, age does not appear to affect the pharmacokinetic disposition of 5'-DFUR or fluorouracil, but a 20% increase in age is associated with a 15% increase in the AUC of FBAL.

The following discussion of the pharmacokinetics of capecitabine and its metabolites is based on data from approximately 200 cancer patients receiving the drug at dosages of 500-3514 mg/mdaily.

Absorption

Capecitabine is readily absorbed from the GI tract; on average, at least 70% of an oral dose of the drug is absorbed. Although in vitro studies have shown that capecitabine is unstable under highly acidic conditions, the drug appears to be absorbed intact immediately upon dissolution without degradation secondary to the acidic pH of the stomach. According to the manufacturer, peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil, its active drug, occur slightly later at 2 hours. In adults with cancer who received a capecitabine dosage of 2510 mg/m daily in 2 divided doses, administered approximately 12 hours apart within 30 minutes following the end of a meal, blood samples drawn on day 1 of the treatment cycle showed that peak plasma concentrations of 3.93 and 0.66 mcg/mL for capecitabine and fluorouracil, respectively, were achieved in about 2 hours. Considerable interindividual variations (i.e., exceeding 85%) in peak plasma concentrations and areas under the concentration-time curves (AUCs) have been reported following oral administration of capecitabine.

Presence of food in the GI tract decreases the rate and extent of absorption of capecitabine and, to a lesser extent, decreases the peak plasma concentration and AUC of its metabolites. Peak plasma concentrations and AUC were decreased by 60 and 35%, respectively, for capecitabine and by 43 and 21%, respectively, for fluorouracil when the drug was administered with food. Times to peak plasma concentration for both capecitabine and fluorouracil were delayed by 1.5 hours when capecitabine was administered with food.(See Drug Interactions: Food.)

Over a dosage range of 500-3500 mg/m daily, the pharmacokinetics of capecitabine and its metabolite, 5'-deoxy-5-fluorocytidine (5'-DFCR), were dose proportional and did not change over time. However, the manufacturer reports that increases in AUCs of metabolites 5'-deoxy-5-fluorouridine (5'-DFUR) and fluorouracil were greater than proportional to the increase in dose, and the AUC of fluorouracil was 34% higher on day 14 than on day 1. In one study of adults with cancer at a capecitabine dosage of 2510 mg/m daily, no change was observed in the pharmacokinetics of capecitabine metabolite 5'-DFUR over time, but concentrations of fluorouracil were 22% higher on day 14 than on day 1.

Distribution

Distribution of capecitabine and its metabolites into body tissues and fluids has not been fully characterized. Capecitabine or its metabolites are distributed into tumors, intestinal mucosa, plasma, liver, and other tissues. Animal studies show that capecitabine and its metabolites do not readily penetrate the blood-brain barrier; it is not known whether capecitabine or its metabolites distribute into CSF and brain tissue in humans.

Studies in animals and humans receiving capecitabine have shown a higher concentration of fluorouracil, its active drug, in tumor than in surrounding normal tissue, plasma, or muscle. In patients with colorectal cancer receiving capecitabine for 5-7 days prior to surgery, the median ratio of fluorouracil concentration in colorectal tumors to adjacent tissues was 2.9 (range: 0.9-8), and the median ratio of fluorouracil concentration in tumor to plasma was 16.6. The relative concentration of fluorouracil in tumor to that in normal tissues or plasma has not been evaluated in patients with breast cancer receiving oral capecitabine or in patients receiving fluorouracil by IV infusion. In studies of human colon cancer xenografts, higher concentrations of fluorouracil in tumor were observed in mice receiving oral capecitabine than in those receiving IV fluorouracil. Whereas fluorouracil concentrations were higher in tumor than in plasma or muscle in mice receiving oral capecitabine, similar fluorouracil concentrations in tumor, plasma, or muscle were observed in mice receiving IV fluorouracil.

Plasma protein binding (mainly to albumin) of capecitabine and its metabolites is less than 60% and is not concentration dependent.

It is not known whether capecitabine or its metabolites cross the placenta. It is not known whether capecitabine or its metabolites are distributed into milk.

Elimination

Capecitabine is extensively metabolized in the liver and tumors. The plasma elimination half-life of capecitabine and its metabolites, including the active drug, fluorouracil, is about 45-60 minutes, except for α-fluoro-β-alanine (FBAL), a catabolite of fluorouracil, which has an initial half-life of about 3 hours.

Because it is designed to be converted to the active drug fluorouracil preferentially in tumor tissue, capecitabine is described as a tumor-activated, tumor-selective antineoplastic agent. Capecitabine and its intermediate metabolites have minimal cytotoxic activity. In the liver, capecitabine is largely hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase, an enzyme almost exclusively located in the liver and hepatoma. 5'-DFCR subsequently is converted to another noncytotoxic intermediate, 5'-deoxy-5-fluorouridine (5'-DFUR), by cytidine deaminase, an enzyme found in most tissues but with high concentrations in the liver and various solid tumors. Hydrolysis of 5'-DFUR to the active drug fluorouracil is catalyzed by thymidine phosphorylase, an enzyme found in many body tissues that also is an angiogenic factor found in higher concentrations in tumor tissue. Once capecitabine is converted to the active drug fluorouracil mainly in tumor tissue, fluorouracil is anabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), the active metabolites of the drug.

Fluorouracil is catabolized to dihydrofluorouracil (FUH2), a much less toxic metabolite, by dihydropyrimidine dehydrogenase. Dihydropyrimidinase cleaves the pyrimidine ring of dihydrofluorouracil, yielding 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by β-ureido-propionase to form α-fluoro-β-alanine (FBAL). Capecitabine and its metabolites are excreted predominantly in urine (95.5%); fecal excretion is minimal (2.6%). Greater than 70% of a dose of capecitabine is excreted in urine within 24 hours. Most of the capecitabine dose is excreted in urine as metabolites, principally FBAL, a catabolite of fluorouracil (57% of an administered dose); about 3% of an administered dose is excreted in urine as unchanged drug.

The effect of renal impairment on the elimination of capecitabine has been evaluated in cancer patients. Renal impairment causes increased systemic exposure to capecitabine and its metabolites. Following oral administration of capecitabine 1250 mg/m twice daily, systemic exposure to FBAL on day 1 was 85% higher in patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) and 258% higher in patients with severe renal impairment (creatinine clearance <30 mL/min) than in patients with normal renal function (creatinine clearance >80 mL/min). Systemic exposure to 5'-DFUR was 42 and 71% greater in patients with moderate or severe renal impairment, respectively, than in those with normal renal function. Systemic exposure to capecitabine was about 25% greater in patients with moderate or severe renal impairment than in those with normal renal function.

The effect of hepatic impairment on the elimination of capecitabine has not been fully established. In a small number of patients with mild to moderate hepatic impairment secondary to liver metastases, nonsignificant increases in AUC and peak plasma concentration of capecitabine and fluorouracil were reported following a single dose of capecitabine 1255 mg/m. The effect of severe hepatic dysfunction on the pharmacokinetics of capecitabine and its metabolites has not been evaluated.

The effect of dialysis on the elimination of capecitabine has not been determined; however, the manufacturer reports that dialysis may reduce circulating concentrations of 5'-DFUR, a low molecular weight metabolite of the drug.

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