*Patients receiving concomitant capecitabine tablets and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use.
* Content
:*Occurrence: Within several days and up to several months after initiating capecitabine therapy; may also be seen within one month after stopping capecitabine tablets.
:*Predisposing factors: age > 60 and diagnosis of cancer.
<!--Adult Indications and Dosage-->
<!--Adult Indications and Dosage-->
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|fdaLIADAdult=
|fdaLIADAdult=
=====Colorectal Cancer=====
=====Condition1=====
*Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine in the adjuvant treatment of Dukes’ C colon cancer.
* Dosing Information
*Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with capecitabine monotherapy. Use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
:* Dosage
=====Breast Cancer=====
=====Condition2=====
*Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
* Dosing Information
*Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer 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 equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
:* Dosage
=====Standard Starting Dose=====
=====Condition3=====
*Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
* Dosing Information
:*The recommended dose of capecitabine is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3 week cycles (see Table 1).
:*Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months i.e., capecitabine 1250 mg/m2 orally twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles for a total of 8 cycles (24 weeks).
:* Dosage
=====Condition4=====
*In Combination With Docetaxel (Metastatic Breast Cancer)
* Dosing Information
:*In combination with docetaxel, the recommended dose of capecitabine is 1250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine tablets plus docetaxel combination. Table 1 displays the total daily dose of capecitabine by body surface area and the number of tablets to be taken at each dose.
=====Dose Management Guidelines=====
*General
:*Capecitabine dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. Toxicity due to capecitabine tablet administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine dose. Once the dose has been reduced, it should not be increased at a later time. Doses of capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
:*The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine tablets [see Drug Interactions (7.1)].
:*Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
:*Capecitabine dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.
:* Dosage
*In Combination with Docetaxel (Metastatic Breast Cancer)
:*Dose modifications of capecitabine tablets for toxicity should be made according to Table 2 above for capecitabine. At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
:*The dose reduction schedule for docetaxel when used in combination with capecitabine for the treatment of metastatic breast cancer is shown in Table 3.
=====Adjustment of Starting Dose in Special Populations=====
*Renal Impairment
:*No adjustment to the starting dose of capecitabine is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the capecitabine starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine monotherapy and capecitabine in combination use with docetaxel.
*Geriatrics
:*Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly. Insufficient data are available to provide a dosage recommendation.
<!--Off-Label Use and Dosage (Adult)-->
<!--Off-Label Use and Dosage (Adult)-->
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|contraindications=
|contraindications=
*Dihydropyrimidine Dehydrogenase (DPD) Deficiency
* Condition1
:*Capecitabine is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
*Severe Renal Impairment
:*Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min).
*Hypersensitivity
:*Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.
<!--Warnings-->
<!--Warnings-->
|warnings=
|warnings=
* Description
====Precautions====
====Precautions====
*Diarrhea
* Description
:*Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption and grade 4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased. Standard antidiarrheal treatments (e.g., loperamide) are recommended.
:*Necrotizing enterocolitis (typhlitis) has been reported.
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
*Coagulopathy
=====Endocrine=====
:*Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly.
*Cardiotoxicity
:*The cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
*Dihydropyrimidine Dehydrogenase Deficiency
:*Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.
*Renal Insufficiency
:*Patients with moderate renal impairment at baseline require dose reduction. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2.
*Pregnancy
=====Hematologic and Lymphatic=====
:*Capecitabine may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy or if a patient becomes pregnant while receiving capecitabine, the patient should be apprised of the potential hazard to the fetus.
*Hand-and-Foot Syndrome
:*Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-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. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine should be decreased.
*Hyperbilirubinemia
:*In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1 week rest period, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 3.9% (n = 34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n = 31) also had post-baseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n = 46) had post-baseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n = 20) and 71.7% (n = 33), had liver metastases at baseline. In addition, 57.5% (n = 96) and 35.3% (n = 59) of the 167 patients had elevations (grades 1 to 4) at both pre-baseline and post-baseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n = 13) and 3% (n = 5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
:*In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.
:*In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 2% (n = 5).
:*If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3 x ULN.
*Hematologic
:*In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1 week rest period, 3.2%, 1.7% and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia and 9.6% had grade 3 or 4 anemia.
:*Patients with baseline neutrophil counts of < 1.5 x 109/L and/or thrombocyte counts of < 100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted.
*Geriatric Patients
=====Metabolic and Nutritional=====
:*Patients ≥ 80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in six (28.6%), nausea in three (14.3%), hand-and-foot syndrome in three (14.3%) and vomiting in two (9.5%) patients. Among the ten patients 70 years of age and greater (no patients were > 80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.
:*Among the 67 patients ≥ 60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the < 60 years of age patient group.
:*In 995 patients receiving capecitabine as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥ 65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in six (1.5%) and nausea in five (1.3%) patients. In patients ≥ 65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine compared to 5-FU/LV were 1.01 (95% C.I. 0.80 to 1.27) and 1.04 (95% C.I. 0.79 to 1.37), respectively.
*Hepatic Insufficiency
:*Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known.
*Combination with Other Drugs
:*Use of capecitabine in combination with irinotecan has not been adequately studied.
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
=====Musculoskeletal=====
|clinicalTrials=
=====Neurologic=====
*Adjuvant Colon Cancer
:*Table 4 shows the adverse reactions occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1 week rest period and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1 to 5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1%) randomized to 5-FU/LV.
:*Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment.
=====Respiratory=====
*Metastatic Colorectal Cancer
*Monotherapy
:*Table 6 shows the adverse reactions occurring in ≥ 5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1 week rest period and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-FU/LV.
=====Skin and Hypersensitivy Reactions=====
*Breast Cancer
*In Combination with Docetaxel
:*The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1 hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3 week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1 hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3 week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
=====Special Senses=====
=====Urogenital=====
*Monotherapy
:*The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1 week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.
=====Clinically Relevant Adverse Events in < 5% of Patients=====
=====Miscellaneous=====
*Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
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Black Box Warning
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ConditionName:
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Overview
Capecitabine is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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Contraindications
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Warnings
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There is limited information regarding Clinical Trial Experience of Capecitabine in the drug label.
Body as a Whole
Cardiovascular
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Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
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Respiratory
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Urogenital
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Postmarketing Experience
There is limited information regarding Postmarketing Experience of Capecitabine in the drug label.
