Altered coagulation parameters (e.g., increased PT, increased INR) and/or bleeding, sometimes fatal, reported in patients, with or without liver metastases, receiving capecitabine concomitantly with coumarin-derivative anticoagulants. Generally occurs within several days to months following initiation of therapy, but has been reported within 1 month following discontinuance of therapy. (See Coagulopathy under Cautions and also see Specific Drugs under Interactions.)
Age >60 years and diagnosis of cancer may independently increase risk of coagulopathy.
Monitor anticoagulant response (PT or INR) frequently in patients receiving concomitant capecitabine and oral coumarin-derivative therapy; adjust anticoagulant dosage accordingly.
Treatment of metastatic breast cancer in combination with docetaxel in patients with disease that failed to respond to, or recurred or relapsed during or following, anthracycline-containing chemotherapy.
Synergistic effect with combination therapy; docetaxel increases the expression of an enzyme found at higher concentrations in many tumor cells that is involved in converting capecitabine to its active moiety, fluorouracil.
Palliative treatment of metastatic breast cancer, as monotherapy, 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., cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents).
Colorectal Cancer
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. May be used as an alternative to fluorouracil/leucovorin when single-agent therapy is desired for convenience or lesser toxicity.
Initial (first-line) treatment of metastatic colorectal cancer when fluoropyrimidine therapy alone is preferred.
Gastric Cancer
Being investigated for use in combination regimens for advanced gastric cancer†.
Dosage and Administration
Administration
Oral Administration
Administer orally with water twice daily within 30 minutes after the end of a meal, in the morning and evening.
If administered concomitantly with docetaxel, patients should be premedicated prior to docetaxel administration. Consult docetaxel manufacturer's labeling for specific information.
Dosage
Adults
Breast Cancer
Combination Therapy
Oral
Initially, 1250 mg/m2 twice daily (2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. (See Table 1.)
Treatment was continued for at least 6 weeks in a clinical trial.
Consult published protocols for dosages in combination regimens and methods and sequence of administration.
After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 2.)
Monotherapy
Oral
Initially, 1250 mg/m2 twice daily (2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. (See Table 1.)
Some experts suggest that a trial of 2 cycles (i.e., 6 weeks) of therapy is adequate to assess response. During a clinical trial, onset of response typically occurred within 6–12 weeks.
After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 3.)
Colorectal Cancer
Adjuvant Therapy for Colon Cancer
Oral
Initially, 1250 mg/m2 twice daily (2500 mg/m2 total daily dose) 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. (See Table 1.)
After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 3.)
First-line Therapy for Metastatic Colorectal Cancer
Oral
Initially, 1250 mg/m2 twice daily (2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. (See Table 1.)
After the initial dose, modify subsequent doses as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. (See Table 3.)
Divide into 2 equal doses given morning and evening.
Dosage Modification for Toxicity
Adjust doses according to the severity and recurrence of the toxicity. (See Table 2 and Table 3.)
When therapy is interrupted because of toxicity, resume according to planned treatment cycles; doses omitted because of toxicity should not be replaced. Once a dosage has been reduced for toxicity, it should not be increased at a later time.
If a patient experiences either no toxicity or NCIC grade 1 toxicity within a course of treatment, maintain the current dose for subsequent courses of therapy until more serious toxicity occurs.
Table 2. Recommended Dosage Modifications for Toxicity with Capecitabine and Docetaxel Therapy
NCIC Toxicity Grade
Number of Appearances
Comments
Grade 2
1st appearance
Interrupt therapy until resolved to grade 0–1, then resume at 100% of the original capecitabine dose; do not replace missed doses
If toxicity persists when the next course of therapy is due, delay therapy until toxicity resolved to grade 0–1, then resume therapy at 100% of the original capecitabine and docetaxel doses
2nd appearance
Interrupt therapy until resolved to grade 0–1, then resume at 75% of the original capecitabine dose; do not replace missed doses
If toxicity persists when the next course of therapy is due, delay therapy until resolved to grade 0–1, then resume therapy at 75% of the original capecitabine dose and at 55 mg/m2 of docetaxel
3rd appearance
Interrupt therapy until resolved to grade 0–1, then resume at 50% of the original capecitabine dose; do not replace missed doses
If toxicity persists when the next course of therapy is due, delay therapy until resolved to grade 0–1, then resume therapy at 50% of the original capecitabine dose and discontinue docetaxel
4th appearance
Discontinue therapy permanently
Grade 3
1st appearance
Interrupt therapy until resolved to grade 0–1, then resume at 75% of the original capecitabine dose; do not replace missed doses
If toxicity persists when the next course of therapy is due, delay therapy until toxicity resolved to grade 0–1, then resume therapy at 75% of the original capecitabine dose and at 55 mg/m2 of docetaxel
2nd appearance
Interrupt therapy until resolved to grade 0–1 and then resume at 50% of the original capecitabine dose; do not replace missed doses
If toxicity persists when the next course of therapy is due, delay therapy until resolved to grade 0–1, then resume therapy at 50% of the original capecitabine dose and discontinue docetaxel
3rd appearance
Discontinue therapy permanently
Grade 4
1st appearance
Discontinue therapy permanently
Or
If deemed in best interest of patient to continue therapy, interrupt therapy until resolved to grade 0–1, then resume therapy at 50% of the original dose of capecitabine
2nd appearance
Discontinue therapy permanently
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 FDA.
Table 3. Recommended Dosage Modifications for Toxicity of Capecitabine Monotherapy
NCIC Grade of Toxicity
Number of Appearances
During a Course of Therapy
Dose Adjustment for Next Cycle (% of Initial Dose)
Grade 2
1st appearance
Interrupt therapy until resolved to grade 0–1
100%
2nd appearance
Interrupt therapy until resolved to grade 0–1
75%
3rd appearance
Interrupt therapy until resolved to grade 0–1
50%
4th appearance
Discontinue therapy permanently
Grade 3
1st appearance
Interrupt therapy until resolved to grade 0–1
75%
2nd appearance
Interrupt therapy until resolved to grade 0–1
50%
3rd appearance
Discontinue therapy permanently
Grade 4
1st appearance
Discontinue therapy permanently
or
If deemed in best interest of patient to continue therapy, interrupt therapy until resolved to grade 0–1
50%
All dose 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 FDA.
Special Populations
Hepatic Impairment
No initial dosage adjustment necessary in patients with mild to moderate hepatic dysfunction secondary to liver metastases. Use with caution; monitor patients carefully during therapy.
Renal Impairment
Contraindicated in patients with severe renal impairment (Clcr <30 mL/minute).
In patients with moderate renal impairment (Clcr 30–50 mL/minute), reduce dosage (as monotherapy or in combination with docetaxel) by 25% of the initial dose (i.e., from 1250 to 950 mg/m2 twice daily).
No adjustment in starting dose recommended in patients with mild renal impairment.
Monitor carefully in patients with mild or moderate renal impairment because the frequency and/or severity of adverse effects may be increased. Discontinue treatment promptly if the patient develops a grade 2, 3, or 4 adverse effect; modify dosage for toxicity. (See Table 2 and Table 3.)
Geriatric Patients
Manufacturer states that insufficient data are available to recommend dosage adjustment for age in geriatric patients; however, the greater frequency of decreased hepatic and/or renal function in the elderly should be considered.
Patients >80 years of age receiving monotherapy: Some experts recommend dosage reduction (e.g., reduce initial dosage by up to 20%). (See Geriatric Use under Cautions.)
Patients >60 years of age receiving capecitabine/docetaxel combination: Some experts recommend dosage reduction (reduce initial dose by 25% [to 950 mg/m2]). (See Geriatric Use under Cautions.)
Cautions
Contraindications
Severe renal impairment (Clcr <30 mL/minute).
Known dihydropyrimidine dehydrogenase (DPD) deficiency.
Known hypersensitivity to capecitabine or any ingredient in the formulation.
Warnings/Precautions
Warnings
Coagulopathy
Altered coagulation parameters and/or bleeding, sometimes fatal, reported in patients receiving capecitabine concomitantly with coumarin anticoagulants (e.g., warfarin, phenprocoumon [no longer commercially available in the US]). Generally occurs within several days to months following initiation of therapy; similar events reported in at least a few patients within 1 month following discontinuance of therapy.
Alterations in anticoagulant effect associated with capecitabine therapy reported in patients with or without liver metastases. Age >60 years and diagnosis of cancer are independent variables predisposing patients to an increased risk of coagulopathy.
Monitor anticoagulant response (PT or INR) frequently, and adjust the anticoagulant dose accordingly in patients receiving concomitant therapy. (See Specific Drugs under Interactions.)
GI Effects
Possible diarrhea, sometimes severe or life-threatening.
If grade 2, 3, or 4 diarrhea occurs, immediately discontinue administration until the diarrhea resolves or decreases in intensity to grade 1. Decrease subsequent doses in patients who have experienced grade 3 or 4 diarrhea or recurring episodes of grade 2 diarrhea. (See Table 2 and Table 3.)
Median time to onset of grade 2 to 4 diarrhea was 34 days (range: 1–369 days) following initiation of therapy; median duration of grade 3 to 4 diarrhea was 5 days.
Diarrhea may respond to standard antidiarrheal therapy (e.g., loperamide). Monitor patients with severe diarrhea closely and give fluid and electrolyte replacement for dehydration as indicated.
Severe adverse GI effects may occur more frequently in geriatric patients. (See Geriatric Use under Cautions.)
May cause fetal harm; avoid pregnancy during therapy. However, potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.
Use during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Hypersensitivity reactions, including bronchospasm,reported.
General Precautions
Hand-foot Syndrome
Palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema (hand-foot syndrome) occurs in 54–63% of patients and is severe (grade 3) in 11–24% of patients. Median time to onset is 79 days (range: 11–360 days).
If grade 2 or 3 hand-foot syndrome occurs, withhold administration of capecitabine until manifestations resolve or decrease in intensity to grade 1. Decrease subsequent doses in patients experiencing grade 3 hand-foot syndrome or recurring episodes of grade 2 hand-foot syndrome. (See Table 2 and Table 3.)
Topical emollients (e.g., hand creams, udder balm) or oral pyridoxine therapy may ameliorate the manifestations of hand-foot syndrome.
Cardiotoxicity
Risk of MI/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. Increased incidence in patients with a history of CAD.
Rarely, severe, unexpected toxicity (e.g., stomatitis, diarrhea, neutropenia, neurotoxicity) associated with fluorouracil has been attributed to a deficiency of dihyropyrimidine dehydrogenase activity. (See Contraindications under Cautions.)
Hyperbilirubinemia
Risk of severe, possibly life-threatening hyperbilirubinemia, occurring alone or in combination with docetaxel.
If grade 2, 3, or 4 elevations in serum bilirubin concentration occur, discontinue administration of capecitabine 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. Monitor liver function carefully during therapy in patients with mild to moderate hepatic impairment secondary to liver metastases.
Distributed into milk in mice. Discontinue nursing because of the potential risk to nursing infants.
Pediatric Use
Safety and efficacy not established in children <18 years of age.
Geriatric Use
Safety and efficacy in geriatric patients not specifically studied to date; however, geriatric individuals may experience increased frequency and severity of toxicity (e.g., grade 3 or 4 diarrhea, nausea, or vomiting; severe hand-foot syndrome). (See GI Effects and also see Hand-foot Syndrome under Cautions.)
Possible increased risk of coagulopathy in patients >60 years receiving concomitant anticoagulant therapy. (See Coagulopathy under Cautions.)
Monitor geriatric patients closely for the occurrence of capecitabine-induced adverse effects.
Hepatic Impairment
Monitor carefully in patients with mild to moderate hepatic impairment due to liver metastases. Safety and efficacy not studied in patients with severe hepatic impairment.
Renal Impairment
Contraindicated in patients with severe renal impairment (Clcr <30 mL/minute).
Frequency and/or severity of adverse effects may be increased in patients with mild or moderate renal impairment. Monitor carefully. Discontinue treatment promptly if the patient develops a grade 2, 3, or 4 adverse effect; modify dosage for toxicity. (See Table 2 and Table 3.)
Increased rate and extent of absorption of capecitabine. Increased plasma concentrations of 5′-deoxy-5-fluorocytidine (5′-DFCR). Concurrent 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])
Clinical effects of concomitant administration are uncertain
Some clinicians advise delay of administration of antacids for ≥2 hours following induction of capecitabine therapy
Use concomitantly with caution and monitor serum concentrations of phenytoin carefully; reduction in phenytoin dosage may be necessary
Pharmacokinetics
Absorption
Bioavailability
Readily absorbed from the GI tract; about 70% is absorbed.
Peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil occur slightly later at 2 hours.
Onset
For treatment of breast cancer, onset of response to monotherapy typically occurred within 6–12 weeks.
Food
Food decreases the rate and extent of absorption and, to a lesser extent, decreases the peak plasma concentration and AUC of its metabolites.
Special Populations
Reduced peak plasma concentration and AUC of capecitabine and its catabolite, α-fluoro-β-alanine (FBAL) reported in Japanese patients compared with white patients. Clinical importance of these differences is not known.
Among patients 27–86 years of age, a 20% increase in age is associated with a 15% increase in the AUC of FBAL.
Distribution
Extent
Distributed into tumors, intestinal mucosa, plasma, liver, and other tissues. Not known whether distributed into CSF and brain tissue in humans; does not readily penetrate the blood-brain barrier in animal studies.
Studies have shown a higher concentration of fluorouracil, its active moiety, in tumor than in surrounding normal tissue, plasma, or muscle.
Not known whether capecitabine or its metabolites cross the placenta or are distributed into milk.
Plasma Protein Binding
<60% (mainly albumin); not concentration dependent.
Elimination
Metabolism
Capecitabine is a prodrug of fluorouracil; metabolized to fluorouracil following oral administration.
Extensively metabolized in the liver and tumors to inactive, intermediate metabolites that are hydrolyzed mainly in tumor tissue to the active moiety fluorouracil.
Fluorouracil is anabolized to active metabolites, 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).
Fluorouracil is catabolized by dihydropyrimidine dehydrogenase to dihydrofluorouracil (FUH2), a much less toxic metabolite.
Elimination Route
Excreted principally in urine (95.5%) as metabolites; fecal excretion is minimal (2.6%).
Half-life
About 45–60 minutes for capecitabine and its metabolites, except for FBAL, which has an initial half-life of about 3 hours.
Special Populations
Increased systemic exposure in patients with renal impairment; systemic exposure to capecitabine was about 25% greater in patients with moderate or severe renal impairment than in those with normal renal function.
Dialysis may reduce circulating concentrations of 5′-DFUR, a low molecular weight metabolite of the drug.
Stability
Storage
Oral
Tablets
Tight containers at 25°C (may be exposed to 15–30°C.)
Actions
Prodrug; has little pharmacologic activity until it is converted to fluorouracil, an antimetabolite.
Converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjacent normal tissues or plasma; high tumor concentrations of the active drug may be achieved with less systemic toxicity.
Fluorouracil is metabolized in both normal and tumor cells to 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). The main mechanism of action may be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor (N5–10-methylenetetrahydrofolate) to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from 2′-deoxyuridylate, thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.
Active in xenograft tumors that are resistant to fluorouracil indicating incomplete cross-resistance between the drugs.
Advice to Patients
Importance of discontinuing the drug and contacting clinician if >4 bowel movements each day or any diarrhea at night occurs.
Importance of discontinuing the drug and contacting clinician if >1 episode of vomiting occurs in a 24-hour period.
Importance of discontinuing the drug and contacting clinician if loss of appetite occurs or if the amount of food consumed each day is much less than usual.
Importance of discontinuing the drug and contacting clinician if pain, redness, swelling, or sores in mouth occur.
Importance of discontinuing the drug and contacting clinician if pain and swelling or redness of hands or feet that prevents normal activity occur.
Importance of notifying clinician if fever (≥100.5°F) or other signs of infection occur.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicans to advise women to avoid pregnancy during therapy and to advise pregnant women of risk to the fetus.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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