Capecitabine (Systemic)


VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): Xeloda.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Accepted

Carcinoma, breast (treatment)—Capecitabine is indicated for treatment of metastatic breast carcinoma that is resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen (i.e., has progressed during, or relapsed within 6 months following completion of, treatment). It is also indicated for treating patients whose disease is resistant to paclitaxel and who should not receive further anthracycline therapy (for example, patients who have received cumulative doses of 400 mg per square meter of body surface area of doxorubicin or doxorubicin equivalents).{01}

Carcinoma, colorectal (treatment)—Capecitabine is indicated as first-line treatment of patients with metastatic colorectal carcinoma{02} when treatment with fluoropyrimidine therapy alone is preferred.{04} Combination therapy with capecitabine has shown a survival benefit comparable to 5–FU/leucovorin monotherapy. Monotherapy with capecitabine has not shown a survival benefit over 5–FU/leucovorin. Capecitabine is not indicated for use in place of 5–FU/leucovorin in combination therapy.{04}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    A fluoropyrimidine carbamate. {01}
Molecular weight—
    359.35 {01}

Solubility
    In water: 26 mg per mL at 20 °C. {01}

Mechanism of action/Effect:

Capecitabine is relatively noncytotoxic in vitro; its activity occurs after in vivo conversion to 5-fluorouracil (5-FU; fluorouracil), which in turn is converted to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). The cytotoxic effect is produced by two different mechanisms. First, FdUMP and the folate cofactor N 5-10-methylenetetrahydrofolate bind to thymidylate synthase to form a ternary complex, thereby inhibiting thymidylate formation. Thymidylate is the precursor of thymidine triphosphate, which is essential for DNA synthesis; deficiency of this precursor leads to inhibition of cell division. Second, nuclear transcriptional enzymes can incorporate FUTP instead of uridine triphosphate during RNA synthesis, resulting in a metabolic error that interferes with RNA processing and protein synthesis. {01}

Absorption:

Readily absorbed. Both the rate and extent of absorption are decreased by concurrent administration with food. {01}

Protein binding:

Moderate (less than 60%), primarily to albumin (approximately 35%). Binding is not concentration-dependent. {01}

Biotransformation:


Capecitabine:

Initially hepatic, hydrolyzed via a carboxylesterase to 5´-deoxy-5-fluorocytidine (5´-DFCR), which in turn is first converted to 5´-deoxy-5-fluorouridine (5´-DFUR) and then hydrolyzed to the active substance, fluorouracil, by cytidine deaminase and thymidine phosphorylase, respectively. These enzymes are found in most tissues, including tumors. Thymidine phosphorylase is expressed in higher concentrations by some human carcinomas than by surrounding normal tissues. {01}



Fluorouracil:

Metabolized in normal and tumor cells to the active metabolites FdUMP and FUTP. Also, metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5,6-dihydro-fluorouracil (FUH 2), which is much less toxic. This compound is further metabolized by cleavage of the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA), which undergoes further cleavage to produce alpha-fluoro-beta-alanine (FBAL). {01}


Half-life:


Elimination:

For both capecitabine and fluorouracil: Approximately 45 minutes. {01}


Time to peak concentration:

In blood—Approximately 1.5 hours for capecitabine and 2 hours for fluorouracil. Peak concentrations of both substances are delayed by 1.5 hours when capecitabine is administered concurrently with food. {01}

Peak blood concentration

There is wide interpatient variability (> 85%) in the maximum concentration (C max) and area under the plasma concentration–time curve (AUC) for fluorouracil. {01}

In studies with doses ranging between 500 and 3500 mg per square meter of body surface area (mg/m 2) per day, the pharmacokinetics of capecitabine and 5´-DFCR were dose-proportional and did not change over time. However, the increases in the AUCs of fluorouracil and 5´-DFUR 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 13 patients with mild to moderate hepatic function impairment given single doses of 1255 mg/m 2 of capecitabine, C max and AUC values for the parent compound were 60% higher than in patients with normal hepatic function, but values for fluorouracil were not affected. {01}

When capecitabine is administered concurrently with food, C max values for capecitabine and fluorouracil are decreased by 60% and 35%, respectively, and AUC values are reduced by 43% and 21%, respectively. {01}

Elimination:
    Renal, more than 70% of a capecitabine dose as drug-related species (approximately 50% as FBAL). {01}


In dialysis—
        Although there is no clinical experience, it is possible that 5´-DFUR (the low–molecular weight capecitabine metabolite that is the immediate precursor of fluorouracil) may be removable by dialysis. {01}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to fluorouracil may also be sensitive to capecitabine. {01}

Carcinogenicity

Long-term studies in animals have not been done. {01}

Mutagenicity

Capecitabine was not found to be mutagenic in in vitro bacterial tests (Ames test) or in mammalian cells (Chinese hamster V79/HPRT gene mutation assay). It was clastogenic to human peripheral blood lymphocytes in vitro but not to mouse bone marrow (micronucleus test) in vivo. {01}

Fluorouracil causes mutations in bacteria and yeast and causes chromosomal abnormalities in the mouse micronucleus test in vivo. {01}

Pregnancy/Reproduction
Fertility—
Studies in female mice given oral doses of 760 mg per kg of body weight (mg/kg) per day found a reversible disturbance of estrus and a subsequent decrease in fertility; in mice that did become pregnant, no fetuses survived. The same dose in male mice produced degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In mice, this dose produces area under the plasma concentration–time curve (AUC) values for the immediate precursor of fluorouracil (5´-deoxy-5-fluorouridine [5´-DFUR]) that are approximately 0.7 times the corresponding values in humans taking the recommended daily dose. {01}

Pregnancy—
Adequate and well-controlled studies in women have not been done. It is recommended that women of childbearing potential be advised to avoid becoming pregnant during treatment because of the potential risks to the fetus. Also, if the medication is used during pregnancy, or the patient becomes pregnant during treatment, the patient should be informed of the potential risks. {01}

Capecitabine caused teratogenicity (cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, dilation of cerebral ventricles) and embryolethality in mice given doses of 198 mg/kg per day (producing AUC values for 5´-DFUR approximately 0.2 times the corresponding value in humans taking the recommended daily dose) during the period of organogenesis. It also caused fetal deaths in monkeys given 90 mg/kg per day (producing AUC values for 5´-DFUR approximately 0.6 times the corresponding value in humans taking the recommended daily dose) during organogenesis. {01}

FDA Pregnancy Category D. {01}

Breast-feeding

It is not known whether capecitabine is distributed into human breast milk. However, breast-feeding is not recommended during treatment because of the potential risks to the infant. {01}

Pediatrics

Studies on the relationship of age to the effects of capecitabine have not been performed in the pediatric population. {01} Safety and efficacy in patients younger than 18 years of age have not been established. {01}


Geriatrics


Geriatric patients may be pharmacodynamically more sensitive to the toxic effects of capecitabine than younger adults. In particular, the risk of severe (National Cancer Institute [NCI] grade 3 or 4) gastrointestinal adverse effects (diarrhea, nausea, vomiting) may be increased in patients 80 years of age and older. Patients 60 years of age and older are independently predisposed to an increased risk of coagulopathy.{05}{06}{07}. Careful monitoring is recommended. Pharmacokinetic studies have not been performed in the geriatric population. {01}


Dental

Capecitabine may cause stomatitis. In clinical trials, stomatitis occurred in up to 24%, and was severe enough to decrease food intake substantially (NCI grade 3) in 4 to 7%, of the patients. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antacids, aluminum and magnesium–containing {01}    (administration of an aluminum and magnesium–containing antacid immediately after capecitabine in 12 patients produced small increases in blood concentrations of capecitabine and the metabolite 5´-deoxy-5-fluorocytidine [5´-DFCR], but did not affect the concentrations of other major metabolites{01})


» Anticoagulants, coumarin-derivative, such as warfarin{02}    (altered coagulation parameters and/or bleeding, including death{05}have been reported in patients receiving capecitabine and coumarin-derived anticoagulants; these events occurred within several days to several months after concurrent therapy was initiated and, in a few cases, within one month after stopping capecitabine {05}; patients receiving oral anticoagulants should be routinely monitored for alterations in their prothrombin time (PT) or International Normalized ratio (INR){02})


Blood dyscrasia-causing medications    (leukopenia and/or thrombocytopenic effects of capecitabine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of capecitabine if necessary, should be based on blood counts )


» Bone marrow depressants, other or
» Radiation therapy    (additive bone marrow depression, including severe dermatitis and/or mucositis, may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


CYP2C9 substrates    (Although no formal drug-drug interaction studies between capecitabine and CYP2C9 substrates other than warfarin have been conducted, care should be exercised during coadministration {05})


Leucovorin {01}    (concurrent use may increase the therapeutic and toxic effects of fluorouracil as a result of increased concentrations; fatalities as a result of severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients who received the two medications concurrently{01})


Phenytoin or
Fosphenytoin    (plasma concentrations and associated clinical symptoms may increase as a result of concurrent use with capecitabine{02})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by capecitabine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by capecitabine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the capecitabine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase and
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin    (elevations of serum bilirubin and concurrent increases in alkaline phosphatase and/or transaminase concentrations may occur, especially in patients with hepatic metastases{01})


» Prothrombin time or INR    (elevations in INR values by as much as 91% have been observed in cancer patients on concomitant capecitabine and warfarin therapy{05}{06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under certain circumstances, this medication should not be used when the following medical problem exists:
» Renal function impairment, severe    (high rate of grade III-IV adverse events in patients with creatinine clearance < 30 mL/min{03})


Sensitivity to capecitabine or fluorouracil {01}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression, existing or
Cancer {05}    (Patients with cancer experienced an increased risk of coagulopathy {05})


» Chickenpox, existing or recent, or
» Herpes zoster    (risk of severe generalized disease)


» Infection
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy
Coronary artery disease, history of{01}    (fluorinated pyrimidine therapy has been associated with cardiotoxicity, which may be more common in patients with a prior history of coronary artery disease{01})


» Hepatic function impairment{01}    (caution is recommended because blood concentrations and AUC values for capecitabine may be increased, and the risk of grade 3 or 4 hyperbilirubinemia with concurrent increases in alkaline phosphatase and/or transaminases is higher, in patients with mild to moderate hepatic function impairment due to hepatic metastases; no information is available for patients with severe hepatic function impairment{01})


» Renal function impairment, moderate    (greater incidence of treatment-related grade III-IV adverse events in patients with creatinine clearance 30-50 mL/min; starting dose is reduced to 75% of the recommended starting dose{03})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hepatic function    (monitoring recommended in patients with pre-existing hepatic function impairment because of the increased risk of hyperbilirubinemia and associated increases in alkaline phosphatase and/or transaminase values; temporary withdrawal of treatment is recommended if hyperbilirubinemia of NCI grade 2 [serum bilirubin 1.5 times normal values] or higher occurs. If treatment is reinstated after hyperbilirubinemia has resolved, a reduction in dosage may be needed{01})


» Prothrombin time or INR    (patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response monitored closely and with great frequency and anticoagulant dose adjustments made accordingly{05}{06})


» Renal function    (monitoring for grade II-IV severe adverse events in patients with creatinine clearance 30-50 mL/min (moderate impairment) to < 30 mL/min (severe impairment); dose adjustments or treatment interruption if necessary{03})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Abdominal or stomach pain{01}
    
anemia{01} (unusual tiredness or weakness)—usually asymptomatic
diarrhea, moderate or severe{01}
    
hand-and-foot syndrome{01} (blistering, peeling, redness, and/or swelling of palms of hands or bottoms of feet; numbness, pain, tingling, or unusual sensations in palms of hands or bottoms of feet)
    
neutropenia{01} —usually asymptomatic
    
stomatitis{01} (pain, redness, and/or swelling in mouth and on lips; sores or ulcers in mouth and on lips)
    
thrombocytopenia{01} —usually asymptomatic

Note: Diarrhea is one of the dose-limiting toxicities of capecitabine. It may be severe and lead to dehydration. In clinical trials, diarrhea of any grade occurred in at least 50% of the patients, but was severe in relatively few, with National Cancer Institute (NCI) grades 3 and 4 diarrhea occurring in fewer than 12% and 3% of the patients, respectively. The median time to first occurrence of NCI grade 2 or higher diarrhea was 31 (range, 1 to 322) days. {01}
Hand-and-foot syndrome (also known as palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) may result in severe discomfort that interferes with the patient's ability to work or perform activities of daily living. A reaction of such severity requires immediate medical attention. {01}
Bone marrow depression during treatment with capecitabine resulted in anemia, neutropenia, or thrombocytopenia in up to 74%, 26%, and 24%, respectively, of the patients in clinical trials. However, each of these hematologic toxicities reached a severity of NCI grade 3 or 4 in only 4% or fewer, and grade 3 or 4 coagulation disorders, pancytopenia, or thrombocytopenic purpura each occurred in only 0.2%, of the patients. {01}


Incidence less frequent or rare
    
Angina pectoris{01} (chest pain)
    
ataxia{01} (clumsiness or unsteadiness; problems with coordination)
    
bronchospasm{01}
dyspnea{01}
or respiratory distress{01} (shortness of breath, troubled breathing, tightness in chest, or wheezing)
    
cardiomyopathy{01} (fast or irregular heartbeat; shortness of breath or troubled breathing; tiredness or weakness, severe)
    
cholestatic hepatitis{01}
hepatic fibrosis{01}
or hepatitis{01} (dark urine; fever; itching; light-colored stools; pain, tenderness, and/or swelling in upper abdominal area; skin rash; swollen glands; yellow eyes or skin)
    
edema{01} (swelling of face, fingers, feet, or lower legs)
    
epistaxis{01} (unexplained nosebleeds)
    
fever{01}
    
gastrointestinal tract toxicity{01} (abdominal or stomach cramping or pain, severe; bloody or black, tarry stools; constipation or diarrhea, severe; difficulty in swallowing or pain in back of throat or chest when swallowing; vomiting blood or material that looks like coffee grounds)
    
hypotension{01} (decreased blood pressure)
    
hypertension{01} (increased blood pressure)
    
infection{01} (cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; sneezing; sore throat; stuffy nose; white spots in mouth or throat)—rarely, may be associated with neutropenia
    
nausea —severe enough to cause loss of appetite
    
phlebitis{01}
thrombophlebitis{01}
or deep vein thrombosis{01} (hot, red skin on feet or legs; painful, swollen feet or legs)
    
pulmonary embolism{01} (shortness of breath or troubled breathing; pain in chest)
    
thrombocytopenic purpura{01} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
    
vomiting —two or more episodes in 24 hours

Note: Gastrointestinal toxicity may affect any area of the gastrointestinal tract and may result in colitis, duodenitis, esophagitis, gastritis, gastrointestinal or rectal bleeding, hematemesis, intestinal obstruction, or necrotizing enterocolitis. {01}
Reported infections include oral, esophageal, or gastrointestinal candidiasis; upper respiratory tract infection; urinary tract infection; bronchitis, pneumonia, or bronchopneumonia; and sepsis. Each of these occurred in fewer than 5%, and was severe (NCI grade 3 or 4) in only 0.2% (0.4% for sepsis), of the patients in clinical trials. {01}
Reported neurologic effects (in addition to ataxia) include decrease or loss of consciousness and encephalopathy. {01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation, mild or moderate{01}
    
dermatitis{01} (skin rash or itching)
    
diarrhea, mild{01}
    
loss of appetite{01}
    
nausea{01}
    
unusual tiredness{01}
    
vomiting{01}

Note: NCI grade 2 or greater nausea or vomiting requires immediate medical attention. {01}


Incidence less frequent
    
Changes in fingernails or toenails{01}
    
dizziness{01}
    
dyspepsia{01} (heartburn)
    
eye irritation{01} (red, sore eyes)
    
headache{01}
    
insomnia{01} (trouble in sleeping)
    
myalgia{01} (muscle pain)
    
photosensitivity{01} (increased sensitivity of skin to sunlight)
    
radiation recall syndrome{01} (pain and redness of skin at place of earlier radiation treatment)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
    
Bone marrow depression{01} (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)
    
gastrointestinal tract toxicity (abdominal or stomach pain, severe{01}; bloody or black, tarry stools; constipation or diarrhea, severe{01}; difficulty in swallowing or pain in back of throat or chest when swallowing; nausea or vomiting, severe; vomiting blood or material that looks like coffee grounds{01})


Treatment of overdose
Supportive care—Appropriate care to address the clinical manifestations. {01}

Dialysis may be effective in removing circulating 5´-DFUR, the low–molecular weight metabolite that is the immediate precursor of fluorouracil. {01}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Capecitabine (Systemic)

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to capecitabine or fluorouracil

Pregnancy—Avoiding pregnancy during treatment; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects





Use in the elderly—Possible increased sensitivity to gastrointestinal adverse effects

Increased risk of coagulopathy
Other medications, especially bone marrow depressants, live virus vaccines, coumarin-derivative anticoagulants, , or previous cytotoxic drug therapy or radiation therapy
Other medical problems, especially severe or moderate renal function impairment, existing or recent chickenpox, herpes zoster infection, hepatic function impairment

Proper use of this medication
Taking within 30 minutes after a meal

Swallowing tablets with water

» Proper dosing
Not taking at all; not doubling doses; checking with physician

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Importance of monitoring prothrombin time or INR in patients on coumarin-derived anticoagulants

» Notifying physician immediately if fever of 100.5 °F or higher, or other evidence of an infection, occurs

» Stopping treatment and notifying physician immediately if symptoms indicative of NCI grade 2 (or higher) diarrhea, hand-and-foot syndrome, nausea, vomiting, or stomatitis occurs

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
May cause adverse effects such as blood problems, hand-and-foot syndrome, and gastrointestinal tract toxicity; importance of discussing possible effects with physician

Signs of potential side effects, especially abdominal or stomach pain; anemia; diarrhea (moderate); hand-and-foot-syndrome; stomatitis; angina; ataxia; bronchospasm, dyspnea, or respiratory distress; cardiomyopathy; cholestatic hepatitis, hepatic fibrosis, or hepatitis; edema; epistaxis; fever; gastrointestinal toxicity; hypotension; hypertension; infection; phlebitis, thrombophlebitis, or deep venous thrombosis; pulmonary embolism; and thrombocytopenic purpura

Physician or nurse can help in dealing with side effects


General Dosing Information
Patients receiving capecitabine should be under the supervision of a physician experienced in cancer chemotherapy. {01}

Dosage must be adjusted to meet the individual requirements of each patient, based on appearance or severity of toxicity. {01}

It is recommended that capecitabine be taken within 30 minutes after a meal and that the tablets be swallowed with water {01}.

It is recommended that capecitabine be discontinued immediately if any of the following occur:

• Diarrhea, grade 2 (an increase of 4 to 6 stools per day or nocturnal stools) or greater. {01}


• Hand-and-foot syndrome, grade 2 (painful erythema and swelling of the palms of the hands and/or the bottoms of the feet that results in discomfort affecting daily living activities) or greater. {01}


• Hyperbilirubinemia, grade 2 (bilirubin concentrations 1.5 times normal) or greater. {01}


• Nausea, grade 2 (sufficient to result in significantly decreased food intake, but the patient is able to eat intermittently) or greater. {01}


• Vomiting, grade 2 (2 to 5 episodes in a 24-hour period) or greater. {01}


• Stomatitis, grade 2 (painful erythema, edema, or ulcers of the mouth or tongue) or greater. {01}



Once the effect has resolved or decreased to grade 1, capecitabine therapy may be reinstituted (depending on the number of times that the problem has occurred), but a reduction of dosage may be required. {01}.

For treatment of adverse effects
Withdrawal of capecitabine therapy is recommended for NCI grade 2 or higher adverse effects; dosage adjustment may be necessary if treatment is reinstituted. {01}

For NCI grade 2 or higher diarrhea: Standard antidiarrheal treatment (e.g., loperamide). Severe diarrhea requires careful monitoring and possibly fluid and electrolyte replacement for dehydration. {01}

For NCI grade 2 or higher nausea, vomiting, hand-and-foot syndrome, or stomatitis: Symptomatic treatment is recommended. {01}


Oral Dosage Forms

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

CAPECITABINE TABLETS

Usual adult dose
Carcinoma, breast or
Carcinoma, colorectal (treatment)
Oral, 2500 mg per square meter (mg/m2) of body surface per day, in two divided doses (approximately twelve hours apart) within 30 minutes after the end of a meal. This dose is given for two weeks, followed by a one-week rest period, i.e., as three-week cycles. {01}{02}{04}


Note: The development of adverse effects may require adjustment of capecitabine dosage, depending on severity (as graded according to NCI common toxicity criteria) as follows:
Grade 1 toxicity—No interruption or modification of therapy is needed. {01}
Grade 2 toxicity—Therapy should be interrupted until the effect has resolved or improved to the grade 1 level, then reinstituted (or not) according to the following guidelines:

• After a first occurrence—Treatment may be reinstituted using 100% of the starting dose. {01}


• After a second occurrence—Treatment may be reinstituted using 75% of the starting dose. {01}


• After a third occurrence—Treatment may be reinstituted using 50% of the starting dose. {01}


• After a fourth occurrence—Treatment should not be reinstituted. {01}

Grade 3 toxicity—Therapy should be interrupted until the effect has resolved or improved to the grade 1 level, then reinstituted (or not) according to the following guidelines:

• After a first occurrence—Treatment may be reinstituted using 75% of the starting dose. {01}


• After a second occurrence—Treatment may be reinstituted using 50% of the starting dose. {01}


• After a third occurrence—Treatment should not be reinstituted. {01}

Grade 4 toxicity—Based on clinician judgement, treatment may be withdrawn permanently or, after the effect has resolved or improved to the grade 1 level, reinstituted using 50% of the starting dose. {01}


Note: Recommended starting dose for patients with moderate renal impairment is 1900 mg/m2 of body surface area daily for 14 days (75% of normal starting dose), followed by a week rest.{03}


Usual pediatric dose
Safety and efficacy in children younger than 18 years of age have not been established. {01}{02}

Strength(s) usually available
U.S.—


150 mg (Rx) [Xeloda (anhydrous lactose) (croscarmellose sodium) (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (talc ) (titanium dioxide) ( synthetic red and yellow iron oxides)]


500 mg (Rx) [Xeloda (anhydrous lactose) (croscarmellose sodium) (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (talc ) (titanium dioxide) ( synthetic red and yellow iron oxides)]

Canada—


150 mg (Rx) [Xeloda (croscarmellose sodium) (hydroxypropyl methylcellulose) (lactose anhydrous) (magnesium stearate) ( microcrystalline cellulose) (talc) (titanium dioxide) (synthetic red and yellow iron oxides)]


500 mg (Rx) [Xeloda (croscarmellose sodium) (hydroxypropyl methylcellulose) (lactose anhydrous) (magnesium stearate) ( microcrystalline cellulose) (talc) (titanium dioxide) (synthetic red and yellow iron oxides)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), preferably at 25 °C (77 °F), in a tight container. {01}

Auxiliary labeling:
   • Take with meals.
   • Take with water.{02}



Developed: 06/25/1998
Revised: 05/14/2002



References
  1. Xeloda package insert (Roche—US), Rev 4/1998, Rec 5/5/1998.
  1. Product Information: Xeloda®, capecitabine. Hoffmann-La Roche Limited, Mississauga, Ontario, Canada, (PI revised 7/2000) PI reviewed 11/2000.
  1. FDA safety letter, Hoffmann-La Roche, US, 11/2000.
  1. Product Information: Xeloda®, capecitabine. Roche Laboratories, Nutley, NJ (PI revised 4/2001) PI reviewed 7/2001.
  1. Product Information: Xeloda®, capecitabine. Roche Pharmaceuticals, Nutley, NJ (PI revised 9/2001) PI reviewed 11/2001.
  1. Manufacturer comment, 1/21/02.
  1. Expert committee consensus, 2/26/02.
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