Usual Adult Dose for Colorectal Cancer

MONOTHERAPY:
For first line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred:

• RECOMMENDED DOSE: 1250 mg/m2 orally 2 times a day (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

ADJUVANT TREATMENT IN PATIENTS WITH DUKES' C COLON CANCER:

• RECOMMENDED DOSE: 1250 mg/m2 orally 2 times a day (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 for a total of 8 cycles (24 weeks)

Comments:

• The tablets should be swallowed whole with water within 30 minutes after a meal.

Use:
Colorectal Cancer:

• As monotherapy 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; this drug 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 this drug as a single-agent in the adjuvant treatment of Dukes' C colon cancer
• 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; survival benefit over 5-FU/LV has not been demonstrated with this drug as monotherapy; use of this drug instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage

Usual Adult Dose for Breast Cancer

MONOTHERAPY:

• RECOMMENDED DOSE: 1250 mg/m2 orally 2 times a day (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period combined with docetaxel 75 mg/m2 as a 1 hour IV infusion, every 3 weeks

IN COMBINATION WITH DOCETAXEL:

• RECOMMENDED DOSE: 1250 mg/m2 orally 2 times a day (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

Comments:

• The manufacturer prescribing information for docetaxel should be consulted for premedication advice.
• The tablets should be swallowed whole with water within 30 minutes after a meal.

Use:
Breast Cancer:

• In combination with docetaxel for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy
• As monotherapy 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

Renal Dose Adjustments

• Mild renal impairment (CrCl 51 to 80 mL/min): No adjustment recommended
• Moderate renal impairment (CrCl 30 to 50 mL/min): Reduce the capecitabine starting dose to 75% (from 1250 mg/m2 to 950 mg/m2 orally 2 times a day)
• Severe renal impairment (CrCl less than 30 mL/min): Contraindicated

Liver Dose Adjustments

• Mild to moderate hepatic impairment due to liver metastases: No adjustment recommended
• Severe hepatic impairment: Data not available

Dose Adjustments

• Patients should be carefully monitored for toxicity and the dose of this drug should be modified as necessary to accommodate individual patient tolerance to treatment.
• Toxicity may be managed by symptomatic treatment, dose interruptions, and adjustment of dose.
• Once the dose has been reduced, it should not be increased at a later time.
• Doses omitted for toxicity should not be replaced. 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 this drug.

MONOTHERAPY (metastatic colorectal cancer, adjuvant colorectal cancer, metastatic breast cancer):
GRADE 1 ADVERSE EVENTS: Dose modifications are not recommended
GRADE 2 ADVERSE EVENTS:

• First appearance: Interrupt therapy until resolved to grade 0 or 1 and maintain the dose level for the next treatment at 100%
• Second appearance: Interrupt therapy until resolved to grade 0 or 1 and maintain the dose level for the next treatment at 75%
• Third appearance: Interrupt therapy until resolved to grade 0 or 1 and maintain the dose level for the next treatment at 50%
• Fourth appearance: Discontinue therapy permanently

GRADE 3 ADVERSE EVENTS:

• First appearance: Interrupt therapy until resolved to grade 0 or 1 and begin the next cycle at 75% of the starting dose
• Second appearance: Interrupt therapy until resolved to grade 0 or 1 and begin the next cycle at 50% of the starting dose
• Third appearance: Discontinue therapy permanently

GRADE 4 ADVERSE EVENTS:

• First appearance: Discontinue therapy permanently, or if the physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0 or 1 and begin the next cycle at 50% of the starting dose

IN COMBINATION WITH DOCETAXEL (Metastatic Breast Cancer): Dose modifications of capecitabine for toxicity should be made according to the monotherapy schedule above. 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.
DOCETAXEL DOSE ADJUSTMENTS (IN COMBINATION WITH CAPECITABINE):
GRADE 1 ADVERSE EVENTS: Dose modifications are not recommended
GRADE 2 ADVERSE EVENTS:

• First appearance: Interrupt therapy until resolved to grade 0 or 1 and resume therapy with the original dose of 75 mg/m2
• Second appearance: Interrupt therapy until resolved to grade 0 or 1 and resume therapy at 55 mg/m2
• Third appearance: Discontinue therapy with docetaxel

GRADE 3 ADVERSE EVENTS:

• First appearance: Interrupt therapy until resolved to grade 0 or 1 and resume therapy at 55 mg/m2
• Second appearance: Discontinue therapy with docetaxel

GRADE 4 ADVERSE EVENTS:

• Discontinue therapy with docetaxel

Precautions

US BOXED WARNINGS:
WARNING: CAPECITABINE/WARFARIN INTERACTION:

• Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy 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 in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.
• Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced.
• These events occurred within several days and up to several months after initiating therapy and, in a few cases, within one month after stopping therapy.
• These events occurred in patients with and without liver metastases.
• Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Tablets should not be chewed, crushed, or divided.
• Tablets should be swallowed with water within 30 minutes after a meal.
• The relevant manufacturer prescribing information should be consulted for premedication advice when used concomitantly with other antineoplastic agents.

Monitoring:

• Cardiovascular: Cardiotoxicity (e.g., myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, ECG changes), particularly in patients with a history of coronary artery disease.
• Dermatologic: Hand and foot syndrome
• Gastrointestinal: Diarrhea, nausea and vomiting, stomatitis
• Hematologic: Full blood count
• Hepatic: Liver function
• Metabolic: Dehydration
• Renal: Renal function

IV compatibility:

• Refer to the manufacturer product information.

General:
Patients receiving therapy should be monitored by a physician experienced in the use of cancer chemotherapeutic agents.

• Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
• This drug can induce diarrhea which may be severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrheal treatments (e.g., loperamide) are recommended. Depending on the severity of the diarrhea, treatment may need to be interrupted followed by a decrease in dosage when treatment is resumed.
• Patients aged 80 years or older may experience more grade 3 or 4 adverse events when this drug is used as monotherapy compared with younger patients.
• Patients aged 65 years or older may experience more grade 3 or 4 adverse events when this drug is used in combination with other agents compared with younger patients.

Frequently asked questions

• Why do you need to take Xeloda with food?