Side Effects of Xeloda (capecitabine)

Xeloda (capecitabine) is an antineoplastic (anti-cancer) medication used to treat

• cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes’ C stage) after surgery;
• cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic);
• breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anti-cancer medicines have not worked; and
• breast cancer that has spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines. 

Xeloda is converted by the body to 5-fluorouracil (5-FU), a drug which has been given intravenously for many years to treat various types of cancer. 5-FU inhibits the production by the cancerous cells of both DNA and protein that are necessary for the cells to divide and the cancer to grow in size. 

Common side effects of Xeloda include

• diarrhea,
• nausea,
• vomiting,
• painful swelling of the mouth,
• fatigue,
• painful rash and swelling of the hands or feet,
• low white blood cell count (which can lead to infections),
• low blood platelet counts (which can lead to bleeding), and
• anemia.

Serious side effects of Xeloda include

• heart attacks,
• chest pain, and
• abnormal heartbeats.

Drug interactions of Xeloda include blood thinner medicines, such as warfarin, because taking Xeloda with these medicines can cause changes in how fast your blood clots, and can cause life-threatening bleeding.

• This can occur as soon as a few days after you start taking Xeloda, or later during treatment, and possibly even within 1 month after you stop taking Xeloda.
• Your risk may be higher because you have cancer, and if you are over 60 years of age.
• If you take warfarin or a similar blood thinner during treatment with Xeloda, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with Xeloda.
• Your doctor may change your dose of the blood thinner medicine if needed. 

Xeloda can damage a fetus. It should not be taken by pregnant women. 

It is unknown if Xeloda is secreted into breast milk. Consult your doctor before breastfeeding. 

The most common side effects with capecitabine are:

• diarrhea,
• nausea,
• vomiting,
• painful swelling of the mouth,
• fatigue,
• painful rash and
• swelling of the hands or feet,
• low white blood cell count (which can lead to infections),
• low blood platelet counts (which can lead to bleeding), and
• anemia.

Other important side effects experienced by some patients include:

• heart attacks,
• chest pain, and
• abnormal heart beats.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 Xeloda 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 1-5 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 Xeloda and 10 (1.0%) 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.

Table 4 Percent Incidence of Adverse Reactions Reported in =5% of Patients Treated With Xeloda or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)

Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in =1% of Patients Receiving Xeloda Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)

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 Xeloda 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 1-5, 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/LVtreated 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 Xeloda and 32 (5.4%) randomized to 5-FU/LV.

Table 6 Pooled Phase 3 Colorectal Trials : Percent Incidence of Adverse Reactions in =5% of Patients

Breast Cancer

In Combination With Docetaxel

• The following data are shown for the combination study with Xeloda and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8.
• In the Xeloda and docetaxel combination arm the treatment was Xeloda 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.

Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in =5% of Patients Participating in the Xeloda and Docetaxel Combination vs Docetaxel Monotherapy Study

Table 8 Percent of Patients With Laboratory Abnormalities Participating in the Xeloda and Docetaxel Combination vs Docetaxel Monotherapy Study

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.

Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in =5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer

Clinically Relevant Adverse Events In <5% Of Patients

• Clinically relevant adverse events reported in <5% of patients treated with Xeloda either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

Xeloda In Combination With Docetaxel (Metastatic Breast Cancer)

Drug-Drug Interactions

Anticoagulants

• Altered coagulation parameters and/or bleeding have been reported in patients taking Xeloda concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.
• These events occurred within several days and up to several months after initiating Xeloda therapy and, in a few cases, within 1 month after stopping Xeloda.
• These events occurred in patients with and without liver metastases.
• In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin.
• The maximum observed INR value increased by 91%.
• This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.

Phenytoin

• The level of phenytoin should be carefully monitored in patients taking Xeloda and phenytoin dose may need to be reduced.
• Postmarketing reports indicate that some patients receiving Xeloda and phenytoin had toxicity associated with elevated phenytoin levels.
• Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.

Leucovorin

• The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin.
• Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

CYP2C9 Substrates

• Other than warfarin, no formal drug-drug interaction studies between Xeloda and other CYP2C9 substrates have been conducted.
• Care should be exercised when Xeloda is coadministered with CYP2C9 substrates.

Drug-Food Interaction

• Food was shown to reduce both the rate and extent of absorption of capecitabine. In all clinical trials, patients were instructed to administer Xeloda within 30 minutes after a meal. It is recommended that Xeloda be administered with food.