Xeloda 150mg and 500mg Film-coated Tablets

Therapeutic indications

Xeloda is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer (see section 5.1).

Xeloda is indicated for the treatment of metastatic colorectal cancer (see section 5.1).

Xeloda is indicated for first-line treatment of advanced gastric cancer in combination with a platinum-based regimen (see section 5.1).

Xeloda in combination with docetaxel (see section 5.1) is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Xeloda is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.

Posology and method of administration

Xeloda should only be prescribed by a qualified physician experienced in the utilisation of anti-neoplastic agents. Xeloda tablets should be swallowed with water within 30 minutes after a meal. Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard and reduced dose calculations according to body surface area for starting doses of Xeloda of 1250 mg/m² and 1000 mg/m² are provided in tables 1 and 2, respectively.

Recommended posology (see section 5.1)

Monotherapy

Colon, colorectal and breast cancer: Given as single agent, the recommended starting dose for Xeloda in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1250 mg/m² administered twice daily (morning and evening; equivalent to 2500 mg/m² total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.

Combination therapy

Colon, colorectal and gastric cancer: In combination treatment, the recommended starting dose of Xeloda should be reduced to 800 – 1000 mg/m² when administered twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m² twice daily when administered continuously (see section 5.1). The inclusion of biological agents in a combination regimen has no effect on the starting dose of Xeloda. Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of product characteristics should be started prior to cisplatin administration for patients receiving the Xeloda plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the Xeloda plus oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended for a duration of 6 months.

Breast cancer: In combination with docetaxel, the recommended starting dose of Xeloda in the treatment of metastatic breast cancer is 1250 mg/m² twice daily for 14 days followed by a 7-day rest period, combined with docetaxel at 75 mg/m² as a 1 hour intravenous infusion every 3 weeks. Pre-medication with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for patients receiving the Xeloda plus docetaxel combination.

Xeloda Dose Calculations

Table 1 – Standard and reduced dose calculations according to body surface area for a starting dose of Xeloda of 1250 mg/m²:

Dose level 1250 mg/m² (twice daily)
Full dose 1250 mg/m²Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)Reduced dose (75%) 950 mg/m²Reduced dose (50%) 625 mg/m²
Body Surface Area (m²)Dose per administration (mg)150 mg500 mgDose per administration (mg)Dose per administration (mg)
≤1.261500-31150800
1.27 – 1.381650131300800
1.39 – 1.521800231450950
1.53 – 1.662000-415001000
1.67 – 1.7821501416501000
1.79 – 1.9223002418001150
1.93 – 2.062500-519501300
2.07 – 2.1826501520001300
≥2.1928002521501450

Table 2 – Standard and reduced dose calculations according to body surface area for a starting dose of Xeloda of 1000 mg/m²:

Dose level 1000 mg/m² (twice daily)
Full dose 1000 mg/m²Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)Reduced dose (75%) 750 mg/m²Reduced dose (50%) 500 mg/m²
Body Surface Area (m²)Dose per administration (mg)150 mg500 mgDose per administration (mg)Dose per administration (mg)
≤1.26115012800600
1.27 – 1.381300221000600
1.39 – 1.521450321100750
1.53 – 1.661600421200800
1.67 – 1.781750521300800
1.79 – 1.921800231400900
1.93 – 2.062000-415001000
2.07 – 2.1821501416001050
≥2.1923002417501100

Posology adjustments during treatment

General

Toxicity due to Xeloda administration may be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time. For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. Patients taking Xeloda should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Xeloda omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity:

Table 3 – Xeloda Dose Reduction Schedule (3-weekly Cycle or Continuous Treatment):

Toxicity grades*Dose changes within a treatment cycleDose adjustment for next cycle/dose (% of starting dose)
Grade 1Maintain dose levelMaintain dose level
Grade 2
1st appearanceInterrupt until resolved to grade 0-1100%
2nd appearance75%
3rd appearance50%
4th appearanceDiscontinue treatment permanentlyNot applicable
Grade 3
1st appearanceInterrupt until resolved to grade 0-175%
2nd appearance50%
3rd appearanceDiscontinue treatment permanentlyNot applicable
Grade 4
1st appearanceDiscontinue permanently or If physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0-150%
2nd appearanceDiscontinue permanentlyNot applicable

* According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 3.0. For hand-foot syndrome and hyperbilirubinemia, see section 4.4.

Haematology: Patients with baseline neutrophil counts of <1.5 × 109/L and/or thrombocyte counts of <100 × 109/L should not be treated with Xeloda. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below 1.0 × 109/L or that the platelet count drops below 75 × 109/L, treatment with Xeloda should be interrupted.

Dose modifications for toxicity when Xeloda is used as a 3 weekly cycle in combination with other agents

Dose modifications for toxicity when Xeloda is used as a 3 weekly cycle in combination with other agents should be made according to Table 3 above for Xeloda and according to the appropriate summary of product characteristics for the other agent(s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either Xeloda or the other agent(s), then administration of all agents should be delayed until the requirements for restarting all drugs are met.

During a treatment cycle for those toxicities considered by the treating physician not to be related to Xeloda, Xeloda should be continued and the dose of the other agent should be adjusted according to the appropriate Prescribing Information.

If the other agent(s) have to be discontinued permanently, Xeloda treatment can be resumed when the requirements for restarting Xeloda are met.

This advice is applicable to all indications and to all special populations.

Dose modifications for toxicity when Xeloda is used continuously in combination with other agents

Dose modifications for toxicity when Xeloda is used continuously in combination with other agents should be made according to Table 3 above for Xeloda and according to the appropriate summary of product characteristics for the other agent(s).

Posology adjustments for special populations

Hepatic impairment: insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.

Renal impairment: Xeloda is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m² is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m². In patients with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose adjustment as outlined in Table 3 above. If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, Xeloda should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use (see also section “Elderly” below).

There is no experience in children (under 18 years)

Elderly

During Xeloda monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-related adverse reactions were more frequent in patients ≥60 years of age compared to younger patients.

When Xeloda was used in combination with other agents, elderly patients (≥65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to discontinuation, compared to younger patients. Careful monitoring of patients ≥60 years of age is advisable.

In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients 60 years of age or more (see section 5.1). For patients 60 years of age or more , a starting dose reduction of Xeloda to 75% (950 mg/m² twice daily) is recommended. If no toxicity is observed in patients ≥60 years of age treated with a reduced Xeloda starting dose in combination with docetaxel, the dose of Xeloda may be cautiously escalated to 1250 mg/m² twice daily.

In combination with irinotecan: for patients 65 years of age or more, a starting dose reduction of Xeloda to 800 mg/m² twice daily is recommended.

Overdose

The manifestations of acute overdose include nausea, vomiting, diarrhoea, mucositis, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.

Shelf life

3 years.

Special precautions for storage

Do not store above 30°C.

Nature and contents of container

Nature: PVC/PVDC blisters

Content:

150 mg: 60 film-coated tablets (6 blisters of 10 tablets)

500 mg: 120 film-coated tablets (12 blisters of 10 tablets)

Special precautions for disposal and other handling

No special requirements.