Capecitabine (Page 4 of 12)

5.11 Hepatic Insufficiency

Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.12 Combination With Other Drugs

Use of capecitabine in combination with irinotecan has not been adequately studied.

6 ADVERSE REACTIONS

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.

6.1 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 1,250 mg/m2

twice a day of capecitabine 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 capecitabine and 10 (1%) 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 Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)
Adjuvant Treatment for Colon Cancer (N=1,969)
Capecitabine ( N=995) 5-FU/LV ( N=974)
B o d y System/Adverse Event All Grades Grade 3/4 All Grades Grade 3/4
Gastrointestinal Disorders Diarrhea Nausea Stomatitis Vomiting Abdominal Pain Constipation Upper Abdominal Pain Dyspepsia 47 34 22 15 14 9 7 6 12 2 2 2 3 — <1 <1 65 47 60 21 16 11 7 5 14 2 14 2 2 <1 <1 –
S kin and Subcutaneous T issue Disorders Hand-and-Foot Syndrome Alopecia Rash Erythema 60 6 7 6 17 — – 1 9 22 8 5 <1 <1 — <1
General Disorders and Administration Site Conditions Fatigue Pyrexia Asthenia Lethargy 16 7 10 10 <1 <1 <1 <1 16 9 10 9 1 <1 1 <1
Nervous System Disorders Dizziness Headache Dysgeusia 6 5 6 <1 <1 – 6 6 9 — <1 –
M e tabolism and Nutrition Disorders Anorexia 9 <1 11 <1
E y e Disorders Conjunctivitis 5 <1 6 <1
Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5
R e s piratory Thoracic and Mediastinal Disorders Epistaxis 2 5
Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)

*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm.

**It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a

bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3

bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN.

Adverse Event Capecitabine ( n = 995) Grade 3/4 % I V 5-FU/LV ( n = 974) Grade 3/4 %
Increased ALAT (SGPT) 1.6 0.6
Increased calcium 1.1 0.7
Decreased calcium 2.3 2.2
Decreased hemoglobin 1.0 1.2
Decreased lymphocytes 13.0 13.0
Decreased neutrophils* 2.2 26.2
Decreased neutrophils/granulocytes 2.4 26.4
Decreased platelets 1.0 0.7
Increased bilirubin** 20 6.3

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