Xeloda

SIDE EFFECTS

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 5FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabinetreated 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)

	Adjuvant Treatment for Colon Cancer (N=1969)
	XELODA (N=995)		5-FU/LV (N=974)
Body System/ Adverse Event	All Grades	Grade 3/4	All Grades	Grade 3/4
Gastrointestinal Disorders
Diarrhea	47	12	65	14
Nausea	34	2	47	2
Stomatitis	22	2	60	14
Vomiting	15	2	21	2
Abdominal Pain	14	3	16	2
Constipation	9	-	11	<1
Upper Abdominal Pain	7	<1	7	<1
Dyspepsia	6	<1	5	-
Skin and Subcutaneous Tissue Disorders
Hand-and-Foot Syndrome	60	17	9	<1
Alopecia	6	-	22	<1
Rash	7	-	8	-
Erythema	6	1	5	<1
General Disorders and Administration Site Conditions
Fatigue	16	<1	16	1
Pyrexia	7	<1	9	<1
Asthenia	10	<1	10	1
Lethargy	10	<1	9	<1
Nervous System Disorders
Dizziness	6	<1	6	-
Headache	5	<1	6	<1
Dysgeusia	6	-	9	-
Metabolism and Nutrition Disorders
Anorexia	9	<1	11	<1
Eye Disorders
Conjunctivitis	5	<1	6	<1
Blood and Lymphatic System Disorders
Neutropenia	2	<1	8	5
Respiratory Thoracic and Mediastinal Disorders
Epistaxis	2	-	5	-

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)

Adverse Event	XELODA (n=995) Grade 3/4 %	IV 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
*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5FU/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.

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/LV-treated 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

Adverse Event	XELODA (n=596)			5-FU/LV (n=593)
	Total %	Grade 3 %	Grade 4 %	Total %	Grade 3 %	Grade 4 %
Number of Patients With > One Adverse Event	96	52	9	94	45	9
Body System/Adverse Event
GI
Diarrhea	55	13	2	61	10	2
Nausea	43	4	-	51	3	<1
Vomiting	27	4	<1	30	4	<1
Stomatitis	25	2	<1	62	14	1
Abdominal Pain	35	9	<1	31	5	-
Gastrointestinal Motility Disorder	10	<1	-	7	<1	-
Constipation	14	1	<1	17	1	-
Oral Discomfort	10	-	-	10	-	-
Upper GI Inflammatory Disorders	8	<1	-	10	1	-
Gastrointestinal Hemorrhage	6	1	<1	3	1	-
Ileus	6	4	1	5	2	1
Skin and Subcutaneous
Hand-and-Foot Syndrome	54	17	NA	6	1	NA
Dermatitis	27	1	-	26	1	-
Skin Discoloration	7	<1	-	5	-	-
Alopecia	6	-	-	21	<1	-
General
Fatigue/Weakness	42	4	-	46	4	-
Pyrexia	18	1	-	21	2	-
Edema	15	1	-	9	1	-
Pain	12	1	-	10	1	-
Chest Pain	6	1	-	6	1	<1
Neurological
Peripheral Sensory Neuropathy	10	-	-	4	-	-
Headache	10	1	-	7	-	-
Dizziness*	8	<1	-	8	<1	-
Insomnia	7	-	-	7	-	-
Taste Disturbance	6	1	-	11	<1	1
Metabolism
Appetite Decreased	26	3	<1	31	2	<1
Dehydration	7	2	<1	8	3	1
Eye
Eye Irritation	13	-	-	10	<1	-
Vision Abnormal	5	-	-	2	-	-
Respiratory
Dyspnea	14	1	-	10	<1	1
Cough	7	<1	1	8	-	-
Pharyngeal Disorder	5	-	-	5	-	-
Epistaxis	3	<1	-	6	-	-
Sore Throat	2	-	-	6	-	-
Musculoskeletal
Back Pain	10	2	-	9	<1	-
Arthralgia	8	1	-	6	1	-
Vascular
Venous Thrombosis	8	3	<1	6	2	-
Psychiatric
Mood Alteration	5	-	-	6	<1	-
Depression	5	-	-	4	<1	-
Infections
Viral	5	<1	-	5	<1	-
Blood and Lymphatic
Anemia	80	2	<1	79	1	<1
Neutropenia	13	1	2	46	8	13
Hepatobiliary
Hyperbilirubinemia	48	18	5	17	3	3
– Not observed * Excluding vertigo NA = Not Applicable

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 monotherapytreated 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

Adverse Event	XELODA 1250 mg/m2/bid With Docetaxel 75 mg/m2/3 weeks (n=251)			Docetaxel 100 mg/m2/3 weeks (n=255)
	Total %	Grade 3 %	Grade 4 %	Total %	Grade 3 %	Grade 4 %
Number of Patients With at Least One Adverse Event	99	76.5	29.1	97	57.6	31.8
Body System/Adverse Event
GI
Diarrhea	67	14	<1	48	5	<1
Stomatitis	67	17	<1	43	5	-
Nausea	45	7	-	36	2	-
Vomiting	35	4	1	24	2	-
Constipation	20	2	-	18	-	-
Abdominal Pain	30	<3	<1	24	2	-
Dyspepsia	14	-	-	8	1	-
Dry Mouth	6	<1	-	5	-	-
Skin and Subcutaneous
Hand-and-Foot Syndrome	63	24	NA	8	1	NA
Alopecia	41	6	-	42	7	-
Nail Disorder	14	2	-	15	-	-
Dermatitis	8	-	-	11	1	-
Rash Erythematous	9	<1	-	5	-	-
Nail Discoloration	6	-	-	4	<1	-
Onycholysis	5	1	-	5	1	-
Pruritus	4	-	-	5	-	-
General
Pyrexia	28	2	-	34	2	-
Asthenia	26	4	<1	25	6	-
Fatigue	22	4	-	27	6	-
Weakness	16	2	-	11	2	-
Pain in Limb	13	<1	-	13	2	-
Lethargy	7	-	-	6	2	-
Pain	7	<1	-	5	1	-
Chest Pain (non-cardiac)	4	<1	-	6	2	-
Influenza-like Illness	5	-	-	5	-	-
Neurological
Taste Disturbance	16	<1	-	14	<1	-
Headache	15	3	-	15	2	-
Paresthesia	12	<1	-	16	1	-
Dizziness	12	-	-	8	<1	-
Insomnia	8	-	-	10	<1	-
Peripheral Neuropathy	6	-	-	10	1	-
Hypoaesthesia	4	<1	-	8	<1	-
Metabolism
Anorexia	13	1	-	11	<1	-
Appetite Decreased	10	-	-	5	-	-
Weight Decreased	7	-	-	5	-	-
Dehydration	10	2	-	7	<1	<1
Eye
Lacrimation Increased	12	-	-	7	<1	-
Conjunctivitis	5	-	-	4	-	-
Eye Irritation	5	-	-	1	-	-
Musculoskeletal
Arthralgia	15	2	-	24	3	-
Myalgia	15	2	-	25	2	-
Back Pain	12	<1	-	11	3	-
Bone Pain	8	<1	-	10	2	-
Cardiac
Edema	33	<2	-	34	<3	1
Blood
Neutropenic Fever	16	3	13	21	5	16
Respiratory
Dyspnea	14	2	<1	16	2	-
Cough	13	1	-	22	<1	-
Sore Throat	12	2	-	11	<1	-
Epistaxis	7	<1	-	6	-	-
Rhinorrhea	5	-	-	3	-	-
Pleural Effusion	2	1	-	7	4	-
Infection
Oral Candidiasis	7	<1	-	8	<1	-
Urinary Tract Infection	6	<1	-	4	-	-
Upper Respiratory Tract	4	-	-	5	1	-
Vascular
Flushing	5	-	-	5	-	-
Lymphoedema	3	<1	-	5	1	-
Psychiatric
Depression	5	-	-	5	1	-
– Not observed NA = Not Applicable

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

Adverse Event	XELODA 1250 mg/m2/bid With Docetaxel 75 mg/m2/3 weeks (n=251)			Docetaxel 100 mg/m2/3 weeks (n=255)
Body System/Adverse Event	Total %	Grade 3 %	Grade 4 %	Total %	Grade 3 %	Grade 4 %
Hematologic
Leukopenia	91	37	24	88	42	33
Neutropenia/Granulocytopenia	86	20	49	87	10	66
Thrombocytopenia	41	2	1	23	1	2
Anemia	80	7	3	83	5	<1
Lymphocytopenia	99	48	41	98	44	40
Hepatobiliary
Hyperbilirubinemia	20	7	2	6	2	2

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

Adverse Event	Phase 2 Trial in Stage IV Breast Cancer (n=162)
Body System/Adverse Event	Total %	Grade 3 %	Grade 4 %
GI
Diarrhea	57	12	3
Nausea	53	4	-
Vomiting	37	4	-
Stomatitis	24	7	-
Abdominal Pain	20	4	-
Constipation	15	1	-
Dyspepsia	8	-	-
Skin and Subcutaneous
Hand-and-Foot Syndrome	57	11	NA
Dermatitis	37	1	-
Nail Disorder	7	-	-
General
Fatigue	41	8	-
Pyrexia	12	1	-
Pain in Limb	6	1	-
Neurological
Paresthesia	21	1	-
Headache	9	1	-
Dizziness	8	-	-
Insomnia	8	-	-
Metabolism
Anorexia	23	3	-
Dehydration	7	4	1
Eye
Eye Irritation	15	-	-
Musculoskeletal
Myalgia	9	-	-
Cardiac
Edema	9	1	-
Blood
Neutropenia	26	2	2
Thrombocytopenia	24	3	1
Anemia	72	3	1
Lymphopenia	94	44	15
Hepatobiliary
Hyperbilirubinemia	22	9	2
– Not observed NA = Not Applicable

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)

Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)

Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)

General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation

Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance

Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia

Eye: conjunctivitis

Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea

Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion

Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)

Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness

Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)

Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)

Psychiatric: depression, confusion (0.1%)

Renal: renal impairment (0.6%)

Ear: vertigo

Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests

Immune System: drug hypersensitivity (0.1%)

XELODA In Combination With Docetaxel (Metastatic Breast Cancer)

Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%)

Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)

Cardiac: supraventricular tachycardia (0.4%)

Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%) Blood &

Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%)

Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)

Renal: renal failure (0.4%)

Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%)

Immune System: hypersensitivity (1.2%)

Postmarketing Experience

The following adverse reactions have been observed in the postmarketing setting: angioedema, hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see WARNINGS AND PRECAUTIONS], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see WARNINGS AND PRECAUTIONS], persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see WARNINGS AND PRECAUTIONS]

In instances of exposure to crushed XELODA tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.

DRUG INTERACTIONS

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 [see BOX WARNING]. 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 [see CLINICAL PHARMACOLOGY]. 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 [see DOSAGE AND ADMINISTRATION]. 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.

Allopurinol

Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see CLINICAL PHARMACOLOGY], which may decrease XELODA efficacy. Avoid the use of allopurinol during treatment with XELODA.

Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of capecitabine [see CLINICAL PHARMACOLOGY]. 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 [see DOSAGE AND ADMINISTRATION].

Read the entire FDA prescribing information for Xeloda (Capecitabine)