Xeloda

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Xeloda uses

• Warning: capecitabine-warfarin interaction
• Recent major changes
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Xeloda reviews

WARNING: CAPECITABINE-WARFARIN INTERACTION

Capecitabine-Warfarin Interaction: Patients receiving concomitant Xeloda 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. A clinically important Capecitabine-Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking Xeloda 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 Xeloda was introduced. 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. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

WARNING: CAPECITABINE-WARFARIN INTERACTION

See full prescribing information for complete boxed warning.

Patients receiving concomitant Xeloda and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon 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 during concomitant use.

• Occurrence: Within several days and up to several months after initiating Xeloda therapy; may also be seen within 1 month after stopping Xeloda
• Predisposing factors: age>60 and diagnosis of cancer

RECENT MAJOR CHANGES

Dosage and Administration (2) 10/2014

Warnings and Precautions (5.1, 5.2, 5.5, and 5.7) 10/2014

Dosage and Administration (2.1) 12/2016

Warnings and Precautions (5.6, 5.7) 12/2016

1 INDICATIONS AND USAGE

Xeloda tablets are a nucleoside metabolic inhibitor with antineoplastic activity indicated for:

• Adjuvant Colon Cancer
  • Patients with Dukes’ C colon cancer
• Metastatic Colorectal Cancer (1.1)
  • First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred
• Metastatic Breast Cancer (1.2)
  • In combination with docetaxel after failure of prior anthracycline-containing therapy
  • As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen

1.1 Colorectal Cancer

• Xeloda tablets are indicated as a single agent 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. Xeloda tablets were 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 single-agent Xeloda tablets in the adjuvant treatment of Dukes’ C colon cancer.
• Xeloda tablets are indicated 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. A survival benefit over 5-FU/LV has not been demonstrated with Xeloda tablets monotherapy. Use of Xeloda tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

1.2 Breast Cancer

• Xeloda tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
• Xeloda tablets monotherapy is also indicated 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.

2 DOSAGE AND ADMINISTRATION

• Take Xeloda tablets with water within 30 min after a meal
• Monotherapy: 1250 mg/m² twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles (2.2)
• Adjuvant treatment is recommended for a total of 6 months (8 cycles) (2.2)
• In combination with docetaxel, the recommended dose of Xeloda tablets is 1250 mg/m² twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m² as a 1-hour IV infusion every 3 weeks (2.2)
• Xeloda tablets dosage may need to be individualized to optimize patient management (2.3)
• Reduce the dose of Xeloda tablets by 25% in patients with moderate renal impairment (2.4)

2.1 Important Administration Instructions

Xeloda tablets should be swallowed whole with water within 30 minutes after a meal. Xeloda tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.¹ If Xeloda tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Xeloda tablets dose is calculated according to body surface area.

2.2 Standard Starting Dose

Monotherapy

The recommended dose of Xeloda tablets is 1250 mg/m² administered orally twice daily (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 (see Table 1).

Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months [ie, Xeloda tablets 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)].

Dose Level 1250 mg/m 2 Twice a Day		Number of Tablets to be Taken at Each Dose (Morning and Evening)
Surface Area (m 2 )	Total Daily Dose* (mg)	150 mg	500 mg
*Total Daily Dose divided by 2 to allow equal morning and evening doses
≤ 1.25	3000	0	3
1.26 to 1.37	3300	1	3
1.38 to 1.51	3600	2	3
1.52 to 1.65	4000	0	4
1.66 to 1.77	4300	1	4
1.78 to 1.91	4600	2	4
1.92 to 2.05	5000	0	5
2.06 to 2.17	5300	1	5
≥ 2.18	5600	2	5

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of Xeloda tablets is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m² as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the Xeloda tablets plus docetaxel combination. Table 1 displays the total daily dose of Xeloda tablets by body surface area and the number of tablets to be taken at each dose.

2.3 Dose Management Guidelines

General

Xeloda tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of Xeloda tablets should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14) ]. Toxicity due to Xeloda tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of Xeloda tablets dose. Once the dose has been reduced, it should not be increased at a later time. Doses of Xeloda tablets omitted for toxicity are not replaced or restored; 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 Xeloda tablets [see Drug Interactions (7.1) ].

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

Xeloda tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

Toxicity NCIC Grades*	During a Course of Therapy	Dose Adjustment for Next Treatment (% of starting dose)
*National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5) ].
Grade 1	Maintain dose level	Maintain dose level
Grade 2
-1st appearance	Interrupt until resolved to grade 0 to 1	100%
-2nd appearance		75%
-3rd appearance		50%
-4th appearance	Discontinue treatment permanently	-
Grade 3
-1st appearance	Interrupt until resolved to grade 0 to 1	75%
-2nd appearance		50%
-3rd appearance	Discontinue treatment permanently	-
Grade 4
-1st appearance	Discontinue permanently OR If physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0 to 1	50%

In Combination With Docetaxel (Metastatic Breast Cancer)

Dose modifications of Xeloda tablets for toxicity should be made according to Table 2 above for Xeloda tablets. At the beginning of a treatment cycle, if a treatment delay is indicated for either Xeloda tablets or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.

The dose reduction schedule for docetaxel when used in combination with Xeloda tablets for the treatment of metastatic breast cancer is shown in Table 3.

Toxicity NCIC Grades*	Grade 2	Grade 3	Grade 4
*National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5) ].
1st appearance	Delay treatment until resolved to grade 0 to 1; Resume treatment with original dose of 75 mg/m2 docetaxel	Delay treatment until resolved to grade 0 to 1; Resume treatment at 55 mg/m2 of docetaxel.	Discontinue treatment with docetaxel
2nd appearance	Delay treatment until resolved to grade 0 to 1; Resume treatment at 55 mg/m2 of docetaxel.	Discontinue treatment with docetaxel	-
3rd appearance	Discontinue treatment with docetaxel	-	-

2.4 Adjustment of Starting Dose in Special Populations

Renal Impairment

No adjustment to the starting dose of Xeloda tablets is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the Xeloda tablets starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m² to 950 mg/m² twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5) ]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both Xeloda tablets monotherapy and Xeloda tablets in combination use with docetaxel.

Cockroft and Gault Equation:

(140 - age [yrs]) (body wt [kg])

Creatinine clearance for males = -------------

(72) (serum creatinine [mg/dL])

Creatinine clearance for females = 0.85 x male value

Geriatrics

Physicians should exercise caution in monitoring the effects of Xeloda tablets, USP in the elderly. Insufficient data are available to provide a dosage recommendation.

3 DOSAGE FORMS AND STRENGTHS

Xeloda tablets, USP are supplied as oblong, film-coated, biconvex, unscored tablets for oral administration. Each light peach-colored tablet contains 150 mg of Xeloda, USP and each peach-colored tablet contains 500 mg of Xeloda, USP.

• Tablets: 150 mg and 500 mg (3)

4 CONTRAINDICATIONS

• Severe Renal Impairment
• Hypersensitivity (4.2)

4.1 Severe Renal Impairment

Xeloda is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

4.2 Hypersensitivity

Xeloda tablets are contraindicated in patients with known hypersensitivity to Xeloda or to any of its components. Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

5 WARNINGS AND PRECAUTIONS

• Coagulopathy: May result in bleeding, death. Monitor anticoagulant response and adjust anticoagulant dose accordingly. (5.1)
• Diarrhea: May be severe. Interrupt Xeloda treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2)
• Cardiotoxicity: Common in patients with a prior history of coronary artery disease. (5.3)
• Increased Risk of Severe or Fatal Adverse Reactions in Patients with Lo w or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue Xeloda in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Xeloda dose has been proven safe in patients with absent DPD activity. (5.4)
• Dehydration and Renal Failure: Interrupt Xeloda treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.6, 8.1, 8.3)
• Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. Xeloda should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment. Xeloda may induce hand-and-foot syndrome.. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification. Interrupt Xeloda treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7)
• Hyperbilirubinemia: Interrupt Xeloda treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8)
• Hematologic: Do not treat patients with neutrophil counts <1.5 x 10⁹/L or thrombocyte counts <100 x 10⁹/L. If grade 3 to 4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9)

5.1 Coagulopathy

Patients receiving concomitant Xeloda and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly [see Boxed Warning and Drug Interactions (7.1)].

5.2 Diarrhea

Xeloda can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received Xeloda monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days. The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of Xeloda should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1 . Standard antidiarrheal treatments (eg, loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

5.3 Cardiotoxicity

The cardiotoxicity observed with Xeloda includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

5.4 Dihydropyrimidine Dehydrogenase Deficiency

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Xeloda. Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by Xeloda.

Withhold or permanently discontinue Xeloda based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Xeloda dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.5 Dehydration and Renal Failure

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant Xeloda with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when Xeloda is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, Xeloda treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary .

Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4) ]. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and Administration (2.3) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ].

5.6 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, Xeloda may cause fetal harm when given to a pregnant woman . Limited available data are not sufficient to inform use of Xeloda in pregnant women. In animal reproduction studies, administration of Xeloda to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively . Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Xeloda .

5.7 Mucocutaneous and Dermatologic Toxicity

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with Xeloda . Xeloda should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to Xeloda treatment.

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving Xeloda monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of Xeloda should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of Xeloda should be decreased [see Dosage and Administration (2.3) ].

5.8 Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of Xeloda 1250 mg/m² twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.

In the 596 patients treated with Xeloda as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of Xeloda monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with Xeloda. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In 251 patients with metastatic breast cancer who received a combination of Xeloda and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 2% (n=5).

If drug-related grade 3 to 4 elevations in bilirubin occur, administration of Xeloda should be immediately interrupted until the hyperbilirubinemia decreases to ≤3 X ULN [see recommended dose modifications under Dosage and Administration (2.3) ].

5.9 Hematologic

In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m² administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of Xeloda in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.

Patients with baseline neutrophil counts of <1.5 x 10⁹/L and/or thrombocyte counts of <100 x 10⁹/L should not be treated with Xeloda. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with Xeloda should be interrupted.

5.10 Geriatric Patients

Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received Xeloda monotherapy, 62% of the 21 patients ≥80 years of age treated with Xeloda experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6, nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with Xeloda in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

Among the 67 patients ≥60 years of age receiving Xeloda in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.

In 995 patients receiving Xeloda as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with Xeloda experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; Xeloda 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for Xeloda compared to 5-FU/LV were 1.01 (95% C.I. 0.80 to 1.27) and 1.04 (95% C.I. 0.79 to 1.37), respectively.

5.11 Hepatic Insufficiency

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

5.12 Combination With Other Drugs

Use of Xeloda 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.

Most common adverse reactions were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 to 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%) Xeloda 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%) 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.

	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	-

Adverse Event	Xeloda (n=995) Grade 3/4 %	IV 5-FU/LV (n=974) Grade 3/4 %
*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the Xeloda 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 × upper limit of normal (ULN) range, and grade 4 a value of > 3 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of >3 to 10 × ULN, and grade 4 values >10 × ULN.
Increased ALAT (SGPT)	1.6	0.6
Increased calcium	1.1	0.7
Decreased calcium	2.3	2.2
Decreased hemoglobin	1	1.2
Decreased lymphocytes	13	13
Decreased neutrophils*	2.2	26.2
Decreased neutrophils/granulocytes	2.4	26.4
Decreased platelets	1	0.7
Increased bilirubin**	20	6.3

6.2 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. 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%) Xeloda 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.

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
– Not observed
* Excluding vertigo
NA = Not Applicable
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

6.3 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.

Adverse Event	Xeloda 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks (n=251)			Docetaxel 100 mg/m 2 /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
– Not observed
NA = Not Applicable
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	–

Adverse Event	Xeloda 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks (n=251)			Docetaxel 100 mg/m 2 /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.

Adverse Event	Phase 2 Trial in Stage IV Breast Cancer (n=162)
Body System/Adverse Event	Total %	Grade 3 %	Grade 4 %
– Not observed
NA = Not Applicable
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

6.4 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%), 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%), 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%)

Postmarketing: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome , cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) , persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints

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%)

7 DRUG INTERACTIONS

• Anticoagulants: Monitor anticoagulant response frequently in order to adjust the anticoagulant dose as needed. (5.1, 7.1)
• Phenytoin: Monitor phenytoin levels in patients taking Xeloda concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1)
• Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1)
• CYP2C9 substrates: Care should be exercised when Xeloda is co-administered with CYP2C9 substrates. (7.1)
• Food reduced both the rate and extent of absorption of Xeloda. (2, 7.1, 12.3)

7.1 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 Boxed 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 (12.3) ]. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by Xeloda 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 (2.3) ]. 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 Xeloda 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 co-administered with CYP2C9 substrates.

7.2 Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of Xeloda [see Clinical Pharmacology (12.3) ]. 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 (2) ].

8 USE IN SPECIFIC POPULATIONS

• Lactation: Advise women not to breastfeed.
• Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of Xeloda. Advise males with female partners of reproductive potential to use effective contraception. (8.3)
• Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5)
• Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6)
• Renal Impairment: Reduce Xeloda starting dose in patients with moderate renal impairment (2.3, 8.7, 12.3)

8.1 Pregnancy

Risk Summary

Based on findings in animal reproduction studies and its mechanism of action, Xeloda can cause fetal harm when administered to a pregnant woman . Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of Xeloda to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively . Apprise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Oral administration of Xeloda to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of Xeloda to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Xeloda in human milk, or on its effects on milk production or the breast-fed infant. Xeloda metabolites were present in the milk of lactating mice . Because of the potential for serious adverse reactions from Xeloda exposure in breast-fed infants, advise women not to breastfeed during treatment with Xeloda and for 2 weeks after the final dose.

Data

Lactating mice given a single oral dose of Xeloda excreted significant amounts of Xeloda metabolites into the milk.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating Xeloda.

Contraception

Females

Xeloda can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of Xeloda.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of Xeloda .

Infertility

Based on animal studies, Xeloda may impair fertility in females and males of reproductive potential .

8.4 Pediatric Use

The safety and effectiveness of Xeloda in pediatric patients have not been established.

Additional information from the two clinical studies in which efficacy was not demonstrated in certain pediatric patients is approved for Hoffmann La Roches' Xeloda (capecitabine) tablets. However, due to Hoffman La Roche's marketing exclusivity rights, this product is not labeled with that information.

8.5 Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of Xeloda in the elderly [see Warnings and Precautions ].

8.6 Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Xeloda. The effect of severe hepatic dysfunction on Xeloda is not known [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3) ].

8.7 Renal Insufficiency

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for Xeloda, 5-DFUR, and FBAL than in those with normal renal function [see Contraindications (4.1) , Warnings and Precautions (5.5) , Dosage and Administration (2.4) , and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for Xeloda overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low-molecular-weight metabolite of the parent compound.

Single doses of Xeloda were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m² basis).

11 DESCRIPTION

Xeloda, USP is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-fluorouracil.

The chemical name for Xeloda, USP is 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Xeloda, USP has the following structural formula:

Xeloda, USP is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20ºC.

Xeloda tablets, USP are supplied as oblong, film-coated, biconvex unscored tablets for oral administration. Each light peach-colored tablet contains 150 mg Xeloda, USP and each peach-colored tablet contains 500 mg Xeloda, USP. The inactive ingredients in Xeloda tablets, USP include: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and purified water. The peach or light peach film-coating contains iron oxide red, iron oxide yellow, macrogol, polyvinyl alcohol, talc and titanium dioxide.

8649c6ce-figure-01

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Enzymes convert Xeloda to 5-fluorouracil in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N^5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

12.3 Pharmacokinetics

Absorption

Following oral administration of 1255 mg/m² BID to cancer patients, Xeloda reached peak blood levels in about 1.5 hours (T_max) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of Xeloda with mean C_max and AUC_0-∞ decreased by 60% and 35%, respectively. The C_max and AUC_0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T_max of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5) , Dosage and Administration (2) , and Drug-Food Interaction (7.2) ].

The pharmacokinetics of Xeloda and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m²/day. Over this range, the pharmacokinetics of Xeloda and its metabolite, 5’-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5’-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the C_max and AUC of 5-FU was greater than 85%.

Distribution

Plasma protein binding of Xeloda and its metabolites is less than 60% and is not concentration-dependent. Xeloda was primarily bound to human albumin (approximately 35%). Xeloda has a low potential for pharmacokinetic interactions related to plasma protein binding.

Bioactivation and Metabolism

Xeloda is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5’-deoxy-5-fluorocytidine (5’-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5’-DFCR to 5’-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5’-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of Xeloda 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.

Metabolic Pathway of Xeloda to 5-FU

The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of Xeloda metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.

In vitro enzymatic studies with human liver microsomes indicated that Xeloda and its metabolites (5’DFUR, 5’-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.

Excretion

Xeloda and its metabolites are predominantly excreted in urine; 95.5% of administered Xeloda dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent Xeloda and 5-FU was about 0.75 hour.

Effect of Age, Gender, and Race on the Pharmacokinetics of Xeloda

A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Xeloda at 1250 mg/m² twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5’-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5’-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4) ].

Following oral administration of 825 mg/m² Xeloda twice daily for 14 days, Japanese patients (n=18) had about 36% lower C_max and 24% lower AUC for Xeloda than the Caucasian patients (n=22). Japanese patients had also about 25% lower C_max and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5’-DFCR, 5’-DFUR, and 5-FU).

Effect of Hepatic Insufficiency

Xeloda has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m² dose of Xeloda. Both AUC_0-∞ and C_max of Xeloda increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC_0-∞ and C_max of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Xeloda is administered. The effect of severe hepatic dysfunction on Xeloda is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6) ].

Effect of Renal Insufficiency

Following oral administration of 1250 mg/m² Xeloda twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5’-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to Xeloda was about 25% greater in both moderately and severely renal impaired patients [see Dosage and Administration (2.4) , Contraindications (4.1) , Warnings and Precautions (5.5) , and Use in Special Populations (8.7) ].

Effect of Xeloda on the Pharmacokinetics of Warfarin

In four patients with cancer, chronic administration of Xeloda (1250 mg/m² bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see Boxed Warning and Drug Interactions (7.1) ].

Effect of Antacids on the Pharmacokinetics of Xeloda

When Maalox ^® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Xeloda (1250 mg/m², n=12 cancer patients), AUC and C_max increased by 16% and 35%, respectively, for Xeloda and by 18% and 22%, respectively, for 5’-DFCR. No effect was observed on the other three major metabolites (5’-DFUR, 5-FU, FBAL) of Xeloda.

Effect of Xeloda on the Pharmacokinetics of Docetaxel and Vice Versa

A Phase 1 study evaluated the effect of Xeloda on the pharmacokinetics of docetaxel (Taxotere^®) and the effect of docetaxel on the pharmacokinetics of Xeloda was conducted in 26 patients with solid tumors. Xeloda was found to have no effect on the pharmacokinetics of docetaxel (C_max and AUC) and docetaxel has no effect on the pharmacokinetics of Xeloda and the 5-FU precursor 5’-DFUR.

8649c6ce-figure-02

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies investigating the carcinogenic potential of Xeloda have not been conducted. Xeloda was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Xeloda was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

In studies of fertility and general reproductive performance in female mice, oral Xeloda doses of 760 mg/kg/day (about 2300 mg/m²/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

14 CLINICAL STUDIES

14.1 Adjuvant Colon Cancer

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C colon cancer provided data concerning the use of Xeloda for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Xeloda to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Xeloda 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m² and 20 mg/m² IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes’ stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5x10⁹/L, platelets ≥ 100x10⁹/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.

The baseline demographics for Xeloda and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.

	Xeloda (n=1004)	5-FU/LV (n=983)
Age (median, years)	62	63
Range	(25 to 80)	(22 to 82)
Gender
Male (n, %)	542 (54)	532 (54)
Female (n, %)	461 (46)	451 (46)
ECOG PS
0 (n, %)	849 (85)	830 (85)
1 (n, %)	152 (15)	147 (15)
Staging – Primary Tumor
PT1 (n, %)	12 (1)	6 (0.6)
PT2 (n, %)	90 (9)	92 (9)
PT3 (n, %)	763 (76)	746 (76)
PT4 (n, %)	138 (14)	139 (14)
Other (n, %)	1 (0.1)	0 (0)
Staging – Lymph Node
pN1 (n, %)	695 (69)	694 (71)
pN2 (n, %)	305 (30)	288 (29)
Other (n, %)	4 (0.4)	1 (0.1)

All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m² orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4) ]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for Xeloda included dose reductions, cycle delays and treatment interruptions (see Table 11).

	Xeloda N = 995	5-FU/LV N = 974
Median relative dose intensity (%)	93	92
Patients completing full course of treatment (%)	83	87
Patients with treatment interruption (%)	15	5
Patients with cycle delay (%)	46	29
Patients with dose reduction (%)	42	44
Patients with treatment interruption, cycle delay, or dose reduction (%)	57	52

The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Xeloda compared to 5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Xeloda was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Xeloda compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 to 1.01). The 5-year overall survival rates were 71.4% for Xeloda and 68.4% for 5-FU/LV (see Figure 2).

All Randomized Population	Xeloda (n=1004)	5-FU/LV (n=983)
aApproximately 93.4% had 5-year DFS information
bBased on Kaplan-Meier estimates
cTest of superiority of Xeloda vs 5-FU/LV (Wald chi-square test)
Median follow-up (months)	83	83
5-year Disease-free Survival Rates (%) b	59.1	54.6
Hazard Ratio	0.88
(Capecitabine/5-FU/LV)	(0.77 to 1.01)
(95% C.I. for Hazard Ratio)
p-valuec	p = 0.068

Figure 1 Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population) ^a

^a Xeloda has been demonstrated to be non-inferior to 5-FU/LV.

Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)

8649c6ce-figure-03 8649c6ce-figure-04

14.2 Metastatic Colorectal Cancer

General

The recommended dose of Xeloda was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with Xeloda (1331 mg/m²/day in two divided doses, n=39), intermittent therapy with Xeloda (2510 mg/m²/day in two divided doses, n=34), and intermittent therapy with Xeloda in combination with oral leucovorin (LV) (capecitabine 1657 mg/m²/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to Xeloda; however, toxicity was increased. Xeloda, 1250 mg/m² twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.

Monotherapy

Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of Xeloda in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with Xeloda at a dose of 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1 to 5, every 28 days).

In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.

The baseline demographics for Xeloda and 5-FU/LV patients are shown in Table 13.

	Study 1		Study 2
	Xeloda (n=302)	5-FU/LV (n=303)	Xeloda (n=301)	5-FU/LV (n=301)
Age (median, years)	64	63	64	64
Range	(23 to 86)	(24 to 87)	(29 to 84)	(36 to 86)
Gender
Male (%)	181 (60)	197 (65)	172 (57)	173 (57)
Female (%)	121 (40)	106 (35)	129 (43)	128 (43)
Karnofsky PS (median)	90	90	90	90
Range	(70 to 100)	(70 to 100)	(70 to 100)	(70 to 100)
Colon (%)	222 (74)	232 (77)	199 (66)	196 (65)
Rectum (%)	79 (26)	70 (23)	101 (34)	105 (35)
Prior radiation therapy (%)	52 (17)	62 (21)	42 (14)	42 (14)
Prior adjuvant 5-FU (%)	84 (28)	110 (36)	56 (19)	41 (14)

The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15.

	Xeloda (n=302)	5-FU/LV (n=303)
Overall Response Rate (%, 95% C.I.)	21 (16 to 26)	11 (8 to 15)
(p-value)	0.0014
Time to Progression (Median, days, 95% C.I.)	128 (120 to 136)	131 (105 to 153)
Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio	0.99 (0.84 to 1.17)
Survival (Median, days, 95% C.I.)	380 (321 to 434)	407 (366 to 446)
Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio	1 (0.84 to 1.18)

	Xeloda (n=301)	5-FU/LV (n=301)
Overall Response Rate (%, 95% C.I.)	21 (16 to 26)	14 (10 to 18)
(p-value)	0.027
Time to Progression (Median, days, 95% C.I.)	137 (128 to 165)	131 (102 to 156)
Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio	0.97 (0.82 to 1.14)
Survival (Median, days, 95% C.I.)	404 (367 to 452)	369 (338 to 430)
Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio	0.92 (0.78 to 1.09)

Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)

Xeloda was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of Xeloda and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that Xeloda has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by Xeloda. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and Xeloda, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs Xeloda difference. These results do not exclude the possibility of true equivalence of Xeloda to 5-FU/LV (see Table 14 , Table 15 , and Figure 3).

8649c6ce-figure-05

14.3 Breast Cancer

Xeloda has been evaluated in clinical trials in combination with docetaxel (Taxotere ^® ) and as monotherapy.

In Combination With Docetaxel

The dose of Xeloda used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of Xeloda (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m² administered in 3week cycles of docetaxel in combination with 1250 mg/m² twice daily for 14 days of Xeloda administered in 3-week cycles. The approved dose of 100 mg/m² of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.

Xeloda in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive Xeloda 1250 mg/m² twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m² as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m² as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.

	Xeloda + Docetaxel (n=255)	Docetaxel (n=256)
1Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
Age (median, years)	52	51
Karnofsky PS (median)	90	90
Site of Disease
Lymph nodes	121 (47%)	125 (49%)
Liver	116 (45%)	122 (48%)
Bone	107 (42%)	119 (46%)
Lung	95 (37%)	99 (39%)
Skin	73 (29%)	73 (29%)
Prior Chemotherapy
Anthracycline1	255 (100%)	256 (100%)
5-FU	196 (77%)	189 (74%)
Paclitaxel	25 (10%)	22 (9%)
Resistance to an Anthracycline
No resistance	19 (7%)	19 (7%)
Progression on anthracycline therapy	65 (26%)	73 (29%)
Stable disease after 4 cycles of anthracycline therapy	41 (16%)	40 (16%)
Relapsed within 2 years of completion of anthracycline-adjuvant therapy	78 (31%)	74 (29%)
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose	51 (20%)	50 (20%)
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
0	89 (35%)	80 (31%)
1	123 (48%)	135 (53%)
2	43 (17%)	39 (15%)
3	0 (0%)	2 (1%)

Xeloda in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.

Efficacy Parameter	Combination Therapy	Monotherapy	p-value	Hazard Ratio
1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
2 NA = Not Applicable
Time to Disease Progression
Median Days	186	128	0.0001	0.643
95% C.I.	(165 to 198)	(105 to 136)
Overall Survival
Median Days	442	352	0.0126	0.775
95% C.I.	(375 to 497)	(298 to 387)
Response Rate 1	32%	22%	0.009	NA2

Figure 4 Kaplan-Meier Estimates for Time to Disease Progression Xeloda and Docetaxel vs Docetaxel

Figure 5 Kaplan-Meier Estimates of Survival Xeloda and Docetaxel vs Docetaxel

Monotherapy

The antitumor activity of Xeloda as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Xeloda was administered at a dose of 1255 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was 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 chemotherapy regimen.

	Patients With Measurable Disease (n=135)	All Patients (n=162)
1Lung, pleura, liver, peritoneum
2Includes 2 patients treated with an anthracenedione
Age (median, years)	55	56
Karnofsky PS	90	90
No. Disease Sites
1 to 2	43 (32%)	60 (37%)
3 to 4	63 (46%)	69 (43%)
>5	29 (22%)	34 (21%)
Dominant Site of Disease
Visceral1	101 (75%)	110 (68%)
Soft Tissue	30 (22%)	35 (22%)
Bone	4 (3%)	17 (10%)
Prior Chemotherapy
Paclitaxel	135 (100%)	162 (100%)
Anthracycline2	122 (90%)	147 (91%)
5-FU	110 (81%)	133 (82%)
Resistance to Paclitaxel	103 (76%)	124 (77%)
Resistance to an Anthracycline2	55 (41%)	67 (41%)
Resistance to both Paclitaxel and an Anthracycline 2	43 (32%)	51 (31%)

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.

	Resistance to Both Paclitaxel and an Anthracycline (n=43)
1Includes 2 patients treated with an anthracenedione
2From date of first response
CR	0
PR1	11
CR + PR1	11
Response Rate1 (95% C.I.)	25.6% (13.5, 41.2)
Duration of Response,1 Median in days2 (Range)	154 (63 to 233)

For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.

8649c6ce-figure-06 8649c6ce-figure-07

15 REFERENCES

• ”OSHA Hazardous Drugs.” OSHA.
  

  http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

Xeloda tablets, USP, 150 mg, are supplied as light peach, oblong, film-coated, biconvex, unscored tablets, debossed with ‘AN’ on one side and ‘843’ on the other side.

They are available as follows:

Bottles of 60: NDC 65162-843-06

Xeloda tablets, USP, 500 mg, are supplied as peach, oblong, film-coated, biconvex, unscored tablets, debossed with ‘AN’ on one side and ‘844’ on the other side

They are available as follows:

Bottles of 60: NDC 65162-844-06

Bottles of 120: NDC 65162-844-16

Bottles of 500: NDC 65162-844-50

Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED.

Xeloda tablets, USP are a cytotoxic drug. Follow applicable special handling and disposal procedures.¹ Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients and patients’ caregivers should be informed of the expected adverse effects of Xeloda, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary [see Dosage and Administration (2.3) ]. As described below, patients taking Xeloda should be informed of the need to interrupt treatment and to call their physician immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Xeloda treatment. See FDA-approved patient labeling (Patient Information).

Dihydropyrimidine Dehydrogenase Deficiency

Patients should be advised to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Xeloda (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) .

Diarrhea

Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever should be instructed to stop taking Xeloda and call their physician immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.

Dehydration

Patients experiencing grade 2 or higher dehydration should be instructed to stop taking Xeloda immediately and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.

Nausea

Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking Xeloda immediately. Initiation of symptomatic treatment is recommended.

Vomiting

Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking Xeloda immediately. Initiation of symptomatic treatment is recommended.

Hand-and-Foot Syndrome

Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients’ activities of daily living) or greater should be instructed to stop taking Xeloda immediately. Initiation of symptomatic treatment is recommended. Hand-and-foot syndrome can lead to loss of fingerprints which could impact your identification.

Stomatitis

Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking Xeloda immediately and to call their physician. Initiation of symptomatic treatment is recommended.

Fever and Neutropenia

Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician immediately.

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with Xeloda and for 6 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Xeloda and for 3 months after the last dose .

Lactation

Advise females not to breastfeed during treatment with Xeloda and for 2 weeks after the last dose .

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 12-2016-00

Patient Information

Xeloda (KAP-e-SYE-ta-been) Tablets USP, Film-Coated

What is the most important information I should know about Xeloda tablets?

Xeloda tablets can cause serious side effects, including:

• Xeloda tablets can interact with blood thinner medicines, such as warfarin (COUMADIN^®). Taking Xeloda tablets with these medicines can cause changes in how fast your blood clots, and can cause bleeding that can lead to death. This can happen as soon as a few days after you start taking Xeloda tablets, or later during treatment, and possibly even within 1 month after you stop taking Xeloda tablets. Your risk may be higher because you have cancer, and if you are over 60 years of age.
  • Before taking Xeloda tablets, tell your doctor if you are taking warfarin (COUMADIN) or another blood thinner medicine.
  • If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with Xeloda tablets, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with Xeloda tablets. Your doctor may change your dose of the blood thinner medicine if needed.

See “What are the possible side effects of Xeloda tablets?” for more information about side effects.

What are Xeloda tablets?

Xeloda tablets are a prescription medicine used to treat people with:

• cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes’ C stage), after they have 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.
• 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.

It is not known if Xeloda tablets are safe and effective in children.

Who should not take Xeloda tablets?

Do not take Xeloda tablets if you:

• have severe kidney problems.
• are allergic to Xeloda, 5-fluorouracil or to any of the ingredients in Xeloda tablets. See the end of this leaflet for a complete list of ingredients in Xeloda tablets.

Talk to your doctor before taking Xeloda tablets if you are not sure if you have any of the conditions listed above.

What should I tell my doctor before taking Xeloda tablets?

See “What is the most important information I should know about Xeloda tablets?”

Before you take Xeloda tablets, tell your doctor if you:

• have had heart problems.
• have kidney or liver problems.
• have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)
• have any other medical conditions.
• are pregnant or plan to become pregnant. Xeloda tablets may harm your unborn baby. You should not become pregnant during treatment with Xeloda tablets. Talk to your doctor about birth control choices that may be right for you during treatment with Xeloda tablets.
• are breastfeeding or plan to breastfeed. It is not known if Xeloda passes into your breast milk. Do not breastfeed during treatment with Xeloda tablets.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Xeloda tablets may affect the way other medicines work, and other medicines may affect the way Xeloda tablets work.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Xeloda tablets?

• Take Xeloda tablets exactly as your doctor tells you to take it.
• Your doctor will tell you how much Xeloda tablets to take and when to take it.
• Take Xeloda tablets 2 times a day, 1 time in the morning and 1 time in the evening.
• Take Xeloda tablets within 30 minutes after finishing a meal. Swallow Xeloda tablets whole with water. Do not crush or cut Xeloda tablets.
• Ask your healthcare provider or pharmacist how to safely throw away any unused Xeloda tablets.
• If you have side effects with Xeloda tablets, if needed your doctor may decide to:
  • change your dose of Xeloda tablets
  • treat you with Xeloda tablets less often
  • tell you to stop taking Xeloda tablets until certain side effects get better or go away
  • stop your treatment with Xeloda tablets if you have certain side effects and they are severe
• If you take too much Xeloda tablets, call your doctor or go to the nearest emergency room right away.

What are the possible side effects of Xeloda tablets?

Xeloda tablets may cause serious side effects including:

See “What is the most important information I should know about Xeloda tablets?”

• diarrhea. Diarrhea is common with Xeloda tablets and can sometimes be severe. Stop taking Xeloda tablets and call your doctor right away if the number of bowel movements you have in a day increases by 4 or more than is usual for you. Ask your doctor about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, call your doctor or go to the nearest emergency room right away.
• heart problems. Xeloda tablets can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle, heart failure, and sudden death. Stop taking Xeloda tablets and call your doctor right away if you get any of the following symptoms:
• unexplained tiredness
• loss of too much body fluid (dehydration) and kidney failure.
  

  Dehydration can happen with Xeloda tablets and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking Xeloda tablets and also take other medicines that can cause kidney problems.

Nausea, and vomiting are common with Xeloda tablets. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated.

Stop taking Xeloda tablets and call your doctor right away if you:

• vomit 2 or more times in a day.
• are only able to eat or drink a little now and then, or not at all due to nausea.
• have diarrhea. See “diarrhea” above.
• serious skin and mouth reactions.
• Xeloda tablets can cause serious skin reactions that may lead to death. Tell your doctor right away if you develop a skin rash, blisters and peeling of your skin. Your doctor may tell you to stop taking Xeloda tablets if you have a serious skin reaction. Do not take Xeloda tablets again if this happens.
• Xeloda tablets can also cause “hand and foot syndrome.” Hand and foot syndrome is common with Xeloda tablets and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking Xeloda tablets and call your doctor right away if you have any of these symptoms and you are not able to do your usual activities. Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.
• you may get sores in your mouth or on your tongue when taking Xeloda tablets. Stop taking Xeloda tablets and call your doctor if you get painful redness, swelling, or ulcers in your mouth and tongue, or if you are having problems eating. Tell your doctor if you have any side effect that bothers you or that does not go away.
• increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with Xeloda tablets. Your doctor will check you for these problems during treatment with Xeloda tablets.
• decreased white blood cells, platelets, and red blood cell counts. Your doctor will do blood tests during treatment with Xeloda tablets to check your blood cell counts.

If your white blood cell count is very low, you are at increased risk for infection. Call your doctor right away if you develop a fever of 100.5°F or greater or have other signs and symptoms of infection.

People 80 years of age or older may be more likely to develop severe or serious side effects with Xeloda tablets.

The most common side effects of Xeloda tablets include:

• diarrhea
• hand and foot syndrome
• nausea
• vomiting
• stomach-area (abdominal) pain
• tiredness
• weakness
• increased amounts of red blood cell breakdown products (bilirubin) in your blood

These are not all the possible side effects of Xeloda tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Xeloda tablets?

• Store Xeloda tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Xeloda tablets in a tightly closed container.
• Keep Xeloda tablets and all medicines out of the reach of children.

General information about the safe and effective use of Xeloda tablets.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Xeloda tablets for a condition for which it was not prescribed. Do not give Xeloda tablets to other people, even if they have the same symptoms you have. It may harm them.

You can ask your pharmacist or doctor for information about Xeloda tablets that is written for health professionals.

For more information, go to www.amneal.com or call 1-877-835-5472.

What are the ingredients in Xeloda tablets?

Active ingredient: Xeloda, USP

Inactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and purified water. The peach or light peach film-coating contains iron oxide red, iron oxide yellow, macrogol, polyvinyl alcohol, talc and titanium dioxide.

XELODA^® is a registered trademark of Hoffmann-La Roche Inc.

For full TAXOTERE prescribing information, please refer to TAXOTERE Package Insert.

This Patient Information has been approved by the U.S. Food and Drug Administration.

All trade names drug products are the property of their respective owners.

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 03-2017-01

Xeloda pharmaceutical active ingredients containing related brand and generic drugs:

• Capecitabine

Xeloda available forms, composition, doses:

• Tablets, Film-Coated; Oral; Capecitabine 150 mg
• Tablets, Film-Coated; Oral; Capecitabine 500 mg
• Tablets; Oral; Capecitabine 150 mg
• Tablets; Oral; Capecitabine 500 mg
• XELODA 150MG TABLET
• XELODA 500MG TABLET

Xeloda destination | category:

• Human:
• Antineoplastic agents
• Cytotoxic chemotherapy

Xeloda Anatomical Therapeutic Chemical codes:

• L01BC06 - Capecitabine

Xeloda pharmaceutical companies:

• DKSH
• Genentech
• HLR
• Roche
• Zuellig Pharma

References

1. Dailymed."CAPECITABINE TABLET [AMNEAL PHARMACEUTICALS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."CAPECITABINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "CAPECITABINE". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Xeloda?

Depending on the reaction of the Xeloda after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Xeloda not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Xeloda addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Xeloda, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Xeloda consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology