CAPECITABINE- capecitabine tablet, film coated 
KAISER FOUNDATION HOSPITALS

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use capecitabine tablets USP safely and effectively. See full prescribing information for capecitabine tablets USP.



Capecitabine Tablets USP, Film-Coated for Oral use

Initial U.S. Approval: 1998

WARNING: CAPECITABINE-WARFARIN INTERACTION

See full prescribing information for complete boxed warning.

Patients receiving concomitant capecitabine 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 capecitabine therapy; may also be seen within 1 month after stopping capecitabine
  • Predisposing factors: age> 60 and diagnosis of cancer

INDICATIONS AND USAGE

Capecitabine Tablets USP are a nucleoside metabolic inhibitor with antineoplastic activity indicated for:

  • Adjuvant Colon Cancer ( 1.1)

– 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

DOSAGE AND ADMINISTRATION

  • Take capecitabine tablets with water within 30 min after a meal ( 2)
  • Monotherapy: 1250 mg/m 2 twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles ( 2.1)
  • Adjuvant treatment is recommended for a total of 6 months (8 cycles) ( 2.1)
  • In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m 2 twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m 2 as a 1-hour IV infusion every 3 weeks ( 2.1)
  • Capecitabine tablets dosage may need to be individualized to optimize patient management
    ( 2.2)
  • Reduce the dose of capecitabine tablets by 25% in patients with moderate renal impairment ( 2.3)

DOSAGE FORMS AND STRENGTHS

  • Tablets: 150 mg and 500 mg ( 3)

CONTRAINDICATIONS

  • Dihydropyrimidine dehydrogenase (DPD) deficiency ( 4.1)
  • Severe Renal Impairment ( 4.2)
  • Hypersensitivity ( 4.3)

WARNINGS AND PRECAUTIONS

  • Diarrhea: May be severe. Interrupt capecitabine treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. ( 5.1)
  • Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. ( 5.2)
  • Cardiotoxicity: Common in patients with a prior history of coronary artery disease. ( 5.3)
  • Pregnancy: Can cause fetal harm. Advise women of the potential risk to the fetus. ( 5.6, 8.1)
  • Hand-and-Foot Syndrome (Grade 2 or 3): Interrupt capecitabine treatment until the event resolves or decreases in intensity. ( 5.7)
  • Hyperbilirubinemia (Grade 2 to 4): Interrupt capecitabine treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. ( 5.8)
  • Hematologic: Do not treat patients with neutrophil counts < 1.5 × 10 9/L or thrombocyte counts < 100 × 10 9/L. If grade 3 to 4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. ( 5.9)

ADVERSE REACTIONS

Most common adverse reactions (≥ 30%) 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 TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

  • Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. ( 5.2, 7.1)
  • Phenytoin: Monitor phenytoin levels in patients taking capecitabine 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 capecitabine is coadministered with CYP2C9 substrates. ( 7.1)
  • Food reduced both the rate and extent of absorption of capecitabine. ( 2, 7.1, 12.3)

USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Discontinue nursing when receiving capecitabine treatment. ( 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 capecitabine starting dose in patients with moderate renal impairment ( 2.3, 8.7, 12.3)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CAPECITABINE-WARFARIN INTERACTION

1 INDICATIONS AND USAGE

1.1 Colorectal Cancer

1.2 Breast Cancer

2 DOSAGE AND ADMINISTRATION

2.1 Standard Starting Dose

2.2 Dose Management Guidelines

2.3 Adjustment of Starting Dose in Special Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Dihydropyrimidine Dehydrogenase (DPD) Deficiency

4.2 Severe Renal Impairment

4.3 Hypersensitivity

5 WARNINGS AND PRECAUTIONS

5.1 Diarrhea

5.2 Coagulopathy

5.3 Cardiotoxicity

5.4 Dihydropyrimidine Dehydrogenase Deficiency

5.5 Renal Insufficiency

5.6 Pregnancy

5.7 Hand-and-Foot Syndrome

5.8 Hyperbilirubinemia

5.9 Hematologic

5.10 Geriatric Patients

5.11 Hepatic Insufficiency

5.12 Combination With Other Drugs

6 ADVERSE REACTIONS

6.1 Adjuvant Colon Cancer

6.2 Metastatic Colorectal Cancer

6.3 Breast Cancer

6.4 Clinically Relevant Adverse Events in < 5% of Patients

7 DRUG INTERACTIONS

7.1 Drug-Drug Interactions

7.2 Drug-Food Interaction

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Insufficiency

8.7 Renal Insufficiency

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Adjuvant Colon Cancer

14.2 Metastatic Colorectal Cancer

14.3 Breast Cancer

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Capecitabine Tablets USP, 500 mg Label

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: CAPECITABINE-WARFARIN INTERACTION

Capecitabine-Warfarin Interaction: Patients receiving concomitant capecitabine 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 ( 5.2) and Drug Interactions ( 7.1) ]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine 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 capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. 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.

1 INDICATIONS AND USAGE

1.1 Colorectal Cancer

  • Capecitabine Tablets USP 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. Capecitabine tablets USP was 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 capecitabine tablets USP in the adjuvant treatment of Dukes' C colon cancer.
  • Capecitabine Tablets USP 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 capecitabine tablets USP monotherapy. Use of capecitabine tablets USP 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

  • Capecitabine Tablets USP in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
  • Capecitabine Tablets USP 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/m 2 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

Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Capecitabine tablets dose is calculated according to body surface area.

2.1 Standard Starting Dose

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

The recommended dose of capecitabine tablets are 1250 mg/m 2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m 2 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 [i.e., capecitabine tablets 1250 mg/m 2 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)].

Table 1: Capecitabine Tablets Dose Calculation According to Body Surface Area
*
Total Daily Dose divided by 2 to allow equal morning and evening doses
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 mg500 mg
≤ 1.25300003
1.26 to 1.37330013
1.38 to 1.51360023
1.52 to 1.65400004
1.66 to 1.77430014
1.78 to 1.91460024
1.92 to 2.05500005
2.06 to 2.17530015
≥ 2.18560025

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of capecitabine tablets are 1250 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m 2 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 capecitabine tablets plus docetaxel combination. Table 1 displays the total daily dose of capecitabine tablets by body surface area and the number of tablets to be taken at each dose.

2.2 Dose Management Guidelines

General

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

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

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

Table 2: Recommended Dose Modifications of Capecitabine Tablets
*
National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [ see Warnings and Precautions ( 5) ].
Toxicity NCIC Grades *
During a Course of Therapy
Dose Adjustment for Next Treatment (% of starting dose)
Grade 1Maintain dose levelMaintain dose level
Grade 2
-1st appearanceInterrupt until resolved to grade 0 to 1100%
-2nd appearance75%
-3rd appearance50%
-4th appearanceDiscontinue treatment permanently-
Grade 3
-1st appearanceInterrupt until resolved to grade 0 to 175%
-2nd appearance50%
-3rd appearanceDiscontinue treatment permanently-
Grade 4
-1st appearanceDiscontinue permanently
OR
If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0 to 1
50%

In Combination With Docetaxel (Metastatic Breast Cancer)

Dose modifications of capecitabine tablets for toxicity should be made according to Table 2 above for capecitabine tablets. At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine 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 capecitabine tablets for the treatment of metastatic breast cancer is shown in Table 3.

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

2.3 Adjustment of Starting Dose in Special Populations

Renal Impairment

No adjustment to the starting dose of capecitabine 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 capecitabine tablets starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m 2 to 950 mg/m 2 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 2and 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 capecitabine tablets monotherapy and capecitabine 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 × male value

Geriatrics

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

3 DOSAGE FORMS AND STRENGTHS

150 mg: Peach to light peach, oblong, film-coated, biconvex, unscored tablets, debossed with 190 on one side and 77 on the other side.

500 mg: Peach to light peach, oblong, film-coated, biconvex, unscored tablets debossed with 191 on one side and 77 on the other side.

4 CONTRAINDICATIONS

4.1 Dihydropyrimidine Dehydrogenase (DPD) Deficiency

Capecitabine is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.

4.2 Severe Renal Impairment

Capecitabine 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) ].

4.3 Hypersensitivity

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

5 WARNINGS AND PRECAUTIONS

General

Patients receiving therapy with capecitabine should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced [ see Dosage and Administration ( 2.2) ].

5.1 Diarrhea

Capecitabine 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 capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 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 capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased [ see Dosage and Administration ( 2.2) ]. Standard antidiarrheal treatments (e.g., loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

5.2 Coagulopathy

Patients receiving concomitant capecitabine 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) ] .

5.3 Cardiotoxicity

The cardiotoxicity observed with capecitabine 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

Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.

5.5 Renal Insufficiency

Patients with moderate renal impairment at baseline require dose reduction [ see Dosage and Administration ( 2.3) ]. 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 ( 2.2), Use in Specific Populations ( 8.6), and Clinical Pharmacology ( 12.3) ].

5.6 Pregnancy

Capecitabine may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving capecitabine, the patient should be apprised of the potential hazard to the fetus [ see Use in Specific Populations ( 8.1) ].

5.7 Hand-and-Foot Syndrome

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 capecitabine 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. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine should be decreased [ see Dosage and Administration ( 2.2) ].

5.8 Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (> 3 × 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 capecitabine 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 capecitabine 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 capecitabine. 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 capecitabine and docetaxel, grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 × ULN) hyperbilirubinemia occurred in 2% (n = 5).

If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3 X ULN [see recommended dose modifications under Dosage and Administration ( 2.2) ].

5.9 Hematologic

In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m 2 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 capecitabine 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 × 10 9/L and/or thrombocyte counts of < 100 × 10 9/L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine 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 capecitabine monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), 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 capecitabine 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 capecitabine 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 capecitabine 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 capecitabine 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; capecitabine 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 capecitabine 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 capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3) ].

5.12 Combination With Other Drugs

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

6 ADVERSE REACTIONS

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

6.1 Adjuvant Colon Cancer

Table 4 shows the adverse reactions occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 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%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1%) randomized to 5-FU/LV.

Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.

Table 4: Percent Incidence of Adverse Reactions Reported in ≥ 5% of Patients Treated With Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)
 Adjuvant Treatment for Colon Cancer (N = 1969)
 Capecitabine
(N = 995)
5-FU/LV
(N = 974)
Body System/
Adverse Event
All GradesGrade 3/4All GradesGrade 3/4
Gastrointestinal Disorders
  Diarrhea47126514
  Nausea342472
  Stomatitis2226014
  Vomiting152212
  Abdominal Pain143162
  Constipation9-11< 1
  Upper Abdominal Pain7< 17< 1
  Dyspepsia6< 15-
Skin and Subcutaneous Tissue Disorders
  Hand-and-Foot Syndrome60179< 1
  Alopecia6-22< 1
  Rash7-8-
  Erythema615< 1
General Disorders and Administration Site Conditions
  Fatigue16< 1161
  Pyrexia7< 19< 1
  Asthenia10< 1101
  Lethargy10< 19< 1
Nervous System Disorders
  Dizziness6< 16-
  Headache5< 16< 1
  Dysgeusia6-9-
Metabolism and Nutrition Disorders
  Anorexia9< 111< 1
Eye Disorders
  Conjunctivitis5< 16< 1
Blood and Lymphatic System Disorders
  Neutropenia2< 185
Respiratory Thoracic and Mediastinal Disorders
  Epistaxis2-5-
Table 5: Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)
*
The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm.
It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3 × 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.
Adverse EventCapecitabine
(n = 995)
Grade 3/4 %
IV 5-FU/LV
(n = 974)
Grade 3/4 %
Increased ALAT (SGPT)1.60.6
Increased calcium1.10.7
Decreased calcium2.32.2
Decreased hemoglobin11.2
Decreased lymphocytes1313
Decreased neutrophils *2.226.2
Decreased neutrophils/granulocytes2.426.4
Decreased platelets10.7
Increased bilirubin 206.3

6.2 Metastatic Colorectal Cancer

Monotherapy

Table 6shows 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/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1 to 5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-FU/LV.

Table 6: Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥ 5% of Patients
– Not observed
NA = Not Applicable
*
Excluding vertigo
Adverse EventCapecitabine
(n = 596)
5-FU/LV
(n = 593)
 Total %Grade 3 %Grade 4 %Total %Grade 3 %Grade 4 %
Number of Patients With > One Adverse Event9652994459
Body System/Adverse Event
GI
  Diarrhea5513261102
  Nausea434513< 1
  Vomiting274< 1304< 1
  Stomatitis252< 162141
  Abdominal Pain359< 1315
  Gastrointestinal Motility Disorder10< 17< 1
  Constipation141< 1171
  Oral Discomfort1010
  Upper GI Inflammatory Disorders8< 1101
  Gastrointestinal Hemorrhage61< 131
  Ileus641521
Skin and Subcutaneous
  Hand-and-Foot Syndrome5417NA61NA
  Dermatitis271261
  Skin Discoloration7< 15
  Alopecia621< 1
General
  Fatigue/Weakness424464
  Pyrexia181212
  Edema15191
  Pain121101
  Chest Pain6161< 1
Neurological
  Peripheral Sensory Neuropathy104
  Headache1017
  Dizziness *8< 18< 1
  Insomnia77
  Taste Disturbance6111< 11
Metabolism
  Appetite Decreased263< 1312< 1
  Dehydration72< 1831
Eye
  Eye Irritation1310< 1
  Vision Abnormal52
Respiratory
  Dyspnea14110< 11
  Cough7< 118
  Pharyngeal Disorder55
  Epistaxis3< 16
  Sore Throat26
Musculoskeletal
  Back Pain1029< 1
  Arthralgia8161
Vascular
  Venous Thrombosis83< 162
Psychiatric
  Mood Alteration56< 1
  Depression54< 1
Infections
  Viral5< 15< 1
Blood and Lymphatic
  Anemia802< 1791< 1
  Neutropenia131246813
Hepatobiliary
  Hyperbilirubinemia481851733

6.3 Breast Cancer

In Combination with Docetaxel

The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7  and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m 2 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/m 2 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/m 2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.

Table 7: Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥ 5% of Patients Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study
– Not observed
NA = Not Applicable
Adverse EventCapecitabine 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 Event9976.529.19757.631.8
Body System/Adverse Event
GI
  Diarrhea6714< 1485< 1
  Stomatitis6717< 1435
  Nausea457362
  Vomiting3541242
  Constipation20218
  Abdominal Pain30< 3< 1242
  Dyspepsia1481
  Dry Mouth6< 15
Skin and Subcutaneous
  Hand-and-Foot Syndrome6324NA81NA
  Alopecia416427
  Nail Disorder14215
  Dermatitis8111
  Rash Erythematous9< 15
  Nail Discoloration64< 1
  Onycholysis5151
  Pruritus45
General
  Pyrexia282342
  Asthenia264< 1256
  Fatigue224276
  Weakness162112
  Pain in Limb13< 1132
  Lethargy762
  Pain7< 151
  Chest Pain (non-cardiac)4< 162
  Influenza-like Illness55
Neurological
  Taste Disturbance16< 114< 1
  Headache153152
  Paresthesia12< 1161
  Dizziness128< 1
  Insomnia810< 1
  Peripheral Neuropathy6101
  Hypoaesthesia4< 18< 1
Metabolism
  Anorexia13111< 1
  Appetite Decreased105
  Weight Decreased75
  Dehydration1027< 1< 1
Eye
  Lacrimation Increased127< 1
  Conjunctivitis54
  Eye Irritation51
Musculoskeletal
  Arthralgia152243
  Myalgia152252
  Back Pain12< 1113
  Bone Pain8< 1102
Cardiac
  Edema33< 234< 31
Blood
  Neutropenic Fever1631321516
Respiratory
  Dyspnea142< 1162
  Cough13122< 1
  Sore Throat12211< 1
  Epistaxis7< 16
  Rhinorrhea53
  Pleural Effusion2174
Infection
  Oral Candidiasis7< 18< 1
  Urinary Tract Infection6< 14
  Upper Respiratory Tract451
Vascular
  Flushing55
  Lymphoedema3< 151
Psychiatric
  Depression551
Table 8: Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study
Adverse EventCapecitabine 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
  Leukopenia913724884233
  Neutropenia/Granulocytopenia862049871066
  Thrombocytopenia41212312
  Anemia8073835< 1
  Lymphocytopenia994841984440
Hepatobiliary
  Hyperbilirubinemia2072622

Monotherapy

The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m 2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.

Table 9: Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥ 5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer
– Not observed
NA = Not Applicable
Adverse EventPhase 2 Trial in Stage IV Breast Cancer
(n = 162)
Body System/Adverse EventTotal %Grade 3 %Grade 4 %
GI
Diarrhea57123
Nausea534
Vomiting374
Stomatitis247
Abdominal Pain204
Constipation151
Dyspepsia8
Skin and Subcutaneous
Hand-and-Foot Syndrome5711NA
Dermatitis371
Nail Disorder7
General
Fatigue418
Pyrexia121
Pain in Limb61
Neurological
Paresthesia211
Headache91
Dizziness8
Insomnia8
Metabolism
Anorexia233
Dehydration741
Eye
Eye Irritation15
Musculoskeletal
Myalgia9
Cardiac
Edema91
Blood
Neutropenia2622
Thrombocytopenia2431
Anemia7231
Lymphopenia944415
Hepatobiliary
Hyperbilirubinemia2292

6.4 Clinically Relevant Adverse Events in < 5% of Patients

Clinically relevant adverse events reported in < 5% of patients treated with capecitabine either as monotherapy or in combination with docetaxol 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

 

Capecitabine 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

7.1 Drug-Drug Interactions

Anticoagulants

Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine 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 capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. 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 capecitabine and/or its metabolites.

Phenytoin

The level of phenytoin should be carefully monitored in patients taking capecitabine and phenytoin dose may need to be reduced [ see Dosage and Administration ( 2.2) ]. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.

Leucovorin

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

CYP2C9 substrates

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

7.2 Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of capecitabine [ see Clinical Pharmacology ( 12.3) ]. In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal. It is recommended that capecitabine be administered with food
[ see Dosage and Administration ( 2) ] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects 

Pregnancy Category D

Capecitabine can cause fetal harm when administered to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding 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. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose.

There are no adequate and well controlled studies of capecitabine in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving capecitabine, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with capecitabine [ see Warnings and Precautions ( 5.6) ] .

8.3 Nursing Mothers

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of capecitabine in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine was similar.

The first trial was conducted in 22 pediatric patients (median age 8 years, range 5 to 17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m 2 to 850 mg/m 2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m 2 capecitabine every 12 hours on Days 1 to 14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m 2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.

The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3 to 16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m 2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m 2 capecitabine every 12 hours on Days 1 to 14 of a 21-day cycle for up to 3 cycles.

There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.

The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥ 40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

.

8.5 Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of capecitabine in the elderly [ see Warnings and Precautions ( 5.11) ].

8.6 Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with capecitabine. The effect of severe hepatic dysfunction on capecitabine 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 capecitabine, 5-FDUR, and FBAL than in those with normal renal function [ see Contraindications ( 4.2), Warnings and Precautions ( 5.5), Dosage and Administration ( 2.3), 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 capecitabine 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 capecitabine 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/m 2 basis).

11 DESCRIPTION

Capecitabine Tablets USP are a fluoropyrimidine carbamate with antineoplastic activity. They are an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.

The chemical name for capecitabine, USP is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has the following structural formula:

Structural Formula

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

Capecitabine Tablets USP are supplied as oblong, film-coated, biconvex, unscored tablets for oral administration. Each peach to light peach-colored tablet contains 150 mg or 500 mg capecitabine, USP. The inactive ingredients are as follows: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide, and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Enzymes convert capecitabine to 5-fluorouracil (5-FU) 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/m 2 BID to cancer patients, capecitabine 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 capecitabine with mean C max and AUC 0 to ∞ decreased by 60% and 35%, respectively. The C max and AUC 0 to ∞ 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 capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m 2/day. Over this range, the pharmacokinetics of capecitabine 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 capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding.

Bioactivation and Metabolism

Capecitabine 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 capecitabine 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

The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH 2). 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 capecitabine 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

Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine 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 capecitabine and 5-FU was about 0.75 hour.

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

A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n = 505) who were administered capecitabine at 1250 mg/m 2 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 ( 2.3) ].

Following oral administration of 825 mg/m 2 capecitabine twice daily for 14 days, Japanese patients (n = 18) had about 36% lower C max and 24% lower AUC for capecitabine 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

Capecitabine 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/m 2 dose of capecitabine. Both AUC 0 to ∞ and C max of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n = 14). The AUC 0 to ∞ 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 capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known [ see Warnings and Precautions ( 5.11) and Use in Specific Populations ( 8.6) ] .

Effect of Renal Insufficiency

Following oral administration of 1250 mg/m 2 capecitabine 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 capecitabine was about 25% greater in both moderately and severely renal impaired patients [ see Dosage and Administration ( 2.3), Contraindications ( 4.2), Warnings and Precautions ( 5.5), and Use in Specific Populations ( 8.7) ].

Effect of Capecitabine on the Pharmacokinetics of Warfarin

In four patients with cancer, chronic administration of capecitabine (1250 mg/m 2 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 Capecitabine

When Maalox ® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1250 mg/m 2, n = 12 cancer patients), AUC and C max increased by 16% and 35%, respectively, for capecitabine 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 capecitabine.

Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine 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.

Impairment of Fertility

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m 2/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 (X-ACT) provided data concerning the use of capecitabine 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 capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with capecitabine 1250 mg/m 2 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/m 2 and 20 mg/m 2 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 ≥ 1.5×10 9/L, platelets ≥ 100×10 9/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 capecitabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.

Table 10: Baseline Demographics
Capecitabine
(n = 1004)
5-FU/LV
(n = 983)
Age (median, years)6263
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/m 2 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 ( 2.3) ]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11).

Table 11: Summary of Dose Modifications in X-ACT Study
Capecitabine
N = 995
5-FU/LV
N = 974
Median relative dose intensity (%)9392
Patients completing full course of treatment (%)8387
Patients with treatment interruption (%)155
Patients with cycle delay (%)4629
Patients with dose reduction (%)4244
Patients with treatment interruption, cycle delay, or dose reduction (%)5752

The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, capecitabine 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 capecitabine 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 capecitabine and 68.4% for 5-FU/LV (see Figure 2).

Table 12: Efficacy of Capecitabine vs 5-FU/LV in Adjuvant Treatment of Colon Cancer *
*
Approximately 93.4% had 5-year DFS information
Based on Kaplan-Meier estimates
Test of superiority of capecitabine vs 5-FU/LV (Wald chi-square test)
All Randomized PopulationCapecitabine
(n = 1004)
5-FU/LV
(n = 983)
Median follow-up (months)8383
5-year Disease-free Survival Rates (%) 59.154.6
Hazard Ratio0.88
(Capecitabine/5-FU/LV)
(0.77 to 1.01)
(95% C.I. for Hazard Ratio)
p-value p = 0.068
Figure 1
Figure 2

14.2 Metastatic Colorectal Cancer

General

The recommended dose of capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m 2/day in two divided doses, n = 39), intermittent therapy with capecitabine (2510 mg/m 2/day in two divided doses, n = 34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m 2/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 capecitabine; however, toxicity was increased. Capecitabine, 1250 mg/m 2 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 capecitabine 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 U.S., 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 capecitabine at a dose of 1250 mg/m 2 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/m 2 leucovorin IV followed by 425 mg/m 2 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 capecitabine and 5-FU/LV patients are shown in Table 13.

Table 13: Baseline Demographics of Controlled Colorectal Trials
 Study 1Study 2
 Capecitabine
(n = 302)
5-FU/LV
(n = 303)
Capecitabine
(n = 301)
5-FU/LV
(n = 301)
Age (median, years)64636464
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)90909090
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.

Table 14: Efficacy of Capecitabine vs. 5-FU/LV in Colorectal Cancer (Study 1)
Capecitabine
(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)0.99
95% C.I. for Hazard Ratio(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)1
95% C.I. for Hazard Ratio(0.84 to 1.18)
Table 15: Efficacy of Capecitabine vs. 5-FU/LV in Colorectal Cancer (Study 2)
Capecitabine
(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)0.97
95% C.I. for Hazard Ratio(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)0.92
95% C.I. for Hazard Ratio(0.78 to 1.09)
Figure 3

Capecitabine was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that capecitabine 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 capecitabine. 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 capecitabine, 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 capecitabine difference. These results do not exclude the possibility of true equivalence of capecitabine to 5-FU/LV (see Table 14, Table 15, and Figure 3).

14.3 Breast Cancer

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

In Combination With Docetaxel

The dose of capecitabine 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 capecitabine (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/m 2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m 2 twice daily for 14 days of capecitabine administered in 3-week cycles. The approved dose of 100 mg/m 2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.

Capecitabine 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 capecitabine 1250 mg/m 2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m 2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m 2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.

Table 16: Baseline Demographics and Clinical Characteristics Capecitabine and Docetaxel Combination vs Docetaxel in Breast Cancer Trial
*
Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
Capecitabine + Docetaxel
(n = 255)
Docetaxel
(n = 256)
Age(median, years) 5251
Karnofsky PS(median) 9090
Site of Disease
  Lymph nodes121 (47%)125 (49%)
  Liver116 (45%)122 (48%)
  Bone107 (42%)119 (46%)
  Lung95 (37%)99 (39%)
  Skin73 (29%)73 (29%)
Prior Chemotherapy
  Anthracycline  *255 (100%)256 (100%)
  5-FU196 (77%)189 (74%)
  Paclitaxel25 (10%)22 (9%)
Resistance to an Anthracycline
  No resistance19 (7%)19 (7%)
  Progression on anthracycline therapy65 (26%)73 (29%)
Stable disease after 4 cycles of anthracycline therapy41 (16%)40 (16%)
Relapsed within 2 years of completion of anthracycline-adjuvant therapy78 (31%)74 (29%)
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose51 (20%)50 (20%)
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
  089 (35%)80 (31%)
  1123 (48%)135 (53%)
  243 (17%)39 (15%)
  30 (0%)2 (1%)

Capecitabine 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.

Table 17: Efficacy of Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy
*
The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
NA = Not Applicable
Efficacy ParameterCombination TherapyMonotherapyp-valueHazard Ratio
Time to Disease Progression
   Median Days1861280.00010.643
   95% C.I.(165 to 198)(105 to 136)
Overall Survival
   Median Days4423520.01260.775
   95% C.I.(375 to 497)(298 to 387)
Response Rate*32%22%0.009NA
Figure 4
Figure 5

Monotherapy

The antitumor activity of capecitabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the U.S. 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. Capecitabine was administered at a dose of 1255 mg/m 2 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.

Table 18: Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial
*
Lung, pleura, liver, peritoneum
Includes 2 patients treated with an anthracenedione
Patients With Measurable Disease (n = 135)
All Patients
(n = 162)
Age  (median, years) 5556
Karnofsky PS9090
No. Disease Sites
  1 to 243 (32%)60 (37%)
  3 to 463 (46%)69 (43%)
  > 529 (22%)34 (21%)
Dominant Site of Disease
  Visceral *101 (75%)110 (68%)
  Soft Tissue30 (22%)35 (22%)
  Bone4 (3%)17 (10%)
Prior Chemotherapy
  Paclitaxel135 (100%)162 (100%)
  Anthracycline 122 (90%)147 (91%)
5-FU110 (81%)133 (82%)
  Resistance to Paclitaxel103 (76%)124 (77%)
  Resistance to an Anthracycline 55 (41%)67 (41%)
  Resistance to both Paclitaxel and an Anthracycline 43 (32%)51 (31%)

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

Table 19: Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial
*
Includes 2 patients treated with an anthracenedione
From date of first response
Resistance to Both Paclitaxel and an Anthracycline
(n = 43)
CR0
PR *11
CR + PR *11
Response Rate *25.6%
(95% C.I.)(13.5, 41.2)
Duration of Response, *
Median in days 154
(Range)(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.

15 REFERENCES

  1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
  2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
  3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. 2006;63:1172-1193.
  4. Polovich M., White JM, Kelleher LO (eds). Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) 2005. Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

Capecitabine Tablets USP are available as follows:

150 mg: Peach to light peach, oblong, film-coated, biconvex, unscored tablets, debossed with 190 on one side and 77 on the other side.

500 mg: Peach to light peach, oblong, film-coated, biconvex, unscored tablets debossed with 191 on one side and 77 on the other side. Available in Box of 30 Unit Dose Tablets.

Storage and Handling

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

KEEP TIGHTLY CLOSED.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Care should be exercised in the handling of capecitabine tablets USP. Capecitabine tablets USP should not be cut or crushed. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of tablets. If powder from broken capecitabine tablets USP contacts the skin, wash the skin immediately and thoroughly with soap and water. If capecitabine tablets USP contact the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. 1 to 4

17 PATIENT COUNSELING INFORMATION

Information for Patients

(See Patient Package Insert)

Patients and patients' caregivers should be informed of the expected adverse effects of capecitabine, 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 ( 2.2) ]. As described below, patients taking capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with capecitabine treatment.

Diarrhea

Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking capecitabine immediately. Standard antidiarrheal treatments (e.g., loperamide) are recommended.

Nausea

Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking capecitabine 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 capecitabine 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 capecitabine immediately.

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 capecitabine immediately. Initiation of symptomatic treatment is recommended [ see Dosage and Administration ( 2.2) ].

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.

Patient Package Insert

Read this leaflet before you start taking capecitabine [KAP-e-SYE-ta-been] tablets USP and each time you refill your prescription in case the information has changed. This leaflet contains important information about capecitabine tablets. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of capecitabine tablets. Your doctor should always be your first choice for discussing your medical condition and this medicine.

What are capecitabine tablets?

Capecitabine tablets are a medicine you take by mouth (orally). Capecitabine is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.

Capecitabine tablets are used to treat:

– cancer of the colon after surgery

– cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, capecitabine tablets were no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.

– breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (TAXOTERE ®)

– breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (TAXOL ®) and anthracycline-containing medicine such as Adriamycin and doxorubicin

What is the most important information about capecitabine tablets?

Capecitabine tablets may increase the effect of other medicines used to thin your blood such as warfarin (COUMADIN ®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because capecitabine tablets may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and capecitabine tablets, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

Who should not take capecitabine tablets?

1. DO NOT TAKE CAPECITABINE TABLETS IF YOU

– are nursing a baby. Tell your doctor if you are nursing. Capecitabine may pass to the baby in your milk and harm the baby.

– are allergic to 5-fluorouracil

– are allergic to capecitabine or to any of the ingredients in capecitabine tablets

– have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)

2. TELL YOUR DOCTOR IF YOU

– take a blood thinner such as warfarin (COUMADIN ®). This is very important because capecitabine may increase the effect of the blood thinner. If you are taking blood thinners and capecitabine tablets, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

– take phenytoin (DILANTIN ®). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.

– are pregnant or think you may be pregnant. Capecitabine tablets may harm your unborn child.

– have kidney problems. Your doctor may prescribe a different medicine or lower the capecitabine tablets dose.

– have liver problems. You may need to be checked for liver problems while you take capecitabine tablets.

– have heart problems because you could have more side effects related to your heart.

– take the vitamin folic acid. It may affect how capecitabine tablets work.

How should I take capecitabine tablets?

Take capecitabine tablets exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are peach to light peach in color with 190 on one side and 77 on the other side. The 500 mg tablets are peach to light peach in color with 191 on one side and 77 on the other side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe capecitabine tablets with docetaxel (TAXOTERE ®) injection.

– Capecitabine tablets are taken in 2 daily doses, a morning dose and an evening dose

– Take capecitabine tablets within 30 minutes after the end of a meal (breakfast and dinner)

Swallow capecitabine tablets whole with water

– If you miss a dose of capecitabine tablets, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.

– Capecitabine tablets are usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.

– If you take too many capecitabine tablets, contact your doctor or local poison control center or emergency room right away.

What should I avoid while taking capecitabine tablets?

– Women should not become pregnant while taking capecitabine tablets. Capecitabine tablets may harm your unborn child. Use effective birth control while taking capecitabine tablets. Tell your doctor if you become pregnant.

– Do not breastfeed. Capecitabine may pass through your milk and harm your baby.

– Men should use birth control while taking capecitabine tablets

What are the most common side effects of capecitabine tablets?

The most common side effects of capecitabine tablets are:

– diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.

– hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss

– tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems

These side effects may differ when taking capecitabine tablets with docetaxel (TAXOTERE ®). Please consult your doctor for possible side effects that may be caused by taking capecitabine tablets with docetaxel (TAXOTERE ®).

If you are concerned about these or any other side effects while taking capecitabine tablets, talk to your doctor.

Stop taking capecitabine tablets immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust capecitabine tablets to a dose that is right for you or stop your capecitabine tablets treatment for a while. This should help to reduce the side effects and stop them from getting worse.

Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night

Vomiting: if you vomit more than once in a 24-hour time period

Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual

Stomatitis: if you have pain, redness, swelling or sores in your mouth

Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity

Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection

Your doctor may tell you to lower the dose or to stop capecitabine tablets treatment for a while. If caught early, most of these side effects usually improve after you stop taking capecitabine tablets. If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking capecitabine tablets again and what dose to take. Adjusting the dose of capecitabine tablets to be right for each patient is an important part of treatment.

How should I store and use capecitabine tablets?

– Never share capecitabine tablets with anyone

– Store capecitabine tablets at normal room temperature (about 68° to 77°F)

– Keep capecitabine tablets and all other medicines out of the reach of children

– If you take too many capecitabine tablets by mistake, contact your doctor or local poison control center or emergency room right away

General advice about prescription medicines:

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

This leaflet summarizes the most important information about capecitabine tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about capecitabine tablets that is written for health professionals.

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

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured In Czech Republic By:

TEVA CZECH INDUSTRIES s.r.o.

Opava-Komarov, Czech Republic

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. B 12/2013

Repackaged By:

KAISER FOUNDATION HOSPITALS

Livermore, CA 94551

PRINCIPLE DISPLAY PANEL

Capecitabine Tablets USP, 500 mg 120s Label

Capecitabine Tablets USP, 500 mg Label

NDC 0179- 0149-70

CAPECITABINE
Tablets USP
500 mg

Cytotoxic Agent

PHARMACIST: PLEASE
DISPENSE WITH ATTACHED
PATIENT INFORMATION LEAFLET

Rx only

BOX OF 30 UNIT DOSE TABLETS

TEVA

REPACKAGED BY:

KAISER FOUNDATION HOSPITALS

LIVERMORE, CA 94551

CAPECITABINE 
capecitabine tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0179-0149(NDC:0093-7474)
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CAPECITABINE (UNII: 6804DJ8Z9U) (CAPECITABINE - UNII:6804DJ8Z9U) CAPECITABINE500 mg
Inactive Ingredients
Ingredient NameStrength
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82)  
HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
FERRIC OXIDE RED (UNII: 1K09F3G675)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
Product Characteristics
Colororange (peach to light peach) Scoreno score
ShapeOVAL (oblong) Size16mm
FlavorImprint Code 191;77
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0179-0149-7030 in 1 BOX, UNIT-DOSE; Type 0: Not a Combination Product05/14/201403/31/2016
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA09164905/14/201403/31/2016
Labeler - KAISER FOUNDATION HOSPITALS (053052619)
Establishment
NameAddressID/FEIBusiness Operations
KAISER FOUNDATION HOSPITALS053052619repack(0179-0149)

Revised: 12/2018
 
KAISER FOUNDATION HOSPITALS