CAPECITABINE- capecitabine tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
CAPECITABINE (UNII: 6804DJ8Z9U) (CAPECITABINE - UNII:6804DJ8Z9U)
Available from:
Mylan Pharmaceuticals Inc.
INN (International Name):
CAPECITABINE
Composition:
CAPECITABINE 150 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Capecitabine tablets are 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)] . Capecitabine tablets are contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine tablets are contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. Based on findings in animal reproduction studies and its mechanism of action,capecitabine tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended d
Product summary:
Capecitabine Tablets, USP are available containing 150 mg or 500 mg of capecitabine, USP. The 150 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and 511 on the other side. They are available as follows: NDC 0378-2511-91 bottles of 60 tablets The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M512 on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-2512-78 bottles of 120 tablets Storage and Handling:   Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.] KEEP TIGHTLY CLOSED. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Capecitabine tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.
Authorization status:
Abbreviated New Drug Application
Authorization number:
0378-2511-91, 0378-2512-78

CAPECITABINE- capecitabine tablet, film coated

Mylan Pharmaceuticals Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use CAPECITABINE TABLETS safely and

effectively. See full prescribing information for CAPECITABINE TABLETS.

CAPECITABINE tablets, for oral use

Initial U.S. Approval: 1998

WARNING: CAPECITABINE TABLETS-WARFARIN INTERACTION

See full prescribing information for complete boxed warning

Patients receiving concomitant capecitabine tablets 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.

INDICATIONS AND USAGE

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

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Occurrence: Within several days and up to several months after initiating capecitabine tablets

therapy; may also be seen within 1 month after stopping capecitabine tablets

Predisposing factors: age > 60 and diagnosis of cancer

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

Take capecitabine tablets with water within 30 min after a meal (2.1)

Monotherapy: 1250 mg/m twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles (2.2)

Adjuvant treatment is recommended for a total of 6 months (8 cycles) (2.2)

In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m twice daily for 2 weeks

followed by a 7-day rest period, combined with docetaxel at 75 mg/m as a 1-hour IV infusion every 3 weeks (2.2)

Capecitabine tablets dosage may need to be individualized to optimize patient management (2.3)

Reduce the dose of capecitabine tablets by 25% in patients with moderate renal impairment (2.4)

Tablets: 150 mg and 500 mg (3)

Severe Renal Impairment (4.1)

Hypersensitivity (4.2)

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 3/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant

dose accordingly. (5.1)

Diarrhea: May be severe. Interrupt capecitabine tablets treatment immediately until diarrhea resolves or decreases

to grade 1. Recommend standard antidiarrheal treatments. (5.2)

Cardiotoxicity: Common in patients with a prior history of coronary artery disease. (5.3)

Increased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine

Dehydrogenase (DPD) Activity: Withhold or permanently discontinue capecitabine tablets in patients with evidence

of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.

No capecitabine tablets dose has been proven safe in patients with absent DPD activity. (5.4)

Dehydration and Renal Failure: Interrupt capecitabine tablets treatment until dehydration is corrected. Potential

risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5)

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a

fetus and to use effective contraception. (5.6, 8.1, 8.3)

Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS)

and Toxic Epidermal Necrolysis (TEN), have been reported. Capecitabine tablets should be permanently

discontinued in patients who experience a severe mucocutaneous reaction during treatment. Capecitabine tablets

may induce hand-and-foot syndrome. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints

which could impact patient identification. Interrupt capecitabine tablets treatment until the hand-and-foot syndrome

event resolves or decreases in intensity. (5.7)

Hyperbilirubinemia: Interrupt capecitabine tablets treatment immediately until the hyperbilirubinemia resolves or

decreases in intensity. (5.8)

Hematologic: Do not treat patients with neutrophil counts < 1.5 x 10 /L or thrombocyte counts < 100 x 10 /L. If

grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9)

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 tablets 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 tablets are coadministered with CYP2C9

substrates. (7.1)

Allopurinol: Avoid the use of allopurinol during treatment with capecitabine tablets.

Food reduced both the rate and extent of absorption of capecitabine. (2, 7.2, 12.3)

Lactation: Advise women not to breastfeed. (8.2)

Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of

capecitabine tablets. Advise males with female partners of reproductive potential to use effective contraception. (8.3)

Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5)

Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6)

Renal Impairment: Reduce capecitabine tablets starting dose in patients with moderate renal impairment (2.4, 8.7,

12.3)

WARNING: CAPECITABINE TABLETS-WARFARIN INTERACTION

1 INDICATIONS AND USAGE

1.1 Colorectal Cancer

1.2 Breast Cancer

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

2.2 Standard Starting Dose

2.3 Dose Management Guidelines

2.4 Adjustment of Starting Dose in Special Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Severe Renal Impairment

4.2 Hypersensitivity

5 WARNINGS AND PRECAUTIONS

5.1 Coagulopathy

5.2 Diarrhea

5.3 Cardiotoxicity

5.4 Dihydropyrimidine Dehydrogenase Deficiency

5.5 Dehydration and Renal Failure

5.6 Embryo-Fetal Toxicity

5.7 Mucocutaneous and Dermatologic Toxicity

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

6.5 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drug-Drug Interactions

7.2 Drug-Food Interaction

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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

FULL PRESCRIBING INFORMATION

WARNING: CAPECITABINE TABLETS-WARFARIN INTERACTION

Capecitabine Tablets-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 tablets-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 tablets 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 tablets were introduced.

These events occurred within several days and up to several months after initiating

capecitabine tablets therapy and, in a few cases, within 1 month after stopping capecitabine

tablets. 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

1.2 Breast Cancer

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

Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes’ C

colon cancer who have undergone complete resection of the primary tumor when treatment with

fluoropyrimidine therapy alone is preferred. Capecitabine tablets were non-inferior to 5-

fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should

consider results of combination chemotherapy trials, which have shown improvement in DFS and

OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes’ C colon

cancer.

Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal

carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination

chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over

5-FU/LV has not been demonstrated with capecitabine tablets monotherapy. Use of capecitabine

tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or

preservation of the survival advantage.

Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with

metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal.

Capecitabine tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.1

If capecitabine tablets must be cut or crushed, this should be done by a professional trained in safe

handling of cytotoxic drugs using appropriate equipment and safety procedures. Capecitabine tablets

dose is calculated according to body surface area.

2.2 Standard Starting Dose

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

The recommended dose of capecitabine tablets is 1250 mg/m administered orally twice daily (morning

and evening; equivalent to 2500 mg/m 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 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

Dose Level 1250 mg/m

Twice a Day

Number of Tablets to be Taken at

Each Dose (Morning and Evening)

Surface Area

(m )

Total Daily Dose (mg)

150 mg

500 mg

≤1.25

3000

1.26-1.37

3300

1.38-1.51

3600

1.52-1.65

4000

1.66-1.77

4300

1.78-1.91

4600

1.92-2.05

5000

2.06-2.17

5300

≥ 2.18

5600

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m twice daily

for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m 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

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 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.

Total Daily Dose divided by 2 to allow equal morning and evening doses

2

2

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.

2.3 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

T oxicity

NCIC Grades

During a Course of Therapy

Dose Adjustment for Next

Treatment (% of starting dose)

Grade 1

Maintain dose level

Maintain dose level

Grade 2

-1 appearance

Interrupt until resolved to grade 0-1

100%

appearance

appearance

appearance

Discontinue treatment permanently

Grade 3

-1 appearance

Interrupt until resolved to grade 0-1

appearance

appearance

Discontinue treatment permanently

Grade 4

-1 appearance

Discontinue permanently

If physician deems it to be in the

patient’s best interest to continue,

interrupt until resolved to grade 0-1

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.

National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot

syndrome [see Warnings and Precautions (5)].

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

T oxicity

NCIC

Grades

Grade 2

Grade 3

Grade 4

1 appearance Delay treatment until resolved to

grade 0-1; Resume treatment with

original dose of 75 mg/m docetaxel

Delay treatment until resolved

to grade 0-1; Resume treatment

at 55 mg/m of docetaxel.

Discontinue

treatment with

docetaxel

appearance Delay treatment until resolved to

grade 0-1; Resume treatment at 55

mg/m of docetaxel.

Discontinue treatment with

docetaxel

appearance Discontinue treatment with docetaxel

2.4 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 to 950 mg/m twice daily) is recommended [see Use in Specific Populations

(8.7) and Clinical Pharmacology (12.3)]. Subsequent dose adjustment is recommended as outlined in

Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see

Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with

moderate renal impairment apply to both capecitabine tablets monotherapy and capecitabine tablets in

combination use with docetaxel.

Cockroft and Gault Equation:

Creatinine clearance for males =

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

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

Creatinine clearance for females = 0.85 x 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

Capecitabine Tablets, USP are available containing 150 mg or 500 mg of capecitabine, USP.

National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome

[see Warnings and Precautions (5)].

The 150 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side

of the tablet and 511 on the other side.

The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M512 on one

4 CONTRAINDICATIONS

4.1 Severe Renal Impairment

Capecitabine tablets are contraindicated in patients with severe renal impairment (creatinine clearance

below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology

(12.3)].

4.2 Hypersensitivity

Capecitabine tablets are contraindicated in patients with known hypersensitivity to capecitabine or to any

of its components. Capecitabine tablets are contraindicated in patients who have a known

hypersensitivity to 5-fluorouracil.

5 WARNINGS AND PRECAUTIONS

5.1 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)].

5.2 Diarrhea

Capecitabine tablets 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 tablets

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 tablets should be immediately interrupted until the

diarrhea resolves or decreases in intensity to grade 1 [see Dosage and Administration (2.3)]. Standard

antidiarrheal treatments (e.g., loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

5.3 Cardiotoxicity

The cardiotoxicity observed with capecitabine tablets includes myocardial infarction/ischemia, angina,

dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and

cardiomyopathy. These adverse reactions may be more common in patients with a prior history of

coronary artery disease.

5.4 Dihydropyrimidine Dehydrogenase Deficiency

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous

mutations in the DPD gene that result in complete or near complete absence of DPD activity are at

increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions

caused by capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with

partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions

caused by capecitabine tablets.

side of the tablet and blank on the other side.

Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset,

duration and severity of the observed toxicities in patients with evidence of acute early-onset or

unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No

capecitabine tablets dose has been proven safe for patients with complete absence of DPD activity.

There is insufficient data to recommend a specific dose in patients with partial DPD activity as

measured by any specific test.

5.5 Dehydration and Renal Failure

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-

existing compromised renal function or who are receiving concomitant capecitabine tablets with known

nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may

rapidly become dehydrated. Monitor patients when capecitabine tablets are administered to prevent and

correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, capecitabine tablets

treatment should be immediately interrupted and the dehydration corrected. Treatment should not be

restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.

Dose modifications should be applied for the precipitating adverse event as necessary [see Dosage and

Administration (2.3)].

Patients with moderate renal impairment at baseline require dose reduction [see Dosage and

Administration (2.4)]. Patients with mild and moderate renal impairment at baseline should be carefully

monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is

recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and

Administration (2.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

5.6 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, capecitabine tablets

may cause fetal harm when given to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited

available data are not sufficient to inform use of capecitabine tablets in pregnant women. In animal

reproduction studies, administration of capecitabine to pregnant animals during the period of

organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2

and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Use in

Specific Populations (8.1)]. Apprise pregnant women of the potential risk to a fetus. Advise females of

reproductive potential to use effective contraception during treatment and for 6 months following the

last dose of capecitabine tablets [see Use in Specific Populations (8.3)].

5.7 Mucocutaneous and Dermatologic Toxicity

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and

Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine tablets [see Adverse

Reactions (6.4)]. Capecitabine tablets should be permanently discontinued in patients who experience a

severe mucocutaneous reaction possibly attributable to capecitabine tablets treatment.

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema)

is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity

range of grades 1 to 3 for patients receiving capecitabine tablets monotherapy in the metastatic setting.

Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless

swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal

activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands

and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-foot

syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet

and/or severe discomfort that causes the patient to be unable to work or perform activities of daily

living. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of

fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs,

administration of capecitabine tablets 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

tablets should be decreased [see Dosage and Administration (2.3)].

5.8 Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of

capecitabine tablets 1250 mg/m twice daily as monotherapy for 2 weeks followed by a 1-week rest

period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (>

3 x ULN) hyperbilirubinemia occurred in 3.9% (n = 34) of patients. Of 566 patients who had hepatic

metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4

hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4

hyperbilirubinemia, 18.6% (n = 31) also had postbaseline elevations (grades 1 to 4, without elevations at

baseline) in alkaline phosphatase and 27.5% (n = 46) had postbaseline elevations in transaminases at any

time (not necessarily concurrent). The majority of these patients, 64.5% (n = 20) and 71.7% (n = 33), had

liver metastases at baseline. In addition, 57.5% (n = 96) and 35.3% (n = 59) of the 167 patients had

elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases,

respectively. Only 7.8% (n = 13) and 3.0% (n = 5) had grade 3 or 4 elevations in alkaline phosphatase or

transaminases.

In the 596 patients treated with capecitabine tablets 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 tablets 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 tablets. 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 tablets and

docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 x

ULN) hyperbilirubinemia occurred in 2% (n = 5).

If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine tablets should

be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3.0 x ULN [see recommended

dose modifications under Dosage and Administration (2.3)].

5.9 Hematologic

In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m

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 tablets in

combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4

thrombocytopenia, and 9.6% had grade 3 or 4 anemia.

Patients with baseline neutrophil counts of < 1.5 x 10 /L and/or thrombocyte counts of < 100 x 10 /L

should not be treated with capecitabine tablets. If unscheduled laboratory assessments during a treatment

cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine tablets 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 tablets

monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine tablets 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 tablets 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 tablets 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 tablets 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

tablets 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 (3.0%), 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 tablets compared to 5-FU/LV were 1.01 (95% C.I. 0.80 - 1.27) and 1.04 (95% C.I. 0.79 -

1.37), respectively.

5.11 Hepatic Insufficiency

Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully

monitored when capecitabine tablets are administered. The effect of severe hepatic dysfunction on the

disposition of capecitabine tablets is not known [see Use in Specific Populations (8.6) and Clinical

Pharmacology (12.3)].

5.12 Combination With Other Drugs

Use of capecitabine tablets 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 twice a day of capecitabine

tablets administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered

5-FU and leucovorin (20 mg/m leucovorin IV followed by 425 mg/m IV bolus 5-FU on days 1-5

every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145

days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated

patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to

all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients

randomized to capecitabine tablets and 10 (1.0%) randomized to 5-FU/LV.

Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial

in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at

least one safety assessment.

Table 4. Percent Incidence of Adverse Reactions Reported in ≥ 5% of Patients Treated With

Capecitabine Tablets or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)

Adjuvant Treatment for Colon Cancer (n =

1969)

Capecitabine Tablets

(n = 995)

5-FU/LV

(n = 974)

Body System/

Adverse Event

All Grades

Grade 3/4

All Grades

Grade 3/4

Gastrointestinal Disorders

Diarrhea

Nausea

Stomatitis

Vomiting

Abdominal Pain

Constipation

< 1

Upper Abdominal Pain

< 1

< 1

Dyspepsia

< 1

Skin and Subcutaneous Tissue Disorders

Hand-and-Foot Syndrome

< 1

Alopecia

< 1

Rash

Erythema

< 1

General Disorders and Administration Site

Conditions

Fatigue

< 1

Pyrexia

< 1

< 1

Asthenia

< 1

Lethargy

< 1

< 1

Nervous System Disorders

Dizziness

< 1

Headache

< 1

< 1

Dysgeusia

Metabolism and Nutrition Disorders

Anorexia

< 1

< 1

Eye Disorders

Conjunctivitis

< 1

< 1

Blood and Lymphatic System Disorders

Neutropenia

< 1

Respiratory Thoracic and Mediastinal Disorders

Epistaxis

Table 5. Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients

Receiving Capecitabine Tablets Monotherapy for Adjuvant Treatment of Colon Cancer (Safety

Population)

Adverse Event

Capecitabine Tablets

(n = 995)

Grade 3/4 %

IV 5-FU/LV

(n = 974)

Grade 3/4 %

Increased ALAT (SGPT)

Increased calcium

Decreased calcium

Decreased hemoglobin

Decreased lymphocytes

13.0

13.0

Decreased neutrophils

26.2

Decreased neutrophils/granulocytes

26.4

Decreased platelets

Increased bilirubin

6.2 Metastatic Colorectal Cancer

Monotherapy

Table 6 shows the adverse reactions occurring in ≥ 5% of patients from pooling the two phase 3 trials

in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were

treated with 1250 mg/m twice a day of capecitabine tablets 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 leucovorin IV followed by 425 mg/m IV bolus 5-FU, on days 1-5, every 28 days). In the pooled

colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and

140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-

treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness.

A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study

drug: 50 (8.4%) patients randomized to capecitabine tablets and 32 (5.4%) randomized to 5-FU/LV.

Table 6. Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥ 5% of

Patients

Adverse Event

Capecitabine Tablets

(n = 596)

5-FU/LV

(n = 593)

Total

%

Grade 3

%

Grade 4

%

Total

%

Grade 3

%

Grade 4

%

Number of Patients With > One Adverse

Event

Body System/Adverse Event

GI

Diarrhea

Nausea

< 1

Vomiting

< 1

< 1

Stomatitis

< 1

Abdominal Pain

< 1

Gastrointestinal Motility Disorder

< 1

< 1

Constipation

< 1

Oral Discomfort

Upper GI Inflammatory Disorders

< 1

Gastrointestinal Hemorrhage

< 1

Ileus

Skin and Subcutaneous

Hand-and-Foot Syndrome

The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine tablets arm and 4 .9% in

the IV 5-FU/LV arm.

It should be noted that grading was according to NCIC CTC Version 1 (May, 1994 ). In the NCIC-CTC Version

1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and

grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of > 3.0 to

10.0 × ULN, and grade 4 values > 10.0 × ULN.

Dermatitis

Skin Discoloration

< 1

Alopecia

<1

General

Fatigue/Weakness

Pyrexia

Edema

Pain

Chest Pain

<1

Neurological

Peripheral Sensory Neuropathy

Headache

Dizziness

< 1

< 1

Insomnia

Taste Disturbance

< 1

Metabolism

Appetite Decreased

< 1

< 1

Dehydration

< 1

Eye

Eye Irritation

< 1

Vision Abnormal

Respiratory

Dyspnea

< 1

Cough

< 1

Pharyngeal Disorder

Epistaxis

< 1

Sore Throat

Musculoskeletal

Back Pain

< 1

Arthralgia

Vascular

Venous Thrombosis

< 1

Psychiatric

Mood Alteration

< 1

Depression

< 1

Infections

Viral

< 1

< 1

Blood and Lymphatic

Anemia

< 1

< 1

Neutropenia

Hepatobiliary

Hyperbilirubinemia

– Not observed

NA = Not Applicable

Excluding vertigo

6.3 Breast Cancer

In Combination with Docetaxel

The following data are shown for the combination study with capecitabine tablets and docetaxel in

patients with metastatic breast cancer in Table 7 and Table 8. In the capecitabine tablets and docetaxel

combination arm the treatment was capecitabine tablets administered orally 1250 mg/m 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 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 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 Tablets and Docetaxel Combination vs

Docetaxel Monotherapy Study

Adverse Event

Capecitabine Tablets

1250 mg/m /bid With Docetaxel

75 mg/m /3 weeks

(n = 251)

Docetaxel

100 mg/m /3 weeks

(n = 255)

Total

%

Grade 3

%

Grade 4

%

Total

%

Grade 3

%

Grade 4

%

Number of Patients With at Least

One Adverse Event

76.5

29.1

57.6

31.8

Body System/Adverse Event

GI

Diarrhea

< 1

< 1

Stomatitis

< 1

Nausea

Vomiting

Constipation

Abdominal Pain

< 3

< 1

Dyspepsia

Dry Mouth

< 1

Skin and Subcutaneous

Hand-and-Foot Syndrome

Alopecia

Nail Disorder

Dermatitis

Rash Erythematous

< 1

Nail Discoloration

< 1

Onycholysis

Pruritus

General

2

2

2

Pyrexia

Asthenia

< 1

Fatigue

Weakness

Pain in Limb

< 1

Lethargy

Pain

< 1

Chest Pain (non-cardiac)

< 1

Influenza-like Illness

Neurological

Taste Disturbance

< 1

< 1

Headache

Paresthesia

< 1

Dizziness

< 1

Insomnia

< 1

Peripheral Neuropathy

Hypoaesthesia

< 1

< 1

Metabolism

Anorexia

< 1

Appetite Decreased

Weight Decreased

Dehydration

< 1

< 1

Eye

Lacrimation Increased

< 1

Conjunctivitis

Eye Irritation

Musculoskeletal

Arthralgia

Myalgia

Back Pain

< 1

Bone Pain

< 1

Cardiac

Edema

< 2

< 3

Blood

Neutropenic Fever

Respiratory

Dyspnea

< 1

Cough

<1

Sore Throat

<1

Epistaxis

< 1

Rhinorrhea

Pleural Effusion

Infection

Oral Candidiasis

< 1

<1

Urinary Tract Infection

< 1

Upper Respiratory Tract

Vascular

Flushing

Lymphoedema

< 1

Psychiatric

Depression

– Not observed

NA = Not Applicable

Table 8. Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine

Tablets and Docetaxel Combination vs Docetaxel Monotherapy Study

Adverse Event

Capecitabine Tablets

1250 mg/m /bid With

Docetaxel 75 mg/m /3 weeks

(n = 251)

Docetaxel

100 mg/m /3 weeks

(n = 255)

Body System/Adverse

Event

Total %

Grade 3 %

Grade 4 %

Total

%

Grade 3

%

Grade 4

%

Hematologic

Leukopenia

Neutropenia/

Granulocytopenia

Thrombocytopenia

Anemia

< 1

Lymphocytopenia

Hepatobiliary

Hyperbilirubinemia

Monotherapy

The following data are shown for the study in stage IV breast cancer patients who received a dose of

1250 mg/m administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration

of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of

adverse reactions/intercurrent illness.

Table 9. Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably

Related to Treatment in ≥ 5% of Patients Participating in the Single Arm Trial in Stage IV Breast

Cancer

Adverse Event

Phase 2 Trial in Stage IV Breast Cancer

(n = 162)

Body System/Adverse Event

Total

%

Grade 3

%

Grade 4

%

GI

Diarrhea

Nausea

Vomiting

Stomatitis

Abdominal Pain

Constipation

2

2

2

Dyspepsia

Skin and Subcutaneous

Hand-and-Foot Syndrome

Dermatitis

Nail Disorder

General

Fatigue

Pyrexia

Pain in Limb

Neurological

Paresthesia

Headache

Dizziness

Insomnia

Metabolism

Anorexia

Dehydration

Eye

Eye Irritation

Musculoskeletal

Myalgia

Cardiac

Edema

Blood

Neutropenia

Thrombocytopenia

Anemia

Lymphopenia

Hepatobiliary

Hyperbilirubinemia

– Not observed

NA = Not Applicable

6.4 Clinically Relevant Adverse Events in < 5% of Patients

Clinically relevant adverse events reported in < 5% of patients treated with capecitabine tablets either as

monotherapy or in combination with docetaxel that were considered at least remotely related to

treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in

parentheses.

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

Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus

(0.3%), toxic dilation of intestine, gastroenteritis (0.1%)

Skin & Subcutaneous: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%),

skin ulceration, pruritus, radiation recall syndrome (0.2%)

General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability,

difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation

Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination,

dysarthria, loss of consciousness (0.2%), impaired balance

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

hypomagnesemia

Eye: conjunctivitis

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

dyspnea

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

myocarditis (0.1%), pericardial effusion

Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%),

keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)

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

Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%),

idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)

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

cerebrovascular accident (0.1%)

Psychiatric: depression, confusion (0.1%)

Renal: renal impairment (0.6%)

Ear: vertigo

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

function tests

Immune System: drug hypersensitivity (0.1%)

Capecitabine Tablets 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%)

6.5 Postmarketing Experience

The following adverse reactions have been observed in the postmarketing setting:hepatic failure,

lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see

Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis,

toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic

Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)], persistent or severe hand-and-foot

syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7)]

In instances of exposure to crushed capecitabine tablets, the following adverse reactions have been

reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation,

vomiting, and nausea.

7 DRUG INTERACTIONS

7.1 Drug-Drug Interactions

Anticoagulants

Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine

tablets 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 tablets therapy and, in a few cases, within 1 month after stopping capecitabine tablets.

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 tablets and

phenytoin dose may need to be reduced [see Dosage and Administration (2.3)]. Postmarketing reports

indicate that some patients receiving capecitabine tablets 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 tablets and other

CYP2C9 substrates have been conducted. Care should be exercised when capecitabine tablets are

coadministered with CYP2C9 substrates.

Allopurinol

Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see

Clinical Pharmacology (12.3)], which may decrease capecitabine tablets efficacy. Avoid the use of

allopurinol during treatment with capecitabine tablets.

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 tablets

within 30 minutes after a meal. It is recommended that capecitabine tablets be administered with food

[see Dosage and Administration (2)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animal reproduction studies and its mechanism of action,capecitabine tablets can

cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited

available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal

reproduction studies, administration of capecitabine to pregnant animals during the period of

organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2

and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data].

Apprise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of

198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this

dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC values in

patients administered the recommended daily dose. Malformations in mice included cleft palate,

anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral

ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis

at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5’-DFUR AUC values that were

approximately 0.6 times the AUC values in patients administered the recommended daily dose.

8.2 Lactation

Risk Summary

There is no information regarding the presence of capecitabine in human milk, or on its effects on milk

production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice

[see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in

breast-fed infants, advise women not to breastfeed during treatment with capecitabine tablets and for 2

weeks after the final dose.

Data

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine

metabolites into the milk.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

tablets.

Contraception

Females

Capecitabine tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific

Populations (8.1)]. Advise females of reproductive potential to use effective contraception during

treatment and for 6 months following the final dose of capecitabine tablets.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential

to use effective contraception during treatment and for 3 months following the last dose of capecitabine

tablets [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, capecitabine tablets may impair fertility in females and males of reproductive

potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of capecitabine tablets 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 tablets was similar.

The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 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 to 850 mg/m every 12 hours for up to 9 weeks. After a 2 week break, patients

received 1250 mg/m capecitabine every 12 hours on Days 1-14 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 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 3-16 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 capecitabine every 12 hours with concomitant radiation

therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m capecitabine every 12

hours on Days 1-14 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 tablets in the

elderly [see Warnings and Precautions (5.10)].

8.6 Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are

treated with capecitabine tablets. The effect of severe hepatic dysfunction on capecitabine tablets is not

known [see Warnings and Precautions (5.11) 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-DFUR, and FBAL than in those

with normal renal function [see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and

Administration (2.4), and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal

irritation and bleeding, and bone marrow depression. Medical management of overdose should include

customary supportive medical interventions aimed at correcting the presenting clinical manifestations.

Although no clinical experience using dialysis as a treatment for capecitabine tablets 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 tablets 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 basis).

11 DESCRIPTION

Capecitabine tablets, USP are a fluoropyrimidine carbamate with antineoplastic activity. It is an orally

administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-

fluorouracil.

The chemical name for capecitabine is Pentyl 1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-

oxo-4-pyrimidinecarbamate and has a molecular weight of 359.35. Capecitabine has the following

structural formula:

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

20ºC.

Capecitabine is supplied as film-coated tablets for oral administration. Each round, white tablet contains

150 mg capecitabine and each oval, white tablet contains 500 mg capecitabine. The inactive ingredients

in capecitabine tablets include: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium

stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.

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,

-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary

5-10

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 BID to cancer patients, capecitabine reached peak blood

levels in about 1.5 hours (T

) 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

and AUC

decreased

by 60% and 35%, respectively. The C

and AUC

of 5-FU were also reduced by food by 43% and

21%, respectively. Food delayed T

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 tablets and its metabolites have been evaluated in about 200

cancer patients over a dosage range of 500 to 3500 mg/m /day. Over this range, the pharmacokinetics of

capecitabine tablets 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

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

tablets have 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 tablets 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 8.0). These ratios have

not been evaluated in breast cancer patients or compared to 5-FU infusion.

0-∞

0-∞

Metabolic Pathway of Capecitabine to 5-FU

The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine

metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH ). 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 tablets at 1250 mg/m twice a day

indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black

patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5’-DFUR, 5-FU and

FBAL. Age has no significant influence on the pharmacokinetics of 5’-DFUR and 5-FU over the range

of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL [see Warnings and

Precautions (5.11) and Dosage and Administration (2.4)].

Following oral administration of 825 mg/m capecitabine twice daily for 14 days, Japanese patients (n =

18) had about 36% lower C

and 24% lower AUC for capecitabine than the Caucasian patients (n =

22). Japanese patients had also about 25% lower C

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 tablets have been evaluated in 13 patients with mild to moderate hepatic dysfunction due to

Capecitabine tablets have 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 dose of capecitabine tablets. Both AUC

and C

of capecitabine

increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function

(n = 14). The AUC

and C

of 5-FU were not affected. In patients with mild to moderate hepatic

dysfunction due to liver metastases, caution should be exercised when capecitabine tablets are

administered. The effect of severe hepatic dysfunction on capecitabine tablets is not known [see

Warnings and Precautions (5.11) and Use in Special Populations (8.6)].

Effect of Renal Insufficiency

Following oral administration of 1250 mg/m 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 (2.4),

Contraindications (4.2), Warnings and Precautions (5.5), and Use in Special Populations (8.7)].

Effect of Capecitabine on the Pharmacokinetics of Warfarin

In four patients with cancer, chronic administration of capecitabine (1250 mg/m 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 tablets (1250 mg/m , n = 12 cancer patients), AUC and C

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 tablets.

Effect of Allopurinol on Capecitabine

Published literature reported that concomitant use with allopurinol may decrease conversion of

capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not

fully characterized.

Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa

A Phase 1 study evaluated the effect of capecitabine tablets on the pharmacokinetics of docetaxel

(Taxotere

) and the effect of docetaxel on the pharmacokinetics of capecitabine tablets was conducted

in 26 patients with solid tumors. Capecitabine tablets were found to have no effect on the

pharmacokinetics of docetaxel (C

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

0-∞

0-∞

mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse

micronucleus test in vivo.

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of

760 mg/kg/day (about 2300 mg/m /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 tablets 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 tablets to those receiving IV 5-FU/LV alone. In this trial, 1987 patients

were randomized either to treatment with capecitabine tablets 1250 mg/m 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 and 20 mg/m 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 x 10 /L, platelets ≥ 100 x 10 /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 tablets and 5-FU/LV patients are shown in Table 10. The

baseline characteristics were well-balanced between arms.

Table 10. Baseline Demographics

Capecitabine Tablets

(n = 1004)

5-FU/LV

(n = 983)

Age (median, years)

Range

(25-80)

(22-82)

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 orally twice daily. The starting dose was reduced in patients with moderate renal

impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration

(2.4)]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose

management for capecitabine tablets included dose reductions, cycle delays and treatment interruptions

(see Table 11).

Table 11. Summary of Dose Modifications in X-ACT Study

Capecitabine

Tablets

n = 995

5-FU/LV

n = 974

Median relative dose intensity (%)

Patients completing full course of treatment (%)

Patients with treatment interruption (%)

Patients with cycle delay (%)

Patients with dose reduction (%)

Patients with treatment interruption, cycle delay, or dose reduction (%)

The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS

for capecitabine tablets compared to 5-FU/LV was 0.88 (95% C.I. 0.77 - 1.01) (see Table 12 and Figure

1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, capecitabine

tablets were 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

tablets 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 tablets and 68.4% for 5-FU/LV (see Figure 2).

Table 12. Efficacy of Capecitabine Tablets vs 5-FU/LV in Adjuvant Treatment of Colon Cancer

All Randomized Population

Capecitabine Tablets

(n = 1004)

5-FU/LV

(n = 983)

Median follow-up (months)

5-year Disease-free Survival Rates (%)

59.1

54.6

Hazard Ratio

0.88

(Capecitabine Tablets/5-FU/LV)

(0.77 to 1.01)

(95% C.I. for Hazard Ratio)

p-value

p = 0.068

*

Approximately 93.4 % had 5-year DFS information

Based on Kaplan-Meier estimates

Test of superiority of capecitabine tablets vs 5-FU/LV (Wald chi-square test)

Fig ure 1. Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)a

Fig ure 2. Kaplan-Meier Estimates of Overall Survival (All Randomized Population)

14.2 Metastatic Colorectal Cancer

General

The recommended dose of capecitabine tablets was determined in an open-label, randomized clinical

study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m /day in two

divided doses, n = 39), intermittent therapy with capecitabine (2510 mg/m /day in two divided doses, n =

34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine

1657 mg/m /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 tablets; however, toxicity was increased.

Capecitabine tablets, 1250 mg/m 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 tablets 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 tablets at a dose of 1250 mg/m 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 leucovorin IV followed by 425 mg/m 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 tablets and 5-FU/LV patients are shown in Table 13.

Table 13. Baseline Demographics of Controlled Colorectal Trials

Study 1

Study 2

Capecitabine

Tablets

(n = 302)

5-FU/LV

(n = 303)

Capecitabine

Tablets

(n = 301)

5-FU/LV

(n = 301)

Age (median, years)

Range

(23-86)

(24-87)

(29-84)

(36-86)

Gender

Male (%)

181 (60)

197 (65)

172 (57)

173 (57)

Female (%)

121 (40)

106 (35)

129 (43)

128 (43)

Karnofsky PS (median)

Range

(70-100)

(70-100)

(70-100)

(70-100)

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 Tablets vs 5-FU/LV in Colorectal Cancer (Study 1)

Capecitabine Tablets

(n = 302)

5-FU/LV

(n = 303)

Overall Response Rate

(%, 95% C.I.)

21 (16-26)

11 (8-15)

(p-value)

0.0014

Time to Progression

(Median, days, 95% C.I.)

128 (120-136)

131 (105-153)

Hazard Ratio (Capecitabine Tablets/5-FU/LV)

0.99

95% C.I. for Hazard Ratio

(0.84-1.17)

Survival

(Median, days, 95% C.I.)

380 (321-434)

407 (366-446)

Hazard Ratio (Capecitabine Tablets/5-FU/LV)

1.00

95% C.I. for Hazard Ratio

(0.84-1.18)

Table 15. Efficacy of Capecitabine Tablets vs 5-FU/LV in Colorectal Cancer (Study 2)

Capecitabine Tablets

(n = 301)

5-FU/LV

(n = 301)

Overall Response Rate

(%, 95% C.I.)

21 (16-26)

14 (10-18)

(p-value)

0.027

Time to Progression

(Median, days, 95% C.I.)

137 (128-165)

131 (102-156)

Hazard Ratio (Capecitabine Tablets/5-FU/LV)

0.97

95% C.I. for Hazard Ratio

(0.82-1.14)

Survival

(Median, days, 95% C.I.)

404 (367-452)

369 (338-430)

Hazard Ratio (Capecitabine Tablets/5-FU/LV)

0.92

95% C.I. for Hazard Ratio

(0.78-1.09)

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

Capecitabine tablets were superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The

similarity of capecitabine tablets and 5-FU/LV in these studies was assessed by examining the potential

difference between the two treatments. In order to assure that capecitabine tablets have 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 tablets. 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 tablets, 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 tablets difference.

These results do not exclude the possibility of true equivalence of capecitabine tablets to 5-FU/LV

(see Table 14, Table 15, and Figure 3).

14.3 Breast Cancer

Capecitabine tablets have been evaluated in clinical trials in combination with docetaxel (Taxotere

and as monotherapy.

In Combination With Docetaxel

The dose of capecitabine tablets 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 tablets (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 administered in 3-week cycles of docetaxel in combination with

1250 mg/m twice daily for 14 days of capecitabine tablets administered in 3-week cycles. The

approved dose of 100 mg/m of docetaxel administered in 3-week cycles was the control arm of the

phase 3 study.

Capecitabine tablets in combination with docetaxel were 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 tablets 1250 mg/m twice daily for 14 days followed by 1 week without

treatment and docetaxel 75 mg/m as a 1-hour intravenous infusion administered in 3-week cycles. In the

monotherapy arm, 256 patients received docetaxel 100 mg/m 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 Tablets and

Docetaxel Combination vs Docetaxel in Breast Cancer Trial

Capecitabine

Tablets +

Docetaxel

(n = 255)

Docetaxel

(n = 256)

Age (median, years)

Karnofsky PS (median)

Site of Disease

Lymph nodes

121 (47%)

125 (49%)

Liver

116 (45%)

122 (48%)

Bone

107 (42%)

119 (46%)

Lung

95 (37%)

99 (39%)

Skin

73 (29%)

73 (29%)

Prior Chemotherapy

Anthracycline

255 (100%)

256 (100%)

5-FU

196 (77%)

189 (74%)

Paclitaxel

25 (10%)

22 (9%)

Resistance to an Anthracycline

No resistance

19 (7%)

19 (7%)

Progression on anthracycline therapy

65 (26%)

73 (29%)

Stable disease after 4 cycles of anthracycline therapy

41 (16%)

40 (16%)

Relapsed within 2 years of completion of anthracycline-adjuvant

therapy

78 (31%)

74 (29%)

Experienced a brief response to anthracycline therapy, with

subsequent progression while on therapy or within 12 months after last

dose

51 (20%)

50 (20%)

No. of Prior Chemotherapy Regimens for Treatment of Metastatic

Disease

89 (35%)

80 (31%)

123 (48%)

135 (53%)

43 (17%)

39 (15%)

0 (0%)

2 (1%)

Capecitabine tablets 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 Tablets and Docetaxel Combination vs Docetaxel

Monotherapy

Efficacy Parameter

Combination Therapy

Monotherapy

p-value

Hazard Ratio

Time to Disease

Progres s ion

Median Days

0.0001

0.643

95% C.I.

(165-198)

(105-136)

Overall Survival

Median Days

0.0126

0.775

95% C.I.

(375-497)

(298-387)

Response Rate

0.009

Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione

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

Fig ure 4 . Kaplan-Meier Estimates for Time to Disease Prog ression Capecitabine Tablets and Docetaxel vs

Docetaxel

Fig ure 5. Kaplan-Meier Estimates of Survival Capecitabine Tablets and Docetaxel vs Docetaxel

Monotherapy

The antitumor activity of capecitabine tablets 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 tablets were

administered at a dose of 1255 mg/m 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

Patients With

Measurable Disease

(n = 135)

All Patients

(n = 162)

Age (median, years)

Karnofsky PS

No. Disease Sites

43 (32%)

60 (37%)

63 (46%)

69 (43%)

>5

29 (22%)

34 (21%)

Dominant Site of Disease

Visceral

101 (75%)

110 (68%)

Soft Tissue

30 (22%)

35 (22%)

Bone

4 (3%)

17 (10%)

Prior Chemotherapy

Paclitaxel

135 (100%)

162 (100%)

Anthracycline

122 (90%)

147 (91%)

5-FU

110 (81%)

133 (82%)

Resistance to Paclitaxel

103 (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

Resistance to Both Paclitaxel and an Anthracycline

(n = 43)

CR + PR

Response Rate

(95% C.I.)

25.6%

(13.5, 41.2)

Duration of Response,

Median in days

(Range)

(63-233)

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

Lung, pleura, liver, peritoneum

Includes 2 patients treated with an anthracenedione

Includes 2 patients treated with an anthracenedione

From date of first response

“OSHA Hazardous Drugs.” OSHA.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Capecitabine Tablets, USP are available containing 150 mg or 500 mg of capecitabine, USP.

The 150 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the

tablet and 511 on the other side. They are available as follows:

NDC 0378-2511-91

bottles of 60 tablets

The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M512 on one side of

the tablet and blank on the other side. They are available as follows:

NDC 0378-2512-78

bottles of 120 tablets

Storage and Handling: Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room

Temperature.]

KEEP TIGHTLY CLOSED.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Capecitabine tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.

Any unused product should be disposed of in accordance with local requirements, or drug take back

programs.

17 PATIENT COUNSELING INFORMATION

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

Diarrhea: Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal

stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop

taking capecitabine tablets. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to

manage diarrhea [see Warnings and Precautions (5.2)].

Cardiotoxicity: Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare

provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or

lightheadedness [see Warnings and Precautions (5.3)].

Dihydropyrimidine Dehydrogenase Deficiency: Advise patients to notify their healthcare provider if they

have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD

activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal

adverse reactions caused by capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and

neurotoxicity) [see Warnings and Precautions (5.4)].

Dehydration and Renal Failure: Instruct patients experiencing grade 2 or higher dehydration (IV fluids

indicated < 24 hours) to stop taking capecitabine tablets immediately and to call their healthcare

provider to correct the dehydration. Advise patients to not restart capecitabine tablets until rehydrated

and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5)].

Important Administration Instructions: Advise patients to swallow capecitabine tablets whole with water

within 30 minutes of a meal. Advise patients and caregivers not to crush or cut capecitabine tablets.

Advise patients if they cannot swallow capecitabine tablets whole, to inform their healthcare provider

[see Dosage and Administration (2.1)].

Nausea: Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to

eat intermittently) or greater to stop taking capecitabine tablets immediately and to contact their

healthcare provider for management of nausea [see Adverse Reactions (6.1)].

Vomiting: Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or

greater to stop taking capecitabine tablets immediately and to contact their healthcare provider for

management of vomiting [see Adverse Reactions (6.1)].

Hand-and-Foot Syndrome: Instruct 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 to stop taking capecitabine tablets immediately and to contact their healthcare

provider. Inform patients that initiation of symptomatic treatment is recommended and hand-and-foot

syndrome can lead to loss of fingerprints which could impact personal identification [see Adverse

Reactions (6.1)].

Stomatitis: Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the

mouth or tongue, but able to eat) or greater to stop taking capecitabine tablets immediately and to contact

their healthcare provider [see Adverse Reactions (6.1)].

Fever and Neutropenia: Inform patients who develop a fever of 100.5°F or greater or other evidence of

potential infection to contact their healthcare provider [see Adverse Reactions (6.1)].

Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to

use effective contraception during treatment with capecitabine tablets and for 6 months after the last

dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see

Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception

during treatment with capecitabine tablets and for 3 months after the last dose [see Use in Specific

Populations (8.3)].

Lactation: Advise females not to breastfeed during treatment with capecitabine tablets and for 2 weeks

after the last dose [see Use in Specific Populations (8.2)].

Patient Information

Patient Information

Capecitabine Tablets, USP

(kap″ e sye′ ta been)

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

Capecitabine tablets can cause serious side effects, including:

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

effects.

What are capecitabine tablets?

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

Capecitabine tablets can interact with blood thinner medicines, such as warfarin (COUMADIN ).

Taking capecitabine tablets with these medicines can cause changes in how fast your blood clots

and can cause bleeding that can lead to death. This can happen as soon as a few days after you start

taking capecitabine tablets, or later during treatment, and possibly even within 1 month after you

stop taking capecitabine tablets. Your risk may be higher because you have cancer, and if you are

over 60 years of age.

Before taking capecitabine tablets, tell your healthcare provider if you are taking warfarin

(COUMADIN) or another blood thinner medicine.

If you take warfarin (COUMADIN) or another blood thinner that is like warfarin

(COUMADIN) during treatment with capecitabine tablets, your healthcare provider should

do blood tests often, to check how fast your blood clots during and after you stop treatment

with capecitabine tablets. Your healthcare provider may change your dose of the blood

thinner medicine if needed.

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

Do not take capecitabine tablets if you:

Talk to your healthcare provider before taking capecitabine tablets if you are not sure if you have any

of the conditions listed above.

Before taking capecitabine tablets, tell your healthcare provider about all your medical

conditions, including if you:

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

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Capecitabine tablets may affect the way other

medicines work, and other medicines may affect the way capecitabine tablets work.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist

when you get a new medicine.

How should I take capecitabine tablets?

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

after they have surgery.

cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic).

breast cancer that has spread to other parts of the body (metastatic) together with another medicine

called docetaxel after treatment with certain other anti-cancer medicines have not worked.

breast cancer that has spread to other parts of the body and has not improved after treatment with

paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with

certain anti-cancer medicines.

have severe kidney problems.

are allergic to capecitabine, 5-fluorouracil, or any of the ingredients in capecitabine tablets. See

the end of this leaflet for a complete list of ingredients in capecitabine tablets.

have had heart problems.

have kidney or liver problems.

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

are pregnant or plan to become pregnant. Capecitabine tablets can harm your unborn baby. Your

healthcare provider should do a pregnancy test before you start treatment with capecitabine

tablets. Tell your healthcare provider right away if you become pregnant or think you might be

pregnant during treatment with capecitabine tablets.

Females who are able to become pregnant should use effective birth control during

treatment and for 6 months after the final dose. Talk to your healthcare provider about birth

control choices that may be right for you during treatment with capecitabine tablets.

Males who have female partners who are able to become pregnant should use effective

birth control during treatment and for 3 months after the final dose.

are breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast

milk. Do not breastfeed during treatment with capecitabine tablets and for 2 weeks after the final

dose.

Take capecitabine tablets exactly as your healthcare provider tells you to take it.

Your healthcare provider will tell you how many capecitabine tablets to take and when to take

them.

What are the possible side effects of capecitabine tablets?

Capecitabine tablets may cause serious side effects including:

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

Take capecitabine tablets 2 times a day, 1 time in the morning and 1 time in the evening.

Take capecitabine tablets within 30 minutes after finishing a meal.

Swallow capecitabine tablets whole with water. Do not crush or cut capecitabine tablets. If you

cannot swallow capecitabine tablets whole, tell your healthcare provider.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment

with capecitabine tablets if you develop side effects.

If you take too many capecitabine tablets, call your healthcare provider or go to the nearest

hospital emergency room right away.

Diarrhea. Diarrhea is common with capecitabine tablets and can sometimes be severe. Stop taking

capecitabine tablets and call your healthcare provider right away if the number of bowel

movements you have in a day increases by 4 or more than is usual for you. Ask your healthcare

provider about what medicines you can take to treat your diarrhea. If you have severe bloody

diarrhea with severe abdominal pain and fever, call your healthcare provider or go to the nearest

hospital emergency room right away.

Heart problems. Capecitabine tablets can cause heart problems including: heart attack and

decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical

activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle,

heart failure, and sudden death. Stop taking capecitabine tablets and call your healthcare provider

right away if you get any of the following symptoms:

chest pain

feeling faint

sudden weight gain

shortness of breath

irregular heartbeats or skipping beats

swollen ankles or legs

Loss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with

capecitabine tablets and may cause sudden kidney failure that can lead to death. You are at higher

risk if you have kidney problems before taking capecitabine tablets and also take other medicines

that can cause kidney problems.

Nausea and vomiting are common with capecitabine tablets. If you lose your appetite, feel weak,

and have nausea, vomiting, or diarrhea, you can quickly become dehydrated.

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

vomit 2 or more times in a day.

are only able to eat or drink a little now and then, or not at all due to nausea.

have diarrhea. See “diarrhea” above

Serious skin and mouth reactions.

capecitabine tablets can cause serious skin reactions that may lead to death. Tell your

Healthcare provider right away if you develop a skin rash, blisters and peeling of your skin.

If your white blood cell count is very low, you are at increased risk for infection. Call your healthcare

provider right away if you develop a fever of 100.5ºF or greater or have other signs and symptoms of

infection.

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

capecitabine tablets.

The most common side effects of capecitabine tablets include:

Capecitabine tablets may cause fertility problems in females and males. This may affect the ability to

have a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of capecitabine tablets.

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

800-FDA-1088.

How should I store capecitabine tablets?

Keep capecitabine tablets and all medicines out of the reach of children.

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

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information

Leaflet. Do not use capecitabine tablets for a condition for which it was not prescribed. Do not give

capecitabine tablets to other people, even if they have the same symptoms you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about capecitabine tablets that is

written for health professionals.

What are the ingredients in capecitabine tablets?

Healthcare provider right away if you develop a skin rash, blisters and peeling of your skin.

Your healthcare provider may tell you to stop taking capecitabine tablets if you have a

serious skin reaction. Do not take capecitabine tablets again if this happens.

capecitabine tablets can also cause “hand and foot syndrome.” Hand and foot syndrome is

common with capecitabine tablets and can cause you to have numbness and changes in

sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet.

Stop taking capecitabine tablets and call your healthcare provider right away if you have any

of these symptoms and you are not able to do your usual activities.

Hand and foot syndrome can lead to loss of fingerprints which could impact your

identification.

you may get sores in your mouth or on your tongue when taking capecitabine tablets. Stop

taking capecitabine tablets and call your healthcare provider if you get painful redness,

swelling, or ulcers in your mouth and tongue, or if you are having problems eating.

Increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood

is common with capecitabine tablets. Your healthcare provider will check you for these problems

during treatment with capecitabine tablets.

Decreased white blood cells, platelets, and red blood cell counts. Your healthcare provider

will do blood tests during treatment with capecitabine tablets to check your blood cell counts.

diarrhea

hand and foot syndrome

nausea

vomiting

stomach-area (abdominal) pain

weakness and tiredness

increased amounts of red blood cell

breakdown products (bilirubin) in your blood

Store capecitabine tablets at room temperature between 20º to 25ºC (68º to 77ºF).

Keep capecitabine tablets in a tightly closed container.

Ask your healthcare provider or pharmacist how to safely throw away any unused capecitabine

tablets.

Active ingredient: capecitabine

Inactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate,

microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

The brands listed are trademarks of their respective owners.

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

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised: 3/2019

CAPE:R8p/PL:CAPE:R5p

PRINCIPAL DISPLAY PANEL – 150 mg

NDC 0378-2511-91

Capecitabine

Tablets, USP

150 mg

Oncology Product

Rx only 60 Tablets

Each film-coated tablet contains:

Capecitabine, USP 150 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Usual Dosage: See accompanying

prescribing information.

Instructions for Patients: Swallow

capecitabine tablets whole with

water within 30 minutes of a meal.

Do not crush or cut capecitabine

tablets .

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

RM2511D1

PRICIPAL DISPLAY PANEL – 500 mg

NDC 0378-2512-78

Capecitabine

Tablets, USP

500 mg

Oncology Product

Rx only 120 Tablets

Each film-coated tablet contains:

Capecitabine, USP 500 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Usual Dosage: See accompanying

prescribing information.

Instructions for Patients: Swallow

capecitabine tablets whole with

water within 30 minutes of a meal.

Do not crush or cut capecitabine

tablets .

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

RM2512DA2

CAPECITABINE

capecitabine tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -2511

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CAPECITABINE (UNII: 6 8 0 4DJ8 Z9 U) (CAPECITABINE - UNII:6 8 0 4DJ8 Z9 U)

CAPECITABINE

150 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 3 MPA.S) (UNII: 0 VUT3PMY8 2)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE 10 2 (UNII: PNR0 YF6 9 3Y)

PO LYDEXTRO SE (UNII: VH2XOU12IE)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

M;511

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 378 -2511-

6 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 8 /0 8 /20 14

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 9 43

0 8 /0 8 /20 14

CAPECITABINE

capecitabine tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -2512

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CAPECITABINE (UNII: 6 8 0 4DJ8 Z9 U) (CAPECITABINE - UNII:6 8 0 4DJ8 Z9 U)

CAPECITABINE

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 3 MPA.S) (UNII: 0 VUT3PMY8 2)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE 10 2 (UNII: PNR0 YF6 9 3Y)

PO LYDEXTRO SE (UNII: VH2XOU12IE)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL

S iz e

15mm

Flavor

Imprint Code

M512

Contains

Packag ing

Mylan Pharmaceuticals Inc.

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 378 -2512-

120 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 8 /0 8 /20 14

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 9 43

0 8 /0 8 /20 14

Labeler -

Mylan Pharmaceuticals Inc. (059295980)

Revised: 3/2019

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