Advertisement

Topics

These highlights do not include all the information needed to use CAPECITABINE TABLETS USP safely and effectively. See full prescribing information for CAPECITABINE TABLETS USP.CAPECITABINE TABLETS USP, Film Coated for Oral useInitial U.S. Approval: 1998 | Capecitabine [Rising Pharmaceuticals, Inc.] | BioPortfolio

13:40 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Capecitabine Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarinderivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important capecitabine-Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Do not crush or cut capecitabine tablets. Capecitabine Tablets dose is calculated according to body surface area.

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

The recommended dose of capecitabine tablets are 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 [ie, 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)].

In Combination With Docetaxel (Metastatic Breast Cancer)

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

Table 1 Capecitabine Tablets Dose Calculation According to Body Surface Area
Dose Level 1250 mg/m2
Twice a Day
Number of Tablets to be Taken at
Each Dose (Morning and Evening)
Surface Area (m2) Total Daily
DoseTotal Daily Dose divided by 2 to allow equal morning and evening doses (mg)
150mg 500mg
≤ 1.25 3000 0 3
1.26-1.37 3300 1 3
1.38-1.51 3600 2 3
1.52-1.65 4000 0 4
1.66-1.77 4300 1 4
1.78-1.91 4600 2 4
1.92-2.05 5000 0 5
2.06-2.17 5300 1 5
≥ 2.18 5600 2 5

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.

In Combination With Docetaxel (Metastatic Breast Cancer)

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

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

Table 2 Recommended Dose Modifications of Capecitabine Tablets
Toxicity
NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5) ].
During a Course of Therapy Dose Adjustment for Next
Treatment (% of starting dose)
Grade 1 Maintain dose level Maintain dose level
Grade 2
-1st appearance  100%
-2nd appearance 
Interrupt until resolved to grade 0-1 75%
-3rd appearance 
50%
-4th appearance  Discontinue treatment permanently -
Grade 3
-1st appearance  Interrupt until resolved to grade 0-1 75%
-2nd appearance  50%
-3rd appearance  Discontinue treatment permanently -
Grade 4
-1st appearance Discontinue permanently
OR
If physician deems it to be in the 
patient’s best interest to continue, 
interrupt until resolved to grade 0-1
50%
Table 3 Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets
Toxicity 
NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5) ].
Grade 2 Grade 3 Grade 4
1st appearance  Delay treatment until
resolved to grade 0-1;
Resume treatment with
original dose of 75 mg/m2
docetaxel 
Delay treatment until
resolved to grade 0-1;
Resume treatment at
55 mg/m2 of docetaxel. 
Discontinue treatment
with docetaxel 
2nd appearance  Delay treatment until
resolved to grade 0-1;
Resume treatment at
55 mg/m2 of docetaxel. 
Discontinue treatment
with docetaxel 
-
3rd appearance  Discontinue treatment
with docetaxel 
- -

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 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 2and Table 3(depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine tablets monotherapy and capecitabine tablets in combination use with docetaxel.

Cockroft and Gault Equation:

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

Creatinine clearance for males = —————————————

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

Creatinine clearance for females = 0.85 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.

Capecitabine tablets USP are supplied in strengths of 150 mg and 500 mg for oral administration.

150 mg: Light pink coloured, capsule shaped, biconvex film coated tablet debossed with one side CAP and other side 150.

500 mg: Dark pink coloured, capsule shaped, biconvex film coated tablet debossed with one side CAP and other side 500.

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.

General

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

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)]

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 monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. [see Dosage and Administration (2.2)]. Standard antidiarrheal treatments (eg, loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

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.

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 (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.

Withhold or permanently discontinue capecitabine 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 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.

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 with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when Capecitabine is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, Capecitabine 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 (2.2)] .

Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.3)] . Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and Administration (2.2 ), Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3)] .

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

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with Capecitabine [see Adverse Reactions (6.4)] . Capecitabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to Capecitabine 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. 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 (2.2)].

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 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 as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5 to 3 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 (2.2)].

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 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. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted.

Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

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

In 995 patients receiving capecitabine as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), 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 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.

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

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

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.

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 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 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 or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)
Adjuvant Treatment for Colon Cancer (N=1969)
Capecitabine (N=995) 5-FU/LV (N=974)
Body System/ Adverse Event All Grades Grade 3/4 All Grades Grade 3/4
Gastrointestinal Disorders



   Diarrhea 
47 
12 
65 
14 
   Nausea 
34 

47 

   Stomatitis 
22 

60 
14 
   Vomiting 
15 

21 

   Abdominal Pain 
14 

16 

   Constipation 

-
11 
<1 
   Upper Abdominal Pain 

<1 

<1 
   Dyspepsia 

<1 

-
Skin and Subcutaneous
Tissue Disorders
   Hand-and-Foot Syndrome  60  17  <1 
   Alopecia  - 22  <1 
   Rash  - -
   Erythema  <1 
General Disorders and
Administration Site Conditions
   Fatigue  16  <1  16 
   Pyrexia  <1  <1 
   Asthenia  10  <1  10 
   Lethargy  10  <1  <1 
Nervous System Disorders
   Dizziness  <1  -
   Headache  <1  <1 
   Dysgeusia  - -
Metabolism and Nutrition
Disorders 
   Anorexia <1  11  <1 
Eye Disorders
   Conjunctivitis <1  <1 
Blood and Lymphatic System
Disorders 




   Neutropenia 2 <1 8 5
Respiratory Thoracic and
Mediastinal Disorders
   Epistaxis 2 - 5 -
Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)
Adverse Event Capecitabine (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 
Decreased neutrophilsThe incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm.
Decreased neutrophils/granulocytes 
Decreased platelets 
Increased bilirubinIt 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.
1.6 
1.1 
2.3 
1.0 
13.0 
2.2 
2.4 
1.0 
20 
0.6 
0.7 
2.2 
1.2 
13.0 
26.2 
26.4 
0.7 
6.3 

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/mtwice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/mleucovorin IV followed by 425 mg/mIV 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 and 32 (5.4%) randomized to 5-FU/LV.

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

In Combination with Docetaxel

The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/mtwice 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/mon 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/mon 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.

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

(n=255)
Body System/Adverse Event Total
Grade 3
%
Grade 4
Total 
%
Grade 3 
%
Grade 4 
%
Hematologic






   Leukopenia 
91 
37 
24 
88 
42 
33 
   Neutropenia/Granulocytopenia 
86 
20 
49 
87 
10 
66 
   Thrombocytopenia 
41 


23 


   Anemia 
80 


83 

<1 
   Lymphocytopenia 
99 
48 
41 
98 
44 
40 
Hepatobiliary 






   Hyperbilirubinemia 20 





Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer
– Not observed
NA = Not Applicable
Adverse Event Phase 2 Trial in Stage IV Breast Cancer
(n=162)
Body System/Adverse Event Total 
Grade 3
Grade 4
GI



   Diarrhea 
57 
12 

   Nausea 
53 

– 
   Vomiting 
37 

– 
   Stomatitis 
24 

– 
   Abdominal Pain 
20 

– 
   Constipation 
15 

– 
   Dyspepsia 

– 
– 
Skin  and  Subcutaneous



   Hand-and-Foot Syndrome 
57 
11 
NA 
   Dermatitis 
37 

– 
   Nail Disorder 

– 
– 
General



   Fatigue 
41 

– 
   Pyrexia 
12 

– 
   Pain in Limb 


– 
Neurological



   Paresthesia 
21 

– 
   Headache 


– 
   Dizziness 

– 
– 
   Insomnia 

– 
– 
Metabolism 



   Anorexia
23
3

   Dehydration
7
4
1
Eye 



   Eye Irritation
15 
– 
– 
Musculoskeletal 



   Myalgia

– 
– 
Cardiac 



   Edema


– 
Blood 



   Neutropenia
26
2
2
   Thrombocytopenia
24
3
1
   Anemia
72
3
1
   Lymphopenia
94
44
15
Hepatobiliary 



   Hyperbilirubinemia
22 


Clinically relevant adverse events reported in <5% of patients treated with capecitabine tablet either as monotherapy or in combination with docetaxol that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
Gastrointestinal:           abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)
Skin & Subcutan.:         nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)
General:                        chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation
Neurological:                insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance
Metabolism:                  increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia
Eye:                               conjunctivitis
Respiratory:                  cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea
Cardiac:                        tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion
Infections:                     laryngitis (1.0%), 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%)
Postmarketing:              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, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)]
Capecitabine tablet 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%)

Anticoagulants

Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning]. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. In a drug interaction study with single dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin [see Clinical Pharmacology (12.3)]. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.

Phenytoin

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

Leucovorin

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

CYP2C9 substrates

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

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

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

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

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

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

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

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

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

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function [see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and Administration (2.3), and Clinical Pharmacology (12.3)].

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

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

Capecitabine tablets USP are 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, USP is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine 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 tablets USP are supplied as capsule shaped, biconvex film coated tablets for oral administraton. Each light pink-colored tablet contains 150 mg capecitabine and each dark pink-colored tablet contains 500 mg capecitabine. The inactive ingredients in Capecitabine tablets USP include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The light or dark pink film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, yellow iron oxide, and red iron oxide.

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

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 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 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 tablet has a low potential for pharmacokinetic interactions related to plasma protein binding.

Bioactivation and Metabolism

Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.

Metabolic Pathway of capecitabine to 5-FU3

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 at 1250 mg/mtwice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.3)].

Following oral administration of 825 mg/m 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 has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m dose of capecitabine. 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 is administered. The effect of severe hepatic dysfunction on capecitabine 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 (2.3), 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/m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see Boxed Warning and Drug Interactions (7.1)].

Effect of Antacids on the Pharmacokinetics of Capecitabine

When Maalox (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (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.

Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa

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

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

Impairment of Fertility

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m/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.

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of capecitabine for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with capecitabine 1250 mg/m 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 ≥ 1.5x10/L, platelets ≥ 100x10/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.

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

All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/morally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.3)]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11).

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

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

Capecitabine has been demonstrated to be non-inferior to 5-FU/LV.

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

Table 10 Baseline Demographics

Capecitabine 
(n=1004)
5-FU/LV
(n=983)
Age (median, years) 
Range 
62
(25-80)
63
(22-82)
Gender 
Male (n, %) 
Female (n, %) 
542 (54)
461 (46)
532 (54)
451 (46)
ECOG PS 
0 (n, %) 
1 (n, %) 
849 (85)
152 (15)
830 (85)
147 (15)
Staging – Primary Tumor 
PT1 (n, %) 
PT2 (n, %) 
PT3 (n, %) 
PT4 (n, %) 
Other (n, %) 
12 (1)
90 (9)
763 (76)
138 (14)
1 (0.1)
6 (0.6)
92 (9)
746 (76)
139 (14)
0 (0)
Staging – Lymph Node 
pN1 (n, %) 
pN2 (n, %) 
Other (n, %) 
695 (69)
305 (30)
4 (0.4)
694 (71)
288 (29)
1 (0.1)
Table 11 Summary of Dose Modifications in X-ACT Study

Capecitabine 
N = 995
5-FU/LV
N = 974
Median relative dose intensity (%) 
93 
92 
Patients completing full course of treatment (%) 
83 
87 
Patients with treatment interruption (%) 
15 

Patients with cycle delay (%) 
46 
29 
Patients with dose reduction (%) 
42 
44 
Patients with treatment interruption, cycle delay, or dose reduction (%) 
57 
52 
Table 12 Efficacy of Capecitabine vs 5-FU/LV in Adjuvant Treatment of Colon CancerApproximately 93.4% had 5-year DFS information
All  Randomized  Population 
Capecitabine 
( n = 1004 ) 
5 - FU / LV 
( n = 983 ) 
Median  follow - up  ( months ) 
83 
83 
5 - year  Disease - free  Survival  Rates  (%) Based on Kaplan-Meier estimates
59.1 
54.6 
Hazard Ratio 
(capecitabine /5-FU/LV) 
(95% C.I. for Hazard Ratio) 
p-valueTest of superiority of capecitabine vs 5-FU/LV (Wald chi-square test)
0.88 
(0.77 -1.01) 

p = 0.068 

General

The recommended dose of capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m/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; however, toxicity was increased. Capecitabine, 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 in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with capecitabine 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 tablet and 5-FU/LV patients are shown in Table 13.

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

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

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

Table 13 Baseline Demographics of Controlled Colorectal Trials

Study  1
Study  2

Capecitabine
( n = 302 )
5 - FU / LV
( n = 303 )
Capecitabine
( n = 301 )
5 - FU / LV
( n = 301 )
Age (median, years) 
64 
63 
64 
64 
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) 
90 
90 
90 
90 
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) 
Table 14 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 1)

Capecitabine  ( n = 302 ) 
5 - FU / LV  ( n = 303 ) 
Overall  Response  Rate 
(%, 95% C.I.) 
21 (16-26) 
11 (8-15) 
(p-value) 
0.0014 
Time  to  Progression 
(Median, days, 95% C.I.) 
128 (120-136) 
131 (105-153) 
Hazard Ratio (capecitabine /5-FU/LV)
95% C.I. for Hazard Ratio 
0.99 
(0.84-1.17) 
Survival 
(Median, days, 95% C.I.) 
380 (321-434) 
407 (366-446) 
Hazard Ratio (capecitabine /5-FU/LV)
95% C.I. for Hazard Ratio
1.00 
(0.84-1.18) 
Table 15 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 2)

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

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

In Combination With Docetaxel

The dose of capecitabine used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of capecitabine (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m administered in 3-week cycles of docetaxel in combination with 1250 mg/m twice daily for 14 days of capecitabine 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 in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline- containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive capecitabine 1250 mg/m 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.

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

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

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

Monotherapy

The antitumor activity of capecitabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Capecitabine was 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.

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

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.

Table 16 Baseline Demographics and Clinical Characteristics Capecitabine And Docetaxel Combination vs Docetaxel in Breast Cancer Trial

Capecitabine  +  Docetaxel 
( n = 255 ) 
Docetaxel  ( n = 256 ) 
Age (median, years) 
52 
51 
Karnofsky  PS (median) 
90 
90 
Site  of  Disease 


   Lymph nodes 
121 (47%) 
125 (49%) 
   Liver 
116 (45%) 
122 (48%) 
   Bone 
107 (42%) 
119 (46%) 
   Lung 
95 (37%) 
99 (39%) 
   Skin 
73 (29%) 
73 (29%) 
Prior  Chemotherapy


   AnthracyclineIncludes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
255 (100%) 
256 (100%) 
   5-FU 
196 (77%) 
189 (74%) 
   Paclitaxel 
25 (10%) 
22 (9%) 
Resistance  to  an  Anthracycline


 No resistance 
19 (7%) 
19 (7%) 
 Progression on anthracycline therapy 
65 (26%) 
73 (29%) 
 Stable disease after 4 cycles of anthracycline therapy 
41 (16%) 
40 (16%) 
 Relapsed within 2 years of completion of  
anthracycline-adjuvant therapy 
78 (31%) 
74 (29%) 
 Experienced a brief response to anthracycline  
therapy, with subsequent progression while on
therapy or within 12 months after last dose 
51 (20%) 
50 (20%) 
No. of Prior Chemotherapy Regimens for
Treatment of Metastatic Disease


 0 
89 (35%) 
80 (31%) 
 1 
123 (48%) 
135 (53%) 
 2 
43 (17%) 
39 (15%) 
 3 
0 (0%) 
2 (1%) 
Table 17 Efficacy of Capecitabine tabletand Docetaxel Combination vs Docetaxel Monotherapy
Efficacy Parameter Combination
Therapy
Monotherapy  p-value  Hazard Ratio
Time to Disease Progression
Median Days
   95% C.I.
186
(165-198)
128
(105-136)

0.0001

0.643
Overall Survival
Median Days
   95% C.I.
442
(375-497)
352
(298-387)

0.0126

0.775
Response RateThe response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm. 32% 22% 0.009 NANA = Not Applicable
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)  55  56 
Karnofsky PS
90  90 
No. Disease Sites
   1-2  43 (32%)  60 (37%) 
   3-4  63 (46%)  69 (43%) 
   >5  29 (22%)  34 (21%) 
Dominant Site of Disease
   VisceralLung, pleura, liver, pertoneum 101 (75%)  110 (68%) 
   Soft Tissue  30 (22%)  35 (22%) 
   Bone  4 (3%)  17 (10%) 
Prior Chemotherapy
   Paclitaxel  135 (100%)  162 (100%) 
   AnthracyclineIncludes 2 patients treated with an anthracenedione 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%) 
Table 19 Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial
Resistance to Both Paclitaxel and
an Anthracycline
(n=43)
CR 0
PRIncludes 2 patients treated with an anthracenedione 11
CR + PR 11
Response Rate
(95% C.I.)
25.6%
(13.5, 41.2)
Duration of Response,
Median in daysFrom date of first response (Range)
154
(63-233)

150 mg: Light pink coloured, capsule shaped, biconvex film coated tablet debossed with one side CAP and other side 150.150 mg tablets are packaged in bottles of 60 (NDC 64980-276-06).

500 mg: Dark pink coloured, capsule shaped, biconvex film coated tablet debossed with one side CAP and other side 500.500 mg tablets are packaged in bottles of 120 (NDC 64980-277-12).

Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.

Care should be exercised in the handling of capecitabine tablets, USP. Capecitabine tablets, USP should not be cut or crushed. Procedures for the proper handling and disposal of anticancer drugs should be considered. Any unused product should be disposed of in accordance with local requirements, or drug take back programs. Several guidelines on the subject have been published.

Information for Patients (see Patient Package Insert)

Patients and patients' caregivers should be informed of the expected adverse effects of Capecitabine tablets, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary [see Dosage and Administration (2.2) ]. As described below, patients taking Capecitabine tablets should be informed of the need to interrupt treatment and to call their physician immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Capecitabine tablets treatment See FDA-approved patient labeling (Patient Information).

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

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

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

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

Hand-and-Foot Syndrome Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.

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

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

Manufactured for: Rising Pharmaceuticals, Inc.Allendale, NJ 07401

Manufactured by: Shilpa Medicare Limited,INDIA.

Patient InformationCapecitabine Tablets USP, Film Coated(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 is Capecitabine tablets? Capecitabine tablets is a prescription medicine used to treat people with:

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

Who should not take Capecitabine tablets? Do not take Capecitabine tablets if you:

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

What should I tell my doctor before taking Capecitabine tablets? See "What is the most important information I should know about Capecitabine tablets?".Before you take Capecitabine tablets, tell your doctor if you:

Tell your doctor 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 works.

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

How should I take Capecitabine tablets?

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?".

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

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

The most common side effects of Capecitabine tablets include:

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

Call your doctor for medical advice about side effects. You may report side effects to Rising Pharmaceuticals, Inc. at 1-866-562-4597 or FDA at 1-800-FDA-1088.

How should I store Capecitabine tablets?

General information about the safe and effective use of Capecitabine tablets. Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. 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 doctor for information about Capecitabine tablets that is written for health professionals.

What are the ingredients in Capecitabine tablets? Active ingredient: capecitabine Inactive ingredients: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.

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

Manufactured for: Rising Pharmaceuticals, Inc.Allendale, NJ 07401

Manufactured by: Shilpa Medicare LimitedINDIA.

Revised: 12/2016

———PRINCIPAL DISPLAY PANEL 150mg———

Rising®    NDC 64980-276-06

CapecitabineTablets, USP

150 mg

60 tablets            Rx only

———PRINCIPAL DISPLAY PANEL 500mg———

Rising®    NDC 64980-277-12

CapecitabineTablets, USP

500 mg

120 tablets            Rx only

Manufacturer

Rising Pharmaceuticals, Inc.

Active Ingredients

Source

Drugs and Medications [24 Associated Drugs and Medications listed on BioPortfolio]

Capecitabine [west-ward pharmaceuticals corp.]

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...

Capecitabine [shilpa medicare limited]

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, Film Coa...

Capecitabine [northstar rxllc]

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...

Capecitabine [accord healthcare inc.]

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...

Capecitabine [avpak]

Capecitabine Tablets, USP These highlights do not include all the information needed to use CAPECITABINE TABLETS safely and effectively. See full prescribing information for CAPECITABINE TABLETS. CAPE...

Clinical Trials [795 Associated Clinical Trials listed on BioPortfolio]

A Study Of Sunitinib In Combination With Capecitabine Compared With Capecitabine In Patients With Breast Cancer

The treatment received with sunitinib plus capecitabine could delay tumor growth longer than with treatment with capecitabine alone.

NX vs TX as 1-line Chemotherapy on MBC

It is a phase III trial to explore the efficacy and safety of vinorelbine plus capecitabine (NX) and docetaxel plus capecitabine (TX) as first line treatment followed by capecitabine alone...

Novel Epothilone Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced Breast Cancer

The purpose of this clinical research study is to learn if BMS-247550 added to the approved therapy of capecitabine is better than capecitabine alone in shrinking or slowing the growth of ...

Capecitabine as NeoAdjuvant Therapy in Locally Advanced Breast Cancer

The purpose of this study is to assess the safety and effectiveness of capecitabine before surgery. The study will also help gain more information about the effects of the capecitabine on...

Epothilone (Ixabepilone) Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced Breast Cancer

The purpose of this clinical research study is to learn if BMS-247550 added to the approved therapy of capecitabine (Xeloda) provides measurable clinical benefits over capecitabine alone i...

PubMed Articles [43 Associated PubMed Articles listed on BioPortfolio]

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: a surrogate biomarker for dihydropyrimidine dehydrogenase activity.

Capecitabine is a 5-fluorouracil (5-FU) derivative that is widely used in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH ) to uracil (Ura) is expected to gain relevance as a...

Identification of the novel capecitabine metabolites in capecitabine-treated patients with hand-foot syndrome.

Hand-foot syndrome (HFS), the most common side effect of capecitabine, is a dose-limiting cutaneous toxicity with only rare therapeutic options. The causative mechanisms of HFS are still unclear. Many...

Capecitabine for the treatment of pancreatic cancer.

Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). ...

Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics.

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU) is extensively used to treat many solid tumors, particularly breast and colorectal cancers. Neurotoxicity of capecitabine has been rarely reporte...

Oncologic outcomes after adjuvant chemotherapy with capecitabine compared to 5-fluorouracil/leucovorin for geriatric stage II colon cancer: a retrospective cohort study.

After curative resection of stage II colon cancer, adjuvant chemotherapy with 5-fluorouracil/leucovorin (FL) or capecitabine is selectively recommended. However, there is little evidence of the effect...

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...

Drug Discovery
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...


Drugs and Medication Quicklinks


Searches Linking to this Drug Record