WARNING:
Capecitabine TABLETS, USP - WARFARIN INTERACTION
Capecitabine
Tablets, USP 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, USP -Warfarin drug interaction was demonstrated in a
clinical pharmacology trial [see 8 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, USP 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, USP was introduced. These events occurred
within several days and up to several months after initiating
Capecitabine Tablets, USP therapy and, in a few cases, within 1 month after
stopping Capecitabine Tablets, USP. 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.
INDICATIONS
& USAGE
Colorectal
Cancer
·
Capecitabine Tablets, USP is 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 referred. Capecitabine Tablets, USP was
non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free
survival (DFS). Physicians should consider results of combination chemotherapy
trials, which have shown improvement in DFS and OS, when prescribing
single-agent Capecitabine Tablets, USP in the adjuvant treatment of Dukes' C
colon cancer.
·
Capecitabine Tablets, USP is indicated as first-line
treatment of patients with metastatic colorectal carcinoma when treatment with
fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown
a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV
has not been demonstrated with Capecitabine Tablets, USP monotherapy. Use of
Capecitabine Tablets, USP instead of 5-FU/LV in combinations has not been
adequately studied to assure safety or preservation of the survival advantage.
Breast Cancer
·
Capecitabine Tablets, USP in combination with docetaxel
is indicated for the treatment of patients with metastatic breast cancer after
failure of prior anthracycline-containing chemotherapy.
·
Capecitabine Tablets, USP monotherapy is also indicated
for the treatment of patients with metastatic breast cancer resistant to both
paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to
paclitaxel and for whom further anthracycline therapy is not indicated (e.g.,
patients who have received cumulative doses of 400 mg/m2 of
doxorubicin or doxorubicin equivalents). Resistance is defined as progressive
disease while on treatment, with or without an initial response, or relapse
within 6 months of completing treatment with an anthracycline-containing
adjuvant regimen.
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DOSAGE &
ADMINISTRATION
Important
Administration Instructions
Capecitabine
Tablets, USP should be swallowed whole with water within 30 minutes after a
meal. Capecitabine Tablets, USP is a cytotoxic drug. Follow applicable special
handling and disposal procedures1. If Capecitabine Tablets, USP 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, USP dose is calculated according to body surface area.
Standard
Starting dose
Monotherapy
(Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast
Cancer)
The recommended
dose of Capecitabine Tablets, USP is 1250 mg/m2 administered
orally twice daily (morning and evening; equivalent to 2500 mg/m2 total
daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles
(see Table 1).
Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a
total of 6 months [ie, Capecitabine Tablets, USP 1250 mg/m2 orally
twice daily for 2 weeks followed by a 1-week rest period, given as 3-week
cycles for a total of 8 cycles (24 week)]
Table 1 Capecitabine Tablets, USP Dose
Calculation According to Body Surface
|
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
Dose* (mg)
|
150 mg
|
500 mg
|
|
≤ 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
|
*Total Daily
Dose divided by 2 to allow equal morning and evening doses
In Combination With Docetaxel (Metastatic Breast Cancer)
In combination
with docetaxel, the recommended dose of Capecitabine Tablets, USP is 1250 mg/m2twice daily for
2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a
1-hour intravenous infusion every 3 weeks. Pre-medication, according to the
docetaxel labeling, should be started prior to docetaxel administration for
patients receiving the Capecitabine Tablets, USP plus docetaxel
combination. Table 1 displays the total daily dose of
Capecitabine Tablets, USP by body surface area and the number of tablets to be
taken at each dose.
Dose Management
Guidelines
General
Capecitabine
Tablets, USP dosage may need to be individualized to optimize patient
management. Patients should be carefully monitored for toxicity and doses of
Capecitabine Tablets, USP should be modified as necessary to accommodate
individual patient tolerance to treatment [see Clinical
Studies (14)]. Toxicity due to Capecitabine Tablets, USP administration may be managed
by symptomatic treatment, dose interruptions and adjustment of Capecitabine
Tablets, USP dose. Once the dose has been reduced, it should not be increased
at a later time. Doses of Capecitabine Tablets, USP 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, USP [see Drug Interactions (7.1)].
Monotherapy
(Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast
Cancer)
Capecitabine
Tablets, USP 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, USP
|
Toxicity 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
|
|
-1st appearance
|
Interrupt until resolved to grade 0-1
|
100 %
|
|
-2nd appearance
|
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%
|
*National Cancer
Institute of Canada Common Toxicity Criteria were used except for the
hand-and-foot syndrome [see Warnings and Precautions (5)].
In Combination
With Docetaxel (Metastatic Breast Cancer)
Dose
modifications of Capecitabine Tablets, USP for toxicity should be made
according to Table 2above for Capecitabine Tablets, USP. At
the beginning of a treatment cycle, if a treatment delay is indicated for
either Capecitabine Tablets, USP 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, USP for the treatment of metastatic breast cancer is shown in Table 3
Table 3
Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets,
USP
|
Toxicity NCIC
Grades *
|
Grade 2
|
Grade 3
|
Grade 4
|
|
1st appearance
|
Delay treatment until resolved to grade 0-1; Resume
treatment with original dose of 75mg/m2 docetaxel
|
Delay treatment until resolved to grade 0-1; Resume
treatment at 55mg/m2 of docetaxel
|
Discontinue treatment
With docetaxel
|
|
2nd appearance
|
Delay treatment until resolved to grade 0-1; Resume
treatment with original dose of 55mg/m2 docetaxel
|
Discontinue treatment
With docetaxel
|
--
|
|
3rd appearance
|
Discontinue treatment
With docetaxel
|
--
|
--
|
*National Cancer
Institute of Canada Common Toxicity Criteria were used except for hand-and-foot
syndrome [see Warnings and Precautions (5)].
Adjustment of
Starting Dose in Special Populations
Renal Impairment
No adjustment to
the starting dose of Capecitabine Tablets, USP 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, USP starting dose when used as monotherapy or in
combination with docetaxel (from 1250mg/m2 to 950
mg/m2 twice daily) is recommended [see Use in
Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Subsequent
dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on
the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings
and Precautions (5.5)]. The starting dose adjustment recommendations for
patients with moderate renal impairment apply to both Capecitabine Tablets, USP
monotherapy and Capecitabine Tablets, USP in combination use with docetaxel.
Cockroft and
Gault Equation:
Creatinine
clearance for (140 - age [yrs])
(body wt [kg])
males
=
_______________________
(72) (serum creatinine [mg/dL])
Creatinine
clearance for females=0.85X male value
Geriatrics
Physicians
should exercise caution in monitoring the effects of Capecitabine Tablets, USP
in the elderly. Insufficient data are available to provide a dosage
recommendation.
DOSAGE FORMS
& STRENGTHS
Capecitabine
Tablets, USP is supplied as oval shaped film coated tablets for oral
administration. Each light peach-colored tablet contains 150 mg of Capecitabine
and each light peach colored tablet contains 500 mg of Capecitabine.
Contraindications
Severe Renal
Impairment
Capecitabine
Tablets, USP is contraindicated in patients with severe renal impairment
(creatinine clearance below 30mL/min [Cockroft and Gault]) [see Use in
Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Hypersensitivity
Capecitabine
Tablets, USP is contraindicated in patients with known hypersensitivity to
Capecitabine or to any of its components. Capecitabine Tablets, USP is
contraindicated in patients who have a known hypersensitivity to
5-fluorouracil.
Warnings and
Precautions
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)]
Diarrhea
Capecitabine
Tablets, USP 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, USP 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, USP 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.
Cardiotoxicity
The
cardiotoxicity observed with Capecitabine Tablets, USP 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.
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, USP (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,
USP.
Withhold or
permanently discontinue Capecitabine Tablets, USP 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, USP
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 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, USP 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, USP is
administered to prevent and correct dehydration at the onset. If grade 2 (or
higher) dehydration occurs, Capecitabine Tablets, USP 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)].
Embryo-Fetal
Toxicity
Based on
findings from animal reproduction studies and its mechanism of action, Capecitabine
Tablets, USP 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, USP 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, USP [see Use in Specific Populations (8.3)].
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, USP [see Adverse Reactions (6.4)]. Capecitabine
Tablets, USP should be permanently discontinued in patients who experience a
severe mucocutaneous reaction possibly attributable to Capecitabine Tablets,
USP 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, USP 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, USP 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, USP should be decreased [see Dosage and
Administration (2.3)].
Hyperbilirubinemia
In 875 patients
with either metastatic breast or colorectal cancer who received at least one
dose of Capecitabine Tablets, USP 1250 mg/m2 twice daily as monotherapy for 2
weeks followed by a 1-week rest period, grade 3 (1.5-3 × ULN)
hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3
×ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients
who had hepatic metastases at baseline and 309 patients without hepatic
metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and
12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia,
18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without
elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had
postbaseline elevations in transaminases at any time (not necessarily
concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had
liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the
167 patients had elevations (grades 1 to 4) at both prebaseline and
postbaseline in alkaline phosphatase or transaminases,respectively. Only 7.8%
(n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or
transaminases.
In the 596
patients treated with Capecitabine Tablets, USP 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, USP 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, USP. 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, USP and docetaxel,grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred
in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 2%
(n=5).If drug-related grade 3 to 4 elevations in bilirubin occur,
administration of Capecitabine Tablets, USP should be immediately interrupted
until the hyperbilirubinemia decreases to ≤3.0 X ULN [see recommended dose
modifications under Dosage and Administration (2.3)].
Hematologic
In 875 patients
with either metastatic breast or colorectal cancer who received a dose of 1250
mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week
rest period, 3.2%, 1.7%,and 2.4% of patients had grade 3 or 4 neutropenia,
thrombocytopenia or decreases in hemoglobin,respectively. In 251 patients with
metastatic breast cancer who received a dose of Capecitabine Tablets, USP 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 × 109 /L and/or thrombocyte counts of
<100 × 109 /L should not be treated with Capecitabine Tablets, USP. If
unscheduled laboratory assessments during a treatment cycle show grade 3 or 4
hematologic toxicity, treatment with Capecitabine Tablets, USP should be
interrupted.
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, USP monotherapy, 62% of the 21 patients ≥80 years of age
treated with Capecitabine Tablets, USP 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, USP 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, USP 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, USP 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, USP 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, USP 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.
Hepatic
Insufficiency
Patients with
mild to moderate hepatic dysfunction due to liver metastases should be
carefully monitored when Capecitabine Tablets, USP is administered. The effect
of severe hepatic dysfunction on the disposition of Capecitabine Tablets, USP
is not known [see Use in Specific Populations (8.6)
and Clinical Pharmacology (12.3)].
Combination With
Other Drugs
Use of
Capecitabine Tablets, USP in combination with irinotecan has not been
adequately studied.
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
Adjuvant Colon
Cancer
Table 4 shows the
adverse reactions occurring in ≥5% of patients from one phase 3 trial in
patients with Dukes' C colon cancer who received at least one dose of study
medication and had at least one safety assessment. A total of 995 patients were
treated with 1250 mg/m2 twice a day of Capecitabine
Tablets, USP administered for 2 weeks followed by a 1-week rest period, and 974
patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin
IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 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, USP 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 Advers e Reactions Reported in ≥5% of Patients Treated
WithCapecitabine Tablets, USP or 5-FU/LV for Colon Cancer in the Adjuvant
Setting (Safety Population)
|
|
Adjuvant Treatment for Colon Cancer (N=1969)
|
|
|
Capecitabine Tablets, USP
(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
Upper Abdominal pain
Dyspepsia
|
47
34
22
15
14
9
7
6
|
12
2
2
2
3
-
<1
<1
|
65
47
60
21
16
11
7
5
|
14
2
14
2
2
< 1
< 1
-
|
|
Skin and Subcutaneous Tissue Disorder
|
|
Hand-and-Foot syndrome
Alopecia
Rash
Erythema
|
60
6
7
6
|
17
-
-
1
|
9
22
8
5
|
<1
<1
-
<1
|
|
General Disorders and Administration site condition
|
|
Fatigue
Pyrexia
Asthenia
Lethargy
|
16
7
10
10
|
< 1
< 1
< 1
< 1
|
16
9
10
9
|
1
< 1
1
< 1
|
|
Nervous System Disorder
|
|
Dizziness
Headache
Dysgeusia
|
6
5
6
|
< 1
< 1
-
|
6
6
9
|
-
< 1
-
|
|
Metabolism and Nutrition Disorders
|
|
Anorexia
|
9
|
< 1
|
11
|
< 1
|
|
Eye Disorders
|
|
Conjunctivitis
|
5
|
< 1
|
6
|
< 1
|
|
Blood and Lymphatic System Disorder
|
|
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 Tablets, USP Monotherapy
for Adjuvant Treatment of Colon Cancer (Safety Population)
|
Adverse Event
|
Capecitabine Tablets, USP
(n=995)
Grade ¾ %
|
Capecitabine Tablets, USP
(n=974)
Grade ¾ %
|
|
Increased ALAT (SGPT)
|
1.6
|
0.6
|
|
Increased calcium
|
1.1
|
0.7
|
|
Decreased calcium
|
2.3
|
2.2
|
|
Decreased hemoglobin
|
1.0
|
1.2
|
|
Decreased lymphocytes
|
13.0
|
13.0
|
|
Decreased neutrophils
|
2.2
|
26.2
|
|
Decreased
neutrophils/granulocytes
|
2.4
|
26.4
|
|
Decreased platelets
|
1.0
|
0.7
|
|
Increased bilirubin †
|
20
|
6.3
|
*The incidence
of grade 3/4 white blood cell abnormalities was 1.3% in the
Capecitabine Tablets, USP 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.
Metastatic
Colorectal Cancer
Monotherapy
Table 6 shows the
adverse reactions occurring in ≥5% of patients from pooling the two phase 3 trials
in first line metastatic colorectal cancer. A total of 596 patients with
metastatic colorectal cancer were treated with 1250 mg/m2 twice a
day of Capecitabine Tablets, USP administered for 2 weeks followed by a 1-week
rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo
regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus
5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median
duration of treatment was 139 days for Capecitabine-treated patients and 140
days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%)
Capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment
because of adverse reactions/intercurrent illness. A total of 82 deaths due to
all causes occurred either on study or within 28 days of receiving study
drug: 50 (8.4%) patients randomized to Capecitabine Tablets, USP 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, USP
(n=596)
|
5-FU/LV (n=593)
|
|
|
Total
%
|
Grade
3%
|
Grade
4%
|
Total
%
|
Grade
3%
|
Grade
4%
|
|
Number of Patients With >
One Adverse Event
|
96
|
52
|
9
|
94
|
45
|
9
|
|
Body System/Adverse Event
|
|
GI
Diarrhea
Nausea
Vomiting
Stomatitis
Abdominal pain
Gastrointestinal Motility disorder
Constipation
Oral Discomfort
Upper GI Inflammatory Disorders
Gastrointestinal Hemorrhage
Ileus
|
55
43
27
25
35
10
14
10
8
6
6
|
13
4
4
2
9
<1
1
-
<1
1
4
|
2
-
<1
<1
<1
-
<1
-
-
<1
1
|
61
51
30
62
31
7
17
10
10
3
5
|
10
3
4
14
5
<1
1
-
1
1
2
|
2
<1
<1
1
-
-
-
-
-
-
1
|
|
Skin and Subcutaneous
Hand-and-Foot Syndrome
Dermatitis
Skin Discoloration
Alopecia
|
54
27
7
6
|
17
1
<1
-
|
NA
-
-
-
|
6
26
5
21
|
1
1
-
<1
|
NA
-
-
-
|
|
General
Fatigue/Weakness
Pyrexia
Edema
Pain
Chest Pain
|
42
18
15
12
6
|
4
1
1
1
1
|
-
-
-
-
-
|
46
21
9
10
6
|
4
2
1
1
1
|
-
-
-
-
<1
|
|
Neurological
Peripheral Sensory Neuropathy
Headache
Dizziness*
Insomnia
Taste Disturbance
|
10
10
8
7
6
|
-
1
<1
-
1
|
-
-
-
-
-
|
4
7
8
7
11
|
-
-
<1
-
<1
|
-
-
-
-
1
|
|
Metabolism
Appetite Decreased
Dehydration
|
26
7
|
3
2
|
<1
<1
|
31
8
|
2
3
|
<1
1
|
|
Eye
Eye Irritation
Vision Abnormal
|
13
5
|
-
-
|
-
-
|
10
2
|
<1
-
|
-
-
|
|
Respiratory
Dyspnea
Cough
Pharyngeal Disorder
Epistaxis
Sore Throat
|
14
7
5
3
2
|
1
<1
-
<1
-
|
-
1
-
-
-
|
10
8
5
6
6
|
<1
-
-
-
-
|
1
-
-
-
-
|
|
Musculoskeletal
Back pain
Arthralgia
|
10
8
|
2
1
|
-
-
|
9
6
|
<1
1
|
-
-
|
|
Vascular
Venous Thrombosis
|
8
|
3
|
<1
|
6
|
2
|
-
|
|
Psychiatric
Mood Alteration
Depression
|
5
5
|
-
-
|
-
-
|
6
4
|
<1
<1
|
-
-
|
|
Infections
Viral
|
5
|
<1
|
-
|
5
|
<1
|
-
|
|
Blood and Lymphatic
Anemia
Neutropenia
|
80
13
|
2
1
|
<1
2
|
79
46
|
1
8
|
<1
13
|
|
Hepatobiliary
Hyperbilirubinemia
|
48
|
18
|
5
|
17
|
3
|
3
|
– Not observed
NA = Not
Applicable
*Excluding
vertigo
Breast Cancer
In Combination
with Docetaxel
The following data are shown for the combination study with Capecitabine
Tablets, USP and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the
Capecitabine Tablets, USP and docetaxel combination arm the treatment was
Capecitabine Tablets, USP administered orally 1250 mg/m2 twice daily as
intermittent therapy (2 weeks of treatment followed by 1 week without
treatment) for at least 6 weeks and docetaxel administered as a 1-hour
intravenous infusion at a dose of 75 mg/m2 on the first day of each 3-week
cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered
as a 1-hour intravenous infusion at a dose of 100 mg/m2 on the first day of
each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129
days in the combination arm and 98 days in the monotherapy arm. A total of 66
patients (26%) in the combination arm and 49 (19%) in the monotherapy arm
withdrew from the study because of adverse reactions. The percentage of
patients requiring dose reductions due to adverse reactions was 65% in the
combination arm and 36% in the monotherapy arm. The percentage of patients
requiring treatment interruptions due to adverse reactions in the combination
arm was 79%. Treatment interruptions were part of the dose modification scheme
for the combination therapy arm but not for the docetaxel monotherapy-treated
patients.
Table 7 Percent Incidence of Adverse Events Considered
Related or Unrelated to treatment in ≥5% of Patients Participating in the
Capecitabine Tablets, USP and Docetaxel Combination vs Docetaxel Monotherapy
Study
|
Adverse Event
|
Capecitabine
Tablets, USP
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 atleast One Adverse Event
|
99
|
76.5
|
29.1
|
97
|
57.6
|
31.8
|
|
Body System/Adverse Event
|
|
GI
Diarrhea
Stomatitis
Nausea
Vomiting
Constipation
Abdominal pain
Dyspepsia
Dry mouth
|
67
67
45
35
20
30
14
6
|
14
17
7
4
2
<3
-
<1
|
<1
<1
-
1
-
<1
-
-
|
48
43
36
24
18
24
8
5
|
5
5
2
2
-
2
1
-
|
<1
-
-
-
-
-
-
-
|
|
Skin and Subcutaneous
Hand-and-Foot Syndrome
Alopecia
Nail disorder
Dermatitis
Rash Erythematous
Nail Discoloration
Oncholysis
Pruritus
|
63
41
14
8
9
6
5
4
|
24
6
2
-
<1
-
1
-
|
NA
-
-
-
-
-
-
-
|
8
42
15
11
5
4
5
5
|
1
7
-
1
-
<1
1
-
|
NA
-
-
-
-
-
-
-
|
|
General
Pyrexia
Asthenia
Fatigue
Weakness
Pain in Limb
Lethargy
Pain
Chest Pain (non-cardiac)
Influenza-like illness
|
28
26
22
16
13
7
7
4
5
|
2
4
4
2
-
<1
-
1
-
|
-
<1
-
-
-
-
-
-
-
|
34
25
27
11
13
6
5
6
5
|
2
6
6
2
2
2
1
2
-
|
-
-
-
-
-
-
-
-
-
|
|
Neurological
Taste Disturbance
Headache
Paresthesia
Dizziness
Insomnia
Peripheral Neuropathy
Hypoaesthesia
|
16
15
12
12
8
6
4
|
<1
3
<1
-
-
-
<1
|
-
-
-
-
-
-
-
|
14
15
16
8
10
10
8
|
<1
2
1
<1
<1
1
<1
|
-
-
-
-
-
-
-
|
|
Metabolism
Anorexia
Appetite Decreased
Weight Decreased
Dehydration
|
13
10
7
10
|
1
-
-
2
|
-
-
-
-
|
11
5
5
7
|
<1
-
-
<1
|
-
-
-
<1
|
|
Eye
Lacrimation Icreased
Conjuctivitis
Eye Irritation
|
12
5
5
|
-
-
-
|
-
-
-
|
7
4
1
|
<1
-
-
|
-
-
-
|
|
Musculoskeletal
Arthralgia
Myalgia
Back pain
Bone pain
|
15
15
12
8
|
2
2
<1
<1
|
-
-
-
-
|
24
25
11
10
|
3
2
3
2
|
-
-
-
-
|
|
Cardiac
Edema
|
33
|
<2
|
-
|
34
|
<3
|
1
|
|
Blood
Neutropenic Fever
|
16
|
3
|
13
|
21
|
5
|
16
|
|
Respiratory
Dyspnea
Cough
Sore Throat
Epistaxis
Rhinorrhea
Pleural Effusion
|
14
13
12
7
5
2
|
2
1
2
<1
-
1
|
<1
-
-
-
-
-
|
16
22
11
6
3
7
|
2
<1
<1
-
-
4
|
-
-
-
-
-
-
|
|
Infections
Oral Candidiasis
Urinary Tract Infection
Upper Respiratory Tract
|
7
6
5
|
<1
<1
-
|
-
-
-
|
8
4
5
|
<1
-
1
|
-
-
-
|
|
Vascular
Flushing
Lymphoedema
|
5
3
|
-
<1
|
-
-
|
5
5
|
-
1
|
-
-
|
|
Psychiatric
Depression
|
5
|
-
|
-
|
5
|
1
|
-
|
– Not observed
NA = Not Applicable
Table 8 Percent of Patients With Laboratory Abnormalities
Participating in the Capecitabine Tablets, USP and Docetaxel Combination vs
Docetaxel Monotherapy Study
|
Adverse Event
|
Capecitabine
Tablets, USP 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
Neutropenia/Granulocytopenia
Thrombocytopenia
Anemia
Lymphocytopenia
|
91
86
41
80
99
|
37
20
2
7
48
|
24
49
1
3
41
|
88
87
23
83
98
|
42
10
1
5
44
|
33
66
2
<1
40
|
|
Hepatobiliary
Hyperbilirubinemia
|
20
|
7
|
2
|
6
|
2
|
2
|
Monotherapy
The following data are shown for the study in stage IV breast cancer patients
who received a dose of 1250 mg/m2 administered twice daily for 2
weeks followed by a 1-week rest period. The mean duration of treatment was 114
days. A total of 13 out of 162 patients (8%) discontinued treatment because of
adverse reactions/intercurrent illness.
Table 9 Percent Incidence of Adverse Reactions Considered
Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients
Participating in the Single Arm Trial in Stage IV Breast Cancer.
|
Adverse Event
|
Phase 2 Trial in stage IV Breast Cancer
(n=162)
|
|
Body System/Adverse Event
|
Total %
|
Grade 3%
|
Grade 4%
|
|
GI
Diarrhea
Nausea
Vomiting
Stomatitis
Abdominal pain
Constipation
Dyspepsia
|
57
53
37
24
20
15
8
|
12
4
4
7
4
1
-
|
3
-
-
-
-
-
-
|
|
Skin and Subcutaneous
Hand-and-Foot Syndrome
Dermatitis
Nail Disorder
|
57
37
7
|
11
1
-
|
NA
-
-
|
|
General
Fatigue
Pyrexia
Pain in Limb
|
41
12
6
|
8
1
1
|
-
-
-
|
|
Neurological
Paresthesia
Headache
Dizziness
Insomnia
|
21
9
8
8
|
1
1
-
-
|
-
-
-
-
|
|
Metabolism
Anorexia
Dehydration
|
23
7
|
3
4
|
-
1
|
|
Eye
Eye Irritation
|
15
|
-
|
-
|
|
Musculoskeletal
Myalgia
|
9
|
-
|
-
|
|
Cardiac
Edema
|
9
|
1
|
-
|
|
Blood
Neutropenia
Thrombocytopenia
Anemia
Lymphopenia
|
26
24
72
94
|
2
3
3
44
|
2
1
1
15
|
|
Hepatobiliary
Hyperbilirubinemia
|
22
|
9
|
2
|
– Not observed
NA = Not Applicable
Clinically
Relevant Adverse Events in <5% of Patients
Clinically
relevant adverse events reported in <5% of patients treated with
Capecitabine Tablets, USP 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, 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)]
|
Capecitabine
Tablets, USP 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%)
|
Drug
Interactions
Drug-Drug
Interactions
Anticoagulants
Altered
coagulation parameters and/or bleeding have been reported in patients taking
Capecitabine Tablets, USP 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, USP therapy and, in a few cases, within 1 month after
stopping Capecitabine Tablets, USP. 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, USP and phenytoin dose may need to be reduced [see Dosage and
Administration (2.3)]. Postmarketing reports indicate that some patients
receiving Capecitabine Tablets, USP 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,
USP and other CYP2C9 substrates have been conducted. Care should be exercised
when Capecitabine Tablets, USP is coadministered with CYP2C9 substrates.
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, USP within 30 minutes after a meal. It is
recommended Capecitabine Tablets, USP be administered with food [see Dosage and
Administration (2)]
USE IN SPECIFIC
POPULATION
Pregnancy
Risk Summary
Based on findings in animal reproduction studies and its mechanism of action,
Capecitabine tablets, USP 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.
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, USP 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.
Females and
Males of Reproductive Potential
Pregnancy
Testing
Pregnancy testing is recommended for females of reproductive potential prior to
initiating Capecitabine tablets, USP.
Contraception
Females
Capecitabine tablets, USP 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,
USP.
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, USP [see Nonclinical
Toxicology (13.1)].
Infertility
Based on animal studies, Capecitabine Tablets, USP may impair fertility in
females and males of reproductive potential [see Nonclinical
Toxicology (13.1)].
Pediatric Use
The safety and effectiveness
of Capecitabine Tablets, USP 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, USP 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/m2 to 850
mg/m2 every 12 hours for up to 9 weeks. After a 2 week
break, patients received 1250 mg/m2 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/m2 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/m2 Capecitabine every 12 hours with
concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients
received 1250 mg/m2 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%).
Geriatric Use
Physicians
should pay particular attention to monitoring the adverse effects of
Capecitabine Tablets, USP in the elderly [see Warnings
and Precautions (5.11)].
Hepatic
Insufficiency
Exercise caution
when patients with mild to moderate hepatic dysfunction due to liver metastases
are treated with Capecitabine Tablets, USP. The effect of severe hepatic
dysfunction on Capecitabine Tablets, USP is not known [see Warnings
and Precautions (5.12) and Clinical Pharmacology (12.3)].
Renal
Insufficiency
Patients with
moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine
clearance <30 mL/min) renal impairment showed higher exposure for
Capecitabine, 5-FDUR, and FBAL than in those with normal renal function [see
Contraindications (4.2), Warnings and Precautions (5.5), Dosage and
Administration (2.4), and Clinical Pharmacology (12.3)].
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, USP 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, USP were not lethal to mice, rats, and monkeys at doses
up to 2000 mg/kg (2.4,4.8, and 9.6 times the recommended human daily dose on a
mg/m2 basis).
Capecitabine
Description
Capecitabine
Tablets, USP (Capecitabine) is a fluoropyrimidine carbamate with antineoplastic
activity. It is an orally administered systemic prodrug of
5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.
The chemical name for Capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy)
carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the
following structural formula:
Capecitabine is
a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL
at 20°C.
Capecitabine
Tablets, USP is supplied as oval shaped film-coated tablets for oral
administration. Each light peach colored tablet contains 150 mg
Capecitabine and each light peach colored tablet contains 500 mg
Capecitabine, USP. The inactive ingredients in Capecitabine Tablets, USP
include: anhydrous lactose, croscarmellose sodium, hypromellose,
magnesium stearate, microcrystalline cellulose, and purified water. The light
peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide,
iron oxide yellow and iron oxide red.
Capecitabine -
Clinical Pharmacology
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,N5-10-methylenetetrahydrofolate,
bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This
binding inhibits the formation of thymidylate from 2'-deoxyuridylate.
Thymidylate is the necessary precursor of thymidine triphosphate, which is
essential for the synthesis of DNA, so that a deficiency of this compound can
inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly
incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of
RNA. This metabolic error can interfere with RNA processing and protein
synthesis.
Pharmacokinetics
Absorption
Following oral administration
of 1255 mg/m2 BID to cancer patients, Capecitabine reached peak
blood levels in about 1.5 hours (Tmax ) with peak 5-FU levels occurring
slightly later, at 2 hours. Food reduced both the rate and extent of
absorption of Capecitabine with mean Cmax and AUC0-¥ decreased
by 60% and 35%, respectively. The Cmax and AUC0-¥ of 5-FU
were also reduced by food by 43% and 21%, respectively. Food delayed Tmax 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, USP and its metabolites have been
evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2 /day. Over
this range, the pharmacokinetics of Capecitabine Tablets, USP 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 Cmax 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, USP 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
Tablets, USP 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-FU
The enzyme
dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of Capecitabine
metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2).
Dihydropyrimidinase cleaves the pyrimidine ring to yield
5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves
FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
In vitro
enzymatic studies with human liver microsomes indicated that 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, USP at 1250 mg/m2 twice a day indicated that gender
(202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients,
and 28 patients of other race) have no influence on the pharmacokinetics of
5'-DFUR, 5-FU and FBAL. Age has no significant influence on the
pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20%
increase in age results in a 15% increase in AUC of FBAL [see Warnings
and Precautions (5.11) and Dosage and Administration (2.4)].
Following
oral administration of 825 mg/m2 Capecitabine twice daily for 14
days, Japanese patients (n=18) had about 36% lower Cmax and 24%
lower AUC for Capecitabine than the Caucasian patients (n=22). Japanese
patients had also about 25% lower Cmax 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, USP has been evaluated in 13 patients with mild to moderate hepatic
dysfunction due to liver metastases defined by a composite score including
bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m2 dose of
Capecitabine Tablets, USP. Both AUC0-¥ and Cmaxof Capecitabine
increased by 60% in patients with hepatic dysfunction compared to patients with
normal hepatic function (n=14). The AUC0-¥ and
Cmax 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, USP is administered. The effect of severe
hepatic dysfunction on Capecitabine Tablets, USP is not known [see Warnings
and Precautions (5.11) and Use in Special Populations
(8.6)].
Effect of Renal
Insufficiency
Following oral
administration of 1250 mg/m2 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/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 Tablets, USP (1250 mg/m2 , n=12
cancer patients), AUC and Cmax 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, USP.
Effect of
Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa
A Phase 1 study
evaluated the effect of Capecitabine Tablets, USP on the pharmacokinetics of
docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of
Capecitabine Tablets, USP was conducted in 26 patients with solid tumors.
Capecitabine Tablets, USP was found to have no effect on the pharmacokinetics
of docetaxel (Cmax and AUC) and docetaxel has no effect on the
pharmacokinetics of Capecitabine and the 5-FU precursor 5'-DFUR.
Nonclinical
Toxicology
Carcinogenesis
& Mutagenesis & Impairment Of Fertility
Adequate studies
investigating the carcinogenic potential of Capecitabine have not been
conducted.Capecitabine was not mutagenic in vitro to
bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation
assay). Capecitabine was clastogenic in vitro to human peripheral blood
lymphocytes but not clastogenic in vivo to mouse
bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and
yeast. Fluorouracil also causes chromosomal abnormalities in the mouse
micronucleus test in vivo.
In studies of
fertility and general reproductive performance in female mice, oral
Capecitabine doses of 760 mg/kg/day (about 2300 mg/m2 /day)
disturbed estrus and consequently caused a decrease in fertility.In mice that
became pregnant, no fetuses survived this dose. The disturbance in estrus was
reversible. In males, this dose caused degenerative changes in the testes,
including decreases in the number of spermatocytes and spermatids. In separate
pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about
0.7 times the corresponding values in patients administered the recommended
daily dose.
Clinical Studies
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, USP
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, USP to those receiving IV 5-FU/LV alone. In this trial,
1987 patients were randomized either to treatment with Capecitabine Tablets,
USP 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week
rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV
bolus 5-FU 425 mg/m2 and 20 mg/m2 IV
leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24
weeks). Patients in the study were required to be between 18 and 75 years of
age with histologically-confirmed Dukes' stage C colon cancer with at least one
positive lymph node and to have undergone (within 8 weeks prior to
randomization) complete resection of the primary tumor without macroscopic or
microscopic evidence of remaining tumor. Patients were also required to have no
prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an
ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×109 /L,
platelets ≥ 100×109 /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, USP and 5-FU/LV patients are
shown in Table 10.The baseline characteristics were well-balanced between
arms.
Table 10
Baseline Demographics
|
|
Capecitabine TABLETS, USP
(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)
|
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, USP included dose reductions, cycle delays
and treatment interruptions (see Table 11).
Table 11 Summary of Dose Modifications in X-ACT Study
|
|
Capecitabine TABLETS, USP
N=995
|
5-FU/LV
N=974
|
|
Median relative dose intensity (%)
|
93
|
92
|
|
Patients completing full course of treatment (%)
|
83
|
87
|
|
Patients with treatment interruption (%)
|
15
|
5
|
|
Patients with cycle delay (%)
|
46
|
29
|
|
Patients with dose reduction (%)
|
42
|
44
|
|
Patients with treatment interruption, cycle delay, or
dose reduction (%)
|
57
|
52
|
The median
follow-up at the time of the analysis was 83 months (6.9 years). The hazard
ratio for DFS for Capecitabine Tablets, USP compared to 5-FU/LV was 0.88 (95%
C.I. 0.77 to 1.01) (see Table 12 and Figure 1).Because the
upper 2-sided 95% confidence limit of hazard ratio was less than 1.20,
Capecitabine Tablets, USP was noninferior 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,
USP 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, USP and 68.4% for 5-FU/LV (see Figure 2).
Table 12
Efficacy of Capecitabine Tablets, USP vs 5-FU/LV in Adjuvant
Treatment of
Colon Cancer*
|
All Randomized population
|
Capecitabine TABLETS, USP
(n=1004)
|
5-FU/LV
(n=983)
|
|
Median follow-up (months )
|
83
|
83
|
|
5-year Disease-free Survival
Rates (%) †
|
59.1
|
54.6
|
|
Hazard Ratio
(Capecitabine TABLETS, USP/5-FU/LV)
(95% C.I. for Hazard Ratio)
p-value‡
|
0.88
(0.77 to 1.01)
p=0.068
|
*Approximately
93.4 % had 5-year DFS information
† Based on
Kaplan-Meier estimates
‡ Test of
superiority of Capecitabine Tablets, USP vs 5-FU/LV (Wald chi-square test)
Figure 1
Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)*
* Capecitabine
Tablets, USP has been demonstrated to be non-inferior to 5-FU/LV.
Figure 2
Kaplan-Meier Estimates of Overall Survival (All Randomized Population)
Metastatic
Colorectal Cancer
General
The recommended
dose of Capecitabine Tablets, USP was determined in an open-label, randomized
clinical study,exploring the efficacy and safety of continuous therapy with
Capecitabine (1331 mg/m2/day in two divided doses, n=39),
intermittent therapy with Capecitabine (2510 mg/m2 /day in
two divided doses,n=34), and intermittent therapy with Capecitabine in
combination with oral leucovorin (LV) (Capecitabine 1657 mg/m2 /day in
two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or
metastatic colorectal carcinoma in the first-line metastatic setting. There was
no apparent advantage in response rate to adding leucovorin to Capecitabine
Tablets, USP; however, toxicity was increased. Capecitabine Tablets, USP, 1250
mg/m2 twice daily for 14 days followed by a 1-week rest,
was selected for further clinical development based on the overall safety and
efficacy profile of the three schedules studied.
Monotherapy
Data from two
open-label, multicenter, randomized, controlled clinical trials involving 1207
patients support the use of Capecitabine Tablets, USP 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 Tablets, USP at a dose of 1250 mg/m2 twice
daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles;
604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin
IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5,
every 28 days).
In both trials,
overall survival, time to progression and response rate (complete plus partial
responses) were assessed. Responses were defined by the World Health
Organization criteria and submitted to a blinded independent review committee
(IRC). Differences in assessments between the investigator and IRC were
reconciled by the sponsor, blinded to treatment arm, according to a specified
algorithm.Survival was assessed based on a non-inferiority analysis.
The baseline
demographics for Capecitabine Tablets, USP and 5-FU/LV patients are shown
in Table 13.
Table 13
Baseline Demographics of Controlled Colorectal Trials
|
|
Study 1
|
Study 2
|
|
|
Capecitabine
TABLETS,USP
(n=302)
|
5-FU/LV
(N=303)
|
Capecitabine
TABLETS,USP
(n=301)
|
5-FU/LV
(N=301)
|
|
Age (median,years)
Range
|
64
(23 to 86)
|
63
(24 to 87)
|
64
(29 to 84)
|
64
(36 to 86)
|
|
Gender
Male (%)
Female (%)
|
181 (60)
121 (40)
|
197 (65)
106 (35)
|
172 (57)
129 (43)
|
173 (57)
128 (43)
|
|
Karnofsky PS
(median)
Range
|
90
(70 to 100)
|
90
(70 to 100)
|
90
(70 to 100)
|
90
(70 to 100)
|
|
Colon (%)
Rectum (%)
|
222 (74)
79 (26)
|
232 (77)
70 (23)
|
199 (66)
101 (34)
|
196 (65)
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, USP vs 5-FU/LV in Colorectal Cancer (Study 1)
|
|
Capecitabine TABLETS, USP
(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, USP/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 TABLETS, USP/5-FU/LV)
95% C.I. for Hazard Ratio
|
1.00
(0.84-1.18)
|
Table 15
Efficacy of Capecitabine TABLETS, USP vs 5-FU/LV in Colorectal Cancer (Study 2)
|
|
Capecitabine TABLETS, USP
(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 to 165)
|
131 (102 to 156)
|
|
Hazard Ratio (Capecitabine TABLETS, USP/5-FU/LV)
95% C.I. for Hazard Ratio
|
0.97
(0.82 to 1.14)
|
|
Survival
(Median, days, 95% C.I.)
|
404 (367 to 452)
|
369 (338 to 430)
|
|
Hazard Ratio (Capecitabine TABLETS, USP/5-FU/LV)
95% C.I. for Hazard Ratio
|
0.92
(0.78 to 1.09)
|
Figure 3
Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)
Capecitabine
Tablets, USP was superior to 5-FU/LV for objective response rate in Study 1 and
Study 2. The similarity of Capecitabine Tablets, USP 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, USP 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
Tablets, USP. 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, USP, 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, USP difference. These results do not exclude the possibility of true
equivalence of Capecitabine Tablets, USP to 5-FU/LV (see Table 14, Table 15, and Figure 3).
Breast Cancer
Capecitabine
Tablets, USP has been evaluated in clinical trials in combination with
docetaxel (Taxotere®) and as monotherapy.
In Combination
With Docetaxel
The dose of
Capecitabine Tablets, USP 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, USP (14 days of treatment,
followed by a 7-day rest period) were evaluated. The combination dose regimen
was selected based on the tolerability profile of the 75 mg/m2 administered
in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice
daily for 14 days of Capecitabine Tablets, USP 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, USP 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 Tablets, USP
1250 mg/m2 twice daily for 14 days followed by 1 week without
treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion
administered in 3-week cycles. In the monotherapy arm, 256 patients received
docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in
3-week cycles. Patient demographics are provided in Table 16.
Table 16
Baseline Demographics and Clinical Characteristics Capecitabine Tablets, USP
and Docetaxel Combination vs Docetaxel in Breast Cancer Trial
|
|
Capecitabine Tablets, USP +
Docetaxel
(n=255)
|
Docetaxel
(n=256)
|
|
Age (median, years)
|
52
|
51
|
|
Karnofsky PS (median)
|
90
|
90
|
|
Site of Disease
Lymph nodes
Liver
Bone
Lung
Skin
|
121 (47%)
116 (45%)
107 (42%)
95 (37%)
73 (29%)
|
125 (49%)
122 (48%)
119 (46%)
99 (39%)
73 (29%)
|
|
Prior Chemotherapy
Anthracycline *
5-FU
Paclitaxel
|
255 (100%)
196 (77%)
25 (10%)
|
256 (100%)
189 (74%)
22 (9%)
|
|
Resistance to an
Anthracycline
No resistance
Progression on anthracycline therapy
Stable disease after 4 cycles of
anthracycline therapy
Relapsed within 2 years of completion of anthracycline-adjuvant therapy
Experienced a brief response to
anthracycline therapy, with subsequent progression while on therapy or within
12 months after last dose
|
19 (7%)
65 (26%)
41 (16%)
78 (31%)
51 (20%)
|
19 (7%)
73 (29%)
40 (16%)
74 (29%)
50 (20%)
|
|
No. of Prior Chemotherapy
Regimens for Treatment of Metastatic Disease
0
1
2
3
|
89 (35%)
123 (48%)
43 (17%)
0 (0%)
|
80 (31%)
135 (53%)
39 (15%)
2 (1%)
|
*Includes 10
patients in combination and 18 patients in monotherapy arms treated with an
anthracenedione
Capecitabine
Tablets, USP 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, USP and
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 to198)
|
128
(105 to 136)
|
0.0001
|
0.643
|
|
Overall Survival Median Days
95 % C.I
|
442
(375 to 497)
|
352
(298 to 387)
|
0.0126
|
0.775
|
|
Response Rate *
|
32 %
|
22 %
|
0.009
|
NA†
|
*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.
Figure 4
Kaplan-Meier Estimates for Time to Disease Progression Capecitabine
Tablets, USP and Docetaxel vs Docetaxel
Figure 5 Kaplan-Meier Estimates of Survival Capecitabine
Tablets, USP and Docetaxel vs Docetaxel
Monotherapy
The antitumor
activity of Capecitabine Tablets, USP 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 Tablets, USP was administered at a dose of 1255 mg/m2 twice
daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles.
The baseline demographics and clinical characteristics for all patients (n=162)
and those with measurable disease (n=135) are shown in Table 18. Resistance was
defined as progressive disease while on treatment, with or without an initial
response, or relapse within 6 months of completing treatment with an
anthracycline-containing adjuvant chemotherapy regimen.
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 to 2
3 to 4
>5
|
43 (32%)
63 (46%)
29 (22%)
|
60 (37%)
69 (43%)
34 (21%)
|
|
Dominant Site of Disease
Visceral*
Soft Tissue
Bone
|
101 (75%)
30 (22%)
4 (3%)
|
110 (68%)
35 (22%)
17 (10%)
|
|
Prior Chemotherapy
Paclitaxel
Anthracycline†
5-FU
Resistance to Paclitaxel
Resistance to an Anthracycline†
Resistance to both Paclitaxel and an Anthracycline†
|
135 (100 %)
122 (90%)
110 (81%)
103 (76%)
55 (41%)
43 (32%)
|
162 (100%)
147 (91%)
133 (82%)
124 (77%)
67 (41%)
51 (31%)
|
*Lung, pleura,
liver, peritoneum
† Includes 2
patients treated with an anthracenedione
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
|
0
|
|
PR*
|
11
|
|
CR+PR*
|
11
|
|
Response rate*
(95% C.I.)
|
25.6%
(13.5,41.2)
|
|
Duration of Response,*
Median in days†
(Range)
|
154
(63 to 233)
|
Includes 2
patients treated with an anthracenedione
†From date
of first response
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.
REFERENCES
1. NIOSH Alert:
Preventing occupational exposures to antineoplastic and other hazardous drugs
in healthcare settings. 2004. U.S. Department of Health and Human Services,
Public Health Service,Centers for Disease Control and Prevention, National
Institute for Occupational Safety and Health,DHHS (NIOSH) Publication No. 2004-165.
2. OSHA
Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational
Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American
Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous
Drugs:Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M.,
White JM, Kelleher LO (eds). Chemotherapy and biotherapy guidelines and
recommendations for practice (2nd ed.) 2005. Pittsburgh, PA: Oncology Nursing
Society.
How Supplied/Storage
and Handling
150 mg
Color: Light peach
Engraving: ‘A015’ on one side and 150 on the other, 150 mg tablets are packaged
in bottles of 30 (NDC 67877-458-30),bottles of 60 (NDC 67877-458-60) and in
bottles of 120
(NDC
67877-458-12).
500 mg
Color: Light Peach
Engraving: ‘A016’ on one side and 500 on the other, 500 mg tablets are packaged
in bottles of 30 (NDC 67877-459-30),bottles of 60 (NDC 67877-459-60) and in
bottles of 120
(NDC
67877-459-12).
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.
Capecitabine
Tablets, USP is a cytotoxic drug. Follow applicable special handling and
disposal procedures1. Any unused product should be disposed of in accordance
with local requirements, or drug take back programs.
Patient
Counseling Information
Advise the
patient to read the FDA-approved patient labeling (Patient Information)
Patients and
patients' caregivers should be informed of the expected adverse effects of
Capecitabine Tablets, USP, particularly nausea, vomiting, diarrhea, and
hand-and-foot syndrome, and
should be made
aware that patient-specific dose adaptations during therapy are expected and
necessary [see Dosage and Administration (2.3)]. As described below, patients
taking Capecitabine Tablets, USP 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, USP treatment See FDA-approved
patient labeling (Patient Information)
Dihydropyrimidine
Dehydrogenase Deficiency
Patients should
be advised to notify their healthcare provider if they have a known DPD deficiency.
Advise patients if they have complete or near complete absence of DPD activity
they are at an increased risk of acute early-onset of toxicity and severe,
life-threatening, or fatal adverse reactions caused by Capecitabine tablets,
USP (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings
and Precautions (5.4)].
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, USP
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, USP 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
Tablets, USP 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 Tablets, USP 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
Tablets, USP immediately. Initiation of symptomatic treatment is recommended.
Hand-and-foot syndrome can lead to loss of fingerprints which could impact your
identification.
Stomatitis
Patients
experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth
or tongue, but able to eat) or greater should be instructed to stop taking
Capecitabine Tablets, USP immediately and to call their physician. Initiation
of symptomatic treatment is recommended.
Fever and
Neutropenia
Patients who
develop a fever of 100.5°F or greater or other evidence of potential infection
should be instructed to call their physician immediately.
Embryo-Fetal
Toxicity
Advise females
of reproductive potential of the potential risk to a fetus and to use effective
contraception during treatment with Capecitabine Tablets, USP 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, USP 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, USP and for 2
weeks after the last dose [see Use in Specific Populations (8.2)].
Manufactured in India by:
Alkem
Laboratories Limited
H.O.: ALKEM
HOUSE,
Senapati Bapat
Marg, Lower Parel,
Mumbai 400 013,
INDIA
Distributed by:
Ascend
Laboratories, LLC
Parsippany, NJ
07054
Revised: 05/2017
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:
·
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 doctor if you are taking warfarin
(COUMADIN) or another blood thinner medicine. If you take warfarin (COUMADIN)
or another blood thinner that is like warfarin (COUMADIN) during treatment with
Capecitabine Tablets, your doctor should do blood tests often, to check how
fast your blood clots during and after you stop treatment with Capecitabine
Tablets. Your doctor may change your dose of the blood thinner medicine if
needed.
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:
·
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 anticancer medicines have not worked.
·
breast cancer that has spread to other parts of the body
and has not improved after treatment with paclitaxel and certain other
anti-cancer medicines, or who cannot receive any more treatment with certain
anti-cancer medicines.
It is not known
if Capecitabine Tablets is safe and effective in children.
Who should not
take Capecitabine Tablets?
Do not take
Capecitabine Tablets if you:
·
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.
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:
·
have had heart problems.
·
have kidney or liver problems.
·
have been told that you lack the enzyme DPD
(dihydropyrimidine dehydrogenase)have any other medical conditions.
·
are pregnant or plan to become pregnant. Capecitabine
Tablets can harm your unborn baby. You should not become pregnant during
treatment with Capecitabine Tablets. Talk to your doctor about birth control
choices that may be right for you during treatment with Capecitabine Tablets.
·
are breastfeeding or plan to breastfeed. It is not known
if Capecitabine Tablets passes into your breast milk. Do not breastfeed during
treatment with Capecitabine Tablets.
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?
Take
Capecitabine Tablets exactly as your doctor tells you to take it.
Your doctor will
tell you how much Capecitabine Tablets to take and when to take it.
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.
Ask your
healthcare provider or pharmacist how to safely throw away any unused
Capecitabine Tablets.
If you have side
effects with Capecitabine Tablets, if needed your doctor may decide to:
·
change your dose of Capecitabine Tablets
·
treat you with Capecitabine Tablets less often
·
tell you to stop taking Capecitabine Tablets until
certain side effects get better or go away
·
stop your treatment with Capecitabine Tablets if you have
certain side effects and they are severe
If you take too
much Capecitabine Tablets, call your doctor or go to the nearest emergency room
right away.
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?
·
diarrhea. Diarrhea is common with
Capecitabine Tablets and can sometimes be severe. Stop taking Capecitabine
Tablets and call your doctor right away if the number of bowel movements you
have in a day increases by 4 or more than is usual for you. Ask your doctor
about what medicines you can take to treat your diarrhea. If you have severe
bloody diarrhea with severe abdominal pain and fever, call your doctor or go to
the nearest emergency room right away.
·
heart problems. 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
doctor right away if you get any of the following symptoms:
o chest pain
o shortness of
breath
o feeling faint
o irregular
heartbeats or skipping beats
o sudden weight
gain
o swollen ankles
or legs
·
unexplained tiredness
·
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.
o Capecitabine
Tablets can cause serious skin reactions that may lead to death. Tell your
doctor right away if you develop a skin rash, blisters and peeling of your
skin. Your doctor may tell you to stop taking Capecitabine Tablets if you have
a serious skin reaction. Do not take Capecitabine Tablets again if this
happens.
o 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 doctor right
away if you have any of these symptoms and you are not able to do your usual
activities. Hand and foot syndrome can lead to loss of fingerprints which could
impact your identification.
o you may get
sores in your mouth or on your tongue when taking Capecitabine Tablets. Stop
taking Capecitabine Tablets and call your doctor if you get painful redness,
swelling, or ulcers in your mouth and tongue, or if you are having problems
eating. Tell your doctor if you have any side effect that bothers you or that
does not go away.
·
increased level of bilirubin in your
blood and liver problems. Increased bilirubin in your blood is common with
Capecitabine Tablets. Your doctor will check you for these problems during
treatment with Capecitabine Tablets.
·
decreased white blood cells, platelets,
and red blood cell counts. Your doctor will do blood tests during treatment
with Capecitabine Tablets to check your blood cell counts.
If your white
blood cell count is very low, you are at increased risk for infection. Call
your doctor right away if you develop a fever of 100.5°F or greater or have
other signs and symptoms of infection.
People 80 years
of age or older may be more likely to develop severe or serious side effects
with Capecitabine Tablets.
The most common
side effects of Capecitabine Tablets include:
·
diarrhea
·
hand and foot syndrome
·
nausea
·
vomiting
·
stomach-area (abdominal) pain
·
tiredness
·
weakness
·
increased amounts of red blood cell breakdown products
(bilirubin) in your blood.
These are not
all the possible side effects of 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 FDA at
1-800-FDA-1088.
How should I
store Capecitabine Tablets?
·
Store Capecitabine Tablets at room temperature between
68°F to 77°F (20°C to 25°C).
·
Keep Capecitabine Tablets in a tightly closed container.
·
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 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, hypromellose, magnesium
stearate, microcrystalline cellulose, and purified water. The light peach film
coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, iron
oxide yellow and iron oxide red.
Manufactured in
India by:
Alkem
Laboratories Limited
H.O.: ALKEM
HOUSE,
Senapati Bapat
Marg, Lower Parel,
Mumbai 400 013,
INDIA
Distributed by:
Ascend
Laboratories, LLC
Parsippany, NJ
07054
Revised: 05/2017
PACKAGE
LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE
LABEL.PRINCIPAL DISPLAY PANEL
PRINCIPAL
DISPLAY PANEL - 150 mg Tablet Bottle Label
NDC67877-458-60
60TABLETS
PRINCIPAL DISPLAY PANEL - 500 mg Tablet Bottle Label
NDC 67877-459-12
120 TABLETS
|
Capecitabine Capecitabine
tablet, film coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:67877-458
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Capecitabine (Capecitabine)
|
Capecitabine
|
150 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
CELLULOSE,
MICROCRYSTALLINE
|
|
|
HYPROMELLOSES
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
ANHYDROUS LACTOSE
|
|
|
MAGNESIUM STEARATE
|
|
|
TALC
|
|
|
TITANIUM DIOXIDE
|
|
|
FERRIC OXIDE YELLOW
|
|
|
FERRIC OXIDE RED
|
|
|
|
Product Characteristics
|
|
Color
|
PINK
|
Score
|
no score
|
|
Shape
|
OVAL (OVAL)
|
Size
|
11mm
|
|
Flavor
|
|
Imprint Code
|
A015
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:67877-458-30
|
30 TABLET, FILM COATED in 1 BOTTLE
|
|
|
2
|
NDC:67877-458-60
|
60 TABLET, FILM COATED in 1 BOTTLE
|
|
|
3
|
NDC:67877-458-12
|
120 TABLET, FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
ANDA
|
ANDA207652
|
11/25/2017
|
|
|
|
Capecitabine Capecitabine
tablet, film coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:67877-459
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Capecitabine (Capecitabine)
|
Capecitabine
|
500 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
CELLULOSE,
MICROCRYSTALLINE
|
|
|
HYPROMELLOSES
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
ANHYDROUS LACTOSE
|
|
|
MAGNESIUM STEARATE
|
|
|
TALC
|
|
|
TITANIUM DIOXIDE
|
|
|
FERRIC OXIDE YELLOW
|
|
|
FERRIC OXIDE RED
|
|
|
|
Product Characteristics
|
|
Color
|
PINK
|
Score
|
no score
|
|
Shape
|
OVAL (OVAL)
|
Size
|
11mm
|
|
Flavor
|
|
Imprint Code
|
A015
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:67877-459-30
|
30 TABLET, FILM COATED in 1 BOTTLE
|
|
|
2
|
NDC:67877-459-60
|
60 TABLET, FILM COATED in 1 BOTTLE
|
|
|
3
|
NDC:67877-459-12
|
120 TABLET, FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
ANDA
|
ANDA207652
|
11/25/2017
|
|
|
|
Labeler - Ascend Laboratories, LLC (141250469)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Alkem Laboratories Limited
|
|
915628612
|
MANUFACTURE(67877-458, 67877-459)
|
Revised: 11/2017
Ascend
Laboratories, LLC
