capecitabine 150 MG Oral Tablet
Generic Name: CAPECITABINE
Brand Name: Capecitabine
- Substance Name(s):
- CAPECITABINE
DRUG INTERACTIONS
7 • Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed.
( 5.2 , 7.1 ) • Phenytoin: Monitor phenytoin levels in patients taking capecitabine tablets concomitantly with phenytoin.
The phenytoin dose may need to be reduced.
( 7.1 ) • Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin.
( 7.1 ) • CYP2C9 substrates: Care should be exercised when capecitabine tablets are coadministered with CYP2C9 substrates.
( 7.1 ) • Allopurinol: Avoid the use of allopurinol during treatment with capecitabine tablets.
• Food reduced both the rate and extent of absorption of capecitabine.
( 2 , 7.2 , 12.3 ) 7.1 Drug-Drug Interactions Anticoagulants Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine tablets concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning ] .
These events occurred within several days and up to several months after initiating capecitabine tablets therapy and, in a few cases, within 1 month after stopping capecitabine tablets.
These events occurred in patients with and without liver metastases.
In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin [see Clinical Pharmacology (12.3) ] .
The maximum observed INR value increased by 91%.
This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.
Phenytoin The level of phenytoin should be carefully monitored in patients taking capecitabine tablets and phenytoin dose may need to be reduced [see Dosage and Administration (2.3) ] .
Postmarketing reports indicate that some patients receiving capecitabine tablets and phenytoin had toxicity associated with elevated phenytoin levels.
Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.
Leucovorin The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin.
Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
CYP2C9 Substrates Other than warfarin, no formal drug-drug interaction studies between capecitabine tablets and other CYP2C9 substrates have been conducted.
Care should be exercised when capecitabine tablets are coadministered with CYP2C9 substrates.
Allopurinol Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see Clinical Pharmacology (12.3) ] , which may decrease capecitabine tablets efficacy.
Avoid the use of allopurinol during treatment with capecitabine tablets.
7.2 Drug-Food Interaction Food was shown to reduce both the rate and extent of absorption of capecitabine [see Clinical Pharmacology (12.3) ] .
In all clinical trials, patients were instructed to administer capecitabine tablets within 30 minutes after a meal.
It is recommended that capecitabine tablets be administered with food [see Dosage and Administration (2) ].
OVERDOSAGE
10 The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression.
Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations.
Although no clinical experience using dialysis as a treatment for capecitabine tablets overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low–molecular-weight metabolite of the parent compound.
Single doses of capecitabine tablets were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m 2 basis).
DESCRIPTION
11 Capecitabine tablets, USP are a fluoropyrimidine carbamate with antineoplastic activity.
It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-fluorouracil.
The chemical name for capecitabine is Pentyl 1-(5-deoxy- β -D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidinecarbamate and has a molecular weight of 359.35.
Capecitabine has the following structural formula: Capecitabine, USP is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20ºC.
Capecitabine is supplied as film-coated tablets for oral administration.
Each round, white tablet contains 150 mg capecitabine and each oval, white tablet contains 500 mg capecitabine.
The inactive ingredients in capecitabine tablets include: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.
Capecitabine Structural Formula
CLINICAL STUDIES
14 14.1 Adjuvant Colon Cancer A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C colon cancer (X-ACT) provided data concerning the use of capecitabine tablets for the adjuvant treatment of patients with colon cancer.
The primary objective of the study was to compare disease-free survival (DFS) in patients receiving capecitabine tablets to those receiving IV 5-FU/LV alone.
In this trial, 1987 patients were randomized either to treatment with capecitabine tablets 1250 mg/m 2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m 2 and 20 mg/m 2 IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks).
Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes’ stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor.
Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5 x 10 9 /L, platelets ≥ 100 x 10 9 /L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.
The baseline demographics for capecitabine tablets and 5-FU/LV patients are shown in Table 10.
The baseline characteristics were well-balanced between arms.
Table 10.
Baseline Demographics Capecitabine Tablets (n = 1004) 5-FU/LV (n = 983) Age (median, years) 62 63 Range (25-80) (22-82) Gender Male (n, %) 542 (54) 532 (54) Female (n, %) 461 (46) 451 (46) ECOG PS 0 (n, %) 849 (85) 830 (85) 1 (n, %) 152 (15) 147 (15) Staging – Primary Tumor PT1 (n, %) 12 (1) 6 (0.6) PT2 (n, %) 90 (9) 92 (9) PT3 (n, %) 763 (76) 746 (76) PT4 (n, %) 138 (14) 139 (14) Other (n, %) 1 (0.1) 0 (0) Staging – Lymph Node pN1 (n, %) 695 (69) 694 (71) pN2 (n, %) 305 (30) 288 (29) Other (n, %) 4 (0.4) 1 (0.1) All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m 2 orally twice daily.
The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4) ] .
Subsequently, for all patients, doses were adjusted when needed according to toxicity.
Dose management for capecitabine tablets included dose reductions, cycle delays and treatment interruptions (see Table 11).
Table 11.
Summary of Dose Modifications in X-ACT Study Capecitabine Tablets n = 995 5-FU/LV n = 974 Median relative dose intensity (%) 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 compared to 5-FU/LV was 0.88 (95% C.I.
0.77 – 1.01) (see Table 12 and Figure 1).
Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, capecitabine tablets were non-inferior to 5-FU/LV.
The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS.
The hazard ratio for capecitabine tablets compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I.
0.74 to 1.01).
The 5-year overall survival rates were 71.4% for capecitabine tablets and 68.4% for 5-FU/LV (see Figure 2).
Table 12.
Efficacy of Capecitabine Tablets vs 5-FU/LV in Adjuvant Treatment of Colon Cancer Approximately 93.4% had 5-year DFS information All Randomized Population Capecitabine Tablets (n = 1004) 5-FU/LV (n = 983) Median follow-up (months) 83 83 5-year Disease-free Survival Rates (%) Based on Kaplan-Meier estimates 59.1 54.6 Hazard Ratio 0.88 (Capecitabine Tablets/5-FU/LV) (0.77 to 1.01) (95% C.I.
for Hazard Ratio) p-value Test of superiority of capecitabine tablets vs 5-FU/LV (Wald chi-square test) p = 0.068 Figure 1.
Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)a Figure 2.
Kaplan-Meier Estimates of Overall Survival (All Randomized Population) Figure 1.
Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population) Figure 2.
Kaplan-Meier Estimates of Overall Survival (All Randomized Population) 14.2 Metastatic Colorectal Cancer General The recommended dose of capecitabine tablets was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m 2 /day in two divided doses, n = 39), intermittent therapy with capecitabine (2510 mg/m 2 /day in two divided doses, n = 34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m 2 /day in two divided doses, n = 35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting.
There was no apparent advantage in response rate to adding leucovorin to capecitabine tablets; however, toxicity was increased.
Capecitabine tablets, 1250 mg/m 2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.
Monotherapy Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of capecitabine tablets in the first-line treatment of patients with metastatic colorectal carcinoma.
The two clinical studies were identical in design and were conducted in 120 centers in different countries.
Study 1 was conducted in the U.S., Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan.
Altogether, in both trials, 603 patients were randomized to treatment with capecitabine tablets at a dose of 1250 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1 to 5, every 28 days).
In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed.
Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC).
Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm.
Survival was assessed based on a non-inferiority analysis.
The baseline demographics for capecitabine tablets and 5-FU/LV patients are shown in Table 13.
Table 13.
Baseline Demographics of Controlled Colorectal Trials Study 1 Study 2 Capecitabine Tablets (n = 302) 5-FU/LV (n = 303) Capecitabine Tablets (n = 301) 5-FU/LV (n = 301) Age (median, years) 64 63 64 64 Range (23-86) (24-87) (29-84) (36-86) Gender Male (%) 181 (60) 197 (65) 172 (57) 173 (57) Female (%) 121 (40) 106 (35) 129 (43) 128 (43) Karnofsky PS (median) 90 90 90 90 Range (70-100) (70-100) (70-100) (70-100) Colon (%) 222 (74) 232 (77) 199 (66) 196 (65) Rectum (%) 79 (26) 70 (23) 101 (34) 105 (35) Prior radiation therapy (%) 52 (17) 62 (21) 42 (14) 42 (14) Prior adjuvant 5-FU (%) 84 (28) 110 (36) 56 (19) 41 (14) The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15.
Table 14.
Efficacy of Capecitabine Tablets vs 5-FU/LV in Colorectal Cancer (Study 1) Capecitabine Tablets (n = 302) 5-FU/LV (n = 303) Overall Response Rate (%, 95% C.I.) 21 (16-26) 11 (8-15) (p-value) 0.0014 Time to Progression (Median, days, 95% C.I.) 128 (120-136) 131 (105-153) Hazard Ratio (Capecitabine Tablets/5-FU/LV) 0.99 95% C.I.
for Hazard Ratio (0.84-1.17) Survival (Median, days, 95% C.I.) 380 (321-434) 407 (366-446) Hazard Ratio (Capecitabine Tablets/5-FU/LV) 1.00 95% C.I.
for Hazard Ratio (0.84-1.18) Table 15.
Efficacy of Capecitabine Tablets vs 5-FU/LV in Colorectal Cancer (Study 2) Capecitabine Tablets (n = 301) 5-FU/LV (n = 301) Overall Response Rate (%, 95% C.I.) 21 (16-26) 14 (10-18) (p-value) 0.027 Time to Progression (Median, days, 95% C.I.) 137 (128-165) 131 (102-156) Hazard Ratio (Capecitabine Tablets/5-FU/LV) 0.97 95% C.I.
for Hazard Ratio (0.82-1.14) Survival (Median, days, 95% C.I.) 404 (367-452) 369 (338-430) Hazard Ratio (Capecitabine Tablets/5-FU/LV) 0.92 95% C.I.
for Hazard Ratio (0.78-1.09) Figure 3.
Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2) Capecitabine tablets were superior to 5-FU/LV for objective response rate in Study 1 and Study 2.
The similarity of capecitabine tablets and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments.
In order to assure that capecitabine tablets have a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by capecitabine tablets.
The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2.
The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and capecitabine tablets, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out.
It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1.
The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV.
It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs capecitabine tablets difference.
These results do not exclude the possibility of true equivalence of capecitabine tablets to 5-FU/LV (see Table 14, Table 15, and Figure 3).
Figure 3.
Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2) 14.3 Breast Cancer Capecitabine tablets have been evaluated in clinical trials in combination with docetaxel (Taxotere ® ) and as monotherapy.
In Combination With Docetaxel The dose of capecitabine tablets used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of capecitabine tablets (14 days of treatment, followed by a 7-day rest period) were evaluated.
The combination dose regimen was selected based on the tolerability profile of the 75 mg/m 2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m 2 twice daily for 14 days of capecitabine tablets administered in 3-week cycles.
The approved dose of 100 mg/m 2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.
Capecitabine tablets in combination with docetaxel were assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia.
A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled.
Two hundred and fifty-five (255) patients were randomized to receive capecitabine tablets 1250 mg/m 2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m 2 as a 1-hour intravenous infusion administered in 3-week cycles.
In the monotherapy arm, 256 patients received docetaxel 100 mg/m 2 as a 1-hour intravenous infusion administered in 3-week cycles.
Patient demographics are provided in Table 16.
Table 16.
Baseline Demographics and Clinical Characteristics Capecitabine Tablets and Docetaxel Combination vs Docetaxel in Breast Cancer Trial Capecitabine Tablets + Docetaxel (n = 255) Docetaxel (n = 256) Age (median, years) 52 51 Karnofsky PS (median) 90 90 Site of Disease Lymph nodes 121 (47%) 125 (49%) Liver 116 (45%) 122 (48%) Bone 107 (42%) 119 (46%) Lung 95 (37%) 99 (39%) Skin 73 (29%) 73 (29%) Prior Chemotherapy Anthracycline Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione 255 (100%) 256 (100%) 5-FU 196 (77%) 189 (74%) Paclitaxel 25 (10%) 22 (9%) Resistance to an Anthracycline No resistance 19 (7%) 19 (7%) Progression on anthracycline therapy 65 (26%) 73 (29%) Stable disease after 4 cycles of anthracycline therapy 41 (16%) 40 (16%) Relapsed within 2 years of completion of anthracycline-adjuvant therapy 78 (31%) 74 (29%) Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose 51 (20%) 50 (20%) No.
of Prior Chemotherapy Regimens for Treatment of Metastatic Disease 0 89 (35%) 80 (31%) 1 123 (48%) 135 (53%) 2 43 (17%) 39 (15%) 3 0 (0%) 2 (1%) Capecitabine tablets in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.
Table 17.
Efficacy of Capecitabine Tablets and Docetaxel Combination vs Docetaxel Monotherapy Efficacy Parameter Combination Therapy Monotherapy p-value Hazard Ratio Time to Disease Progression Median Days 186 128 0.0001 0.643 95% C.I.
(165-198) (105-136) Overall Survival Median Days 442 352 0.0126 0.775 95% C.I.
(375-497) (298-387) Response Rate The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
32% 22% 0.009 NA NA = Not Applicable Figure 4.
Kaplan-Meier Estimates for Time to Disease Progression Capecitabine Tablets and Docetaxel vs Docetaxel Figure 5.
Kaplan-Meier Estimates of Survival Capecitabine Tablets and Docetaxel vs Docetaxel Figure 4.
Kaplan-Meier Estimates for Time to Disease Progression Capecitabine Tablets and Docetaxel vs.
Docetaxel Figure 5.
Kaplan-Meier Estimates of Survival Capecitabine Tablets and Docetaxel vs.
Docetaxel Monotherapy The antitumor activity of capecitabine tablets as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the U.S.
and Canada.
A total of 162 patients with stage IV breast cancer were enrolled.
The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥ 50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month.
Capecitabine tablets were administered at a dose of 1255 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles.
The baseline demographics and clinical characteristics for all patients (n = 162) and those with measurable disease (n = 135) are shown in Table 18.
Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.
Table 18.
Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial Patients With Measurable Disease (n = 135) All Patients (n = 162) Age (median, years) 55 56 Karnofsky PS 90 90 No.
Disease Sites 1-2 43 (32%) 60 (37%) 3-4 63 (46%) 69 (43%) >5 29 (22%) 34 (21%) Dominant Site of Disease Visceral Lung, pleura, liver, peritoneum 101 (75%) 110 (68%) Soft Tissue 30 (22%) 35 (22%) Bone 4 (3%) 17 (10%) Prior Chemotherapy Paclitaxel 135 (100%) 162 (100%) Anthracycline Includes 2 patients treated with an anthracenedione 122 (90%) 147 (91%) 5-FU 110 (81%) 133 (82%) Resistance to Paclitaxel 103 (76%) 124 (77%) Resistance to an Anthracycline 55 (41%) 67 (41%) Resistance to both Paclitaxel and an Anthracycline 43 (32%) 51 (31%) 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 Includes 2 patients treated with an anthracenedione 11 CR + PR 11 Response Rate (95% C.I.) 25.6% (13.5, 41.2) Duration of Response, Median in days From date of first response (Range) 154 (63-233) For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days.
The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18 ).
The median time to progression was 90 days and the median survival was 306 days.
HOW SUPPLIED
16 /STORAGE AND HANDLING Capecitabine Tablets, USP are available containing 150 mg or 500 mg of capecitabine, USP.
The 150 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and 511 on the other side.
They are available as follows: NDC 0378-2511-91 bottles of 60 tablets The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M512 on one side of the tablet and blank on the other side.
They are available as follows: NDC 0378-2512-78 bottles of 120 tablets Storage and Handling: Store at 20º to 25ºC (68º to 77ºF).
[See USP Controlled Room Temperature.] KEEP TIGHTLY CLOSED.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Capecitabine tablets are a cytotoxic drug.
Follow applicable special handling and disposal procedures.
1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.
GERIATRIC USE
8.5 Geriatric Use Physicians should pay particular attention to monitoring the adverse effects of capecitabine tablets in the elderly [see Warnings and Precautions (5.10) ] .
DOSAGE FORMS AND STRENGTHS
3 Capecitabine Tablets, USP are available containing 150 mg or 500 mg of capecitabine, USP.
• The 150 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and 511 on the other side.
• The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M512 on one side of the tablet and blank on the other side.
• Tablets: 150 mg and 500 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo .
Both normal and tumor cells metabolize 5-FU to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).
These metabolites cause cell injury by two different mechanisms.
First, FdUMP and the folate cofactor, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex.
This binding inhibits the formation of thymidylate from 2’-deoxyuridylate.
Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division.
Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA.
This metabolic error can interfere with RNA processing and protein synthesis.
INDICATIONS AND USAGE
1 Capecitabine tablets are a nucleoside metabolic inhibitor with antineoplastic activity indicated for: • Adjuvant Colon Cancer ( 1.1 ) • Patients with Dukes’ C colon cancer • Metastatic Colorectal Cancer ( 1.1 ) • First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred • Metastatic Breast Cancer ( 1.2 ) • In combination with docetaxel after failure of prior anthracycline-containing therapy • As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen 1.1 Colorectal Cancer • Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred.
Capecitabine tablets were non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS).
Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes’ C colon cancer.
• Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone.
A survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy.
Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
1.2 Breast Cancer • Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
• Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m 2 of doxorubicin or doxorubicin equivalents).
Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of capecitabine tablets in pediatric patients have not been established.
No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas.
In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions).
The relative bioavailability of the investigational formulation to capecitabine tablets was similar.
The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas.
In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m 2 to 850 mg/m 2 every 12 hours for up to 9 weeks.
After a 2 week break, patients received 1250 mg/m 2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.
The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m 2 every 12 hours.
The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.
The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial.
All patients received 650 mg/m 2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks.
After a 2 week break, patients received 1250 mg/m 2 capecitabine every 12 hours on Days 1-14 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%).
PREGNANCY
8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action,capecitabine tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] .
Limited available human data are not sufficient to inform the drug-associated risk during pregnancy.
In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data ] .
Apprise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data Animal Data Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality.
In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose.
Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles.
Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality.
This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.
BOXED WARNING
WARNING: CAPECITABINE TABLETS-WARFARIN INTERACTION Capecitabine Tablets-Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.
A clinically important capecitabine tablets-warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] .
Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine tablets concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.
Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time capecitabine tablets were introduced.
These events occurred within several days and up to several months after initiating capecitabine tablets therapy and, in a few cases, within 1 month after stopping capecitabine tablets.
These events occurred in patients with and without liver metastases.
Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
WARNING: CAPECITABINE TABLETS-WARFARIN INTERACTION See full prescribing information for complete boxed warning Patients receiving concomitant capecitabine tablets and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.
Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use.
• Occurrence: Within several days and up to several months after initiating capecitabine tablets therapy; may also be seen within 1 month after stopping capecitabine tablets • Predisposing factors: age > 60 and diagnosis of cancer
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Coagulopathy : May result in bleeding, death.
Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly.
( 5.1 ) • Diarrhea : May be severe.
Interrupt capecitabine tablets treatment immediately until diarrhea resolves or decreases to grade 1.
Recommend standard antidiarrheal treatments.
( 5.2 ) • Cardiotoxicity : Common in patients with a prior history of coronary artery disease.
( 5.3 ) • Increased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue capecitabine tablets in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.
No capecitabine tablets dose has been proven safe in patients with absent DPD activity.
( 5.4 ) • Dehydration and Renal Failure : Interrupt capecitabine tablets treatment until dehydration is corrected.
Potential risk of acute renal failure secondary to dehydration.
Monitor and correct dehydration.
( 5.5 ) • Embryo-Fetal Toxicity: Can cause fetal harm.
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
( 5.6 , 8.1 , 8.3 ) • Mucocutaneous and Dermatologic Toxicity : Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported.
Capecitabine tablets should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment.
Capecitabine tablets may induce hand-and-foot syndrome.
Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification.
Interrupt capecitabine tablets treatment until the hand-and-foot syndrome event resolves or decreases in intensity.
( 5.7 ) • Hyperbilirubinemia : Interrupt capecitabine tablets treatment immediately until the hyperbilirubinemia resolves or decreases in intensity.
( 5.8 ) • Hematologic : Do not treat patients with neutrophil counts < 1.5 x 10 9 /L or thrombocyte counts < 100 x 10 9 /L.
If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves.
( 5.9 ) 5.1 Coagulopathy Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly [see Boxed Warning and Drug Interactions (7.1) ].
5.2 Diarrhea Capecitabine tablets can induce diarrhea, sometimes severe.
Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated.
In 875 patients with either metastatic breast or colorectal cancer who received capecitabine tablets monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days).
The median duration of grade 3 to 4 diarrhea was 5 days.
National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support.
If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine tablets should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1 [see Dosage and Administration (2.3) ] .
Standard antidiarrheal treatments (e.g., loperamide) are recommended.
Necrotizing enterocolitis (typhlitis) has been reported.
5.3 Cardiotoxicity The cardiotoxicity observed with capecitabine tablets includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy.
These adverse reactions may be more common in patients with a prior history of coronary artery disease.
5.4 Dihydropyrimidine Dehydrogenase Deficiency Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).
Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine tablets.
Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.
No capecitabine tablets dose has been proven safe for patients with complete absence of DPD activity.
There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.
5.5 Dehydration and Renal Failure Dehydration has been observed and may cause acute renal failure which can be fatal.
Patients with pre-existing compromised renal function or who are receiving concomitant capecitabine tablets with known nephrotoxic agents are at higher risk.
Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated.
Monitor patients when capecitabine tablets are administered to prevent and correct dehydration at the onset.
If grade 2 (or higher) dehydration occurs, capecitabine tablets treatment should be immediately interrupted and the dehydration corrected.
Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.
Dose modifications should be applied for the precipitating adverse event as necessary [see Dosage and Administration (2.3) ] .
Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4) ] .
Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions.
Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and Administration (2.3) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ] .
5.6 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and its mechanism of action, capecitabine tablets may cause fetal harm when given to a pregnant woman [see Clinical Pharmacology (12.1) ] .
Limited available data are not sufficient to inform use of capecitabine tablets in pregnant women.
In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Use in Specific Populations (8.1) ] .
Apprise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of capecitabine tablets [see Use in Specific Populations (8.3) ] .
5.7 Mucocutaneous and Dermatologic Toxicity Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine tablets [see Adverse Reactions (6.4) ] .
Capecitabine tablets should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to capecitabine tablets treatment.
Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity.
Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine tablets monotherapy in the metastatic setting.
Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities.
Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living.
Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living.
Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification.
If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine tablets should be interrupted until the event resolves or decreases in intensity to grade 1.
Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine tablets should be decreased [see Dosage and Administration (2.3) ] .
5.8 Hyperbilirubinemia In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine tablets 1250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 3.9% (n = 34) of patients.
Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively.
Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n = 31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n = 46) had postbaseline elevations in transaminases at any time (not necessarily concurrent).
The majority of these patients, 64.5% (n = 20) and 71.7% (n = 33), had liver metastases at baseline.
In addition, 57.5% (n = 96) and 35.3% (n = 59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively.
Only 7.8% (n = 13) and 3.0% (n = 5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
In the 596 patients treated with capecitabine tablets as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine tablets monotherapy.
The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine tablets.
Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.
In 251 patients with metastatic breast cancer who received a combination of capecitabine tablets and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 2% (n = 5).
If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine tablets should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3.0 x ULN [ see recommended dose modifications under Dosage and Administration (2.3) ] .
5.9 Hematologic In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively.
In 251 patients with metastatic breast cancer who received a dose of capecitabine tablets in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.
Patients with baseline neutrophil counts of < 1.5 x 10 9 /L and/or thrombocyte counts of < 100 x 10 9 /L should not be treated with capecitabine tablets.
If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine tablets should be interrupted.
5.10 Geriatric Patients Patients ≥ 80 years old may experience a greater incidence of grade 3 or 4 adverse reactions.
In 875 patients with either metastatic breast or colorectal cancer who received capecitabine tablets monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine tablets experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients.
Among the 10 patients 70 years of age and greater (no patients were > 80 years of age) treated with capecitabine tablets in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.
Among the 67 patients ≥ 60 years of age receiving capecitabine tablets in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the < 60 years of age patient group.
In 995 patients receiving capecitabine tablets as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥ 65 years of age treated with capecitabine tablets experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients.
In patients ≥ 65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine tablets compared to 5-FU/LV were 1.01 (95% C.I.
0.80 – 1.27) and 1.04 (95% C.I.
0.79 – 1.37), respectively.
5.11 Hepatic Insufficiency Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine tablets are administered.
The effect of severe hepatic dysfunction on the disposition of capecitabine tablets is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .
5.12 Combination With Other Drugs Use of capecitabine tablets in combination with irinotecan has not been adequately studied.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ).
Diarrhea: Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop taking capecitabine tablets.
Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.2) ] .
Cardiotoxicity: Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.3) ] .
Dihydropyrimidine Dehydrogenase Deficiency: Advise patients to notify their healthcare provider if they have a known DPD deficiency.
Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings and Precautions (5.4) ] .
Dehydration and Renal Failure: Instruct patients experiencing grade 2 or higher dehydration (IV fluids indicated < 24 hours) to stop taking capecitabine tablets immediately and to call their healthcare provider to correct the dehydration.
Advise patients to not restart capecitabine tablets until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5) ] .
Important Administration Instructions: Advise patients to swallow capecitabine tablets whole with water within 30 minutes of a meal.
Advise patients and caregivers not to crush or cut capecitabine tablets.
Advise patients if they cannot swallow capecitabine tablets whole, to inform their healthcare provider [see Dosage and Administration (2.1) ] .
Nausea: Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider for management of nausea [see Adverse Reactions (6.1) ] .
Vomiting: Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1) ] .
Hand-and-Foot Syndrome: Instruct patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients’ activities of daily living) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider.
Inform patients that initiation of symptomatic treatment is recommended and hand-and-foot syndrome can lead to loss of fingerprints which could impact personal identification [see Adverse Reactions (6.1) ] .
Stomatitis: Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider [see Adverse Reactions (6.1) ] .
Fever and Neutropenia: Inform patients who develop a fever of 100.5°F or greater or other evidence of potential infection to contact their healthcare provider [see Adverse Reactions (6.1) ] .
Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with capecitabine tablets and for 6 months after the last dose.
Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1 and 8.3) ] .
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with capecitabine tablets and for 3 months after the last dose [see Use in Specific Populations (8.3) ] .
Lactation: Advise females not to breastfeed during treatment with capecitabine tablets and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ] .
DOSAGE AND ADMINISTRATION
2 • Take capecitabine tablets with water within 30 min after a meal ( 2.1 ) • Monotherapy: 1250 mg/m 2 twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles ( 2.2 ) • Adjuvant treatment is recommended for a total of 6 months (8 cycles) ( 2.2 ) • In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m 2 twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m 2 as a 1-hour IV infusion every 3 weeks ( 2.2 ) • Capecitabine tablets dosage may need to be individualized to optimize patient management ( 2.3 ) • Reduce the dose of capecitabine tablets by 25% in patients with moderate renal impairment ( 2.4 ) 2.1 Important Administration Instructions Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal.
Capecitabine tablets are a cytotoxic drug.
Follow applicable special handling and disposal procedures.1 If capecitabine tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures.
Capecitabine tablets dose is calculated according to body surface area.
2.2 Standard Starting Dose Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) The recommended dose of capecitabine tablets is 1250 mg/m 2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m 2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1).
Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months [i.e., capecitabine tablets 1250 mg/m 2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)].
Table 1.
Capecitabine Tablets Dose Calculation According to Body Surface Area Dose Level 1250 mg/m 2 Twice a Day Number of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area (m 2 ) Total Daily Dose Total Daily Dose divided by 2 to allow equal morning and evening doses (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 In Combination With Docetaxel (Metastatic Breast Cancer) In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m 2 as a 1-hour intravenous infusion every 3 weeks.
Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine tablets plus docetaxel combination.
Table 1 displays the total daily dose of capecitabine tablets by body surface area and the number of tablets to be taken at each dose.
2.3 Dose Management Guidelines General Capecitabine tablets dosage may need to be individualized to optimize patient management.
Patients should be carefully monitored for toxicity and doses of capecitabine tablets should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14) ] .
Toxicity due to capecitabine tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine tablets dose.
Once the dose has been reduced, it should not be increased at a later time.
Doses of capecitabine tablets omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine tablets [see Drug Interactions (7.1) ] .
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) Capecitabine tablets dose modification scheme as described below (see Table 2 ) is recommended for the management of adverse reactions.
Table 2.
Recommended Dose Modifications of Capecitabine Tablets Toxicity NCIC Grades National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5) ] .
During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) Grade 1 Maintain dose level Maintain dose level Grade 2 -1 st appearance Interrupt until resolved to grade 0-1 100% -2 nd appearance 75% -3 rd appearance 50% -4 th appearance Discontinue treatment permanently – Grade 3 -1 st appearance Interrupt until resolved to grade 0-1 75% -2 nd appearance 50% -3 rd appearance Discontinue treatment permanently – Grade 4 -1 st 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% In Combination With Docetaxel (Metastatic Breast Cancer) Dose modifications of capecitabine tablets for toxicity should be made according to Table 2 above for capecitabine tablets.
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine tablets or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
The dose reduction schedule for docetaxel when used in combination with capecitabine tablets for the treatment of metastatic breast cancer is shown in Table 3.
Table 3.
Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets Toxicity NCIC Grades National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5) ] .
Grade 2 Grade 3 Grade 4 1 st appearance Delay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m 2 docetaxel Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m 2 of docetaxel.
Discontinue treatment with docetaxel 2 nd appearance Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m 2 of docetaxel.
Discontinue treatment with docetaxel – 3 rd appearance Discontinue treatment with docetaxel – – 2.4 Adjustment of Starting Dose in Special Populations Renal Impairment No adjustment to the starting dose of capecitabine tablets is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]).
In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the capecitabine tablets starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m 2 to 950 mg/m 2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .
Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5) ] .
The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine tablets monotherapy and capecitabine tablets in combination use with docetaxel.
Cockroft and Gault Equation: Creatinine clearance for males = (140 – age [yrs]) (body wt [kg]) (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 x male value Geriatrics Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly.
Insufficient data are available to provide a dosage recommendation.