Capetero

Capetero

capecitabine

Manufacturer:

Hetero Labs

Distributor:

Medicell Pharma
Full Prescribing Info
Contents
Capecitabine.
Description
Capetero 150 mg: Each film coated tablet contains 150 mg of Capecitabine.
Capetero 500 mg: Each film coated tablet contains 500 mg of Capecitabine.
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.
Capecitabine is supplied as capsule shaped biconvex tablets for oral administration.
Capecitabine is supplied as capsule shaped biconvex tablets for oral administration. Each light peach coloured film coated tablet contain 500 mg. The inactive ingredients in capecitabine include: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate, opadry pink (Hypromellose, Titanium dioxide, Talc, Red iron oxide and Yellow iron oxide) and purified water.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Capecitabine is a fluoropyrimidine carbamate derivative that was designed as an orally administered, tumor-activated and tumor-selective cytotoxic agent.
Capecitabine is non-cytotoxic in vitro. However, in vivo, it is sequentially converted to the cytotoxic moiety 5-fluorouracil (5-FU), which is further metabolised.
Formation of 5-FU is catalysed preferentially at the tumor-associated angiogenic factor thymidine phosphorylase (dThdPase), thereby minimising the exposure of healthy tissues to systemic 5-FU.
The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations of 5-FU within tumor tissues. Following oral administration of capecitabine to patients with colorectal cancer (N=8), the ratio of 5-FU concentration in colorectal tumors vs adjacent tissues was 3.2 (range 0.9 to 8.0). The ratio of 5-FU concentration in tumor vs plasma was 21.4 (range 3.9 to 59.9) whereas the ratio in healthy tissues to plasma was 8.9 (range 3.0 to 25.8). Thymidine phosphorylase activity was 4 times greater in primary colorectal tumor than in adjacent normal tissue.
Several human tumors, such as breast, gastric, colorectal, cervical and ovarian cancers, have a higher level of thymidine phosphorylase (capable of converting 5'-DFUR [5'deoxy-5-fluorouridine] to 5-FU) than corresponding normal tissues.
Normal cells and tumor cells metabolise 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 uracil.
Thymidate is the necessary precursor of thymidate 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.
Clinical/Efficacy Studies: Colon and Colorectal Cancer: Monotherapy in adjuvant colon cancer: Data from one multicenter, randomized, controlled phase 3 clinical trial in patients with stage III (Dukes C) colon cancer supports the use of Capecitabine for the adjuvant treatment of patients with colon cancer (XACT Study: M66001). In this trial, 1987 patients were randomized to treatment with Capecitabine (1250 mg/m2 twice daily for 2 weeks by a 1-week rest period and given as 3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks).
Capecitabine was at least equivalent to i.v. 5-FU/LV in disease-free survival (p=0.0001, non-inferiority margin 1.2). In the all-randomized population, tests for difference of Capecitabine vs 5-FU/LV in disease-free survival and overall survival showed hazard ratios of 0.88 (95% Cl 0.77-1.01; p=0.068) and 0.86 (0.74-1.01; p=0.060), respectively. The median follow up at the time of the analysis was 6.9 years.
Combination therapy in adjuvant colon cancer: Data from one multicentre, randomised, controlled phase 3 clinical trial in patients with stage III (Dukes' C) colon cancer supports the use of Capecitabine in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer (N016968 study). In this trial, 944 patients were randomised to 3-week cycles for 24 weeks with Capecitabine (1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) in combination with oxaliplatin (130 mg/m2 intravenous infusion over 2-hours on day 1 every 3 weeks); 942 patients were randomized to bolus 5-FU and leucovorin. In the primary analysis for DFS, in the ITT population, XELOX was shown to be significantly superior to 5-FU/LV (HR=0.80, 95% Cl=[0.69; 0.93]; p=0.0045). The 3 year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of relapse free survival (RFS) supports these results with a HR of 0.78 (95% Cl=[0.67; 0.92]; p=0.024) for XELOX vs. 5-FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% Cl=[0.72; 1.05]; p=0.1486) which translates into a 13% reduction in risk of death. The 5 year OS rate was 78% for XELOX versus 74% for 5-FU/LV. The efficacy data provided is based on a median observation time of 59 months for OS and 57 months for DFS. The rate of withdrawal due to adverse events was higher in the XELOX combination therapy arm (21%) as compared with that of the 5-FU/LV monotherapy arm (9%) in the ITT population.
Monotherapy in metastatic colorectal cancer: Data from two identically multicenter, randomised, controlled, phase 3 clinical trials support the use of Capecitabine for first-line treatment of metastatic colorectal (S014695; S014796). In these trials, 603 patients were randomised to treatment with Capeciatbine (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles) and 604 patients were randomised to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m2 i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days).
The overall objective response rates in the all-randomised population (investigator assessment) were 25.7% (Capecitabine) vs 16.7% (Mayo regimen); p<0.0002. The median time to progression was 140 days (Capecitabine) vs 144 days (Mayo regimen). Median survival was 392 days (Capecitabine) vs 391 days (Mayo regimen).
Combination therapy - first-line treatment of colorectal cancer: Data from a multicenter, randomized, controlled phase 3 clinical study (N016966) support the use of Capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab (BV) for the first-line treatment of metastastic colorectal cancer. The study contained two parts: an initial 2-arm part in which patients were randomized to two different treatment groups, including XELOX or FOLFOX-4, and a subsequent 2x2 factorial part with four different treatment groups, including XELOX+placebo(P), FOLFOX-4+P, XELOX+BV, and FOLFOX-4+ BV. The treatment regimens are summarized in the table as follows. (See Table 1.)

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Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival in the eligible patient population and the intent-to-treat population (see table as follows). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival. A comparison of XELOX plus bevacizumab versus FOLFOX-4 plus bevacizumab was a pre-specified exploratory analysis. In this treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus bevacizumab in terms of progression-free survival (hazard ratio 1.01 [97.5% CI 0.84, 1.22]). The median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses following an additional 1 year of follow up are also included in Table 2. (See Table 2.)

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Combination therapy - Second-line treatment of colorectal cancer: Data from a multicenter, randomized, controlled phase III clinical study (NO16967) support the use of Xeloda in combination with oxaliplatin for the second-line treatment of metastastic colorectal cancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received prior treatment with irinotecan in combination with a fluoropyrimidine regimen as first-line therapy were randomized to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and FOLFOX-4 (without addition of placebo or bevacizumab), refer to Table 1. XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population and intent-to-treat population (see Table 3). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival. The median follow up at the time of the primary analyses in the intent-to-treat population was 2.1 years; data from analyses following an additional 6 months of follow up are also included in Table 3. (See Table 3.)

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A pooled analysis of the efficacy data from first-line (study NO16966; initial 2-arm part) and second-line treatment (study NO16967) further support the non-inferiority results of XELOX versus FOLFOX-4 as obtained in the individual studies: progression-free survival in the perprotocol population (hazard ratio 1.00 [95% CI: 0.88; 1.14]) with a median progression-free survival of 193 days (XELOX; 508 patients) versus 204 days (FOLFOX-4; 500 patients). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival (hazard ratio 1.01 [95% CI: 0.87; 1.17]) with a median overall survival of 468 days (XELOX) versus 478 days (FOLFOX-4).
Combination therapy - breast cancer: Data from one multicenter, randomised, controlled phase 3 clinical trial support the use of Xeloda in combination with docetaxel for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were randomised to treatment with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 1-hour intravenous infusion every 3 weeks). A total of 256 patients were randomised to treatment with docetaxel alone (100 mg/m2 as a 1-hour intravenous infusion every 3 weeks). Survival was superior in the Xeloda+docetaxel combination arm (p=0.0126). Median survival was 442 days (Xeloda+docetaxel) vs 352 days (docetaxel alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (Xeloda+docetaxel) vs 29.7% (docetaxel alone); p=0.0058. Time to disease progression or death was superior in the Xeloda+docetaxel combination arm (p<0.0001). The median time to progression was 186 days (Xeloda+docetaxel) vs 128 days (docetaxel alone).
Monotherapy-Breast carcinoma: Data from two multicenter phase 2 clinical trials support the use of Xeloda monotherapy for treatment of patients with locally advanced or metastatic breast cancer after failure of a taxane and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients were treated with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). The overall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial). The median time to progression was 93 and 98 days. Median survival was 384 and 373 days.
Pharmacokinetics: Absorption: After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR.
Administration with food decreases the rate of capecitabine absorption but has only a minor effect on the areas under the curve (AUC) of 5'-DFUR and the subsequent metabolite 5-FU.
At the dose of 1250 mg/m2 on day 14 with administration after food intake, the peak plasma concentrations (Cmax in pg/ml) for capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 4.47, 3.05, 12.1, 0.95 and 5.46 respectively. The times to peak plasma concentrations (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-8 values in µg·h/ml were 7.75, 7.24, 24.6, 2.03 and 36.3.
Distribution: Protein binding: In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.
Metabolism: Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumor tissues.
Formation of 5-FU occurs preferentially at the tumor site by the tumor-associated angiogenic factor dThdPase, thereby minimising the exposure of healthy body tissues to systemic 5-FU.
The plasma AUC of 5-FU is 6 to 22 times lower than that following an i.v. bolus of 5-FU (dose of 600 mg/m2). The metabolites of capecitabine become cytotoxic only after conversion to 5-FU and anabolites of 5-FU (see previously mentioned in Pharmacology: Pharmacodynamics: Mechanism of Action). 5-FU is further catabolized to the inactive metabolites dihydro-5-fluorouracil (FUH2), 5-fluoro-ureidopropionic acid (FUPA) and a-fluoro-1-alanine (FBAL) via dihydropyrimidine dehydrogenase (DPD), which is rate limiting.
Elimination: The elimination half-lifes (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively.
The pharmacokinetics of capecitabine have been evaluated over a dose range of 502 - 3514 mg/m2/day. The parameters of capecitabine, 5'-DFCR and 5'-DFUR measured on days 1 and 14 were similar. The AUC of 5-FU was 30% - 35% higher on day 14 but did not increase subsequently (day 22). At therapeutic doses, the pharmacokinetics of capecitabine and its metabolites were dose proportional, except for 5-FU.
After oral administration, capecitabine metabolites are primarily recovered in the urine. Most (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.
Combination therapy: Phase I studies evaluating the effect of Capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the most important metabolite of capecitabine).
Pharmacokinetics in Special Populations: A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients with colorectal cancer dosed at 1250 mg/m2 twice daily. Gender, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.
Patients with hepatic impairment due to liver metastases: No clinically significant effect on the bioactivation and pharmacokinetics of capecitabine was observed in cancer patients with mildly to moderately impaired liver function due to liver metastases (see Dosage & Administration).
There are no pharmacokinetic data on patients with severe hepatic impairment.
Patients with renal impairment: Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic exposure to 5'- DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite without antiproliferative activity; 5'-DFUR is the direct precursor of 5-FU (see Dosage & Administration).
Elderly: Based on a population pharmacokinetic analysis that included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater than or equal to 65 years, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL).
This increase is likely due to a change in renal function (see previously mentioned in Pharmacokinetics in Special Populations: Patients with renal impairment and Dosage & Administration).
Race: In a population pharmacokinetic analysis of 455 white patients (90.1%), 22 black patients (4.4%) and 28 patients of other race or ethnicity (5.5%), the pharmacokinetics of capecitabine in black patients were not different from those in white patients.
Indications/Uses
Colorectal Cancer: Capecitabine 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 preferred.
Capecitabine is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
Breast Cancer: Capecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
Capecitabine 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.
Dosage/Direction for Use
Standard Dosage: Capecitabine should only be prescribed by a qualified physician experienced in the utilisation of anti-neoplastic agents. Capecitabine tablets should be swallowed with water within 30 minutes after a meal. Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard and reduced dose calculations according to body surface area for starting doses of Capecitabine of 1250 mg/m2 and 1000 mg/m2 are provided in Tables 4 and 5, respectively.
Monotherapy: Colon, colorectal and breast cancer: The recommended monotherapy starting dose of Capecitabine in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 7-day rest period.
Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.
Combination therapy: Breast cancer: In combination with docetaxel, the recommended starting dose of Capecitabine is 1250 mg/m2 twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks.
Pre-medication with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for patients receiving the Capecitabine plus docetaxel combination.
Colon and colorectal cancer: In combination treatment, the recommended starting dose of Capecitabine should be reduced to 1000 mg/m2 administered twice daily for 2 weeks followed by a 7-day rest period. The inclusion of biological agents in a combination regimen has no effect on the starting dose of Capecitabine.
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin and oxaliplatin product information should be started prior to cisplatin administration for patients receiving the Capecitabine plus cisplatin or oxaliplatin combination.
Adjuvant treatment in patients with stage III colon cancer is recommended fora total of 6 months.
Capecitabine dose is calculated according to body surface area. The following tables show examples of the standard and reduced dose calculations (see Dosage adjustments during treatment as follows) for a starting dose of Capecitabine of either 1250 mg/m2 or 1000 mg/m2. (See Tables 4 and 5.)

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Dosage adjustments during treatment: General: Toxicity due to Capecitabine administration may be managed by symptomatic treatment and/or modification of the Capecitabine dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time.
For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening treatment can be continued at the same dose without reduction or interruption.
Patients taking Capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Capecitabine omitted for toxicity are not replaced.
Hematology: Patients with baseline neutrophil counts of <1.5 x 109/l and/or thrombocyte counts of <100 x 109/l should not be treated with Capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with Capecitabine should be interrupted.
If the neutrophil count drops below 1.0 x 109/L or if the platelet count drops below 75 x 109/L, discontinue capecitabine. At recovery, restart capecitabine at full dose.
The following table shows the recommended dose modifications following toxicity related to Capecitabine: (See Table 6.)

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General combination therapy: Dose modifications for toxicity when Capecitabine is used in combination with other therapies should be made according to the previously mentioned Table 6 for Capecitabine and according to the appropriate Prescribing Information for the other agent(s).
At the beginning of a treatment cycle, if a treatment delay is indicated for either Capecitabine or the other agent(s), then administration of all agents should be delayed until the requirements for restarting all drugs are met. During a treatment cycle for those toxicities considered by the treating physician not to be related to Capecitabine, Capecitabine should be continued and the dose of the other agent adjusted according to the appropriate Prescribing Information.
If the other agent(s) have to be discontinued permanently, Capecitabine treatment can be resumed when the requirements for restarting Capecitabine are met.
This advice is applicable to all indications and to all special populations.
Special Dosage Instructions: Patients with hepatic impairment due to liver metastases: In patients with mild to moderate hepatic impairment due to liver metastases, no starting dose adjustment is necessary. However, such patients should be carefully monitored (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions and Precautions). Patients with severe hepatic impairment have not been studied.
Patients with renal impairment: In patients with moderate renal impairment (creatinine clearance 30 - 50 ml/min [Cockroft and Gault]) at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m2 is recommended. In patients with mild renal impairment (creatinine clearance 51 - 80 ml/min), no adjustment in starting dose is recommended.
Careful monitoring and prompt treatment interruption is recommended if the patient develops a Grade 2, 3, or 4 adverse event with subsequent dose adjustment as outlined in Table 6 above (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, Capecitabine should be discontinued. The dose adjustment recommendations for patients with moderate renal impairment apply both to monotherapy and combination use. For dosage calculations, see Tables 4 and 5.
Children: The safety and efficacy of Capecitabine in children have not been established.
Elderly: For Capecitabine monotherapy, no adjustment of the starting dose is needed. However, severe grade 3 or 4 treatment-related adverse events were more frequent in patients over 80 years of age compared to younger patients. When Capecitabine was used in combination with otheragents, elderly patients (= 65 years) experienced more grade 3 and grade 4 adverse drug reactions (ADRs) and ADRs that led to discontinuation, than younger patients. Careful monitoring of elderly patients is advisable.
In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse events and treatment-related serious adverse events was observed in patients 60 years of age or more. For patients 60 years of age or more treated with the combination of Capecitabine plus docetaxel, a starting dose reduction of Capecitabine to 75% (950 mg/m2 twice daily) is recommended. For dosage calculations, see Table 5.
In combination with irinotecan: for patients 65 years of age or more, a starting dose reduction of Capecitabine to 800 mg/m2 twice daily is recommended.
Overdosage
The manifestations of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, and bone marrow depression.
Medical management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.
Contraindications
Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components.
Capecitabine is contraindicated in patients who have a history of severe and unexpected reactions to fluoropyrimidine therapy or with known hypersensitivity to fluorouracil.
As with other fluoropyrimidines, Capecitabine is contraindicated in patients with known DPD deficiency. Capecitabine should not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see Interactions).
Capecitabine is contraindicated in patients with severe leukopenia, neutropenia or thrombocytopenia.
Capecitabine is contraindicated in patients with severe hepatic impairment.
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min).
If contraindications exist to any of the agents in a combination regimen, that agent should not be used.
Warnings
Diarrhea: Capecitabine can induce diarrhea, which can sometimes be severe. Patients with severe diarrhea should be carefully monitored and, if they become dehydrated, should be given fluid and electrolyte replacement. Standard anti-diarrhea treatments (e.g. loperamide) should be initiated, as medically appropriate, as early as possible. Dose reduction should be applied as necessary (see Dosage & Administration).
Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. If Grade 2 (or higher) dehydration occurs, Capecitabine treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary (see Dosage & Administration).
Dehydration may cause acute renal failure, especially in patients with pre-existing compromised renal function or when capecitabine is given concomitantly with known nephrotoxic agents. Acute renal failure secondary to dehydration is potentially fatal, (see Adverse Reactions).
Special Precautions
General: Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmarplantar erythrodysesthesia). Most adverse events are reversible and do not require permanent discontinuation of therapy, although doses may have to be withheld or reduced (see Dosage & Administration).
Cardiotoxicity: Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes. These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias, angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving Capecitabine. Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris.
Hypo- or hypercalcaemia: Hypo- or hypercalcaemia has been reported during Capecitabine treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia.
Central or peripheral nervous system disease: Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy.
Diabetes mellitus or electrolyte disturbances: Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during Capecitabine treatment.
Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-FU therefore cannot be excluded.
Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN), [see Adverse Reactions]. Capecitabine should be permanently discontinued in patients who experience a severe skin reaction possibly attributable to Capecitabine treatment.
Capecitabine can induce hand-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema), which is a cutaneous toxicity. For patients receiving Capecitabine monotherapy in the metastatic setting, the median time to onset was 79 days (range 11 to 360 days), with a severity range of Grades 1 to 3. Grade 1 hand-foot syndrome is defined by numbness, dysesthesia/paresthesia, tingling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 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 is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If Grade 2 or 3 hand-foot syndrome occurs, administration of Capecitabine should be interrupted until the event resolves or decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome, subsequent doses of Capecitabine should be decreased (see Dosage & Administration). When Capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin.
Capecitabine can induce hyperbilirubinemia. Administration of Capecitabine should be interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with Capecitabine monotherapy may be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferases decrease to ≤2.5 x ULN.
As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin.
These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients receiving concomitant Capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly (see Interactions).
Renal Impairment: Physicians should exercise caution when Capecitabine is administered to patients with impaired renal function. As seen with 5-FU the incidence of treatment-related Grade 3 or 4 adverse events was higher in patients with moderate renal impairment (creatinine clearance 30-50 ml/min) (see Dosage & Administration).
Hepatic Impairment: Patients with hepatic impairment should be carefully monitored when Capecitabine is administered. The effect of hepatic impairment not due to liver metastases or severe hepatic impairment on the disposition of Capecitabine is not known (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions and Dosage & Administration).
Effects on ability to drive and use machines: Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause dizziness, fatigue and nausea.
Use in Elderly: Among patients with colorectal cancer aged 60-79 years receiving Capecitabine monotherapy in the metastatic setting, the incidence of gastrointestinal toxicity was similar to that in the overall population. In patients aged 80 years or older, a larger percentage experienced reversible Grade 3 or 4 gastrointestinal adverse events, such as diarrhea, nausea and vomiting (see Dosage & Administration). When Capecitabine was used in combination with other agents elderly patients (≥65 years) experienced more grade 3 and grade 4 ADRs and ADRs that led to discontinuation than younger patients. An analysis of safety data in patients equal to or greater than 60 years of age treated with Capecitabine plus docetaxel combination therapy showed an increase in the incidence of treatment-related Grade 3 and 4 adverse events, treatment-related serious adverse events and early withdrawals from treatment due to adverse events compared to patients less than 60 years of age.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy category D.
There are no studies in pregnant women using Capecitabine; however, based on the pharmacological and toxicological properties of Capecitabine, it can be assumed that Capecitabine may cause fetal harm if administered to pregnant women. In reproductive toxicity studies in animals, capecitabine administration caused embryolethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Capecitabine should be considered a potential human teratogen. Capecitabine should not be used during pregnancy. If Capecitabine is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient must be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Capecitabine.
Nursing Mothers: It is not known whether the drug is excreted in human milk. In a study of single oral administration of Capecitabine to lactating mice, a significant amount of capecitabine metabolites was detected in the milk. Nursing should be discontinued during Capecitabine treatment.
Adverse Reactions
Clinical Trials: Summary of the safety profile: The overall safety profile of Capecitabine is based on data from over 3000 patients treated with Capecitabine as monotherapy or Capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of Capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable. See Pharmacology: Pharmacodynamics under Actions for details of major studies, including study designs and major efficacy results.
The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.
Tabulated summary of adverse reactions: ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of Capecitabine are listed in Table 7 for Capecitabine given as a single agent and in Table 8 for Capecitabine given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by frequency: very common (≥1/10), common (≥1/100, <1/10) and uncommon (≥1/1,000, <1/100). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
Capecitabine Monotherapy: Table 7 lists ADRs associated with the use of Capecitabine monotherapy based on a pooled analysis of safety data from three major studies including over 1900 patients (studies M66001, S014695, and S014796). ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis. (See Table 7.)

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Capecitabine in combination therapy: Table 8 lists ADRs associated with the use of Capecitabine in combination with different chemotherapy regimens in multiple indications based on safety data from over 1400 patients. ADRs are added to the appropriate frequency grouping (Very common or Common) according to the highest incidence seen in any of the major clinical trials and are only added when they were seen in addition to those seen with Capecitabine monotherapy or seen at a higher frequency grouping compared to Capecitabine monotherapy (see Table 7). Uncommon ADRs reported for Capecitabine in combination therapy are consistent with the ADRs reported for Capecitabine monotherapy or reported for monotherapy with the combination agent (in literature and/or respective summary of product characteristics).
Some of the ADRs are reactions commonly seen with the combination agent (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however an exacerbation by Capecitabine therapy can not be excluded. (See Table 8.)

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Post Marketing: The following additional serious adverse reactions have been identified during post-marketing exposure: Rare: Acute renal failure secondary to dehydration including fatal outcome, see Precautions. Very rare: Cutaneous lupus erythematosus, Severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN), see Precautions. Very rare: lacrimal duct stenosis, corneal disorders including keratitis. Very rare: hepatic failure and cholestatic hepatitis have been reported during clinical trials and post-marketing exposure.
Drug Interactions
Interaction studies have only been performed in adults.
Coumarin anticoagulants: Altered coagulation parameters and/or bleeding have been reported in patients taking Capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating Capecitabine therapy and, in a few cases, within one month after stopping Capecitabine. In a clinical interaction study, after a single 20 mg dose of warfarin, Capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin derivative anticoagulants concomitantly with Capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anti-coagulant dose adjusted accordingly.
Cytochrome P450 2C9 substrates: No formal drug-drug interaction studies with capecitabine and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme have been conducted. Care should be exercised when Capecitabine is co-administered with these drugs.
Phenytoin: Increased phenytoin plasma concentrations have been reported during concomitant use of Capecitabine with phenytoin. 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 system by capecitabine (see previously mentioned in Coumarin anticoagulants). Patients taking phenytoin concomitantly with Capecitabine should be regularly monitored for increased phenytoin plasma concentrations.
Drug-food interaction: In all clinical trials, patients were instructed to take Capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that Capecitabine be administered with food. Administration with food decreases the rate of capecitabine absorption.
Antacid: The effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of Capecitabine was investigated in cancer patients. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL).
Leucovorin (folinic acid): A combination study with Capecitabine and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of Capecitabine and its metabolites. However, folinic acid has an effect on the pharmacodynamics of Capecitabine: the maximum tolerated dose (MTD) of Capecitabine alone using the intermittent regimen is 3000 mg/m2 per day whereas it is only 2000 mg/m2 per day when Capecitabine was combined with folinic acid (30 mg orally bid).
Sorivudine and analogues: A clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described in the literature. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal.
Therefore, Capecitabine should not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see Contraindications). There must be at least a 4-week waiting period between the end of treatment with sorivudine or its chemically related analogues, such as brivudine and start of Capecitabine therapy.
Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU. Concomitant use of allopurinol with Capecitabine should be avoided.
Interferon alpha: the MTD of Capecitabine was 2000 mg/m2 per day when combined with interferon alpha-2a (3 MIU/m2 per day) compared to 3000 mg/m2 per day when Capecitabine was used alone.
Radiotherapy: the MTD of Capecitabine alone using the intermittent regimen is 3000 mg/m2 per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of Capecitabine is 2000 mg/m2 per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy.
Oxaliplatin: No clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occur when capecitabine and oxaliplatin were administered in combination, with or without bevacizumab.
Bevacizumab: There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites.
Storage
Store below 30°C and protect from moisture.
ATC Classification
L01BC06 - capecitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Presentation/Packing
Tab 150 mg (light peach colored, capsule shaped, biconvex film-coated debossed with '6' on one side and 'H' on the other side) x 30's. 500 mg (peach colored, oval shaped, biconvex film-coated debossed with '3' on one side and 'H' on the other side) x 30's.
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