Caxeta

Capecitabine.

Each tablet contains Capecitabine 500 mg.

Pharmacotherapeutic group: Cytostatic agent. ATC code: L01BC06.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Capecitabine is a fluoropyrimidine carbamate derivative that was designed as an orally administered, tumour-activated and tumour-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 tumour site by the tumour-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 tumour tissues. Following oral administration report of capecitabine to patients with colorectal cancer (N=8), the ratio of 5-FU concentration in colorectal tumours vs adjacent tissues was 3.2 (range 0.9 to 8.0). The ratio of 5-FU concentration in tumour 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 tumour than in adjacent normal tissue.
Several human tumours, 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 tumour cells metabolise 5-FU to 5-fluoro-2-deoxyuridine mono-phosphate (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 uracil. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
Pharmacokinetics: Absorption: 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 (C_max in ug/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 (T_max in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC values in ug·h/mL were 7.75, 7.24, 24.6, 2.03 and 36.3.
Distribution: Protein binding: In vitro human plasma studies have reported 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 tumour tissues.
Formation of 5-FU occurs preferentially at the tumour site by the tumours-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 Mechanism of action as previously mentioned).
5-FU is further catabolized to the inactive metabolites of dihydro-5-fluorouracil (FUH₂), 5-fluoro-ureidopropionic acid (FUPA) and a-fluoro-B-alanine (FBAL) via dihydro-pyrimidine dehydrogenase (DPD), which is rate limiting.
Elimination: The elimination half-lives (t_½ 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 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 5-FU.
After oral administration, capecitabine metabolites are primarily recovered in urine. Most (95.5%) of administered capecitabine dose is recovered in urine. Faecal excretion 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 reported 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 (C_max 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 reported 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, Kamofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.
Hepatic impairment due to liver metastases: No clinically significant effect on the bioactivation and pharmacokinetics of capecitabine was reported in cancer patients with mildly to moderately impaired liver function due to liver metastases (see RECOMMENDED DOSE under Dosage & Administration).
No formal pharmacokinetic study has been reported and no population pharmacokinetic data was reported in patients with severe hepatic impairment.
Renal impairment: Based on a reported 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 RECOMMENDED DOSE under Dosage & Administration).
Geriatric Population: Based on a reported 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 RECOMMENDED DOSE under Dosage & Administration and previous text).
Race: In a reported 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.

Breast cancer: Capecitabine in combination with docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
Capecitabine is also indicated as monotherapy for the 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.
Colon and colorectal cancer: Capecitabine is indicated as adjuvant treatment of patients with colon cancer.
Capecitabine is indicated for the treatment of patients with metastatic colorectal cancer.
Oesophagogastric cancer: Capecitabine is indicated as first-line treatment of patients with advanced oesophagogastric cancer.
Gastric cancer: Capecitabine in combination with oxaliplatin is indicated as adjuvant treatment of patients following complete resection of stage II and III gastric adenocarcinoma.

MODE OF ADMINISTRATION: Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Capecitabine tablets should not be crushed or cut. If patients cannot swallow capecitabine tablets whole and tablets must be crushed or cut, this should be done by a professional trained in the safe handling of cytotoxic drugs (see Special instruction for use, handling and disposal under Cautions for Usage).
RECOMMENDED DOSE: Monotherapy: Colon, colorectal and breast cancer: The recommended monotherapy starting dose of capecitabine 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.
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.
Premedication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine plus docetaxel combination.
Colon, colorectal, gastric and oesophagogastric cancer: In combination treatment (except with irinotecan), the recommended starting dose of capecitabine is 800 to 1000 mg/m² administered twice daily for 2 weeks followed by a 7-day rest period, or 625 mg/m² twice daily when administered continuously.
For combination with irinotecan (XELIRI), the recommended starting dose of capecitabine is 800 mg/m² administered twice daily for 2 weeks followed by a 7-day rest period in combination with irinotecan 200 mg/m² on day 1 of each three week cycle.
The inclusion of bevacizumab in a combination regimen has no effect on the starting dose of capecitabine. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin or oxaliplatin product information should be started prior to cisplatin administration for patients receiving the capecitabine plus cisplatin or oxaliplatin combination.
Dose calculation: Capecitabine dose is calculated according to body surface area. The following tables show examples of the standard and reduced dose calculations (see Dose adjustments during treatment as follows) for a starting dose of capecitabine of either 1250 mg/m² or 1000 mg/m². (See Tables 1 and 2.)

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Dose 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.
Dosage modifications are not recommended for Grade 1 events. Therapy with capecitabine should be interrupted if a Grade 2 or 3 adverse drug reaction (ADR) occurs. Once the ADR has resolved or decreased in intensity to Grade 1, capecitabine therapy may be restarted at full dose or as adjusted according to Table 3. If a Grade 4 ADR occurs, therapy should be discontinued or interrupted until the ADR has resolved or decreased to Grade 1, and therapy can then be restarted at 50% of the original dose. 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.
Haematology: Patients with baseline neutrophil counts of <1.5x 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 haematologic toxicity, treatment with capecitabine should be interrupted.
The following table shows the recommended dose modifications following toxicity related to capecitabine. (See Table 3.)

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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 Table 3 as previously mentioned 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: Pediatric and adolescent use: The safety and efficacy of capecitabine in children and adolescents (<18 years) have not been established.
Geriatric use: For capecitabine monotherapy, no adjustment of the starting dose is needed. However, severe Grade 3 or 4 treatment-related ADRs were more frequent in patients over 80 years of age compared to younger patients.
When capecitabine was used in combination with other antineoplastic agents, geriatric patients (≥65 years) experienced more Grade 3 and Grade 4 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 ADRs and treatment-related serious ADRS 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 1.
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 clearance 51-80 mL/min), no adjustment in starting dose 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 ADRS with subsequent dose adjustment as outlined in Table 3 as previously mentioned (see PHARMACOLOGY: Pharmacokinetics 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 1 and 2.
Hepatic impairment: 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 under Actions and PRECAUTIONS). Patients with severe hepatic impairment have not been reported.

OVERDOSE AND TREATMENT: The manifestations of acute overdose include nausea, vomiting, diarrhoea, 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.

Capecitabine is contraindicated in patients with a known hypersensitivity to capecitabine or to any of its excipients.
Capecitabine is contraindicated in patients who have a history of severe and unexpected reactions to fluoropyrimidine therapy or with known hypersensitivity to fluorouracil.
Capecitabine is contraindicated in patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see WARNINGS).
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 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.

Diarrhoea: 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 RECOMMENDED DOSE under Dosage & Administration).
Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated.
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. Fatal outcome of renal failure has been reported in these situations (see ADVERSE REACTIONS).
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 ADRs as necessary (see RECOMMENDED DOSE under Dosage & Administration).
Dihydropyrimidine dehydrogenase (DPD) deficiency: Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity, an enzyme involved in fluorouracil degradation.
Patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus that cause complete or near complete absence of DPD activity, are at the highest risk for severe, life-threatening, or fatal adverse reactions caused by fluorouracil. These patients should not be treated with capecitabine. No dose has been proven safe for patients with complete absence of DPD activity (see CONTRAINDICATIONS).
Patients with certain heterozygous DPYD variants (e.g. DPYD*2A variant) that may cause partial DPD deficiency have been reported to have increased risk of severe toxicity when treated with capecitabine. For patients with partial DPD deficiency where the benefits of capecitabine are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution, initially with a substantial dose reduction and frequent subsequent monitoring and dose adjustment according to toxicity.
Testing for DPD deficiency should be considered based on the local availability and current guidelines.
In patients with unrecognised DPD deficiency treated with capecitabine, as well as patients who test negative for specific DPYD variations, life threatening toxicities manifesting as acute overdose may occur. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities (see OVERDOSE AND TREATMENT under Overdosage).

The spectrum of cardiotoxicity observed with capecitabine is similar to that of other fluorinated pyrimidines. This includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, and electrocardiographic changes. These ADRs may be more common in patients with a prior history of coronary artery disease.
Capecitabine can induce hand-foot syndrome (palmar-plantar erythrodysesthesia or chemo-therapy-induced acral erythema) which is a cutaneous toxicity. Persistent or severe hand-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints, which could impact patient identification. 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 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 RECOMMENDED DOSE under Dosage & Administration). When capecitabine and cisplatin are used in combination, use of vitamin B6 (pyridoxine) is not advised for the symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated with capecitabine.
Capecitabine can induce hyperbilirubinemia. Administration of capecitabine should be interrupted if treatment-related elevations in bilirubin of >3.0x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5x ULN occur. Treatment may be resumed when bilirubin decreases to ≤3.0x ULN or hepatic aminotransferases decrease to ≤ 2.5x ULN.
Care should be exercised when capecitabine is co-administered with drugs, which are metabolized by cytochrome P450 2C9 such as for example warfarin or phenytoin. 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. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations (see INTERACTIONS).
General: Patients treated with capecitabine should be carefully monitored for toxicity. Most ADRs are reversible and do not require permanent discontinuation of therapy, although doses may have to be withheld or reduced (see RECOMMENDED DOSE under Dosage & Administration).
Drug abuse and dependence: Not applicable.
Ability to drive and use machines: Capecitabine has moderate influence on the ability to drive and use machines. Patients should be advised to use caution when driving or using machines if they experience ADRS such as dizziness, fatigue, and or nausea during treatment with capecitabine (see ADVERSE REACTIONS).

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 administered to pregnant women. In reported 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.
Lactation: It is not known whether capecitabine is excreted in human milk. No studies have been reported to assess the impact of capecitabine on milk production or its presence in human breast milk. In a reported study of single oral administration of capecitabine to lactating mice, a significant amount of capecitabine metabolites was detected in the milk. As the potential for harm to the nursing infant is unknown, breastfeeding should be discontinued during treatment with capecitabine and for 2 weeks after the final dose.

Reported clinical trials: Adverse drug reactions (ADRS) considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine have been obtained from clinical studies reported with capecitabine monotherapy (in adjuvant therapy of colon cancer, in metastatic colorectal cancer and metastatic breast cancer), and clinical studies conducted with capecitabine in combination with different chemotherapy regimens for multiple indications. ADRs are added to the appropriate category in the tables as follows according to the highest incidence from the pooled analysis of seven clinical trials. Within each frequency grouping ADRs are listed in descending order of seriousness. Frequencies are defined as very common ≥1/10, common ≥1/100 to <1/10 and uncommon ≥ 1/1,000 to <1/100.
Capecitabine monotherapy: Safety data of capecitabine monotherapy were reported for patients who received adjuvant treatment for colon cancer and for patients who received treatment for metastatic breast cancer or metastatic colorectal cancer. The safety information includes reported data from a phase III trial in adjuvant colon cancer (995 patients treated with capecitabine and 974 treated with i.v. 5-FU/LV) and from 4 phase II trials in female patients with breast cancer (N=319) and 3 trials (1 phase II and 2 phase III trials) in male and female patients with colorectal cancer (N=630). The safety profile of capecitabine monotherapy is comparable in patients who received adjuvant treatment for colon cancer and in those who received treatment for metastatic breast cancer or metastatic colorectal cancer. The intensity of ADRs was graded according to the toxicity categories of the NCIC CTC Grading System. (See Table 4.)

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Skin fissures were reported to be at least remotely related to Capecitabine in less than 2% of the patients in seven completed clinical trials (N=949). The following ADRs represent known toxicities with fluoropyrimidine therapy and were reported to be at least remotely related to capecitabine in less than 5% of patients in seven completed clinical trials (N=949): Gastrointestinal disorders: dry mouth, flatulence, ADRS related to inflammation/ulceration of mucous membranes such as esophagitis, gastritis, duodenitis, colitis, gastrointestinal hemorrhage.
Cardiac disorders: edema lower limb, cardiac chest pain including angina, cardiomyopathy, myocardial ischemia/infarction, cardiac failure, sudden death, tachycardia, atrial arrhythmias including atrial fibrillation, and ventricular extrasystoles.
Nervous system disorders: taste disturbance, insomnia, confusion, encephalopathy, and cerebellar signs such as ataxia, dysarthria, impaired balance, abnormal coordination.
Infections and infestations: ADRs related to bone marrow depression, immune system compromise, and/or disruption of mucous membranes, such as local and fatal systemic infections including bacterial, viral, fungal etiologies) and sepsis.
Blood and lymphatic system disorders: anemia, bone marrow depression/pancytopenia.
Skin and subcutaneous tissue disorders: pruritus, localized exfoliation, skin hyperpigmentation, nail disorders, photosensitivity reactions, radiation recall syndrome.
General disorders and administration site conditions: pain in limb, chest pain (non-cardiac).
Eye: eye irritation.
Respiratory: dyspnoea, cough.
Musculoskeletal: back pain, myalgia, arthralgia.
Psychiatric disorders: depression.
Hepatic failure and cholestatic hepatitis have been reported during clinical trials and post-marketing exposure. A causal relationship with capecitabine treatment has not been reported.
Capecitabine in combination therapy: Table 5 lists ADRs associated with the use of capecitabine in combination therapy with different chemotherapy regimens in multiple indications and occurred in addition to those seen with monotherapy and/or at a higher frequency grouping. The safety profile was similar across all indications and combination regimens. These reactions occurred in ≥5% of patients treated with capecitabine in combination with other chemotherapies. Adverse drug reactions are added to the appropriate category in the table as follows according to the highest incidence reported in any of the major clinical trials. Some of the adverse reactions are reactions commonly reported with chemotherapy (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin) or with bevacizumab (e.g. hypertension); however, an exacerbation by capecitabine therapy cannot be excluded. (See Table 5.)

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Hypersensitivity reactions (2%) and cardiac ischaemia/infarction (3%) have been reported commonly for capecitabine in combination with other chemotherapy but in less than 5% of patients.
Rare uncommon ADRS reported for capecitabine in combination with other chemotherapy are consistent with the ADRS reported for capecitabine monotherapy or the combination product monotherapy (see prescribing information for the combination product).
Laboratory abnormalities: The following table displays laboratory abnormalities reported in 995 patients (adjuvant colon cancer) and 949 patients (metastatic breast and colorectal cancer), regardless of relationship to treatment with capecitabine. (See Table 6.)

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Post-marketing experience report: The following ADRs have been reported during post-marketing experience with capecitabine based on spontaneous case reports and literature cases. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥ 1/10); common (≥1/100 to <1/10); and uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); unknown (cannot be estimated from the available data). (See Table 7.)

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Exposure to crushed or cut capecitabine tablets: In the instance of exposure to crushed or cut capecitabine tablets, the following ADRs have been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, gastric irritation, and vomiting.

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 reported 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. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. 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 (see PRECAUTIONS).
Cytochrome P-450 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 reported. 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 reported, but the mechanism of interaction is presumed to be inhibition of the CYP 2C9 isoenzyme system by capecitabine. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.
Drug-food interaction: In all reported 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.
Antacid: The effect of an aluminium hydroxide and magnesium hydroxide containing antacid on the pharmacokinetics of capecitabine was reported 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): The effect of leucovorin on the pharmacokinetics of capecitabine was reported in cancer patients. Leucovorin has no effect on the pharmacokinetics of capecitabine and its metabolites. However, leucovorin has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by leucovorin.
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.
Oxaliplatin: No clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occurred 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.

Special instruction for use, handling and disposal: Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Special handling using appropriate equipment and disposal procedures, should be taken as capecitabine is a cytotoxic drug. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C.

Cytotoxic Chemotherapy

L01BC06 - capecitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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