Bdocin 500

Buff colour, oval shape film-coated tablet, plain on both side.
Each film-coated tablet contains: Capecitabine USP 500 mg.

Antineoplastic (Pyrimidine Analogue).
Pharmacology: Pharmacodynamics: Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeit usually at lower levels. In human cancer xenograft models, Capecitabine demonstrated a synergistic effect in combination with docetaxel, which may be related to the upregulation of thymidine phosphorylase by docetaxel.
Pharmacokinetics: The pharmacokinetics of Capecitabine have been evaluated over a dose range of 502-3,514 mg/m²/day. The parameters of Capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30%-35% higher on day 14. Capecitabine dose reduction decreases systemic exposure to 5-FU more than dose-proportionally, due to non-linear pharmacokinetics for the active metabolite.
Absorption: After oral administration, Capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of Capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of the subsequent metabolite 5-FU. At the dose of 1,250 mg/m² on day 14 with administration after food intake, the peak plasma concentrations (C_max in μg/mL) for Capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 4.67, 3.05, 12.1, 0.95 and 5.46 respectively. The time to peak plasma concentrations (T_max in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC 0-∞ values in μg h/mL were 7.75, 7.24, 24.6, 2.03 and 36.3.
Distribution: 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.
Biotransformation: 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. Further catalytic activation of 5'-DFUR then occurs by thymidine phosphorylase (ThyPase). The enzymes involved in the catalytic activation are found in tumour tissues but also in normal tissues, albeit usually at lower levels. The sequential enzymatic biotransformation of Capecitabine to 5-FU leads to higher concentrations within tumour tissues. In the case of colorectal tumours, 5-FU generation appears to be in large part localised in tumour stromal cells. Following oral administration of Capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal tumours to adjacent tissues was 3.2 (ranged from 0.9 to 8.0). The ratio of 5-FU concentration in tumour to plasma was 21.4 (ranged from 3.9 to 59.9, n=8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 to 25.8, n=8). Thymidine phosphorylase activity was measured and found to be 4 times greater in primary colorectal tumour than in adjacent normal tissue. According to immunohistochemical studies, thymidine phosphorylase appears to be in large part localised in tumour stromal cells.
Deficiency of DPD may lead to increased toxicity of Capecitabine.
Elimination: The elimination half-life (t_1/2 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. Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered Capecitabine dose is recovered in urine. Faecal 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 unchanged.

Colorectal Cancer: Capecitabine (BDOCIN 500) is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
Capecitabine (BDOCIN 500) 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.
Breast Cancer: Capecitabine (BDOCIN 500) 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. Capecitabine (BDOCIN 500) in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

Monotherapy: Colon, colorectal and breast cancer: Given as monotherapy, the recommended starting dose for Capecitabine in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1,250 mg/m² administered twice daily (morning and evening; equivalent to 2,500 mg/m² total daily dose) for 14 days 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: Colon, colorectal and gastric cancer: In combination treatment, the recommended starting dose of Capecitabine should be reduced to 800-1,000 mg/m² when administered twice daily for 14 days followed by a 7-day rest period or to 625 mg/m² twice daily when administered continuously.
Breast cancer: In combination with docetaxel, the recommended starting dose of Capecitabine in the treatment of metastatic breast cancer is 1,250 mg/m² twice daily for 14 days 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 should be started prior to docetaxel administration for patients receiving the Capecitabine plus docetaxel combination.
Or as prescribed by the physician.
Standard and reduced dose calculations according to body surface area for a starting dose of Capecitabine of 1,250 mg/m² (see Table 1).

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Standard and reduced dose calculations according to body surface area for a starting dose of Capecitabine of 1,000 mg/m² (see Table 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 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, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. Doses of Capecitabine omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity: (see Table 3).

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Haematology: 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 that the neutrophil count drops below 1.0 x 10⁹/L or that the platelet count drops below 75 x 10⁹/L, treatment with Capecitabine should be interrupted.
Posology adjustments for special populations: Hepatic impairment: Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.
Renal impairment: Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockcroft and Gault] at baseline).
Elderly: During Capecitabine monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-related adverse reactions were more frequent in patients >60 years of age compared to younger patients.
Pediatric population: There is no relevant use of Capecitabine in the pediatric population in the indications for colon, colorectal, gastric and breast cancer.
Method of administration: Capecitabine tablets should be swallowed with water within 30 minutes after a meal.

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.

History of severe and unexpected reactions to fluoropyrimidine therapy.
Hypersensitivity to Capecitabine or to any of the excipients.
In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity.
During pregnancy and lactation.
In patients with severe leukopenia, neutropenia, or thrombocytopenia.
In patients with severe hepatic impairment. In patients with severe renal impairment (creatinine clearance below 30 mL/min).
Treatment with sorivudine or its chemically related analogues, such as brivudine.
If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product should not be used.

Dose-limiting toxicities: Dose-limiting toxicities include diarrhea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.
Diarrhea: Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrheal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of ≥10 stools/day or grossly bloody diarrhoea or the need for parenteral support. Dose reduction should be applied as necessary.
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 medicinal products. Acute renal failure secondary to dehydration might be potentially fatal. 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 applied should be applied for the precipitating adverse event as necessary.
Hand-foot syndrome (also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema): Grade 1 hand-foot syndrome is defined as numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patient's normal activities.
Cardiotoxicity: Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, and bradycardia), 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.
Coumarin-derivative anticoagulation: In an 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.
Brivudine: Brivudine must not be administered concomitantly with Capecitabine. Fatal cases have been reported following this drug interaction. There must be at least a 4-week waiting period between end of treatment with brivudine and start of Capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of Capecitabine. In the event of accidental administration of brivudine to patients being treated with Capecitabine, effective measures should be taken to reduce the toxicity of Capecitabine. Immediate admission to hospital is recommended. All measures should be initiated to prevent systemic infections and dehydration.
Dihydropyrimidine dehydrogenase (DPD) deficiency: Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity.
Ophthalmologic complications: Patients should be carefully monitored for ophthalmological complications such as keratitis and corneal disorders, especially if they have a prior history of eye disorders. Treatment of eye disorders should be initiated as clinically appropriate.
Severe skin reactions: Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Capecitabine should be permanently discontinued in patients who experience a severe skin reaction during treatment.
Patients with Hepatic Impairment: Caution should be exercised when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Capecitabine.
In the absence of safety and efficacy data in patients with hepatic impairment, Capecitabine use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis. 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.
Patients with Renal Impairment: Patients with moderate (creatinine clearance=30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for Capecitabine, 5-FDUR, and FBAL than in those with normal renal function.
The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) is increased compared to the overall population.
Use in Children: The safety and effectiveness of Capecitabine in pediatrics have not been established.
Use in the Elderly: Geriatric population must be monitored for adverse effects of Capecitabine.

Pregnancy: Pregnancy Category D.
There are no adequate and well-controlled studies of Capecitabine in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Capecitabine, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with Capecitabine.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Summary of related ADRs reported in patients treated with Capecitabine monotherapy (see Table 4).

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Summary of related ADRs reported in patients treated with Capecitabine in combination treatment in addition to those seen with Capecitabine monotherapy or seen at a higher frequency grouping compared to Capecitabine monotherapy (see Table 5).

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ADR Reporting Statement: Seek medical attention immediately at the first sign of any adverse drug reaction.

Interaction with other medicinal products: Brivudine: A clinically significant interaction between brivudine and fluoropyrimidines (e.g. Capecitabine, 5-Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with Capecitabine. There must be at least a 4-week waiting period between end of treatment with brivudine and start of Capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of Capecitabine.
Cytochrome P-450 2C9 substrates: Other than warfarin, no formal interaction studies between Capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when Capecitabine is co-administered with 2C9 substrates (e.g. phenytoin).
Coumarin-derivative 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 reactions 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 pharmacokinetic 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 anticoagulant dose adjusted accordingly.
Phenytoin: Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of Capecitabine with phenytoin. Patients taking phenytoin concomitantly with Capecitabine should be regularly monitored for increased phenytoin plasma concentrations.
Folinic acid/folic 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 and its toxicity may be enhanced by folinic acid: the maximum tolerated dose (MTD) of Capecitabine alone using the intermittent regimen is 3,000 mg/m² per day whereas it is only 2,000 mg/m² per day when Capecitabine was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV to a Capecitabine regimen. This may also be relevant with folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid.
Antacid: The effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of Capecitabine was investigated. 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).
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 2,000 mg/m² per day when combined with interferon alpha-2a (3 MIU/m² per day) compared to 3,000 mg/m² per day when Capecitabine was used alone.
Radiotherapy: The MTD of Capecitabine alone using the intermittent regimen is 3,000 mg/m² per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of Capecitabine is 2,000 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 occurred when Capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.
Bevacizumab: There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of Capecitabine or its metabolites in the presence of oxaliplatin.
Food interaction: In all clinical trials, patients were instructed to administer 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.

Store at temperatures not exceeding 30°C.

Cytotoxic Chemotherapy

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

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