Taceral

Capecitabine.

Each film-coated tablet contains capecitabine 500 mg.

Pharmacology: Mechanism of Action: Capecitabine is a non-cytotoxic fluoropyramide 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.
There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of DNA and RNA deprivation are most marked on those cells which proliferate more rapidly and which metabolize 5-FU at a more rapid rate.

Breast cancer: Taceral in combination with docetaxel is indicated for the treatment of patient with locally advanced or metastatic breast cancer after failure or cytotoxic chemotherapy. Previous chemotherapy should have included an anthracycline. Taceral 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.
Colorectal cancer: Taceral is indicated as adjuvant treatment of patients following surgery of stage III (Dukes stage C) colon cancer. Taceral is indicated as first-line treatment of patients with metastatic colorectal carcinoma.
Gastric cancer: Taceral is indicated for treatment of advanced gastric cancer.

Capecitabine should only be prescribed by a qualified physician experienced in the utilization of antineoplastic 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 dose capecitabine of 1,250 mg/m² and 1,000 mg/m² are provided in tables 1 and 2, respectively. (See Tables 1 and 2).


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Recommended posology: Colon and colorectal cancer: The recommended dose for capecitabine in the adjuvant treatment in colon cancer or in the treatment of metastatic colorectal 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, i.e. capecitabine 1,250 mg/m² administered twice daily for 14 days followed by a 7-day rest period, given as 3-week cycles for a total of 8 cycles (24 weeks).
Advanced gastric cancer: In combination with a platinum-based compound, the recommended dose of capecitabine for the treatment of advanced gastric cancer is 1,000 mg/m² administered twice daily for 14 days followed by a 7-day rest period. The first dose of capecitabine should be given on the evening of day 1 and the last dose should be given on the morning of day 15.
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary product characteristics should be started prior to cisplatin administration for patients receiving in the capecitabine plus cisplatin combination.
Breast cancer: Given as a single agent, the recommended dose of capecitabine in treatment of locally advanced or metastatic breast cancer is 1,250 mg/m² twice daily for 14 days followed by a 7-day rest period.
In combination with docetaxel, the recommended 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 a docetaxel at 75 mg/m² as a 1-hour intravenous infusion every 3 weeks. Premedication 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.
Posology 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 later time. Patients taking capecitabine should be informed of the need to interrupt treatment immediately if moderate or worse toxicity occurs. Doses of capecitabine omitted for toxicity are not replaced or restored, instead the patient should resume the planned treatment cycle. (See Table 3.)


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Dose modification for toxicity when capecitabine is used as a 3-weekly cycle in combination with other agents: Dose modifications for toxicity when capecitabine is used as a 3-weekly cycle in combination with other agents should be made according to Table 3 for capecitabine and according to the appropriate summary of product characteristics for the other agent.
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the other agent, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
During a treatment cycle for those toxicities considered by the treating physician not to be related to capecitabine (for example, neurotoxicity or ototoxicity), then capecitabine should be continued and the other agent should be discontinued 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 starting capecitabine are met.
This advice is applicable to all indications and to all special populations.
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.
Dose modifications for toxicity when capecitabine is used continuously in combination with other agents: Dose modification for toxicity when capecitabine is used continuously in combination with other agents should be made according to Table 3 for capecitabine and according to the appropriate summary of product characteristics for the other agents(s).
Haematology: Capecitabine treatment may continue throughout a grade 3 neutropenic episode. However, the patient should be closely monitored and administration of capecitabine should be interrupted if any grade 2 clinical event (e.g. diarrhea, stomatitis, fever) coincides with the grade 3 neutropenic episode. If grade 4 neutropenia occurs, treatment with capecitabine should be interrupted until recovery to grade 0-1. Treatment should only be re-administered when the neutrophil count is ≥1.5 x 10⁹/L (grade 0-1).
Patients with baseline neutrophil counts <1.5 x 10⁹/L and/or thrombocyte counts of <100 x 10⁹/L should not be treated with the capecitabine.
If the neutrophil counts drops below 1.0 x 10⁹/L or if the platelet count drops below 75 x 10⁹/L, stop capecitabine. At recovery, restart capecitabine at full dose.
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 modification applied should be those for the precipitating adverse event in accordance with the above guidelines.
Posology adjustments for special populations: Hepatic impairment: Insufficient safety and efficacy data are available in patients with hepatic impairment to provide 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 at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 mL/min at baseline) is increased compared to the overall population.
In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1,250 mg/m² is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1,000 mg/m². 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 during treatment and subsequent dose adjustment as outlined in the table previously. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use.
Children: There is no experience in children (under 18 years).
Elderly: No adjustment of the starting dose is needed during capecitabine monotherapy. However, severe grade 3 or 4 treatment-related adverse events were more frequent in patients ≥ 60 years of age compared to younger patients. Careful monitoring of elderly patients is advisable. In combination with docetaxel, an increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were 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. If no toxicity is observed in patients ≥ 60 years of age treated with a reduced capecitabine starting dose in combination with docetaxel, the dose of capecitabine may be cautiously escalated to 1,250 mg/m² twice daily.

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 or fluorouracil.
In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
During pregnancy and lactation.
In patients with severe leucopenia, 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 other agents in the combination regimens, that agent should not be used.

Dose limiting toxicities: include diarrhea, abdominal pain, nausea, stomatitis, and hand-foot syndrome (hand-foot reaction, palmar-plantar erythrodysesthesia). Most adverse events are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.
Diarrhea: Capecitabine can induce the occurrence of diarrhea which has been observed in 50% of patients. 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 diarrhea as an increase of 7 to 9 stools/day or incontinence or malabsorption. Grade 4 diarrhea is an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3, or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolved or decreases in intensity to grade 1. Following grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased or treatment discontinued permanently (grade 4).
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/parathesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patient's normal activities. Grade 2-hand-foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities daily of living.
Grade 3 hand-foot syndrome is moist desquamation, ulceration, blistering and 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. 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.
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 pectroris.
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 system disease, e.g. brain metastasis or neuropathy.
Diabetes mellitus or electrolyte disturbances: Caution must be exercised in patients with diabetes mellitus or electrolyte disturbance, as these may be aggravated during treatment with capecitabine.
Coumarin-derivative anticoagulation: 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 inhibition of the cytochrome P450 2C9 isoenzyme system by the 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.
Hepatic impairment: 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 evaluations in bilirubin of > 3.0 x ULN (Upper Limit Normal) or treatment-related elevations in hepatic aminotransferase (ALT, AST) of > 2.5 x ULN occur. Treatment with capecitabine monotherapy may be resumed when biliburin decreases to ≤ 3.0 x ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN. For combination treatment with capecitabine and docetaxel, see Dosage & Administration.
Renal impairment: The incidence of grade 3 or 4 adverse events in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) is increased compared to the overall population.
As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary problems intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Capecitabine has minor to moderate influence on the ability to drive and use machines. Capacitabine may cause dizziness, fatigue and nausea.

There are no studies in pregnant women using capecitabine; however it should 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 is contraindicated during pregnancy. Woman of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine. If patient becomes pregnant while receiving capecitabine, the potential hazard to the fetus must be explained.
It is not known whether capecitabine is excreted in human breast milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. Breast-feeding should be discontinued while receiving treatment with capecitabine.

The adverse drug reactions considered to be possibly, probably, or remotely related to the administration of capecitabine have been obtained from studies in patients conducted with capecitabine monotherapy (in adjuvant therapy of colon cancer, in metastatic colorectal cancer and metastatic breast cancer), capecitabine in combination with docetaxel in metastatic breast cancer after failure of cytotoxic chemotherapy and capecitabine in combination with various agents in advanced gastric cancer.
The most commonly reported treatment-related adverse drug reactions were gastrointestinal disorders (especially diarrhea, nausea, vomiting, abdominal pain, stomatitis), fatigue and hand-foot syndrome (palmar-plantar erythrodysesthesia).
The following headings are used to rank the adverse drug reactions by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10) and uncommon (≥ 1,1000, < 1/100). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.
Capecitabine monotherapy: The most frequently reported treatment-related adverse drug reactions were gastrointestinal disorders, especially diarrhea, nausea, vomiting, stomatitis, and hand-foot syndrome (palmar-plantar erythrodysesthesia). (See Table 4.)


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Laboratory abnormality observed with capecitabine monotherapy: (See Table 5.)


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Capecitabne in combination with cisplatin: (See Table 6.)


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Capecitabine in combination with docetaxel: (See Table 7.)


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Capecitabine in combination with oxaliplatin: Adverse drug reactions reported in patients treated with capecitabine in combination with oxaliplatin in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: very common adverse drug reactions: anemia, leukopenia, neutropenia, thrombocytopenia, neuropathy; common adverse drug reactions: bleeding.
Capecitabine in combination with epirubicin and oxaliplatin: Grade 3 and grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with epirubicin and oxaliplatin in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: very common: leukopenia, neutropenia, lethargy; common: anemia, thrombocytopenia, febrile neutropenia, peripheral neuropathy, infection, fever, thromboembolism.
Capecitabine in combination with epirubicin and cisplatin: Grade 3 and grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with epirubicin and cisplatin in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: very common: leukopenia, neutropenia, anemia, lethargy, thromboembolism; common: thrombocytopenia, febrile neutropenia, peripheral neuropathy, infection, fever.

Interaction studies have only been performed in adults.
Interaction with other medicinal products: 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. 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: 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 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).
Sonvudine 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. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, capecitabine must not be administered with sorivudine or its chemically related analogues, such as brivudine.
Antacid: the effect of an aluminum hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was 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.
Interaction with cytochrome P450: for potential interactions with isoenzymes 1A2, 2C9 and 3A4, see interactions with coumarin-derivative anticoagulation.
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.
Food interaction: 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 below 30°C.

Cytotoxic Chemotherapy

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

FC tab 500 mg x 12 x 10's.