Capecitabine Alvogen

Capecitabine Alvogen

capecitabine

Manufacturer:

Alvogen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Capecitabine.
Description
Each film-coated tablet contains 500 mg capecitabine.
Excipients/Inactive Ingredients: Tablet core: Croscarmellose Sodium, microcrystalline cellulose, hypromellose, silica colloidal anhydrous, magnesium stearate.
Tablet coating: Hypromellose, titanium dioxide (E171), talc, macrogol, red iron oxide (E172), yellow iron oxide (E172).
Action
Pharmacotherapeutic Group: Cytostatic (antimetabolite). ATC Code: L01BC06.
Pharmacology: Pharmacodynamics: Capecitabine is relatively noncytotoxic in vitro. This drug is enzymatically converted to 5-fluorouracil in vivo.
With normal and tumor cells metabolize 5-fluorouracil to 5-fluoro-2-deoxyuridine monophosphate and 5-fluorouridine triphosphate. These metabolites cause cell injury by 2 different mechanisms. First, 5-fluoro-2-deoxyuridine monophosphate and the folate cofactor, N-ethylenetetrahydrofolate, bind to thymidylate synthase to form a valently bound ternary complex. This binding inhibits the formation of thymidylate from 2-deoxy-uridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of deoxynucleic acid (DNA), so that a deficiency of this compound can inhibit cell vision. Second, nuclear transcriptional enzymes can mistakenly incorpolate 5-fluorouridine triphosphate in place of uridine triphosphate during the synthesis of ribonucleic acid (RNA). This metabolic error can interfere with DNA processing and protein synthesis.
Pharmacokinetics: Absorption: Capecitabine is readily absorbed from the GI tract. Capecitabine reached peak blood in about 1.5 hour (Tmax) with peak 5-fluorouracil levels occurring slightly later, at 2 hours. Food reduced both of rate and extent of absorption of capecitabine with mean maximum plasma concentration (Cmax) and area under the curve (AUC0-ᾳ) decreased 60% and 35%, respectively. The Cmax and AUC0-ᾳ of 5-fluorouracil were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-fluorouracil by 1.5 hours.
The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5-deoxy-5-fluorocytidine were dose proportional and did not change over time. The increases in the AUCs of 5-deoxy-5-fluorouracil and 5-fluorouracil, however, were greater than proportional to the increase in dose, and the AUC of 5-fluorouracil was 34% higher on day 14 than on day 1.
The interpatient variability in the Cmax and AUC of 5-fluorouracil was greater than 85%.
Distribution: Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%).
Metabolism: Capecitabine is extensively metabolized enzymatically to 5-fluorouracil. The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-fluorouracil, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5,6-dihydro-fluorouracil. Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid. Finally, beta-ureido-propionase cleaves 5-fluoro-ureido-propionic acid to alpha-fluoro-beta-alanine, which is cleared in the urine.
Excretion: Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is alpha-fluoro-beta-alanine, which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-fluorouracil was about three fourths of an hour.
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.
Special populations: Renal function impairment: Following oral administration of 1250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance less than 30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to alpha-fluoro-beta-alanine on day 1 compared with healthy renal function patients (creatinine clearance greater than 80 mL/min). Systemic exposure to 5'-deoxy-5-fluorouridine was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in healthy patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients. Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
Hepatic function impairment: Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score, including bilirubin, AST/ALT, and alkaline phosphatase following a single 1255 mg/m2 dose of capecitabine. Both AUC0-ᾳ and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared with patients with healthy hepatic function (n=14). The AUC0-ᾳ and Cmax of 5-fluorouracil were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, exercise caution when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known.
Toxicology: Preclinical safety data: In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised by degenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepatic and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing (1379 mg/m2/day).
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.
During standard fertility studies, impairment of fertility was observed in female mice receiving capecitabine; however, this effect was reversible after a drug-free period. In addition, during a 13-week study, atrophic and degenerative changes occurred in reproductive organs of male mice; however these effects were reversible after a drug-free period.
In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of teratogenicity.
Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
Indications/Uses
Capecitabine is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer (see Pharmacology: Pharmacodynamics under Actions).
Capecitabine is indicated for the treatment of metastatic colorectal cancer (see Pharmacology: Pharmacodynamics under Actions).
Capecitabine is indicated for first-line treatment of advanced gastric cancer in combination with a platinum-based regimen (see Pharmacology: Pharmacodynamics under Actions).
Capecitabine in combination with docetaxel (see Pharmacology: Pharmacodynamics under Actions) 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 taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.
Dosage/Direction for Use
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. Although some clinicians state that capecitabine may be administered concomitantly with antacids containing aluminium and magnesium hydroxide, other clinicians advise delay of administration of antacids for at least 2 hours following induction of capecitabine therapy.
Dosage: Breast cancer: Combination Therapy: When used in combination therapy with docetaxel for the treatment of metastatic breast cancer in patients with disease that failed to respond to or recurred following anthracycline-containing chemotherapy, the recommended initial dosage of capecitabine is 1250 mg/m2 twice daily (morning and evening), equivalent to a total daily dose of 2500 mg/m2, for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles. Docetaxel 75 mg/m2 is administered as a 1-hour IV infusion on the first day of each 3-week cycle. Patients should be premedicated prior to docetaxel administration. Treatment with the combination regimen was continued for at least 6 weeks in the randomized trial.
Monotherapy: For the palliative treatment of metastatic breast cancer in patients with disease resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or in patients with disease resistant to paclitaxel who are not candidates for further anthracycline therapy, the recommended initial dosage of capecitabine is 1250 mg/m2 twice daily (morning and evening), equivalent to 2500 mg/m2 total daily dose, for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles.
Colorectal Cancer: Adjuvant Therapy for Colon Cancer: For adjuvant therapy following the complete resection of primary tumor in patients with stage III (Dukes' C) colon cancer when treatment with fluoropyrimidine therapy alone is preferred, the recommended dosage of capecitabine is 1250 mg/m2 twice daily (morning and evening) for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles for a total of 8 cycles and a treatment period of 6 months.
First-line Therapy for Metastatic Colorectal Cancer: For the first-line treatment of metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred, the recommended initial dosage of capecitabine is 1250 mg/m2 twice daily (morning and evening), equivalent to 2500 mg/m2 total daily dose, for 2 weeks followed by a 1-week rest period; courses of therapy are given in 3-week cycles.
Dosage Calculation: Round to the nearest dose that gives a whole tablet rather than cutting tablets in half. (See Table 1.)

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Dosage modification for Age-related Effects: Some clinicians recommend that capecitabine dosage be reduced (eg; initial dosage reduced by up to 20%) in patients older than 80 years of age receiving capecitabine monotherapy. Because of decreased tolerance of the combination regimen of capecitabine and docetaxel for advanced breast cancer in patients 60 years of age or older, a 25% reduction of the initial capecitabine dose (to 950 mg/m2) should be considered.
Dosage Modification for Toxicity: After the initial dose of capecitabine, subsequent doses should be modified as necessary based on individual patient tolerance with careful monitoring to obtain optimal therapeutic response with minimal toxicity. The dose-limiting toxicities of capecitabine include diarrhea, nausea, vomiting, abdominal pain, palmar-plantar erythrodysesthesia (hand-foot syndrome), and leukopenia.
If a patient experience a grade 4 toxicity, the drug should be discontinued or therapy interrupted until the toxicity resolves or decreases in intensity to grade 1; if capecitabine therapy is resumed, the dose should be decreased to 50% of the original dose. If a patient experiences a grade 2 or 3 toxicity, capecitabine therapy should be interrupted until the toxicity resolves or decreases in severity to grade 1.
At the start of the next treatment cycle, subsequent doses should be reduced according to the severity and recurrence of the toxicity as shown in the following table on Recommended Dosage Modifications for Toxicity of Capecitabine Monotherapy. The manufacturer states that once the capecitabine dosage has been reduced, the dosage should not be increased at a later time.
When capecitabine therapy is interrupted because of toxicity, therapy should be resumed according to planned treatment cycles; doses of the drug omitted because of toxicity should not be replaced. (See Table 2 and 3.)

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All dose modifications should be based on the worst preceding toxicity.
Dosage in Renal and Hepatic Impairment: Capecitabine is contraindication in patients severe renal impairment (i.e; creatinine clearance less than 30 mL/minute calculated with the formula of Cockroft-Gault). In patients with moderate renal impairment (i.e creatinine clearance 30-50 mL/minute calculated with the formula of Cockroft-Gault), a dosage reduction to 75% of the initial capecitabine dose when used as monotherapy or in combination with docetaxel (i.e; from 1250 to 950 mg/m2 twice daily) is recommended. No adjustment in starting dose is recommended in patients with mild renal impairment. Careful monitoring is required in patients with mild or moderate renal impairment receiving capecitabine because the frequency and/or severity of adverse effects of capecitabine may be increased. If the patient develops a grade 2, 3, or 4 adverse effect, treatment with capecitabine should be discontinued prompty, and subsequent dose modification for toxicity should be made.
The effects of hepatic impairment on the pharmacokinetics of capecitabine have not been fully evaluated. The manufacturer states that no adjustment in initial dosage of capecitabine is necessary in patients with mild to moderate hepatic dysfunction secondary to liver metastases. However, caution is advised and patients with mild to moderate hepatic dysfunction should be monitored carefully during capecitabine therapy. The safety and efficacy of capecitabine in patients with severe hepatic impairment have not been evaluated.
Paediatric population: There is no experience in children (under 18 years).
Overdosage
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.
Contraindications
History of severe and unexpected reactions to fluoropyrimidine therapy.
Hypersensitivity to the active substance or to any of the excipients listed in Excipients/Inactive Ingredients under Description 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).
If contraindications exist to any of the agents in the combination regimen, that agent should not be used.
Special Precautions
Diarrhoea: Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhoea 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 (see Dosage & Administration).
Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea 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 applied should be applied for the precipitating adverse event as necessary.
Hand-foot syndrome: Hand-and-foot syndrome (palmar-plantar erythrodysesthesianor chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range, 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort that does not disrupt normal activities. Grade 2 hand- foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand- foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand- foot syndrome occurs, interrupt administration of Capecitabine until the event resolves or decreases in intensity to grade 1. Following grade 3 handfoot syndrome, decrease subsequent doses of Capecitabine.
Cardiotoxicity: The cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes and cardiomyopathy. These adverse reaction may be more common in patients with a history of coronary artery disease.
Hematologic: In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapyfor 2 weeks followed by a 1-week rest period, 3.2%, 1.7% and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia, or decreases in haemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.
Renal function impairment: Patients with moderate renal impairment at baseline require dose reduction. Carefully monitor patients with mild and moderate renal impairment at baseline for adverse reactions. Prompt in interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse reaction. Once the adverse reaction has resolved or decreased in intensity to grade 1, then capecitabine therapy may be restarted at full dose or reduced by 25% for each subsequent appearance of grade 2 toxicity. With the fourth appearance of grade 2 toxicity, discontinue treatment permanently. Interrupt therapy with capecitabine upon the occurrence of a grade 3 adverse experience. Once the adverse reaction has resolved or decreased in intensity to grade 1, then capecitabine therapy may be restarted at 75% of starting dose or reduced by 25% for the second appearance of a grade 3 adverse experience. Discontinue treatment permanently at the third appearance. If a grade 4 experience occurs, discontinue therapy permanently or interrupt until resolved or decreased to grade 1, and then restart at 50% of the original dose if it is in the patient's best interest to continue. Doses of capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
Hepatic function impairment: Carefully monitor patients with mild to moderate hepatic dysfunction due to liver metastases when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known.
Use in Elderly: Patients 80 years of age or older may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast of colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients greater than or equal to 80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse reaction: Diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand and foot syndrome in 3 (14.3%) and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and older (no patients were older than 80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand and foot syndrome.
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 Pregnancy & Lactation
Women of childbearing potential: Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine. If the patient becomes pregnant while receiving capecitabine, the potential hazard to the foetus must be explained.
Use in Pregnancy: There are no studies in pregnant women using capecitabine; however, it should be assumed that capecitabine may cause foetal 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.
Use in Lactation:
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.
Adverse Reactions
Capecitabine is considered to have moderate potential for nausea and vomiting.
Adjuvant colon cancer: The following table shows the adverse reactions occurring in at least 5% of patients from one phase 3 trial in patients with patients with Duke stage C colon cancer who received at least 1 dose of study medication and had at least 1 safety assessment.
A total of 995 patients were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period and 974 patients were administered 5-fluorouracil and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-fluorouracil, on days 1 to 5 every 28 days). The median duration of treatment was 164 days for capecitabine treated patients and 145 days for 5-fluorouracil/leucovorin-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-fluorouracil/leucovorin-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1%) randomized to 5-fluorouracil/leucovorin. (See Tables 4 and 5.)

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Metastatic colorectal cancer:
The following table shows the adverse reactions occurring in greater than or equal to 5% of patients from pooling the 2 phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period and 593 patients were administered 5-fluorouracil and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-fluorouracil, on days 1 to 5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-fluorouracil/leucovorin treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-fluorouracil/leucovorin-treated patients, respectively, discontinued treatment because of adverse reaction/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-fluorouracil/leucovorin. (See Table 6.)

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Breast cancer combination: The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administrated as a 1-hour IV infusion at a dose of 75 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm, docetaxel was administered as a 1-hour IV infusion at a dose of 100 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions were 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients. (See Table 7.)

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Breast cancer capecitabine monotherapy: The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 62 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness. (See Table 8.)

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Capecitabine and docetaxel in combination:
Shown by body system are the clinically relevant adverse reactions in less than 5% of patients in the overall clinical trial safety database of 251 patients (study details) reported as related to the administration of capecitabine in combination with docetaxel and that were clinically at least remoted relevant. In parentheses is the incidence of grade 3 and 4 occurrence of each adverse reaction. It is anticipated that the same types of adverse reactions observed in the capecitabine monotherapy studies may be observed in patients treated with the combination of capecitabine plus docetaxel.
Cardiovascular: Hypotension (1.2%), postural hypotension (0.8%) supraventricular tachycardia (0.39%), syncope (1.2%), venous phlebitis and thrombophlebitis (0.39%).
CNS: Ataxia (0.39%), polyneuropathy (0.39%), migraine (0.39%).
GI: Ileus (0.39%), necrotizing enterocolitis (0.39%), esophageal ulcer (0.39%), hemorrhagic diarrhea (0.8%), taste loss (0.8%).
Hematologic/Lymphatic: Agranulocytosis (0.39%), prothrombin decreased (0.39%).
Hepatic: Abnormal liver function tests, hepatic coma, hepatic failure, hepatotoxic, jaundice (0.39%).
Miscellaneous: Bronchopneumonia (0.39%), hypersensitivity (1.2%), neutropenic sepsis (2.39%), renal failure (0.39), sepsis (0.39%).
Capecitabine monotherapy metastatic breast and colorectal cancer: Shown by body system are the clinically relevant adverse reactions in less than 5% patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies 596 patients, phase 2 colorectal study 34 patients, phase 2 breast cancer studies 245 patients reported as related to the administration of capecitabine and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurences of each adverse reaction.
Cardiovascular: Atrial fibrillation, bradycardia, cerebrovascular accident, extrasystoles, hypertension, myocarditis, tachycardia, ventricular extrasystoles (0.1%), hypotension, pulmonary embolism (0.2%), pericardial effusion.
CNS: Ataxia, insomnia (0.5%), confusion, depression, difficult walking, dysphasia, encephalopathy, irritability, tremor (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance, sedation, vertigo.
Dermatologic: Nail disorder, photosensitivity reaction, sweating increased (0.1%), pruritus, radiation recall syndrome, skin ulceration (0.2%).
GI: Abdominal distension, ascites, dysphagia, gastric ulcer, gastroenteritis, proctalgia, toxic dilation of dilation of intestine (0.1%), ileus (0.3%).
Hematologic/Lymphatic: Leukopenia (0.2%), bone marrow depression, coagulation disorder, lymphedema, pancytopenia (0.1%), idiopathic thrombocytopenia purpura (1%).
Hepatic: Cholestatic hepatitis, hepatic fibrosis, hepatitis (0.1%), abnormal liver function tests.
Metabolic/Nutritional: Cachexia, increased weight (0.4%), hypertriglyceridemia (0.1%), edema, hypokalemia, hypomagnesemia.
Musculoskeletal: Arthritis, bone pain, myalgia (0.1%), muscle weakness.
Respiratory: Cough, epitaxis, hemoptysis, respiratory distress (0.1%), asthma, bronchitis, bronchopneumonia, pneumonia (0.2%), dyspnea.
Postmarketing: Hepatic failure, lacrimal duct stenosis.
Drug Interactions
Interaction studies have only been performed in adults.
Interaction with other medicinal products: Drug Affecting Hepatic Microsomal Enzymes: Capecitabine and/or its metabolites inhibit the metabolism of warfarin, probably through inhibition of the cytochrome P-450 (CYP) 2C9 isoenzyme. No formal drug-drug interaction studies between capecitabine and CYP2C9 substrates other than warfarin have been performed. Caution is advised when capecitabine is administered concomitantly with other CYP2C9 substrates (eg; phenytoin) and the need for dosage adjustment should be considered.
Results of in vitro studies indicate that capecitabine and its metabolites do not inhibit the metabolism of substrates of the major cytochrome P-450 isoenzymes.
Antacids: In a small number of patients, administration of an antacid containing aluminium hydroxide and magnesium hydroxide immediately following capecitabine (1250 mg/m2) resulted in an increased rate and extent of absorption of capecitabine; AUC and peak plasma concentration increased by 16 and 35%, respectively, for capecitabine and by 18 and 22% respectively, for 5'-deoxy-5-fluorocytidine (5'-DFCR). Antacid administration had no effect on the other 3 major metabolites of capecitabine, fluorouracil.
Anticoagulants: Altered coagulation parameters and/or bleeding, sometimes fatal, have been reported in patients receiving capecitabine and concomitant therapy with coumarin anticoagulants (e.g. warfarin, phenprocoumon). In patients receiving coumarin anticoagulants, altered coagulation parameters (e.g. increased prothrombin time, increased international normalized ratio) and/or bleeding episodes have occurred within several days to months following initiation of capecitabine therapy; similar events have been reported in at least a few patients within 1 month following discontinuance of capecitabine therapy. Alterations in anticoagulant effect associated with capecitabine therapy have been reported in patients with or without liver metastases. Age exceeding 60 years and diagnosis of cancer are independent variables predisposing patients to an increased risk of coagulopathy.
Phenytoin: Concomitant use of phenytoin and capecitabine may result in toxicity from increased serum phenytoin concentrations. The mechanism of interaction is presumed to be inhibition of the metabolism of phenytoin by capecitabine and/or its metabolites through inhibition of the cytochrome P-450 (CYP) 2C9 isoenzyme. In patients receiving capecitabine, serum concentrations of phenytoin must be monitored carefully, and reduction in the phenytoin dosage may be necessary.
Leucovorin: Leucovorin potentiates the antineoplastic activity of fluorouracil (the active drug of capecitabine) and also may increase its toxicity. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving a weekly regimen of combination therapy with leucovorin and fluorouracil.
Leucovorin potentiated the antitumor activity of capecitabine in some xenograft tumors in mice but did not increase the toxicity of the drug; however, evidence from an open-label, randomized trial in patients with advanced colorectal cancer demonstrated comparable efficacy but greater toxicity for combination therapy with capecitabine and leucovorin compared with capecitabine alone.
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 and its toxicity may be enhanced by folinic acid: 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).
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.
Caution For Usage
Handling and Disposal: Do not use this medicine after the expiry date (EXP) indicated on the box.
Discard the unused portion/expired medicine.
Decrease the drop-out to an external environment. Do not dispose of drugs through sewer and household waste.
When there is need to use the system, send it to collection agencies that are responsible for the defeat.
Incompatibilities: Not applicable.
Special Precautions for Disposal: No special requirements.
Storage
Do not store above 30°C.
Shelf-Life:2 years.
ATC Classification
L01BC06 - capecitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Presentation/Packing
FC tab 500 mg (peach parallel, capsule-shaped, film-cooated tablets embossed with "500" on one side of approximate dimensions 17.1 mm x 8.1 mm) x 120's.
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