Each film-coated tablet contains: Capecitabine USP 500 mg; Excipients q.s.
Colour: Approved Colours.
Capecitabine is white to off-white crystalline powder. Capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.3. It is Freely soluble in Methanol, Sparingly soluble in Water and soluble in Alcohol and Acetonitrile.
Pharmacotherapeutic Group: Antineoplastic.
Pharmacology: Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'- deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a deficiency of this compound can inhibit cell division. Secondly, 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 through the production of fraudulent RNA.
Pharmacokinetics: Absorption: Following oral administration of 1255 mg/m² BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cmax and AUC 0-∞ decreased by 60% and 35%, respectively. The Cmax and AUC 0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours.
The pharmacokinetics of CAPVEX 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 CAPVEX and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cmax and AUC of 5-FU 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%). CAPVEX has a low potential for pharmacokinetic interactions related to plasma protein binding.
Bioactivation and Metabolism: Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of CAPVEX 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.
The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
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 FBAL 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-FU was about 0.75 hour.
For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relapsed during or following anthracycline-containing chemotherapy. Capecitabine is used alone as an adjuvant therapy following the complete resection of primary tumor in patients with stage III colon cancer when monotherapy with fluoropyrimidine is preferred.
Take Capecitabine with water within 30 min after a meal.
Monotherapy: 1250 mg/m2 twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles. Adjuvant treatment is recommended for a total of 6 months (8 cycles).
In combination with docetaxel, the recommended 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 IV infusion every 3 weeks.
Capecitabine dosage may need to be individualized to optimize patient management. Reduce the dose of Capecitabine by 25% in patients with moderate renal impairment.
The anticipated manifestations of acute overdose are nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. It should be managed with supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience has been reported, dialysis may be of benefit in reducing circulating concentrations of 5-DFUR, a low-molecular weight metabolite of the parent compound.
Capecitabine is contraindicated in patients who have known hypersensitivity to 5-fluorouracil.
Coagulopathy: Altered coagulation parameters and/or bleeding
have been reported in patients taking Capecitabine concomitantly with
coumarin-derivative anticoagulants such as warfarin and phenprocoumon.
Diarrhea: Capecitabine can induce diarrhea, sometimes
severe. Necrotizing enterocolitis has been reported with Capecitabine usage.
in Pregnancy: Capecitabine may
cause fetal harm when given to a pregnant woman. If the drug is used during
pregnancy, or if the patient becomes pregnant while receiving this drug, the
patient should be apprised of the potential hazard to the fetus. Women of
childbearing potential should be advised to avoid to avoid becoming pregnant
while receiving treatment with Capecitabine.
Use in Lactation: It is not known whether the
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, it is recommended that nursing be discontinued when
receiving Capecitabine therapy.
A physician experienced in the use of cancer chemotherapeutic agents should monitor patients receiving therapy with Capecitabine. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
Hand-and-Foot Syndrome: Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema) may occur.
If grade 2 or 3 hand-and-foot syndrome occurs, administration of Capecitabine should be interrupted until the event resolve or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of Capecitabine should be decreased.
Capecitabine is not known.
Cardiac: There has been cardiotoxicity associated with fluorinated pyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiograph changes. These adverse events may be more common in patients with a prior history of coronary artery disease.
Drug-Food Interaction: Since current safety and efficacy data are based upon administration of Capecitabine with food, it is recommended that Capecitabine be administered with food.
Hematologic: Capecitabine can lead to neutropenia, thrombocytopenia and decreases in hemoglobin.
Hepatic Insufficiency: Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when Capecitabine is administered.
The effect of severe hepatic dysfunction on the disposition of Capecitabine should decrease.
Hyperbilirubinemia: If drug related grade 2-4 elevations in bilirubin occur, administration of Capecitabine should be immediately interrupted until the Hyperbilirubinemia resolves or decreases in intensity to grade 1.
Renal Insufficiency: There is little experience in patients with renal impairment. Physicians should exercise caution when Capecitabine is administered.
Carcinogenesis and Mutagenesis: Long-term studies in animals to evaluate the carcinogenic potential of Capecitabine have not been conducted. Capecitabine has not been shown to be mutagenic in vitro or in vivo.
Impairment of Fertility: Capecitabine causes a decrease in fertility by disturbing the estrus. In male mice, Capecitabine causes degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids.
Nursing mother: It is not known whether the 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, it is recommended that nursing be discontinued when receiving Capecitabine therapy.
Use in children: The safety and effectiveness of Capecitabine in persons < 18 years of age have not been established.
Use in the elderly: Patients >/=80 years old may experience a greater incidence of gastrointestinal grade 4 or 4 adverse events. Physicians should pay particular attention to monitoring the adverse effects of Capecitabine in the elderly.
Adverse events occurring in >/5% of patients taking Capecitabine are as follows.
Diarrhea, nausea, vomiting, stomatitis, abdominal pain, constipation and dyspepsia.
Skin and subcutaneous:
Hand-and-foot Syndrome, dermatitis and nail disorder.
Fatigue, pyrexia, pain in limb.
Paresthesia, headache, dizziness and insomnia.
Anorexia and dehydration.
Edema, blood, neutropenia, thrombocytopenia, anemia, lymphopenia.
Antacid: Aluminum hydroxide- and magnesium hydroxide-containing antacid cause a small increase in plasma concentration of Capecitabine and one metabolite (5'-DFCR).
Coumarin Anticoagulants: Patients taking coumarin-derivative anticoagulants concomitantly with Capecitabine should be monitored regularly for alterations in their coagulation parameters.
Phenytoin: The level of phenytoin should be carefully monitored in patients taking Capecitabine and phenytoin dose may need to be reduced.
Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by Leucovorin.
Store at temperatures not exceeding 30°C.
Shelf Life: 2 years from Date of Manufacturing.
L01BC06 - capecitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
FC tab 500 mg (light pink colored, elongated, biconvex) x 120's.