Capiibine

Each Film-coated Tablet contains Capecitabine USP 500 mg.
Excipients/Inactive Ingredients: Croscarmellose sodium 22.00 mg, Microcrystalline Cellulose 23.00 mg, Hydroxypropyl methyl cellulose 18.00 mg, Anhydrous Lactose 50.00 mg, Magnesium stearate 9.00 mg, Purified water Q.S & Opadry pink 12.44 mg.
Colours: Titanium dioxide, Red oxide of lron and Yellow oxide of lron.

Pharmacology: Pharmacodynamics: Capecitabine is relatively non-cytotoxic in vitro. This drug is enzymatically converted to 5-fluorouracil (5-FU) in vivo.
Mechanism of Action: Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). 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 uracil. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
Pharmacokinetics: Absorption: Capecitabine is readily absorbed from the gastrointestinal tract. Capecitabine reached peak blood levels in about 1.5 hours (T_max) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean C_max and AUC_0-∞ decreased by 60% and 35%, respectively. The C_max and AUC_0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T_max of both parent and 5-FU 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'-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 day 1.
The inter-patient variability in the C_max 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%).
Metabolism: Capecitabine is extensively metabolized enzymatically to 5-FU. 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.
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 three fourths of an hour.
Special populations: Renal function impairment: Following oral administration of 1,250 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'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal 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 AUC_0-∞ and C_max of Capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC_0-∞ and C_max of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Capecitabine is administered. The effect of severe hepatic dysfunction on Capecitabine is not known.

Breast cancer: Capecitabine in combination with docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Capecitabine is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.
Colon, colorectal cancer: Capecitabine is indicated for the adjuvant treatment of patients with colon cancer.
Capecitabine is indicated for the treatment of patients with metastatic colorectal cancer.
Oesophagogastric cancer: Capecitabine is indicated for first-line treatment of patients with advanced Oesophagogastric cancer.

Recommended Dose: Monotherapy: Colon, colorectal and breast cancer: The recommended monotherapy, starting dose of capecitabine is 1250 mg/m² administered twice daily (morning and evening; equivalent to 2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period.
Combination therapy: Breast cancer: In combination with docetaxel, the recommended starting dose of capecitabine is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m² as a 1 hour intravenous infusion every 3 weeks.
Pre-medication, according to docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine plus docetaxel combination.
Colon, colorectal and Oesophagogastric cancer: In combination treatment, the recommended starting dose of capecitabine should be reduced to 800 - 1000 mg/m² when administered twice daily for 2 weeks followed by a 1-week rest period or 625 mg/m² twice daily when administered continuously. The inclusion of bevacizumab in a combination regimen has no effect on the starting dose of capecitabine. Adjuvant treatment in patients with stage III colon cancer is recommended for duration of 6 months.
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin and oxaliplatin product information should be started prior to cisplatin administration for patients receiving the capecitabine plus cisplatin or oxaliplatin combination.
Capecitabine dose is calculated according to body surface area. The following tables show examples of the standard and reduced dose calculations for a starting dose of capecitabine 1250 mg/m² or 1000 mg/m². (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Dose adjustments during treatment: General: Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or modification of the capecitabine dose (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time.
For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening treatment can be continued at the same dose without reduction or interruption.
Dosage modifications are not recommended for grade 1 events. Therapy with capecitabine should be interrupted if a grade 2 or 3 adverse experience occurs. Once the adverse event has resolved or decreased in intensity to grade 1, capecitabine therapy may be restarted at full dose or as adjusted according to Table 3. If a grade 4 experience occurs, therapy should be discontinued or interrupted until the experience has resolved or decreased to grade 1, and therapy can then be restarted at 50% of the original dose. Patients taking capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of capecitabine omitted for toxicity are not replaced.
Hematology: 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 grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted.
The following table shows the recommended dose modifications following toxicity related to capecitabine: see Table 3.

Click on icon to see table/diagram/image

General combination therapy: Dose modifications for toxicity when capecitabine is used in combination with other therapies should be made according to Table 3 for capecitabine and according to the appropriate prescribing information for the other agent(s).
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the other agent(s), then administration of all agents should be delayed until the requirements for restarting all drugs are met.
During a treatment cycle for those toxicities considered by the treating physician not to be related to capecitabine, capecitabine should be continued and the dose of the other medicinal product should be adjusted according to the appropriate Prescribing Information.
If the other agent(s) have to be discontinued permanently, capecitabine treatment can be resumed when the requirements for restarting capecitabine are met.
This advice is applicable to all indications and to all special populations.
Special dosage instructions: Patients with Hepatic impairment due to liver metastases: In patients with mild to moderate hepatic impairment due to liver metastases, no starting dose adjustment is necessary. However, such patients should be carefully monitored. Patients with severe hepatic impairment have not been studied.
Patient with renal impairment: In patients with moderate renal impairment (creatinine clearance below 30 - 50ml/min [Cockcroft and Gault]) at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m² is recommended. In patients with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the 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 Table 3. If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, capecitabine should be discontinued. These dose adjustment recommendations for patients with moderate renal impairment apply both to monotherapy and combination use.
Children: The safety and efficacy of capecitabine in children have not been established.
Elderly: For capecitabine monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-related adverse reactions were more frequent in patients over 80 years of age compared to younger patients.
When capecitabine was used in combination with other agents, elderly patients (≥65 years) experienced more grade 3 and grade 4 adverse drug reactions (ADRS) and ADRs that led to discontinuation than younger patients. Careful monitoring of elderly patients is advisable.
In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse events and treatment-related serious adverse events were observed in patients 60 years of age or more. For patients 60 years of age or more treated with combination of capecitabine with docetaxel, a starting dose in the dose of reduction of capecitabine to 75% (950 mg/m² twice daily) is recommended. For dose calculations see Table 1.
Mode of Administration: Capecitabine tablets should be swallowed with water within 30 minutes after a meal.

Clinical effects of overdose: The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate) - not necessary inclusive.
Acute and chronic: Bone marrow depression: (Black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusable bleeding or bruising).
Diarrhea; Gastrointestinal tract toxicity: (Abdominal or stomach pain; severe; bloody or black tarry stools; constipation or diarrhea, severe; difficulty in swallowing or pain in back of throat or chest when swallowing; nausea or vomiting, severe; vomiting blood or material that looks like coffee grounds); Nausea vomiting.
Treatment of overdose: Supportive care: Appropriate care to address the clinical manifestations. Dialysis may be effective in removing circulating 5'-DFUR, the low molecular weight metabolite that is the immediate precursor of fluorouracil.

Hypersensitivity to capecitabine or fluorouracil or any component of formulation.
In patients with severe renal impairment (creatinine clearance below 30 ml/min).
In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
Treatment with folic acid may affect the metabolism of capecitabine.
In patients with severe hepatic impairment.
In patients with severe neutropenia.

Coagulopathy: Capecitabine may increase the anticoagulant effects of warfarin; the bleeding events including death, have occurred with concomitant use clinically significant increases in PT and INR have occurred within several days to months after capecitabine initiation (in patients previously stabilized on anticoagulants), and may continue up to 1 month after capecitabine discontinuation. May occur in patients with or without liver metastases. Monitor PT and INR frequently and adjust anticoagulation dosing accordingly. An increased risk of coagulopathy is correlated with cancer diagnosis and age older than 60 years.
GI toxicity: May cause diarrhea (may be severe); median time to first occurrence of grade 2 to 4 diarrhea was 34 days and median duration of grades 3 or 4 diarrhea was 5 days. Withhold treatment for grade 2 to 4 diarrhea subsequent doses should be reduced after grade 3 or 4 diarrhea on occurrence of grade 2 diarrhea. Antidiarrheal therapy (eg, loperamide) is recommended. Dehydration may occur rapidly in patients with diarrhea, nausea, vomiting, anorexia, and/or weakness; adequately hydrate prior to treatment initiation. Elderly patients may be at higher risk for dehydration interrupt treatment for grade 2 or higher dehydration; correct precipitating factors and ensure rehydration prior to resuming therapy; may require dose modification (based on precipitating factor). Necrotizing enterocolitis has been reported.
Cardiotoxicity: Cardiotoxicity has been observed with capecitabine including myocardial infarction, ischemia, angina, dysrhythmias, cardiogenic arrest, cardiac failure, sudden death, electrocardiogram changes, and cardiomyopathy. These adverse reactions may be more common in patients with a history of coronary artery disease.
Dihydropyrimidine dehydrogenase deficiency: Patients with certain homozygous or heterozygous mutations of the Dihydropyrimidine dehydrogenase (DPD) enzymes are at increased risk for acute early - onset (potentially severe, life threatening, or fatal) toxicity due to total or near total absence of DPD activity. Toxicity may include mucositis/stomatitis, diarrhea, neutropenia and neurotoxicity. Patients with partial DPD activity are also at risk for severe, life threatening or fatal toxicity. May require therapy interruption or permanent discontinuation, depending on the onset duration and severity of toxicity observed. No capecitabine dose has been shown to be safe in patients with complete DPD deficiency, data are insufficient to recommend a dose in patients with partial DPD deficiency.
Dermatologic toxicity: Stevens - Johnson syndrome and toxic epidermal necrolysis (TEN) have been reported (some fatal); permanently discontinue capecitabine if a severe dermatologic or mucocutaneous reaction occurs.
Hand-foot syndrome: May cause hand-and-foot syndrome (Palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema); characterized by numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering and severe pain. The median onset is 79 days (range: 11 to 360 days). If grade 2 or 3 hand-and-foot syndrome occurs, interrupt administration of capecitabine until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, decrease subsequent doses of therapy.
Hepatotoxicity: Grade 3 and 4 hyperbilirubinemia have been observed in patients with and without hepatic metastases at baseline (median onset; 64 days). Transaminase and alkaline phosphatase elevation have also been reported. If capecitabine-related grade 3 or 4 hyperbilirubinemia occurs, interrupt treatment until bilirubin 3 or less times the ULN. Bilirubin elevations may require dose reductions.
Bone marrow suppression: Bone marrow suppression may occur, hematologic toxicity is more common when used in combination therapy; use with caution; dosage adjustments may be required. The product labeling recommends that patients with baseline platelets <100,000/mm³ and/or neutrophils < 1,500/mm³ not receive capecitabine therapy and also to withhold therapy for grade 3 or 4 hematologic toxicity during treatment.
Fluorouracil/leucovorin (FU/LV): In patients with colorectal cancer, treatment with capecitabine immediately following 6 weeks of FU/LV therapy has been associated with an increased incidence of grade ≥3 toxicity, when compared to patients receiving the reverse sequence, capecitabine (two 3-week courses) followed by Fluorouracil/leucovorin.
Fluoropyrimidine overdose: Uridine triacetate (formerly called vistonuridine), has been studied in cases of fluoropyrimidine overdose. In a clinical study of 98 patients who received uridine triacetate for fluorouracil toxicity (due to overdose, accidental capecitabine ingestion, or possible DPD deficiency), 96 patients recovered fully. Of 17 patients receiving uridine triacetate beginning within 8 to 96 hours after fluorouracil overdose, all patients fully recovered. An additional case report describes accidental capecitabine ingestion by a 22-month-old child; uridine triacetate was initiated approximately 7 hours after exposure. The patient received uridine triacetate every 6 hours for a total of 20 doses through nasogastric tube administration; he was asymptomatic throughout his course and was discharged with normal laboratory values.
Hazardous agent: Use appropriate precautions for receiving, handling, administration, and disposal. (NIOSH 2016 [group 1]).
Renal function impairment: Dehydration may occur, resulting in acute renal failure (may be fatal); concomitant use with nephrotoxic agents and baseline renal dysfunction may increase the risk. Use with caution in patients with mild to moderate renal impairment; reduce dose with moderate impairment (exposure to capecitabine and metabolites is increased) and carefully monitor and reduce subsequent dose (with any grade 2 or higher adverse effect) with mild to moderate impairment. Use is contraindicated in severe impairment.
Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment due to liver metastases. The effect of severe hepatic impairment has not been studied.
Monitoring: Renal function should be estimated at baseline to determine initial dose. During therapy, complete blood cell count (CBC) with differential, hepatic function, and renal function should be monitored. Monitor INR closely if receiving concomitant warfarin. Pregnancy test prior to treatment initiation (in females of reproductive potential). Monitor for diarrhea, dehydration, hand-foot syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, stomatitis, and cardiotoxicity.
Use in the Elderly: Use with caution in patients ≥60 years of age; the incidence of treatment-related adverse events may be higher.

Pregnancy: Category D. Adverse effects were observed in animal reproduction studies. Fetal harm may occur if administered during pregnancy. Women of child bearing potential should use effective contraceptives to avoid pregnancy during treatment.
Lactation: It is not known if 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.

See Tables 4a and 4b.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Frequency not defined: Cardiovascular: Angina pectoris, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG changes, ischemic heart disease, myocardial infarction.
Gastrointestinal: necrotizing enterocolitis.
Less than 1%, postmarketing, and/or case reports: Cardiovascular: Cerebrovascular accident, hypertension, hypotension, myocarditis, phlebitis (venous), pulmonary embolism, syncope, tachycardia.
Central Nervous system: Confusion, leukoencephalopathy (toxic), loss of consciousness.
Dermatologic: Cutaneous lupus erythematosus, diaphoresis, ecchymoses, Stevens - Johnson syndrome; toxic epidermal necrolysis.
Endocrine & metabolic: Cachexia, hypertriglyceridemia.
Gastrointestinal: Esophagitis, gastric ulcer, gastroenteritis, gastrointestinal perforation.
Genitourinary: Nocturia.
Hematologic & Oncologic: Bone marrow depression, leukopenia, pancytopenia.
Hepatic: Ascitis, blood coagulation disorder, cholestatic hepatitis, hepatic failure, hepatic fibrosis, hepatitis, jaundice.
Hypersensitivity: Hypersensitivity.
Infection: Fungal infection, sepsis.
Miscellaneous: Fibrosis, radiation recall phenomenon.
Neuromuscular & skeletal: Arthritis, ostealgia.
Ophthalmic: Keratitis, lacrimal stenosis, photopobia.
Renal: Acute renal failure, renal insufficiency.
Respiratory: Asthma, bronchitis, bronchopneumonia, bronchospasm, pneumonia, respiratory distress.

Metabolism/Transport Effects: Inhibits CYP2C9 (strong): see Table 5.

Click on icon to see table/diagram/image

Drug/food interactions: Food reduced the rate and extent of absorption of capecitabine.
Management: Administer within 30 minutes after a meal.

Store below 30°C.
Shelf-Life: 24 months.

Cytotoxic Chemotherapy

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

D