Naprocap

Each film-coated tablet of Naprocap-500 contains Capecitabine USP 500 mg.
Excipients q.s.
Colour: Red oxide of Iron and titanium dioxide.
Capecitabine tablet is a film coated, buff to peach colour, caplet shape tablet with break line on one side.
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.
The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentoxyloxy)carbonyl]-cytidine and has a molecular weight of 359.35.
Excipients/Inactive Ingredients: It contains lactose monohydrate, microcrystalline cellulose PH102, croscarmellose sodium, hydroxypropylmethyl cellulose, purified water, magnesium stearate, ready-mix coating material (opadry AMB 80W 540016 pink).

Pharmacology: Pharmacodynamics: Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. 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 2'-deoxyuridylate. 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: Following oral administration of 1255 mg/m² BID in cancer patients, Capecitabine reaches 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 also reduces by food by 43% and 21%, respectively. Food delays T_max of both parent and 5-FU by 1.5 hours. Pharmacokinetics of Capecitabine and its metabolite, 5'-DFCR were dose proportional in the dose range 500 to 3500 mg/m²/day and did not change over time.
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%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding.
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.
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 0.75 hour.

Gastric Cancer: First line treatment of advanced gastric cancer in combination with platinum based regimen.
Colorectal Cancer: Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent Capecitabine tablets in the adjuvant treatment of Dukes' C colon cancer.
Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with Capecitabine monotherapy. Use of Capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
Breast Cancer: Capecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
Capecitabine monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m² of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Capecitabine dose is calculated according to body surface area.
Standard Starting Dose: Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer): The recommended dose of Capecitabine is 1250 mg/m² administered orally twice daily (morning and evening; equivalent to 2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles.
Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months [i.e., Capecitabine 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)]. (See Table 1.)

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In Combination with Docetaxel (Metastatic Breast Cancer): In combination with docetaxel, the recommended 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 the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the Capecitabine plus docetaxel combination. Table 1 displays the total daily dose of Capecitabine by body surface area and the number of tablets to be taken at each dose.
Dose Management Guidelines: General: Capecitabine tablet dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of Capecitabine should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to Capecitabine tablet administration may be managed by symptomatic treatment, dose interruptions and adjustment of Capecitabine dose. Once the dose has been reduced, it should not be increased at a later time. Doses of Capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles. The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with Capecitabine Tablets.
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer): Capecitabine dose modification scheme as described in Table 2 as follows is recommended for the management of adverse reactions. (See Table 2.)

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In Combination With Docetaxel (Metastatic Breast Cancer): Dose modifications of Capecitabine for toxicity should be made according to Table 2. At the beginning of a treatment cycle, if a treatment delay is indicated for either Capecitabine or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met. The dose reduction schedule for docetaxel when used in combination with Capecitabine for the treatment of metastatic breast cancer is shown in Table 3. (See Table 3.)

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Adjustment of Starting Dose in Special Populations: Renal Impairment: No adjustment to the starting dose of Capecitabine is recommended in patients with mild renal impairment (creatinine clearance=51 to 80 mL/min [Cockroft and Gault, as shown as follows]). In patients with moderate renal impairment (baseline creatinine clearance=30 to 50 mL/min), a dose reduction to 75% of the Capecitabine starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m² to 950 mg/m² twice daily) is recommended. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both Capecitabine monotherapy and Capecitabine in combination use with Docetaxel. (See equation.)

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Geriatrics: Physicians should exercise caution in monitoring the effects of Capecitabine in the elderly. Insufficient data are available to provide a dosage recommendation.

The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for Capecitabine overdose 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 with known dihydropyrimidine dehydrogenase (DPD) deficiency.
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30mL/min).
Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components.
Capecitabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

Capecitabine Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarinderivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking Capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Post marketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time Capecitabine was introduced. These events occurred within several days and up to several months after initiating Capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy

General: Patients receiving therapy with Capecitabine should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
Diarrhea: Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. If grade 2, 3 or 4 diarrheas occurs, administration of Capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following are occurrence of grade 2 diarrheas or occurrence of any grade 3 or 4 diarrhea, subsequent doses of Capecitabine should be decreased. Standard antidiarrheal treatments (e.g. loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has been reported.
Coagulopathy: Patients receiving concomitant Capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly.
Cardiotoxicity: The cardiotoxicity observed with Capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
Dihydropyrimidine Dehydrogenase Deficiency: Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidinedehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.
Renal Insufficiency: Patients with moderate renal impairment at baseline require dose reduction. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event outlined in Table 2.
Hand-and-Foot Syndrome: Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 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 which does not disrupt normal activities.
Grade 2 hand-and-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-and-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-and-foot syndrome occurs, administration of Capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of Capecitabine should be decreased.
Hyperbilirubinemia: Patients with either metastatic breast or colorectal cancer who received at least one dose of Capecitabine 1250 mg/m² twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3×ULN) and grade 4 (>3×ULN) Hyperbilirubinemia have been reported some of patients. Patients who had hepatic metastases at baseline and those who were without hepatic metastases, grade 3 or 4 Hyperbilirubinemia have been reported in some patients.
Some patients also had postbaseline elevations (grades 1 to 4 without elevations at baseline) in alkaline phosphatase and had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, had liver metastases at baseline. In addition, some patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Few patients had grade 3 or 4 elevations in alkaline phosphatase or transaminases. If drug-related grade 3 to 4 elevations in bilirubin occur, administration of Capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 X ULN.
Hematologic: In patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m² administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, may have grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin. In patients with metastatic breast cancer who received a dose of Capecitabine in combination with docetaxel, may show grade 3 or 4 neutropenia, grade 3 or 4 thrombocytopenia, and grade 3 or 4 anemia.
Patients with baseline neutrophil counts of <1.5×10⁹/L and/or thrombocyte counts of <100×10⁹/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.
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 is not known.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation for further information.
Use in Children: The safety and effectiveness of Capecitabine tablets in persons <18 years of age have not been established.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pregnancy: Capecitabine can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Capecitabine, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with Capecitabine.

Gastrointestinal Disorders: Diarrhea, nausea, stomatitis, vomiting, abdominal pain, constipation, upper abdominal pain, dyspepsia; GI motility disorder, oral discomfort, Upper GI inflammatory disorder, GI haemorrhage, ileus; dry mouth.
Skin and Subcutaneous Tissue Disorders: Hand and foot syndrome, alopecia, rash, erythema, dermatitis, skin discoloration, nail disorder, rash erythematous, nail discoloration, onycholysis, pruritus.
General Disorders and Administration Site Conditions: Fatigue, pyrexia, asthenia, lethargy, fatigue, weakness, chest pain, pain in limb, influenza like illness.
Nervous System Disorders: Dizziness, headache, dysgeusia, peripheral sensory neuropathy, insomnia, paresthesia, hypoaesthesia.
Metabolism and Nutrition Disorders: Anorexia, appetite decreased, dehydration, weight decreased.
Eye Disorders: Conjunctivitis, eye irritation, abnormal vision, increased lacrimation.
Blood and lymphatic system disorders: Neutropenia, anemia, neutropenic fever, thrombocytopenia, lymphocytopenia, granulocytopenia.
Respiratory thoracic and mediastinal disorders: Epistaxis, dyspnea, cough, pharyngeal disorder, sore throat, rhinorrhea, pleural effusion.
Musculoskeletal: Back pain, Arthralgia, myalgia, bone pain.
Vascular: Venous thrombosis, flushing, lymphoedema.
Psychiatric: Mood alteration, depression.
Infection: Viral, oral candidiasis, urinary tract infection, upper respiratory tract infection.

Anticoagulants: Altered coagulation parameters and/or bleeding in patients taking Capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events may occur within several days and up to several months after initiating Capecitabine therapy and, in a few cases, within 1 month after stopping Capecitabine. These events may occur in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.
Phenytoin: The level of phenytoin should be carefully monitored in patients taking Capecitabine and phenytoin dose may need to be reduced. Post marketing reports indicate that some patients receiving Capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.
Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
CYP2C9: Care should be exercised when Capecitabine is coadministered with CYP2C9 substrates.
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).
Sorivudine 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 concomitantly with sorivudine or its chemically related analogues, such as brivudine. There must be at least a 4 week waiting period between end of treatment with sorivudine or its chemically related analogues such as brivudine and start of Capecitabine therapy.
Antacids: The effect of an aluminum hydroxide and magnesium hydroxide-containing antacidon the pharmacokinetics of capecitabine is reported. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3major metabolites (5'-DFUR, 5-FU and FBAL).
Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU. Concomitant use of allopurinol with Capecitabine should be avoided.
Interferon alpha: the MTD of Capacitabine was 2000 mg/m² per day when combined with interferon alpha-2a (3 MIU/m per day) compared to 3000 mg/m² per day when Capecitabine was used alone.
Radiotherapy: the MTD of Capecitabine alone using the intermittent regimen is 3000 mg/m² per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of Capecitabine is 2000 mg/m² per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy.
Oxaliplatin: no clinically significant differences in exposure to Capecitabine or its metabolites, free platinum or total platinum occurred when Capecitabine was administered in combination with Oxaliplatin or in combination with Oxaliplatin and bevacizumab.
Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of Capecitabine or its metabolites in the presence of Oxaliplatin.

Store at a temperature not exceeding 25°C. Protect from light and moisture.

Cytotoxic Chemotherapy

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

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