NDC 67877-458 Capecitabine

Capecitabine

NDC Product Code 67877-458

NDC 67877-458-12

Package Description: 120 TABLET, FILM COATED in 1 BOTTLE

NDC 67877-458-30

Package Description: 30 TABLET, FILM COATED in 1 BOTTLE

NDC 67877-458-60

Package Description: 60 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Capecitabine with NDC 67877-458 is a a human prescription drug product labeled by Ascend Laboratories, Llc. The generic name of Capecitabine is capecitabine. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Ascend Laboratories, Llc

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Capecitabine Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CAPECITABINE 150 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)

Administration Route(s)

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  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Nucleic Acid Synthesis Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Metabolic Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Ascend Laboratories, Llc
Labeler Code: 67877
FDA Application Number: ANDA207652 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 11-25-2017 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Capecitabine

Capecitabine is pronounced as (ka pe site' a been)

Why is capecitabine medication prescribed?
Capecitabine is used in combination with other medications to treat breast cancer that has come back after treatment with other medications. It is also used alone to trea...
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Capecitabine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Capecitabine Tablets, Usp - Warfarin Interaction

Capecitabine Tablets, USP Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important Capecitabine Tablets, USP -Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see 8 Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking Capecitabine Tablets, USP concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time Capecitabine Tablets, USP was introduced. These events occurred within  several days and up to several months after initiating Capecitabine Tablets, USP therapy and, in a few cases, within 1 month after stopping Capecitabine Tablets, USP. 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.

1.1 Colorectal Cancer

  • Capecitabine Tablets, USP is 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 referred. Capecitabine Tablets, USP 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, USP in the adjuvant treatment of Dukes' C colon cancer.Capecitabine Tablets, USP is 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 Tablets, USP monotherapy. Use of Capecitabine Tablets, USP instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

1.2 Breast Cancer

  • Capecitabine Tablets, USP in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.Capecitabine Tablets, USP 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.

2.1 Important Administration Instructions

Capecitabine Tablets, USP should be swallowed whole with water within 30 minutes after a meal. Capecitabine Tablets, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures1. If Capecitabine Tablets, USP tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Capecitabine Tablets, USP dose is calculated according to body surface area.

2.2 Standard Starting Dose

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)The recommended dose of Capecitabine Tablets, USP 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 (see Table 1).Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months [ie, Capecitabine Tablets, USP 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 week)]Table 1 Capecitabine Tablets, USP Dose Calculation According to Body Surface Dose Level 1250 mg/m2 Twice a DayNumber of Tablets to be Takenat Each Dose (Morning and Evening)Surface Area (m2 )Total DailyDose* (mg)150 mg500 mg≤ 1.253000031.26-1.373300131.38-1.513600231.52-1.654000041.66-1.774300141.78-1.914600241.92-2.055000052.06-2.17530015≥ 2.18560025*Total Daily Dose divided by 2 to allow equal morning and evening dosesIn Combination With Docetaxel (Metastatic Breast Cancer)In combination with docetaxel, the recommended dose of Capecitabine Tablets, USP 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 Tablets, USP plus docetaxel combination. Table 1 displays the total daily dose of Capecitabine Tablets, USP by body surface area and the number of tablets to be taken at each dose.

2.3 Dose Management Guidelines

GeneralCapecitabine Tablets, USP dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of Capecitabine Tablets, USP should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. Toxicity due to Capecitabine Tablets, USP administration may be managed by symptomatic treatment, dose interruptions and adjustment of Capecitabine Tablets, USP dose. Once the dose has been reduced, it should not be increased at a later time. Doses of Capecitabine Tablets, USP 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, USP [see Drug Interactions (7.1)].Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)Capecitabine Tablets, USP dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.Table 2 Recommended Dose Modifications of Capecitabine Tablets, USP Toxicity NCICGrades *  During a Course of Therapy  Dose Adjustment for Next Treatment (% of starting dose) Grade 1Maintain dose level Maintain dose level Grade 2-1st appearanceInterrupt until resolved to grade 0-1100 %-2nd appearance75 %-3rd appearance50 %-4th appearanceDiscontinue treatmentpermanently--Grade 3-1st appearanceInterrupt until resolved to grade 0-175%-2nd appearance50%-3rd appearanceDiscontinue treatmentpermanently--Grade 4-1st appearanceDiscontinue permanentlyORIf physician deems it to be in the patient's best interest to continue,interrupt until resolved to grade 0-150%*National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)].In Combination With Docetaxel (Metastatic Breast Cancer)Dose modifications of Capecitabine Tablets, USP for toxicity should be made according to Table 2 above for Capecitabine Tablets, USP. At the beginning of a treatment cycle, if a treatment delay is indicated for either Capecitabine Tablets, USP 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 Tablets, USP for the treatment of metastatic breast cancer is shown in Table 3 Table 3 Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets, USP Toxicity NCICGrades * Grade 2Grade 3Grade 41st appearanceDelay treatment until resolved to grade 0-1; Resume treatment with original dose of 75mg/m2 docetaxelDelay treatment until resolved to grade 0-1; Resume treatment at 55mg/m2 of docetaxel Discontinue treatmentWith docetaxel2nd appearanceDelay treatment until resolved to grade 0-1; Resume treatment with original dose of 55mg/m2 docetaxel Discontinue treatmentWith docetaxel  --3rd appearanceDiscontinue treatmentWith docetaxel----*National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5)].

2.4 Adjustment Of Starting Dose In Special Populations

Renal ImpairmentNo adjustment to the starting dose of Capecitabine Tablets, USP is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the Capecitabine Tablets, USP starting dose when used as monotherapy or in combination with docetaxel (from 1250mg/m2 to 950 mg/m2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 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 [see Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both Capecitabine Tablets, USP monotherapy and Capecitabine Tablets, USP in combination use with docetaxel.Cockroft and Gault Equation:Creatinine clearance for         (140 - age [yrs]) (body wt [kg])males =                                    _______________________                                                    (72) (serum creatinine [mg/dL]) Creatinine clearance for females=0.85X male value Geriatrics  Physicians should exercise caution in monitoring the effects of Capecitabine Tablets, USP in the elderly. Insufficient data are available to provide a dosage recommendation.

3 Dosage Forms & Strengths

Capecitabine Tablets, USP is supplied as oval shaped film coated tablets for oral administration. Each light peach-colored tablet contains 150 mg of capecitabine and each light peach colored tablet contains 500 mg of capecitabine.

4.1 Severe Renal Impairment

Capecitabine Tablets, USP is contraindicated in patients with severe renal impairment (creatinine clearance below 30mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

4.2 Hypersensitivity

Capecitabine Tablets, USP is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine Tablets, USP is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

5.1 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 [see Boxed Warning and Drug Interactions (7.1)]

5.2 Diarrhea

Capecitabine Tablets, USP can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received Capecitabine Tablets, USP monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of  ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of Capecitabine Tablets, USP should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1 [see Dosage and Administration (2.3)]. Standard antidiarrheal treatments (e.g., loperamide) are recommended.Necrotizing enterocolitis (typhlitis) has been reported.

5.3 Cardiotoxicity

The cardiotoxicity observed with Capecitabine Tablets, USP 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.

5.4 Dihydropyrimidine Dehydrogenase Deficiency

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Capecitabine Tablets, USP (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by Capecitabine Tablets, USP.Withhold or permanently discontinue Capecitabine Tablets, USP based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Capecitabine Tablets, USP dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.5 Dehydration And Renal Failure

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant Capecitabine Tablets, USP with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when Capecitabine Tablets, USP is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, Capecitabine Tablets, USP 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 should be applied for the precipitating adverse event as necessary [see Dosage and Administration (2.3)].Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4)]. 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 as outlined in Table 2 [see Dosage and Administration (2.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

5.6 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, Capecitabine Tablets, USP may cause fetal harm when given to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data are not sufficient to inform use of Capecitabine Tablets, USP in pregnant women. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Use in Specific Populations (8.1)]. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Capecitabine Tablets, USP [see Use in Specific Populations (8.3)].

5.7 Mucocutaneous And Dermatologic Toxicity

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with Capecitabine Tablets, USP [see Adverse Reactions (6.4)]. Capecitabine Tablets, USP should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to Capecitabine Tablets, USP treatment.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 Tablets, USP 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. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of Capecitabine Tablets, USP 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 Tablets, USP should be decreased [see Dosage and Administration (2.3)].

5.8 Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of Capecitabine Tablets, USP 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 × ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 ×ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases,respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.In the 596 patients treated with Capecitabine Tablets, USP as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of Capecitabine Tablets, USP monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with Capecitabine Tablets, USP. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of  which 46 had liver metastases at baseline.In 251 patients with metastatic breast cancer who received a combination of Capecitabine Tablets, USP and docetaxel,grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 2% (n=5).If drug-related grade 3 to 4 elevations in bilirubin occur, administration of Capecitabine Tablets, USP should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 X ULN [see recommended dose modifications under Dosage and Administration (2.3)].

5.9 Hematologic

In 875 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, 3.2%, 1.7%,and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin,respectively. In 251 patients with metastatic breast cancer who received a dose of Capecitabine Tablets, USP 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.Patients with baseline neutrophil counts of <1.5 × 109 /L and/or thrombocyte counts of <100 × 109 /L should not be treated with Capecitabine Tablets, USP. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with Capecitabine Tablets, USP should be interrupted.

5.10 Geriatric Patients

Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received Capecitabine Tablets, USP monotherapy, 62% of the 21 patients ≥80 years of age treated with Capecitabine Tablets, USP experienced a treatment-related grade 3 or 4 adverse event: 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 greater (no patients were >80 years of age) treated with Capecitabine Tablets, USP in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.Among the 67 patients ≥60 years of age receiving Capecitabine Tablets, USP in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.In 995 patients receiving Capecitabine Tablets, USP as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with Capecitabine Tablets, USP experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor,the hazard ratios for disease-free survival and overall survival for Capecitabine Tablets, USP compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively.

5.11 Hepatic Insufficiency

Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when Capecitabine Tablets, USP is administered. The effect of severe hepatic dysfunction on the disposition of Capecitabine Tablets, USP is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.12 Combination With Other Drugs

Use of Capecitabine Tablets, USP in combination with irinotecan has not been adequately studied.

6 Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice

6.1 Adjuvant Colon Cancer

Table 4 shows the adverse reactions occurring in ≥5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of Capecitabine Tablets, USP administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-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 days of receiving study drug: 8 (0.8%) patients randomized to Capecitabine Tablets, USP and 10 (1.0%) randomized to 5-FU/LV.Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.Table 4 Percent Incidence of Advers e Reactions Reported in ≥5% of Patients Treated With Capecitabine Tablets, USP or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1969) Capecitabine Tablets, USP (N=995)5-FU/LV(N=974)Body system /Adverse EventAll GradesGrade 3/4All GradesGrade 3/4Gastrointestinal DisordersDiarrheaNauseaStomatitisVomitingAbdominal painConstipationUpper Abdominal painDyspepsia4734221514976122223-<1<1654760211611751421422< 1< 1-Skin and Subcutaneous Tissue DisorderHand-and-Foot syndromeAlopeciaRashErythema60 67617 --19 2285<1 <1-<1General Disorders and Administration site conditionFatiguePyrexiaAstheniaLethargy1671010< 1< 1< 1< 11691091< 11< 1Nervous System DisorderDizzinessHeadacheDysgeusia656< 1< 1-669-< 1-Metabolism and Nutrition DisordersAnorexia9< 111< 1Eye DisordersConjunctivitis5< 16< 1Blood and Lymphatic System DisorderNeutropenia2< 185Respiratory Thoracic and Mediastinal DisordersEpistaxis2-5-Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Tablets, USP Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)Adverse EventCapecitabine Tablets, USP(n=995)Grade ¾ %Capecitabine Tablets, USP(n=974)Grade ¾ %Increased ALAT (SGPT)1.60.6Increased calcium1.10.7Decreased calcium2.32.2Decreased hemoglobin1.01.2Decreased lymphocytes13.013.0Decreased neutrophils2.226.2Decreasedneutrophils/granulocytes2.426.4Decreased platelets1.00.7Increased bilirubin †206.3*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the    Capecitabine Tablets, USP arm and 4 .9% in the IV 5-FU/LV arm.† It should be noted that grading was according to NCIC CTC Version 1 (May, 1994 ). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN.

6.2 Metastatic Colorectal Cancer

MonotherapyTable 6 shows the adverse reactions occurring in ≥5% of patients from pooling the two 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 Tablets, USP administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, 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-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/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 Tablets, USP and 32 (5.4%) randomized to 5-FU/LV.Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of PatientsAdverse EventCapecitabine Tablets, USP (n=596) 5-FU/LV (n=593)  Total%Grade 3%Grade 4%Total %Grade 3%Grade 4%Number of Patients With > One Adverse Event 9652994459Body System/Adverse Event GIDiarrheaNauseaVomitingStomatitisAbdominal painGastrointestinal Motility disorderConstipationOral DiscomfortUpper GI Inflammatory DisordersGastrointestinal HemorrhageIleus 5543272535101410866 134429<11-<114 2-<1<1<1-<1--<11 6151306231717101035 1034145<11-112 2<1<11------1Skin and SubcutaneousHand-and-Foot SyndromeDermatitisSkin DiscolorationAlopecia 542776 171<1- NA--- 626521 11-<1 NA---GeneralFatigue/WeaknessPyrexiaEdemaPainChest Pain 421815126 41111 ----- 46219106 42111 ----<1NeurologicalPeripheral Sensory NeuropathyHeadacheDizziness*InsomniaTaste Disturbance 1010876 -1<1-1 ----- 478711 --<1-<1 ----1MetabolismAppetite DecreasedDehydration 267 32 <1<1 318 23 <11EyeEye IrritationVision Abnormal 135 -- -- 102 <1- --RespiratoryDyspneaCoughPharyngeal DisorderEpistaxisSore Throat 147532 1<1-<1- -1--- 108566 <1---- 1----MusculoskeletalBack painArthralgia 108 21 -- 96 <11 --VascularVenous Thrombosis 8 3 <1 6 2 -PsychiatricMood AlterationDepression 55 -- -- 64 <1<1 --InfectionsViral5<1-5<1-Blood and LymphaticAnemiaNeutropenia801321<12794618<113HepatobiliaryHyperbilirubinemia481851733– Not observedNA = Not Applicable*Excluding vertigo

6.3 Breast Cancer

In Combination with DocetaxelThe following data are shown for the combination study with Capecitabine Tablets, USP and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the Capecitabine Tablets, USP and docetaxel combination arm the treatment was Capecitabine Tablets, USP 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 administered as a 1-hour intravenous 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 intravenous 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 was 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.Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to treatment in ≥5% of Patients Participating in the Capecitabine Tablets, USP and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse EventCapecitabine Tablets, USP 1250 mg/m2 /bidWith Docetaxel75 mg/m2 /3 weeks(n=251)       Docetaxel100 mg/m2 /3 weeks(n=255) Total %Grade 3%Grade 4%Total %Grade 3%Grade 4%Number of Patients With  atleast One Adverse Event9976.529.19757.631.8Body System/Adverse EventGIDiarrheaStomatitisNauseaVomitingConstipationAbdominal painDyspepsiaDry mouth6767453520301461417742<3-<1<1<1-1-<1--484336241824855522-21-<1-------Skin and SubcutaneousHand-and-Foot SyndromeAlopeciaNail disorderDermatitisRash ErythematousNail DiscolorationOncholysisPruritus 63411489654 2462-<1-1- NA------- 84215115455 17-1-<11- NA-------GeneralPyrexiaAstheniaFatigueWeaknessPain in LimbLethargyPainChest Pain (non-cardiac)Influenza-like illness282622161377452442-<1-1--<1------- 3425271113656526622212----------NeurologicalTaste DisturbanceHeadacheParesthesiaDizzinessInsomniaPeripheral NeuropathyHypoaesthesia16151212864<13<1---<1-------141516810108<121<1<11<1-------MetabolismAnorexiaAppetite DecreasedWeight DecreasedDehydration13107101--2----11557<1--<1---<1EyeLacrimation IcreasedConjuctivitisEye Irritation1255------741<1-----MusculoskeletalArthralgiaMyalgiaBack painBone pain151512822<1<1----242511103232----CardiacEdema33<2-34<31BloodNeutropenic Fever1631321516RespiratoryDyspneaCoughSore ThroatEpistaxisRhinorrheaPleural Effusion141312752212<1-1<1-----1622116372<1<1--4------InfectionsOral CandidiasisUrinary Tract InfectionUpper Respiratory Tract765<1<1----845<1-1---VascularFlushingLymphoedema53-<1--55-1--PsychiatricDepression5--51-– Not observedNA = Not ApplicableTable 8 Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine Tablets, USP and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse Event     Capecitabine Tablets, USP 1250 mg/m2 /bid With Docetaxel 75 mg/ m2 /3 weeks(n=251)Docetaxel 100 mg/ m2 /3 weeks (n=255)Body System /Adverse EventTotal %Grade 3%Grade 4%Total %Grade 3%Grade 4%HematologicLeukopeniaNeutropenia/GranulocytopeniaThrombocytopeniaAnemiaLymphocytopenia 9186418099 37202748 24491341 8887238398 42101544 33662<140HepatobiliaryHyperbilirubinemia 20 7 2 6 2 2MonotherapyThe 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 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer.Adverse EventPhase 2 Trial in stage IV Breast Cancer(n=162)Body System/Adverse EventTotal %Grade 3%Grade 4%GIDiarrheaNauseaVomitingStomatitisAbdominal painConstipationDyspepsia 5753372420158 1244741- 3------Skin and SubcutaneousHand-and-Foot SyndromeDermatitisNail Disorder 57377 111- NA--GeneralFatiguePyrexiaPain in Limb 41126 811 ---NeurologicalParesthesiaHeadacheDizzinessInsomnia 21988 11-- ----MetabolismAnorexiaDehydration 237 34 -1EyeEye Irritation 15 - -MusculoskeletalMyalgia 9 - -CardiacEdema 9 1 -BloodNeutropeniaThrombocytopeniaAnemiaLymphopenia 26247294 23344 21115HepatobiliaryHyperbilirubinemia 22 9 2 – Not observedNA = Not Applicable

6.4 Clinically Relevant Adverse Events In <5% Of Patients

Clinically relevant adverse events reported in <5% of patients treated with Capecitabine Tablets, USP either as monotherapy or in combination with docetaxol that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)Gastrointestinal:abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%),ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)Skin & Subcutan.:nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%),skin ulceration, pruritus, radiation recall syndrome (0.2%)General:chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness,irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%),hemorrhage, edema, sedationNeurological:insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balanceMetabolism:increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemiaEye:conjunctivitisRespiratory:cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspneaCardiac:tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles,extrasystoles, myocarditis (0.1%), pericardial effusionInfections:laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%),keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)Musculoskeletal:myalgia, bone pain (0.1%), arthritis (0.1%), muscle weaknessBlood & Lymphatic:leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%),idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)Vascular:hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)Psychiatric:depression, confusion (0.1%)Renal:renal impairment (0.6%)Ear:vertigoHepatobiliary:hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function testsImmune System:drug hypersensitivity (0.1%)Postmarketing:hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)], persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7)]Capecitabine Tablets, USP In Combination With Docetaxel (Metastatic Breast Cancer)Gastrointestinal:ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%),hemorrhagic diarrhea (0.8%)Neurological:ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)Cardiac:supraventricular tachycardia (0.4%)Infection:neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%)Blood & Lymphatic:agranulocytosis (0.4%), prothrombin decreased (0.4%)Vascular:hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)Renal:renal failure (0.4%)Hepatobiliary:jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%),hepatic coma (0.4%), hepatotoxicity (0.4%)Immune System:hypersensitivity (1.2%)

7.1 Drug-Drug Interactions

AnticoagulantsAltered coagulation parameters and/or bleeding have been reported in patients taking Capecitabine Tablets, USP concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning]. These events occurred within several days and up to several months after initiating Capecitabine Tablets, USP therapy and, in a few cases, within 1 month after stopping Capecitabine Tablets, USP. These events occurred 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 [see Clinical Pharmacology (12.3)]. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.PhenytoinThe level of phenytoin should be carefully monitored in patients taking Capecitabine Tablets, USP and phenytoin dose may need to be reduced [see Dosage and Administration (2.3)]. Postmarketing reports indicate that some patients receiving Capecitabine Tablets, USP 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.LeucovorinThe 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 substratesOther than warfarin, no formal drug-drug interaction studies between Capecitabine Tablets, USP and other CYP2C9 substrates have been conducted. Care should be exercised when Capecitabine Tablets, USP is coadministered with CYP2C9 substrates.

7.2 Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of capecitabine [see Clinical Pharmacology (12.3)]. In all clinical trials, patients were instructed to administer Capecitabine Tablets, USP within 30 minutes after a meal. It is recommended Capecitabine Tablets, USP be administered with food [see Dosage and Administration (2)]

8.1 Pregnancy

Risk SummaryBased on findings in animal reproduction studies and its mechanism of action, Capecitabine tablets, USP can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data]. Apprise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. DataAnimal DataOral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

8.2 Lactation

Risk SummaryThere is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with Capecitabine tablets, USP and for 2 weeks after the final dose.DataLactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.

8.3 Females And Males Of Reproductive Potential

Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating Capecitabine tablets, USP. ContraceptionFemalesCapecitabine tablets, USP can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of Capecitabine tablets, USP.MalesBased on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of Capecitabine tablets, USP [see Nonclinical Toxicology (13.1)].InfertilityBased on animal studies, Capecitabine Tablets, USP may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Capecitabine Tablets, USP in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to Capecitabine Tablets, USP was similar.The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%),thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%),hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

8.5 Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of Capecitabine Tablets, USP in the elderly [see Warnings and Precautions (5.11)].

8.6 Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Capecitabine Tablets, USP. The effect of severe hepatic dysfunction on Capecitabine Tablets, USP is not known [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)].

8.7 Renal Insufficiency

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function [see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

10 Overdosage

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 Tablets, USP 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. Single doses of Capecitabine Tablets, USP were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4,4.8, and 9.6 times the recommended human daily dose on a mg/m2 basis).

11 Description

Capecitabine Tablets, USP (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-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.Capecitabine Tablets, USP is supplied as oval shaped film-coated tablets for oral administration. Each light peach colored tablet contains 150 mg capecitabine and each light peach colored tablet contains 500 mg capecitabine, USP. The inactive ingredients in Capecitabine Tablets, USP include:  anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and purified water. The light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, iron oxide yellow and iron oxide red.

12.1 Mechanism Of Action

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.

12.3 Pharmacokinetics

AbsorptionFollowing 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 AUC0-¥ decreased by 60% and 35%, respectively. The Cmax and AUC0-¥ 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 [see Warnings and Precautions (5), Dosage and Administration (2), and Drug-Food Interaction (7.2)].The pharmacokinetics of Capecitabine Tablets, USP 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 Tablets, USP 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%.DistributionPlasma 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 Tablets, USP has a low potential for pharmacokinetic interactions related to plasma protein binding.Bioactivation and MetabolismCapecitabine 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 ofCapecitabine Tablets, USP 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. Metabolic Pathway of capecitabine to 5-FUThe 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. ExcretionCapecitabine 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. Effect of Age, Gender, and Race on the Pharmacokinetics of CapecitabineA population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Capecitabine Tablets, USP at 1250 mg/m2 twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4)]. Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU). Effect of Hepatic InsufficiencyCapecitabine Tablets, USP 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 Tablets, USP. Both AUC0-¥  and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0-¥  and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Capecitabine Tablets, USP is administered. The effect of severe hepatic dysfunction on Capecitabine Tablets, USP is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6)].        Effect of Renal InsufficiencyFollowing 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 <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >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 [see Dosage and Administration (2.4), Contraindications (4.2), Warnings and Precautions (5.5), and Use in Special Populations (8.7)]. Effect of Capecitabine on the Pharmacokinetics of WarfarinIn four patients with cancer, chronic administration of capecitabine (1250 mg/m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see Boxed Warning and Drug Interactions (7.1)]. Effect of Antacids on the Pharmacokinetics of CapecitabineWhen Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Capecitabine Tablets, USP (1250 mg/m2 , n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of Capecitabine Tablets, USP. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice VersaA Phase 1 study evaluated the effect of Capecitabine Tablets, USP on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of Capecitabine Tablets, USP was conducted in 26 patients with solid tumors. Capecitabine Tablets, USP was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted.Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m2 /day) disturbed estrus and consequently caused a decrease in fertility.In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

14.1 Adjuvant Colon Cancer

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of Capecitabine Tablets, USP for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Capecitabine Tablets, USP to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Capecitabine Tablets, USP 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) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes' stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×109 /L, platelets ≥ 100×109 /L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤2.5 ULN and CEA within normal limits at time of randomization. The baseline demographics for Capecitabine Tablets, USP and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.  Table 10 Baseline Demographics CAPECITABINE TABLETS, USP(n=1004)5-FU/LV(n=983)Age (median, years)Range62(25-80)63(22-82)GenderMale (n,%)Female (n,%) 542 (54)461 (46) 532 (54)451 (46)ECOG PS0 (n,%)1 (n,%) 849 (85)152 (15) 830 (85)147 (15)Staging-Primary TumorPT1 (n, %)PT2 (n, %)PT3 (n, %)PT4 (n, %)Other (n, %) 12 (1)90 (9)763 (76)138 (14)1 (0.1) 6 (0.6)92 (9)746 (76)139 (14)0 (0)Staging-Lymph nodepN1 (n, %)pN2 (n, %)Other (n, %) 695 (69)305 (30)4 (0.4) 694 (71)288 (29)1 (0.1)All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4)]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for Capecitabine Tablets, USP included dose reductions, cycle delays and treatment interruptions (see Table 11).Table 11 Summary of Dose Modifications in X-ACT Study CAPECITABINE TABLETS, USPN=9955-FU/LVN=974Median relative dose intensity (%)9392Patients completing full course of treatment (%)8387Patients with treatment interruption (%)155Patients with cycle delay (%)4629Patients with dose reduction (%)4244Patients with treatment interruption, cycle delay, or dose reduction (%)5752The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Capecitabine Tablets, USP compared to 5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12 and Figure 1).Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Capecitabine Tablets, USP was noninferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Capecitabine Tablets, USP compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 to 1.01). The 5-year overall survival rates were 71.4% for Capecitabine Tablets, USP and 68.4% for 5-FU/LV (see Figure 2).Table 12 Efficacy of Capecitabine Tablets, USP vs 5-FU/LV in Adjuvant Treatment of Colon Cancer*All Randomized populationCAPECITABINE TABLETS, USP(n=1004)5-FU/LV(n=983)Median follow-up (months )83835-year Disease-free Survival Rates (%) †59.154.6Hazard Ratio(CAPECITABINE TABLETS, USP/5-FU/LV)(95% C.I. for Hazard Ratio)p-value‡0.88(0.77 to 1.01) p=0.068*Approximately 93.4 % had 5-year DFS information† Based on Kaplan-Meier estimates‡ Test of superiority of Capecitabine Tablets, USP vs 5-FU/LV (Wald chi-square test) Figure 1 Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)** Capecitabine Tablets, USP has been demonstrated to be non-inferior to 5-FU/LV.Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)

14.2 Metastatic Colorectal Cancer

GeneralThe recommended dose of Capecitabine Tablets, USP was determined in an open-label, randomized clinical study,exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2 /day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2 /day in two divided doses,n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2 /day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to Capecitabine Tablets, USP; however, toxicity was increased. Capecitabine Tablets, USP, 1250 mg/m2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.MonotherapyData from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of Capecitabine Tablets, USP in the first-line treatment of patients with metastatic colorectal carcinoma.The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with Capecitabine Tablets, USP at a dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days).In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm.Survival was assessed based on a non-inferiority analysis.The baseline demographics for Capecitabine Tablets, USP and 5-FU/LV patients are shown in Table 13.Table 13 Baseline Demographics of Controlled Colorectal Trials Study 1Study 2 CAPECITABINETABLETS,USP(n=302)5-FU/LV(N=303)CAPECITABINETABLETS,USP(n=301)5-FU/LV(N=301)Age (median,years)Range64(23 to 86)63(24 to 87)64(29 to 84)64(36 to 86)GenderMale (%)Female (%)181 (60)121 (40)197 (65)106 (35)172 (57)129 (43)173 (57)128 (43)Karnofsky PS(median)Range90(70 to 100)90(70 to 100)90(70 to 100)90(70 to 100)Colon (%)Rectum (%)222 (74)79 (26)232 (77)70 (23)199 (66)101 (34)196 (65)105 (35)Prior radiation therapy(%)52 (17)62 (21)42 (14)42 (14)Prior adjuvant 5-FU (%)84 (28)110 (36)56 (19)41 (14)The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15. Table 14 Efficacy of CAPECITABINE TABLETS, USP vs 5-FU/LV in Colorectal Cancer (Study 1) CAPECITABINE TABLETS, USP(n=302)5-FU/LV(n=303)Overall Response Rate(%, 95% C.I.)21 (16-26)11 (8-15)(p value)0.0014Time to Progression(Median, days, 95% C.I.)128 (120-136)131 (105-153)Hazard Ratio (CAPECITABINE TABLETS, USP/5-FU/LV)95% C.I. for Hazard Ratio0.99(0.84-1.17)Survival(Median, days, 95% C.I.)380 (321-434)407 (366-446)Hazard Ratio (CAPECITABINE TABLETS, USP/5-FU/LV)95% C.I. for Hazard Ratio1.00(0.84-1.18) Table 15 Efficacy of CAPECITABINE TABLETS, USP vs 5-FU/LV in Colorectal Cancer (Study 2)  CAPECITABINE TABLETS, USP(n=301) 5-FU/LV(n=301) Overall Response Rate(%, 95% C.I.)21 (16-26)14 (10-18)(p-value)0.027Time to Progression(Median, days, 95% C.I.)137 (128 to 165)131 (102 to 156)Hazard Ratio (CAPECITABINE TABLETS, USP/5-FU/LV)95% C.I. for Hazard Ratio0.97(0.82 to 1.14) Survival(Median, days, 95% C.I.)404 (367 to 452)369 (338 to 430)Hazard Ratio (CAPECITABINE TABLETS, USP/5-FU/LV)95% C.I. for Hazard Ratio0.92(0.78 to 1.09)Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)Capecitabine Tablets, USP was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of Capecitabine Tablets, USP and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that Capecitabine Tablets, USP has a clinically meaningful survival effect,statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by Capecitabine Tablets, USP. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between  5-FU/LV and Capecitabine Tablets, USP, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs Capecitabine Tablets, USP difference. These results do not exclude the possibility of true equivalence of Capecitabine Tablets, USP to 5-FU/LV (see Table 14, Table 15, and Figure 3).

14.3 Breast Cancer

Capecitabine Tablets, USP has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy. In Combination With DocetaxelThe dose of Capecitabine Tablets, USP used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of Capecitabine Tablets, USP (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of Capecitabine Tablets, USP administered in 3-week cycles. The approved dose of 100 mg/m of docetaxel administered in 3-week cycles was the control arm of the phase 3 study. Capecitabine Tablets, USP in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive Capecitabine Tablets, USP 1250 mg/m2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.Table 16 Baseline Demographics and Clinical Characteristics Capecitabine Tablets, USP and Docetaxel Combination vs Docetaxel in Breast Cancer Trial Capecitabine Tablets, USP + Docetaxel(n=255)Docetaxel(n=256)Age (median, years)5251Karnofsky PS (median)9090Site of DiseaseLymph nodesLiverBoneLungSkin 121 (47%)116 (45%)107 (42%)95 (37%)73 (29%) 125 (49%)122 (48%)119 (46%)99 (39%)73 (29%)Prior ChemotherapyAnthracycline *5-FUPaclitaxel 255 (100%)196 (77%)25 (10%) 256 (100%)189 (74%)22 (9%)Resistance to an AnthracyclineNo resistanceProgression on anthracycline therapyStable disease after 4 cycles ofanthracycline therapyRelapsed within 2 years of completion of anthracycline-adjuvant therapyExperienced a brief response toanthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose 19 (7%)65 (26%) 41 (16%) 78 (31%)  51 (20%) 19 (7%)73 (29%) 40 (16%) 74 (29%)  50 (20%)No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease0123   89 (35%)123 (48%)43 (17%)0 (0%)   80 (31%)135 (53%)39 (15%)2 (1%)*Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedioneCapecitabine Tablets, USP in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.Table 17 Efficacy of Capecitabine Tablets, USP and Docetaxel Combination vs Docetaxel Monotherapy.EfficacyParameterCombinationTherapyMonotherapyp-valueHazardRatioTime to DiseaseProgression Median Days 95 % C.I.186(165 to198)128(105 to 136)0.00010.643Overall Survival Median Days95 % C.I442(375 to 497)352(298 to 387)0.01260.775Response Rate *32 %22 %0.009NA†*The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.† NA = Not Applicable.Figure 4 Kaplan-Meier Estimates for Time to Disease Progression Capecitabine Tablets, USP and Docetaxel vs DocetaxelFigure 5 Kaplan-Meier Estimates of Survival Capecitabine Tablets, USP and Docetaxel vs Docetaxel MonotherapyThe antitumor activity of Capecitabine Tablets, USP as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Capecitabine Tablets, USP was administered at a dose of 1255 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was 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 chemotherapy regimen.Table 18 Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial Patients WithMeasurableDisease (n=135)All Patients(n=162)Age (median, years)5556Karnofsky PS9090No. Disease Sites1 to 23 to 4>5 43 (32%)63 (46%)29 (22%) 60 (37%)69 (43%)34 (21%)Dominant Site of DiseaseVisceral*Soft TissueBone 101 (75%)30 (22%)4 (3%) 110 (68%)35 (22%)17 (10%)Prior ChemotherapyPaclitaxelAnthracycline†5-FUResistance to PaclitaxelResistance to an Anthracycline†Resistance to both Paclitaxel and an Anthracycline† 135 (100 %)122 (90%)110 (81%)103 (76%)55 (41%)43 (32%) 162 (100%)147 (91%)133 (82%)124 (77%)67 (41%)51 (31%)*Lung, pleura, liver, peritoneum† Includes 2 patients treated with an anthracenedione  Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.Table 19 Response Rates in Doubly-Resistant Patients Single-Arm BreastCancer Trial  Resistance to Both Paclitaxel and an Anthracycline (n=43)CR0PR*11CR+PR*11Response rate*(95% C.I.)25.6%(13.5,41.2)Duration of Response,*Median in days†(Range) 154(63 to 233)Includes 2 patients treated with an anthracenedione †From date of first responseFor the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.

15 References

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service,Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health,DHHS (NIOSH) Publication No. 2004-165.2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs:Am J Health-Syst Pharm. 2006;63:1172-1193.4. Polovich M., White JM, Kelleher LO (eds). Chemotherapy and biotherapy guidelines and    recommendations for practice (2nd ed.) 2005. Pittsburgh, PA: Oncology Nursing Society.

16 How Supplied/Storage And Handling

150 mg Color: Light peach Engraving: ‘A015’ on one side and 150 on the other, 150 mg tablets are packaged in bottles of 30 (NDC 67877-458-30),bottles of 60 (NDC 67877-458-60) and in bottles of 120 (NDC 67877-458-12).500 mg Color: Light Peach Engraving: ‘A016’ on one side and 500 on the other, 500 mg tablets are packaged in bottles of 30 (NDC 67877-459-30),bottles of 60 (NDC 67877-459-60) and in bottles of 120 (NDC 67877-459-12). Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.Capecitabine Tablets, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures1. Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

17 Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Patient Information) Patients and patients' caregivers should be informed of the expected adverse effects of Capecitabine Tablets, USP, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary [see Dosage and Administration (2.3)]. As described below, patients taking Capecitabine Tablets, USP should be informed of the need to interrupt treatment and to call their physician immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Capecitabine Tablets, USP treatment See FDA-approved patient labeling (Patient Information)Dihydropyrimidine Dehydrogenase DeficiencyPatients should be advised to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Capecitabine tablets, USP (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings and Precautions (5.4)].DiarrheaPatients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever should be instructed to stop taking Capecitabine tablets, USP and to call their physician immediately. Standard antidiarrheal treatments (eg,loperamide) are recommended.DehydrationPatients experiencing grade 2 or higher dehydration should be instructed to stop taking Capecitabine Tablets, USP immediately and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. NauseaPatients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking Capecitabine Tablets, USP immediately. Initiation of symptomatic treatment is recommendedVomiting Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking Capecitabine Tablets, USP immediately. Initiation of symptomatic treatment is recommended. Hand-and-Foot SyndromePatients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking Capecitabine Tablets, USP immediately. Initiation of symptomatic treatment is recommended. Hand-and-foot syndrome can lead to loss of fingerprints which could impact your identification. StomatitisPatients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking Capecitabine Tablets, USP immediately and to call their physician. Initiation of symptomatic treatment is recommended. Fever and NeutropeniaPatients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician immediately. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with Capecitabine Tablets, USP and for 6 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Capecitabine Tablets, USP and for 3 months after the last dose [see Use in Specific Populations (8.3)].LactationAdvise females not to breastfeed during treatment with Capecitabine Tablets, USP and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].Manufactured in India by:Alkem Laboratories LimitedH.O.: ALKEM HOUSE,Senapati Bapat Marg, Lower Parel,Mumbai 400 013, INDIADistributed by:Ascend Laboratories, LLCParsippany, NJ 07054 Revised: 05/2017 Patient Information Capecitabine Tablets, USP (KAP-e-SYE-ta-been)What is the most important information I should know about Capecitabine Tablets?Capecitabine Tablets can cause serious side effects, including: Capecitabine Tablets can interact with blood thinner medicines, such as warfarin (COUMADIN®). Taking Capecitabine Tablets with these medicines can cause changes in how fast your blood clots, and can cause bleeding that can lead to death. This can happen as soon as a few days after you start taking Capecitabine Tablets, or later during treatment, and possibly even within 1 month after you stop taking Capecitabine Tablets. Your risk may be higher because you have cancer, and if you are over 60 years of age. Before taking Capecitabine Tablets, tell your doctor if you are taking warfarin (COUMADIN) or another blood thinner medicine. If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with Capecitabine Tablets, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with Capecitabine Tablets. Your doctor may change your dose of the blood thinner medicine if needed. See "What are the possible side effects of Capecitabine Tablets?" for more information about side effects.What is Capecitabine Tablets?Capecitabine Tablets is a prescription medicine used to treat people with:cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes'C stage), after they have surgery.cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic).breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anticancer medicines have not worked.breast cancer that has spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines.It is not known if Capecitabine Tablets is safe and effective in children.Who should not take Capecitabine Tablets?Do not take Capecitabine Tablets if you:have severe kidney problems.are allergic to capecitabine, 5-fluorouracil, or any of the ingredients in Capecitabine Tablets. See the end of this leaflet for a complete list of ingredients in Capecitabine Tablets.Talk to your doctor before taking Capecitabine Tablets if you are not sure if you have any of the conditions listed above.What should I tell my doctor before taking Capecitabine Tablets?See "What is the most important information I should know about Capecitabine Tablets?"Before you take Capecitabine Tablets, tell your doctor if you:have had heart problems.have kidney or liver problems.have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)have any other medical conditions.are pregnant or plan to become pregnant. Capecitabine Tablets can harm your unborn baby. You should not become pregnant during treatment with Capecitabine Tablets. Talk to your doctor about birth control choices that may be right for you during treatment with Capecitabine Tablets.are breastfeeding or plan to breastfeed. It is not known if Capecitabine Tablets passes into your breast milk. Do not breastfeed during treatment with Capecitabine Tablets.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Capecitabine Tablets may affect the way other medicines work, and other medicines may affect the way Capecitabine Tablets works.Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.How should I take CAPECITABINE TABLETS?Take Capecitabine Tablets exactly as your doctor tells you to take it.Your doctor will tell you how much Capecitabine Tablets to take and when to take it.Take Capecitabine Tablets 2 times a day, 1 time in the morning and 1 time in the evening.Take Capecitabine Tablets within 30 minutes after finishing a meal. Swallow Capecitabine Tablets whole with water. Do not crush or cut Capecitabine Tablets.Ask your healthcare provider or pharmacist how to safely throw away any unused Capecitabine Tablets.If you have side effects with Capecitabine Tablets, if needed your doctor may decide to:change your dose of Capecitabine Tabletstreat you with Capecitabine Tablets less oftentell you to stop taking Capecitabine Tablets until certain side effects get better or go awaystop your treatment with Capecitabine Tablets if you have certain side effects and they  are severeIf you take too much Capecitabine Tablets, call your doctor or go to the nearest emergency room right away.What are the possible side effects of Capecitabine Tablets?Capecitabine Tablets may cause serious side effects including:See "What is the most important information I should know about Capecitabine Tablets?diarrhea. Diarrhea is common with Capecitabine Tablets and can sometimes be severe. Stop taking Capecitabine Tablets and call your doctor right away if the number of bowel movements you have in a day increases by 4 or more than is usual for you. Ask your doctor about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, call your doctor or go to the nearest emergency room right away. heart problems. Capecitabine Tablets can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle, heart failure, and sudden death. Stop taking Capecitabine Tablets and call your doctor right away if you get any of the following symptoms: chest painshortness of breathfeeling faintirregular heartbeats or skipping beatssudden weight gainswollen ankles or legs unexplained tirednessloss of too much body fluid (dehydration) and kidney failureDehydration can happen with Capecitabine Tablets and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking Capecitabine Tablets and also take other medicines that can cause kidney problems.Nausea, and vomiting are common with Capecitabine Tablets. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated. Stop taking Capecitabine Tablets and call your doctor right away if you:vomit 2 or more times in a dayare only able to eat or drink a little now and then, or not at all due to nausea.have diarrhea.See "diarrhea" above.serious skin and mouth reactions.Capecitabine Tablets can cause serious skin reactions that may lead to death. Tell your doctor right away if you develop a skin rash, blisters and peeling of your skin. Your doctor may tell you to stop taking Capecitabine Tablets if you have a serious skin reaction. Do not take Capecitabine Tablets again if this happens.Capecitabine Tablets can also cause “hand and foot syndrome.” Hand and foot syndrome is common with Capecitabine Tablets and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking Capecitabine Tablets and call your doctor right away if you have any of these symptoms and you are not able to do your usual activities. Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.you may get sores in your mouth or on your tongue when taking Capecitabine Tablets. Stop taking Capecitabine Tablets and call your doctor if you get painful redness, swelling, or ulcers in your mouth and tongue, or if you are having problems eating. Tell your doctor if you have any side effect that bothers you or that does not go away.increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with Capecitabine Tablets. Your doctor will check you for these problems during treatment with Capecitabine Tablets.decreased white blood cells, platelets, and red blood cell counts. Your doctor will do blood tests during treatment with Capecitabine Tablets to check your blood cell counts. If your white blood cell count is very low, you are at increased risk for infection. Call your doctor right away if you develop a fever of 100.5°F or greater or have other signs and symptoms of infection.People 80 years of age or older may be more likely to develop severe or serious side effects with Capecitabine Tablets.The most common side effects of Capecitabine Tablets include:diarrheahand and foot syndromenauseavomitingstomach-area (abdominal) paintirednessweaknessincreased amounts of red blood cell breakdown products (bilirubin) in your blood.These are not all the possible side effects of Capecitabine Tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should I store Capecitabine Tablets?Store Capecitabine Tablets at room temperature between 68°F to 77°F (20°C to 25°C).Keep Capecitabine Tablets in a tightly closed container.Keep Capecitabine Tablets and all medicines out of the reach of children.General information about the safe and effective use of Capecitabine Tablets.Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Capecitabine Tablets for a condition for which it was not prescribed. Do not give Capecitabine Tablets to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or doctor for information about Capecitabine Tablets that is written for health professionals. What are the ingredients in Capecitabine Tablets?Active ingredient: capecitabineInactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and purified water. The light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, iron oxide yellow and iron oxide red. Manufactured in India by:Alkem Laboratories LimitedH.O.: ALKEM HOUSE,Senapati Bapat Marg, Lower Parel,Mumbai 400 013, INDIA Distributed by:Ascend Laboratories, LLCParsippany, NJ 07054Revised: 05/2017

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