Capecitabine

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. Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 1,250 mg/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 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 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 Adverse Reactions Reported in ≥5% of Patients Treated With Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1969) Capecitabine (N=995) 5-FU/LV (N=974) Body System/Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal Pain 14 3 16 2 Constipation 9 - 11 <1 Upper Abdominal Pain 7 <1 7 <1 Dyspepsia 6 <1 5 - Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome 60 17 9 <1 Alopecia 6 - 22 <1 Rash 7 - 8 - Erythema 6 1 5 <1 General Disorders and Administration Site Conditions Fatigue 16 <1 16 1 Pyrexia 7 <1 9 <1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Nervous System Disorders Dizziness 6 <1 6 - Headache 5 <1 6 <1 Dysgeusia 6 - 9 - Metabolism and Nutrition Disorders Anorexia 9 <1 11 <1 Eye Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 Respiratory Thoracic and Mediastinal Disorders Epistaxis 2 - 5 - Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse Event Capecitabine (n=995) Grade 3/4 % IV 5-FU/LV (n=974) Grade 3/4 % Increased ALAT (SGPT) 1.6 0.6 Increased calcium 1.1 0.7 Decreased calcium 2.3 2.2 Decreased hemoglobin 1.0 1.2 Decreased lymphocytes 13.0 13.0 Decreased neutrophils The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the Capecitabine arm and 4.9% in the IV 5-FU/LV arm. 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 1.0 0.7 Increased bilirubin

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.

20 6.3 6.2 Metastatic Colorectal Cancer Monotherapy Table 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 1,250 mg/m 2 twice a day of capecitabine 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/m 2 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 and 32 (5.4%) randomized to 5-FU/LV. Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of Patients Ad v er s e Event Capecitabine (n=596) 5-FU/LV (n=593) Total % Gr ade 3 % Gr ade 4 % Total % Gr ade 3 % Gr ade 4 % Nu m b e r of Patients With ˃ O n e Adverse Event 96 52 9 94 45 9 B o d y System/Adverse Event GI Diarrhea Nausea Vomiting Stomatitis Abdominal Pain Gastrointestinal Motility Disorder Constipation Oral Discomfort Upper GI Inflammatory Disorders Gastrointestinal Hemorrhage Ileus 55 43 27 25 35 10 14 10 8 6 6 13 4 4 2 9 ˂1 1 – ˂1 1 4 2 – ˂1 ˂1 ˂1 – ˂1 – – ˂1 1 61 51 30 62 31 7 17 10 10 3 5 10 3 4 14 5 ˂1 1 – 1 1 2 2 ˂1 ˂1 1 – – – – – – 1 S kin and Subcutaneous Hand-and-Foot Syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Skin Discoloration 7 ˂1 – 5 – – Alopecia 6 – – 21 ˂1 – G e n e r al Fatigue/Weakness 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Chest Pain 6 1 – 6 1 ˂1 N e ur ological Peripheral Sensory Neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Dizziness* 8 ˂1 – 8 ˂1 – Insomnia 7 – – 7 – – Taste Disturbance 6 1 – 11 ˂1 1 M et abolism Appetite Decreased 26 3 ˂1 31 2 ˂1 Dehydration 7 2 ˂1 8 3 1 E y e Eye Irritation 13 – – 10 ˂1 – Vision Abnormal 5 – – 2 – – Respiratory Dyspnea 14 1 – 10 ˂1 1 Cough 7 ˂1 1 8 – – Pharyngeal Disorder 5 – – 5 – – Epistaxis 3 ˂1 – 6 – – Sore Throat 2 – – 6 – – Mus c u l oskeletal Back Pain 10 2 – 9 ˂1 – Arthralgia 8 1 – 6 1 – V ascular Venous Thrombosis 8 3 ˂1 6 2 – P s yc h i atric Mood Alteration 5 – – 6 ˂1 – Depression 5 – – 4 ˂1 – In fections Viral 5 ˂1 – 5 ˂1 – Blood and Lymphatic Anemia 80 2 ˂1 79 1 ˂1 Neutropenia 13 1 2 46 8 13 He patobiliary Hyperbilirubinemia 48 18 5 17 3 3 – Not observed * Excluding vertigo NA = Not Applicable 6.3 Breast Cancer In Combination with Docetaxel The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8 . In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1,250 mg/m 2 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/m 2 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/m 2 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 and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine1,250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks Docetaxel 100 mg/m 2 /3 weeks (n=251) (n=255) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8 Body System/Adverse Event GI Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Constipation 20 2 – 18 – – Abdominal Pain 30 <3 <1 24 2 – Dyspepsia 14 – – 8 1 – Dry Mouth 6 <1 – 5 – – Skin and Subcutaneous Hand-and-Foot Syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail Disorder 14 2 – 15 – – Dermatitis 8 – – 11 1 – Rash Erythematous 9 <1 – 5 – – Nail Discoloration 6 – – 4 <1 – Onycholysis 5 1 – 5 1 – Pruritus 4 – – 5 – – General Pyrexia 28 2 – 34 2 – Asthenia 26 4 <1 25 6 – Fatigue 22 4 – 27 6 – Weakness 16 2 – 11 2 – Pain in Limb 13 <1 – 13 2 – Lethargy 7 – – 6 2 – Pain 7 <1 – 5 1 – Chest Pain (non-cardiac) 4 <1 – 6 2 – Influenza-like Illness 5 – – 5 – – Neurological Taste Disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Insomnia 8 – – 10 <1 – Peripheral Neuropathy 6 – – 10 1 – Hypoaesthesia 4 <1 – 8 <1 – Metabolism Anorexia 13 1 – 11 <1 – Appetite Decreased 10 – – 5 – – Weight Decreased 7 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation Increased 12 – – 7 <1 – Conjunctivitis 5 – – 4 – – Eye Irritation 5 – – 1 – – Musculoskeletal Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Bone Pain 8 <1 – 10 2 – Cardiac Edema 33 <2 – 34 <3 1 Blood Neutropenic Fever 16 3 13 21 5 16 Respiratory Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Epistaxis 7 <1 – 6 – – Rhinorrhea 5 – – 3 – – Pleural Effusion 2 1 – 7 4 – Infection Oral Candidiasis 7 <1 – 8 <1 – Urinary Tract Infection 6 <1 – 4 – – Upper Respiratory Tract 4 – – 5 1 – Vascular Flushing 5 – – 5 – – Lymphoedema 3 <1 – 5 1 – Psychiatric Depression 5 – – 5 1 – Table 8 Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1,250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks Docetaxel 100 mg/m 2 /3 weeks (n=251) (n=255) Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Hematologic Leukopenia 91 37 24 88 42 33 Neutropenia/Granulocytopenia 86 20 49 87 10 66 Thrombocytopenia 41 2 1 23 1 2 Anemia 80 7 3 83 5 <1 Lymphocytopenia 99 48 41 98 44 40 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Monotherapy The following data are shown for the study in stage IV breast cancer patients who received a dose of 1,250 mg/m 2 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 Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable GI Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal Pain 20 4 – Constipation 15 1 – Dyspepsia 8 – – Skin and Subcutaneous Hand-and-Foot Syndrome 57 11 NA Dermatitis 37 1 – Nail Disorder 7 – – General Fatigue 41 8 – Pyrexia 12 1 – Pain in Limb 6 1 – Neurological Paresthesia 21 1 – Headache 9 1 – Dizziness 8 – – Insomnia 8 – – Metabolism Anorexia 23 3 – Dehydration 7 4 1 Eye Eye Irritation 15 – – Musculoskeletal Myalgia 9 – – Cardiac Edema 9 1 – Blood Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Anemia 72 3 1 Lymphopenia 94 44 15 Hepatobiliary Hyperbilirubinemia 22 9 2 6.4 Clinically Relevant Adverse Events in <5% of Patients Clinically relevant adverse events reported in <5% of patients treated with capecitabine either as monotherapy or in combination with docetaxel 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, sedation Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion Infections: 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 weakness Blood & 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: vertigo Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests Immune System: drug hypersensitivity (0.1%) Capecitabine 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%) 6.5 Postmarketing Experience The following adverse reactions have been observed in the postmarketing setting: 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 ) ] In instances of exposure to crushed capecitabine tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.

4 CONTRAINDICATIONS Severe Renal Impairment ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Severe Renal Impairment Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 4.2 Hypersensitivity Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

11 DESCRIPTION Capecitabine, USP 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, USP is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20 ºC. Capecitabine tablets, USP are supplied as oblong shaped, biconvex film coated tablets for oral administration. Each light peach to peach colored tablet contains 150 mg or 500 mg capecitabine, USP. The inactive ingredients in capecitabine tablets, USP include: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate and microcrystalline cellulose. The light peach or peach film coating contains hypromellose, talc, titanium dioxide, iron oxide red, ferrosoferric oxide and Iron oxide yellow. stru

2 DOSAGE AND ADMINISTRATION Take capecitabine tablets with water within 30 min after a meal ( 2.1 ) Monotherapy: 1,250 mg/m 2 twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles ( 2.2 ) Adjuvant treatment is recommended for a total of 6 months (8 cycles) ( 2.2 ) In combination with docetaxel, the recommended dose of capecitabine tablets is 1,250 mg/m 2 twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m 2 as a 1-hour IV infusion every 3 weeks ( 2.2 ) Capecitabine tablets dosage may need to be individualized to optimize patient management ( 2.3 ) Reduce the dose of capecitabine tablets by 25% in patients with moderate renal impairment ( 2.4 ) 2.1 Important Administration Instructions Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal.Capecitabine is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 If Capecitabine 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 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 are 1,250 mg/m 2 administered orally twice daily (morning and evening; equivalent to 2,500 mg/m 2 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 1,250 mg/m 2 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)]. Table 1 Capecitabine tablets Dose Calculation According to Body Surface Area Dose Level 1,250 mg/m 2 T wice a Day Number of Tablets to be Taken at E ach Dose (Morning and Evening) Su r f a c e Area ( m 2 ) T otal Daily Dose* (mg) 150 mg 500 mg ≤ 1.25 3,000 0 3 1.26 to 1.37 3,300 1 3 1.38 to 1.51 3,600 2 3 1.52 to 1.65 4,000 0 4 1.66 to 1.77 4,300 1 4 1.78 to 1.91 4,600 2 4 1.92 to 2.05 5,000 0 5 2.06 to 2.17 5,300 1 5 ≥ 2.18 5,600 2 5 *Total Daily Dose divided by 2 to allow equal morning and evening doses In Combination With Docetaxel (Metastatic Breast Cancer) In combination with docetaxel, the recommended dose of capecitabine tablets is 1,250 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m 2 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 plus docetaxel combination. Table 1 displays the total daily dose of capecitabine tablets by body surface area and the number of tablets to be taken at each dose. 2.3 Dose Management Guidelines General Capecitabine tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine tablets should be modified as necessary to accommodate individual patient tolerance to treatment [ see Clinical Studies (14)]. Toxicity due to capecitabine tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine tablets dose. Once the dose has been reduced, it should not be increased at a later time. Doses of capecitabine tablets 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 [ see Drug Interactions (7.1)]. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) Capecitabine tablets 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 Toxicity NCIC Grades* During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) Grade 1 Maintain dose level Maintain dose level Grade 2 -1st appearance Interrupt until resolved to grade 0 to 1 100% -2nd appearance 75% -3rd appearance 50% -4th appearance Discontinue treatment permanently - Grade 3 -1st appearance Interrupt until resolved to grade 0 to 1 75% -2nd appearance 50% -3rd appearance Discontinue treatment permanently - Grade 4 -1st appearance Discontinue permanently OR If physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0 to 1 50% *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 for toxicity should be made according to Table 2 above for capecitabine tablets. At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine tablets 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 for the treatment of metastatic breast cancer is shown in Table 3 Table 3 Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets T oxicity NCIC Grades* Grade 2 Grade 3 Grade 4 1st appearance Delay treatment until resolved to grade 0 to 1; Resume treatment with original dose of 75 mg/m 2 docetaxel Delay treatment until resolved to grade 0 to 1; Resume treatment at 55 mg/m 2 of docetaxel. Discontinue treatment with docetaxel 2nd appearance Delay treatment until resolved to grade 0 to 1; Resume treatment at 55 mg/m 2 of docetaxel. Discontinue treatment with docetaxel - 3rd appearance Discontinue treatment with 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 Impairment No adjustment to the starting dose of capecitabine tablets are 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 tablet starting dose when used as monotherapy or in combination with docetaxel (from 1,250 mg/m 2 to 950 mg/m 2 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 monotherapy and capecitabine tablets in combination use with docetaxel. Cockroft and Gault Equation: (140 - age [yrs]) (body wt [kg]) Creatinine clearance for males = —————————————— (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value Geriatrics Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly. Insufficient data are available to provide a dosage recommendation.

1 INDICATIONS AND USAGE Capecitabine is a nucleoside metabolic inhibitor with antineoplastic activity indicated for: • Adjuvant Colon Cancer ( 1.1 ) – Patients with Dukes’ C colon cancer • Metastatic Colorectal Cancer ( 1.1 ) – First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred • Metastatic Breast Cancer ( 1.2 ) – In combination with docetaxel after failure of prior anthracycline- containing therapy - As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen 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 preferred. Capecitabine was non-inferior to 5- fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine in the adjuvant treatment of Dukes’ C colon cancer. Capecitabine tablets USP are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets 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 are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. Capecitabine tablets 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/m 2 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.

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 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 were not lethal to mice, rats, and monkeys at doses up to 2,000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m 2 basis).

7 DRUG INTERACTIONS Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. ( 5.2 , 7.1 ) Phenytoin: Monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin. The phenytoin dose may need to be reduced. ( 7.1 ) Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. ( 7.1 ) CYP2C9 substrates: Care should be exercised when capecitabine is coadministered with CYP2C9 substrates. ( 7.1 ) Allopurinol: Avoid the use of allopurinol during treatment with capecitabine. Food reduced both the rate and extent of absorption of capecitabine. ( 2 , 7.2 , 12.3 ) 7.1 Drug-Drug Interactions Anticoagulants Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine 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 therapy and, in a few cases, within 1 month after stopping capecitabine. 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. Phenytoin The level of phenytoin should be carefully monitored in patients taking capecitabine and phenytoin dose may need to be reduced [ see Dosage and Administration (2.3) ]. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites. Leucovorin The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. CYP2C9 substrates Other than warfarin, no formal drug-drug interaction studies between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when capecitabine is coadministered with CYP2C9 substrates. Allopurinol Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see Clinical Pharmacology (12.3) ] , which may decrease capecitabine efficacy. Avoid the use of allopurinol during treatment with capecitabine. 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 within 30 minutes after a meal. It is recommended that capecitabine be administered with food [see Dosage and Administration (2 ) ] .

12 CLINICAL PHARMACOLOGY 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, N 5-10 -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 Absorption Following oral administration of 1,255 mg/m 2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T max ) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean C max and AUC 0-∞ decreased by 60% and 35%, respectively. The C max and AUC 0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T max of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5) , Dosage and Administration (2) , and Drug-Food Interaction (7.2) ]. The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3,500 mg/m 2 /day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the C max and AUC of 5-FU was greater than 85%. Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding. Bioactivation and Metabolism Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of capecitabine 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-FU The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH 2 ). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine. In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1. Excretion Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour. Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered capecitabine at 1,250 mg/m 2 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/m 2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower C max and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower C max 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 Insufficiency Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1,255 mg/m 2 dose of capecitabine. Both AUC 0-∞ and C max of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC 0-∞ and C max of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) and Use in Specific Population (8.6) ]. Effect of Renal Insufficiency Following oral administration of 1,250 mg/m 2 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 Specific Populations (8.7) ] . Effect of Capecitabine on the Pharmacokinetics of Warfarin In four patients with cancer, chronic administration of capecitabine (1,250 mg/m 2 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 Interaction (7.1) ]. Effect of Antacids on the Pharmacokinetics of Capecitabine When Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1,250 mg/m 2 , n=12 cancer patients), AUC and C max 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. Effect of Allopurinol on Capecitabine Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not fully characterized. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa A Phase 1 study evaluated the effect of capecitabine on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of capecitabine was conducted in 26 patients with solid tumors. Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR. for

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, N 5-10 -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 Absorption Following oral administration of 1,255 mg/m 2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T max ) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean C max and AUC 0-∞ decreased by 60% and 35%, respectively. The C max and AUC 0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T max of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5) , Dosage and Administration (2) , and Drug-Food Interaction (7.2) ]. The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3,500 mg/m 2 /day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the C max and AUC of 5-FU was greater than 85%. Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding. Bioactivation and Metabolism Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of capecitabine 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-FU The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH 2 ). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine. In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1. Excretion Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour. Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered capecitabine at 1,250 mg/m 2 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/m 2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower C max and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower C max 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 Insufficiency Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1,255 mg/m 2 dose of capecitabine. Both AUC 0-∞ and C max of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC 0-∞ and C max of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) and Use in Specific Population (8.6) ]. Effect of Renal Insufficiency Following oral administration of 1,250 mg/m 2 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 Specific Populations (8.7) ] . Effect of Capecitabine on the Pharmacokinetics of Warfarin In four patients with cancer, chronic administration of capecitabine (1,250 mg/m 2 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 Interaction (7.1) ]. Effect of Antacids on the Pharmacokinetics of Capecitabine When Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1,250 mg/m 2 , n=12 cancer patients), AUC and C max 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. Effect of Allopurinol on Capecitabine Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not fully characterized. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa A Phase 1 study evaluated the effect of capecitabine on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of capecitabine was conducted in 26 patients with solid tumors. Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR. for

20220729

3

3 DOSAGE FORMS AND STRENGTHS 150 mg Tablets Capecitabine tablets, USP are supplied as light peach to peach colored, oblong shaped, biconvex film coated tablets, debossed with “C” on one side and “150”on other side for oral administration. Each light peach to peach colored tablet contains 150 mg of capecitabine, USP. 500 mg Tablets Capecitabine tablets, USP are supplied as light peach to peach colored, oblong shaped, biconvex film coated tablets, debossed with “C” on one side and “500”on other side for oral administration. Each light peach to peach colored tablet contains 500 mg of capecitabine, USP. Tablets: 150 mg and 500 mg ( 3 )

Capecitabine Capecitabine CAPECITABINE CAPECITABINE CELLULOSE, MICROCRYSTALLINE ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED FERRIC OXIDE RED FERRIC OXIDE YELLOW TITANIUM DIOXIDE TALC FERROSOFERRIC OXIDE Lightpeach oblong C;150 Capecitabine Capecitabine CAPECITABINE CAPECITABINE CELLULOSE, MICROCRYSTALLINE ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED FERRIC OXIDE RED FERRIC OXIDE YELLOW TITANIUM DIOXIDE TALC FERROSOFERRIC OXIDE Lightpeach oblong C;500

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 2,300 mg/m 2 /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.

13 NONCLINICAL TOXICOLOGY 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 2,300 mg/m 2 /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.

ANDA209365

Capecitabine

Capecitabine

72205-007

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 150mg-60s-count-container-label 500mg-120s-count-container-label capcetabine-150mg-60s-count capcetabine-500mg-120s-count

PATIENT INFORMATION Capecitabine (KAP e SYE ta been) tablets USP What is the most important information I should know about Capecitabine tablets? Capecitabine can cause serious side effects, including: Capecitabine 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 healthcare provider 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 healthcare provider should do blood tests often, to check how fast your blood clots during and after you stop treatment with capecitabine tablets . Your healthcare provider 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 are 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 anti-cancer 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 are safe and effective in children. 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 healthcare provider before taking capecitabine tablets if you are not sure if you have any of the conditions listed above. Before you take capecitabine tablets, tell your healthcare provider about all your medical conditions, including if you: See “What is the most important information I should know about capecitabine tablets?”. have had heart problems. have kidney or liver problems. have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase) are pregnant or plan to become pregnant. Capecitabine tablets can harm your unborn baby. Your healthcare provider should do a pregnancy test before you start treatment with capecitabine tablets. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with capecitabine tablets. Females who are able to become pregnant should use effective birth control during treatment and for 6 months after the final dose. Talk to your healthcare provider about birth control choices that may be right for you during treatment with capecitabine tablets. Males who have female partners who are able to become pregnant should use effective birth control during treatment and for 3 months after the final dose. are breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capacetabine and for 2 weeks after the final dose. Tell your healthcare provider 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 healthcare provider and pharmacist when you get a new medicine. How should I take capecitabine tablets ? Take capecitabine tablets exactly as your healthcare provider tells you to take it. Your healthcare provider 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. If you cannot swallow capecitabine tablets whole, tell your healthcare provider. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with capecitabine tablets if you develop side effects. If 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 tablet and call your healthcare provider 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 healthcare provider about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, call your healthcare provider or go to the nearest hospital 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 healthcare provider right away if you get any of the following symptoms: o chest pain o shortness of breath o feeling faint o irregular heartbeats or skipping beats o sudden weight gain o swollen ankles or legs Loss of too much body fluid (dehydration) and kidney failure. Dehydration 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 day. are 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 Healthcare provider right away if you develop a skin rash, blisters and peeling of your skin. Your healthcare provider 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 healthcare provider 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. increased level of bilirubin in your blood and liver problems . Increased bilirubin in your blood is common with capecitabine tablets. Your healthcare provider will check you for these problems during treatment with capecitabine tablets . decreased white blood cells, platelets, and red blood cell counts . Your healthcare provider 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 healthcare provider 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: • diarrhea • hand and foot syndrome • nausea • vomiting • stomach-area (abdominal) pain • weakness and tiredness • increased amounts of red blood cell breakdown products (bilirubin) in your blood Capecitabine tablets may cause fertility problems in females and males. This may affect the ability to have a child. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of capecitabine tablets. 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. Ask your healthcare provider or pharmacist how to safely throw away any unused capecitabine tablets. 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 purposes other than those listed in a Patient Information leaflet. 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 healthcare provider for information about capecitabine tablets that is written for health professionals. What are the ingredients in capecitabine tablets? Active ingredient: capecitabine Inactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate and microcrystalline cellulose.The peach or light peach film coating contains hypromellose, talc, titanium dioxide, iron oxide red, ferrosoferric oxide and iron oxide yellow. For more information, call 1-855-668-2369. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured by : MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by : Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 Issued on: August 2019

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Diarrhea Inform patients 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 to stop taking capecitabine tablets. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.2) ] . Cardiotoxicity Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.3) ] . Dihydropyrimidine Dehydrogenase Deficiency Advise patients 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 (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings and Precautions (5.4) ] . Dehydration and Renal Failure Insrruct patients experiencing grade 2 or higher dehydration (IV fluids indicated < 24 hours) to stop taking capecitabine tablets immediately and to call their healthcare provider to correct the dehydration.Advise patients to not restart capecitabine until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5) ] . Important Administration Instructions Advise patients to swallow capecitabine tablets whole with water within 30 minutes of a meal. Advise patients and caregivers not to crush or cut capecitabine tablets. Advise patients if they cannot swallow capecitabine tablets whole, to inform their healthcare provider [see Dosage and Administration (2.1) ] . Nausea Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking capecitabine immediately and to contact their healthcare provider for management of nausea [see Adverse Reactions (6.1) ] . Vomiting Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1) ] . Hand-and-Foot Syndrome Patients 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 to stop taking capecitabine tablets immediately and to contact their healthcare provider. Inform patients that initiation of symptomatic treatment is recommended and hand-and-foot syndrome can lead to loss of fingerprints which could impact your identification [see Adverse Reactions (6.1) ] . Stomatitis Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking capecitabine tablets immediately and to contact healthcare provider [see Adverse Reactions (6.1) ] . Fever and Neutropenia Inform patients who develop a fever of 100.5°F or greater or other evidence of potential infection to contact their healthcare provider [see Adverse Reactions (6.1) ] . Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with capecitabine 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 and for 3 months after the last dose [see Use in Specific Populations(8.3) ]. Lactation Advise females not to breastfeed during treatment with capecitabine and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ]. Manufactured by : MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by : Novadoz Pharmaceuticals LLC Piscataway, NJ 08854 -3714 Issued on : August 2019

14 CLINICAL STUDIES 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 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 to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with capecitabine 1,250 mg/m 2 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/m 2 and 20 mg/m 2 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 ≥ 1.5x10 9 /L, platelets ≥ 100x10 9 /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 and 5-FU/LV patients are shown in Table 10 . The baseline characteristics were well-balanced between arms. Table 10 Baseline Demographics Capecitabine (n=1,004) 5-FU/LV (n=983) Age (median, years) 62 63 Range (25 to 80) (22 to 82) Gender Male (n, %) 542 (54) 532 (54) Female (n, %) 461 (46) 451 (46) ECOG PS 0 (n, %) 849 (85) 830 (85) 1 (n, %) 152 (15) 147 (15) Staging – Primary Tumor PT1 (n, %) 12 (1) 6 (0.6) PT2 (n, %) 90 (9) 92 (9) PT3 (n, %) 763 (76) 746 (76) PT4 (n, %) 138 (14) 139 (14) Other (n, %) 1 (0.1) 0 (0) Staging – Lymph Node pN1 (n, %) 695 (69) 694 (71) pN2 (n, %) 305 (30) 288 (29) Other (n, %) 4 (0.4) 1 (0.1) All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1,250 mg/m 2 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 included dose reductions, cycle delays and treatment interruptions (see Table 11 ). Table 11 Summary of Dose Modifications in X-ACT Study Capecitabine N = 995 5-FU/LV N = 974 Median relative dose intensity (%) 93 92 Patients completing full course of treatment (%) 83 87 Patients with treatment interruption (%) 15 5 Patients with cycle delay (%) 46 29 Patients with dose reduction (%) 42 44 Patients with treatment interruption, cycle delay, or dose reduction (%) 57 52 The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 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 was non-inferior 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 compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for capecitabine and 68.4% for 5- FU/LV (see Figure 2 ). Table 12 Efficacy of Capecitabine vs 5-FU/LV in Adjuvant Treatment of Colon Cancer a All Randomized Population Capecitabine (n=1,004) 5-FU/LV ( n = 983) M e d ian follow-up (months) 83 83 5-year Disease-free Survival Rates (%) b 59.1 54.6 Hazard Ratio (capecitabine /5-FU/LV) (95% C.I. for Hazard Ratio) p-value c 0.88 (0.77 to 1.01) p = 0.068 a Approximately 93.4% had 5-year DFS information b Based on Kaplan-Meier estimates C Test of superiority of capecitabine vs 5-FU/LV (Wald chi-square test) Figure 1 Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population) a a Capecitabine has been demonstrated to be non-inferior to 5-FU/LV. Figure 2 Kaplan-Meier Estimates of Overall Survival(All Randomized Population) fig-01 fig-02 14.2 Metastatic Colorectal Cancer General The recommended dose of capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1,331 mg/m 2 /day in two divided doses, n=39), intermittent therapy with capecitabine (2,510 mg/m 2 /day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1,657 mg/m 2 /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 ; however, toxicity was increased. Capecitabine ,1,250 mg/m 2 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. Monotherapy Data from two open-label, multicenter, randomized, controlled clinical trials involving 1,207 patients support the use of capecitabine 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 at a dose of 1,250 mg/m 2 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/m 2 leucovorin IV followed by 425 mg/m 2 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 and 5-FU/LV patients are shown in Table 13 . Table 13 Baseline Demographics of Controlled Colorectal Trials Study 1 Study 2 Capecitabine (n=302) 5-FU/LV (n=303) Capecitabine (n=301) 5-FU/LV (n=301) Age (median, years) 64 63 64 64 Range (23 to 86) (24 to 87) (29 to 84) (36 to 86) Gender Male (%) 181 (60) 197 (65) 172 (57) 173 (57) Female (%) 121 (40) 106 (35) 129 (43) 128 (43) Karnofsky PS (median) 90 90 90 90 Range (70 to100) (70 to100) (70 to100) (70 to100) Colon (%) 222 (74) 232 (77) 199 (66) 196 (65) Rectum (%) 79 (26) 70 (23) 101 (34) 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 vs 5-FU/LV in Colorectal Cancer (Study 1) Capecitabine (n=302) 5-FU/LV (n=303) Overall Response Rate (%, 95% C.I.) 21 (16 to 26) 11 (8 to15) (p-value) 0.0014 Time to Progression (Median, days, 95% C.I.) 128 (120 to136) 131 (105 to153) Hazard Ratio (Capecitabine/5-FU/LV) 0.99 95% C.I. for Hazard Ratio (0.84-1.17) Survival (Median, days, 95% C.I.) 380 (321 to 434) 407 (366 to 446) Hazard Ratio (capecitabine/5-FU/LV) 1.00 95% C.I. for Hazard Ratio (0.84 to1.18) Table 15 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 2) Capecitabine (n=301) 5-FU/LV (n=301) Overall Response Rate (%, 95% C.I.) 21 (16 to 26) 14 (10 to18) (p-value) 0.027 Time to Progression (Median, days, 95% C.I.) 137 (128 to165) 131 (102 to156) Hazard Ratio (capecitabine/5-FU/LV) 0.97 95% C.I. for Hazard Ratio (0.82 to1.14) Survival (Median, days, 95% C.I.) 404 (367 to 452) 369 (338 to 430) Hazard Ratio (capecitabine/5-FU/LV) 0.92 95% C.I. for Hazard Ratio (0.78 to1.09) Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2) Capecitabine was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that capecitabine 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. 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, 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 difference. These results do not exclude the possibility of true equivalence of capecitabine to 5-FU/LV (see Table 14, Table 15 and Figure-3 ). fig-03 14.3 Breast Cancer Capecitabine has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy. In Combination With Docetaxel The dose of capecitabine 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 (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/m 2 administered in 3-week cycles of docetaxel in combination with 1,250 mg/m 2 twice daily for 14 days of capecitabine administered in 3-week cycles. The approved dose of 100 mg/m 2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study. Capecitabine 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 1,250 mg/m 2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m 2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m 2 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 and Docetaxel Combination vs Docetaxel in Breast Cancer Trial Capecitabine + Docetaxel (n=255) D o ce taxel (n=256) Age (median, years) 52 51 Karnofsky PS (median) 90 90 S it e of Disease Lymph nodes Liver Bone Lung Skin 121 (47%) 116 (45%) 107 (42%) 95 (37%) 73 (29%) 125 (49%) 122 (48%) 119 (46%) 99 (39%) 73 (29%) P r i or Chemotherapy Anthracycline 1 5-FU Paclitaxel 255 (100%) 196 (77%) 25 (10%) 256 (100%) 189 (74%) 22 (9%) Resistance to an Anthracycline No resistance Progression on anthracycline therapy Stable disease after 4 cycles of anthracycline therapy Relapsed within 2 years of completion of anthracycline-adjuvant therapy Experienced a brief response to anthracycline 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%) N o. of Prior Chemotherapy Regimens for T r e atment of Metastatic Disease 0 1 2 3 89 (35%) 123 (48%) 43 (17%) 0 (0%) 80 (31%) 135 (53%) 39 (15%) 2 (1%) 1 Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione Capecitabine 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 and Docetaxel Combination vs Docetaxel Monotherapy E f f icacy Parameter Combination T h e r apy M onotherapy p - value Hazard Ratio T ime to Disease P r ogression M e d ian Days 95% C.I. 186 (165 to 198) 128 (105 to 136) 0.0001 0.643 Overall Survival M e d ian Days 95% C.I. 442 (375 to 497) 352 (298 to 387) 0.0126 0.775 Response Rate 1 32% 22% 0.009 NA 2 1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm. 2 NA = Not Applicable Figure 4 Kaplan-Meier Estimates for Time to Disease Progression Capecitabine and Docetaxel vs Docetaxel Figure 5 Kaplan-Meier Estimates of Survival Capecitabine and Docetaxel vs Docetaxel Monotherapy The antitumor activity of capecitabine 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 was administered at a dose of 1,255 mg/m 2 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 P atients With Measurable Disease (n=135) All Patients ( n = 162) A ge (median, years) 55 56 K arnofsky PS 90 90 No. Disease Sites 1-2 3-4 >5 43 (32%) 63 (46%) 29 (22%) 60 (37%) 69 (43%) 34 (21%) Dominant Site of Disease Visceral 1 Soft Tissue Bone 101 (75%) 30 (22%) 4 (3%) 110 (68%) 35 (22%) 17 (10%) P r ior Chemotherapy Paclitaxel Anthracycline 2 5-FU Resistance to Paclitaxel Resistance to an Anthracycline 2 Resistance to both Paclitaxel and an Anthracycline 2 135 (100%) 122 (90%) 110 (81%) 103 (76%) 55 (41%) 43 (32%) 162 (100%) 147 (91%) 133 (82%) 124 (77%) 67 (41%) 51 (31%) 1 Lung, pleura, liver, peritoneum 2 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 Breast Cancer Trial Resistance to Both Paclitaxel and an Anthracycline ( n = 43) CR 0 PR 1 11 CR + PR 1 11 Response Rate 1 (95% C.I.) 25.6% (13.5, 41.2) Duration of Response, 1 Median in days 2 (Range) 154 (63 to 233) 1 Includes 2 patients treated with an anthracenedione 2 From date of first response For 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. fig-4 fig-5

15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

8.5 Geriatric Use Physicians should pay particular attention to monitoring the adverse effects of capecitabine in the elderly [see Warnings and Precautions (5.10) ].

8.4 Pediatric Use The safety and effectiveness of capecitabine 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 was similar. The first trial was conducted in 22 pediatric patients (median age 8 years, range 5 to 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/m 2 to 850 mg/m 2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1,250 mg/m 2 capecitabine every 12 hours on Days 1 to 14 of a 21­day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m 2 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 to 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/m 2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1, 250 mg/m 2 capecitabine every 12 hours on Days 1 to 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%).

8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, capecitabine 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 to 4% and 15 to 20%, respectively. Data Animal Data Oral 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 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed.( 8.2 ) Females and Males of Reproductive Potential : Verify pregnancy status of females prior to initiation of capecitabine. Advise males with female partners of reproductive potential to use effective contraception.( 8.3 ) Geriatric : Greater incidence of adverse reactions. Monitoring required. ( 8.5 ) Hepatic Impairment : Monitoring is recommended in patients with mild to moderate hepatic impairment. ( 8.6 ) Renal Impairment : Reduce capecitabine starting dose in patients with moderate renal impairment ( 2.4, 8.7 , 12.3 ) 8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, capecitabine 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 to 4% and 15 to 20%, respectively. Data Animal Data Oral 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 Summary There 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 and for 2 weeks after the final dose. Data Lactating 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 Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating capecitabine. Contraception Females Capecitabine 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. Males Based 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 [see Nonclinical Toxicology (13.1)] . Infertility Based on animal studies, capacetabine 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 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 was similar. The first trial was conducted in 22 pediatric patients (median age 8 years, range 5 to 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/m 2 to 850 mg/m 2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1,250 mg/m 2 capecitabine every 12 hours on Days 1 to 14 of a 21­day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m 2 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 to 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/m 2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1, 250 mg/m 2 capecitabine every 12 hours on Days 1 to 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 in the elderly [see Warnings and Precautions (5.10) ]. 8.6 Hepatic Insufficiency Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with capecitabine. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) 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-DFUR, 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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 150 mg •Capecitabine tablets, USP, 150 mg are supplied as light peach to peach colored, oblong shaped, biconvex film coated tablets, debossed with “C” on one side and “150” on other side. Bottles of 60 tablets 72205-006-60 500 mg •Capecitabine tablets, USP, 500 mg are supplied as light peach to peach colored, oblong shaped, biconvex film coated tablets, debossed with “C” on one side and “500” on other side. Bottles of 120 tablets 72205-007-92 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 is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

WARNING:CAPECITABINE-WARFARIN INTERACTION Capecitabine 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 -Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see 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 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 was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. WARNING: CAPECITABINE-WARFARIN INTERACTION See full prescribing information for complete boxed warning. Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use. Occurrence: Within several days and up to several months after initiating capecitabine therapy; may also be seen within 1 month after stopping capecitabine Predisposing factors: age>60 and diagnosis of cancer