Capecitabine

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/m2 of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

2 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/m2 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 *Total Daily Dose divided by 2 to allow equal morning and evening doses Dose Level 1,250 mg/m 2 Twice a Day Number of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area (m 2 ) T otal Daily Dose* ( m g) 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 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 *National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)] . 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% 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 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 tablets starting dose when used as monotherapy or in combination with docetaxel (from 1,250 mg/m2 to 950 mg/m2 twice daily) is recommended [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions ( 5.5 )] . The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine tablets 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 x 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.

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.

Not available.

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 Cipla Limited, at 1-866-604-3268 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/m2 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/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5- FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine- treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1%) 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=1,969) Capecitabine ( N=995) 5-FU/LV ( N=974) B o d y System/Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders Diarrhea Nausea Stomatitis Vomiting Abdominal Pain Constipation Upper Abdominal Pain Dyspepsia 47 34 22 15 14 9 7 6 12 2 2 2 3 - <1 <1 65 47 60 21 16 11 7 5 14 2 14 2 2 <1 <1 - S kin and Subcutaneous T issue Disorders Hand-and-Foot Syndrome Alopecia Rash Erythema 60 6 7 6 17 - - 1 9 22 8 5 <1 <1 - <1 General Disorders and Administration Site Conditions Fatigue Pyrexia Asthenia Lethargy 16 7 10 10 <1 <1 <1 <1 16 9 10 9 1 <1 1 <1 Nervous System Disorders Dizziness Headache Dysgeusia 6 5 6 <1 <1 - 6 6 9 - <1 - M e tabolism and Nutrition Disorders Anorexia 9 <1 11 <1 E y e Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 R e s piratory 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) *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. **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. Adverse Event Capecitabine ( n = 995) Grade 3/4 % I V 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* 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 1.0 0.7 Increased bilirubin** 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/m 2 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 – Not observed * Excluding vertigo NA = Not Applicable 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 ˃ One Ad v er s e 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 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. 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%), 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%), pancytopenia (0.1%) Vascular : hypotension (0.2%), hypertension (0.1%), lymphedema (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.