February 11, David Grimes, PharmD Duke Raleigh Hospital 3400 Wake Forest Road Raleigh, NC Dear Dr. Grimes:

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1 David Grimes, PharmD Duke Raleigh Hospital 3400 Wake Forest Road Raleigh, NC Dear Dr. Grimes: This letter responds to your request for information on: Xeloda - Extemporaneous Preparation This information is sent as a professional courtesy to provide you with data to assist in making your own practice decisions. The information enclosed is a summary of the best available clinical data selected using principles of evidence-based medicine and may include products or uses that have not been approved by the U.S. Food and Drug Administration. Please refer to the enclosed full prescribing information for complete product indication and safety information. If you have any additional questions, please contact the Medical Communications Department toll free at or via the online Medical Information Request Form at Alternatively, if you would like to speak with a Genentech Medical Science Liaison, please mslmgrs-d@gene.com. Additional resources for Xeloda may be available on Sincerely, Niyati P. Freeman, Pharm.D. Medical Communications Department Encl. Xeloda PI and Patient Information C# NPF/nf 1 DNA WAY, SOUTH SAN FRANCISCO, CA USA

2 Page 2 of 6 Xeloda (capecitabine) INDICATIONS AND USAGE Colorectal Cancer XELODA 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. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5- FU/LV. Physicians should consider these results when prescribing single-agent XELODA in the adjuvant treatment of Dukes C colon cancer. XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage. Breast Cancer XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. XELODA monotherapy is 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. IMPORTANT SAFETY INFORMATION Boxed WARNING 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. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Contraindications XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil. XELODA is also contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, or severe renal impairment. Monotherapy in Adjuvant Colon Cancer In a phase 3 study of XELODA monotherapy in colon cancer in the adjuvant setting, serious adverse events (grade 3/4) occurring in 5% of patients receiving either XELODA or 5-FU/LV (%;%) were increase in bilirubin (20;6), hand-foot syndrome (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), decrease in neutrophils/granulocytes (2;26), stomatitis (2;14), and neutropenia (<1;5).

3 Page 3 of 6 Monotherapy in MCRC In two phase 3 trials of XELODA monotherapy in metastatic colorectal cancer, serious adverse events (grade 3/4) occurring in 5% of patients receiving either XELODA or 5-FU/LV (%;%) were hyperbilirubinemia (23;6), hand-foot syndrome (17;1), diarrhea (15;12), abdominal pain (<10;5), vomiting (<5;<5), ileus (5;3), stomatitis (<3;15), and neutropenia (3;21). Monotherapy in MBC In a single-arm study of XELODA monotherapy in metastatic breast cancer, serious adverse events (grade 3/4) occurring in 5% of patients receiving XELODA (%) were lymphopenia (59), diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia (11), fatigue (8), stomatitis (7), and dehydration (5). Combination Therapy with Docetaxel in MBC In a phase 3 study of XELODA combination therapy (XELODA plus docetaxel) in metastatic breast cancer, serious adverse events (grade 3/4) occurring at a 2% higher incidence in patients receiving XELODA plus docetaxel vs. docetaxel alone (%;%) were lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail disorder (2;0). IMPORTANT TREATMENT CONSIDERATIONS Dose Modifications XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced it should not be increased at a later time. Please consult XELODA Prescribing Information for recommended dose modifications. Women of Childbearing Potential XELODA may cause fetal harm when given to a pregnant woman. There are no adequate and wellcontrolled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

4 Page 4 of 6 This letter responds to your request for information on extemporaneous preparation of Xeloda (capecitabine) tablets. Extemporaneous Preparation In Brief The safety and efficacy of Xeloda tablets outside of the approved dosage form described in the package insert have not been established. Therefore, there are no recommendations for use of the product in any dosage form outside the approved package insert. A small randomized crossover study evaluating the bioequivalence of whole Xeloda tablets to crushed Xeloda tablets dispersed in 40 ml of water has been conducted. The 2 formulations had bioequivalence based on the area under the curve (AUC) for capecitabine and the active metabolite, 5-fluorouracil (5-FU). Bioequivalence could not be established for maximum plasma concentration (C max ) since the crushed tablets were associated with a statistically significant increase in the rate and extent of absorption. Similar findings were observed for the active metabolite, 5-FU. Another pharmacokinetic study evaluating a drinking solution of Xeloda powder in 200 ml of water showed that the absorption of capecitabine was rapid and almost complete. The excretion of the intact drug and its metabolites was rapid and almost exclusive to the urine. Xeloda tablets are film-coated tablets and are water soluble. A search of the published literature revealed 1 ongoing Phase III study, which anecdotally mentioned that Xeloda may be administered orally in a suspension or via feeding tube for patients with dysphagia. No additional information surrounding the suspension was provided. Package Insert Xeloda is supplied as biconvex, oblong film-coated tablets. 1 The recommended dose of Xeloda is 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. Xeloda tablets should be swallowed with water within 30 minutes after a meal. The pharmacokinetics of Xeloda and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500-3,500 mg/m 2 /day. Capecitabine is readily absorbed from the gastrointestinal tract. Capecitabine reached peak blood levels (T max ) in about 1.5 hours with peak 5-FU levels occurring slightly later, at 2 hours. The elimination half-life of both parent capecitabine and 5-FU was about 3/4 of an hour. Pharmacokinetic Studies Crushed Xeloda Tablets vs Whole Tablets Chaigneau L et al. conducted a small randomized crossover study comparing the bioequivalence of whole Xeloda tablets to crushed Xeloda tablets dispersed in 40 ml of water. 2 Cancer patients (n=14) received whole Xeloda tablets on Day 1 (1,250 mg/m 2 twice daily) and crushed tablets dispersed in 40 ml of water on Day 2 in the first arm and the opposite in the second arm. Over 6 hours, in the morning, 8 samples were taken to measure the concentration of capecitabine and its metabolites. The 2 formulations had bioequivalence based on the AUC for both capecitabine and the active metabolite 5-FU. Bioequivalence could not be established for C max since the crushed tablets were associated with a statistically significant increase in the rate and extent of absorption. The AUC ratio for the 2 formulations was 101.1% (88.0% to 116.2%) for capecitabine and 94.6% (82.8% to 108.2%) for the active metabolite 5-FU. The C max ratio for the 2 formulations was 153.6% (109.3% to 215.9%) for capecitabine and 164.3% (119.1% to 226.7%) for the active metabolite 5-FU. Significant inter-patient variability for pharmacokinetic parameters was noted by the investigators.

5 Page 5 of 6 Xeloda Powder A pharmacokinetic study evaluating a drinking solution of Xeloda powder in cancer patients with solid tumors showed that the absorption of capecitabine was rapid and almost complete. 3 The excretion of the intact drug and its metabolites was rapid and almost exclusive to the urine. This pharmacokinetic study was conducted to provide a better understanding of the excretion of capecitabine and its metabolites. We are not aware of any clinical studies that have evaluated a drinking solution of capecitabine; therefore, we can not provide information on the clinical significance of these findings. Patients received a single dose of Xeloda 2,000 mg where Xeloda was provided in a powder form and reconstituted on the day of administration by adding 200 ml of water. This drinking solution was given 30 minutes after completing a standard breakfast. Six of 7 patients were eligible for pharmacokinetic analysis. The dose was almost completely recovered in the urine (mean 95.5%, range ) over 7 days after drug administration. Eight-four percent of the dose was recovered in the first 12 hours, indicating rapid excretion of capecitabine and its metabolites. The investigators reported that their results were in general agreement with those of previous studies. 4-6 The input rate (earlier t max ) was higher in this study, as would be expected after administration of a drinking solution compared with administration of tablets. 3 After absorption, the t max for the intact drug (capecitabine) and the precursors of 5-FU (5 -deoxyfluorocytidine [5-DFCR], 5 -deoxy-5-fluorouridine [5-DFUR]) was within 30 minutes (t max 0.51 hours [range, ]), indicating rapid transformation of capecitabine to the active species 5-FU, while the catabolites of 5-FU, dihydro-5-fluorouracil (FUH 2 ) and α-fluoro-β-alanine (FBAL), had a longer t max ( hours). Table 1: Pharmacokinetic Parameters of Xeloda and Its Metabolites in Plasma 3 Parameter Radioactivity Capecitabine 5 -DFCR 5 -DFUR 5-FU FUH 2 FBAL C max (g/ml) 2573 (30%)* 10.3 (93%) 6.9 (60%) 11.3 (35%) 0.4 (65%) 1.4 (21%) 5.0 (21%) t max (h) 0.51 ( ) 0.25 ( ) 0.51 ( ) 0.51 ( ) 0.51 ( ) 1.50 ( ) 1.75 ( ) AUC 0t (g.h/ml) 10,836 (24%) 7.0 (50%) 9.7 (54%) 17.6 (38%) 0.4 (32%) 4.3 (24%) 26.8 (22%) AUC 0-00 NC c 7.0 (50%) 9.7 (54%) 17.7 (37%) 0.4 (32%) 4.4 (23%) 27.3 (22%) (g.h/ml) t 1/2 (h) NC 0.62 (36%) 0.80 (21%) 0.71 (19%) 0.78 (30%) 1.1 (19%) 4.95 (26%) Note: Mean values (coefficient of variation in %) were reported for C max, AUC and t 1/2. Median values (range) were reported for t max. Abbreviations: 5-DFCR=5 -deoxy-fluorocytidine; 5-DFUR=5 -deoxy-5-fluorouridine; 5-FU=5-fluorouracil; AUC=area under the curve; C max =maximum plasma concentration; FUH 2 =dihydro-5-fluorouracil; FBAL=α-fluoro-β-alanine; h=hour(s); NC=not calculated; t 1/2 =half life. a Values in dpm/ml; b Values in dpm.h/ml. The parent drug (capecitabine) and the precursors (5 DFCR, 5 DFUR) of 5-FU were not detectable in the plasma 12 hours post dosing, which reflected their short half-lives. 3 The half-life for FBAL was 4.95 hours, and FBAL was detectable in the plasma up to 48 hours post dosing. Splitting or Crushing Tablets Xeloda is supplied as film-coated tablets. 1 Capecitabine is water soluble. The tablets are film-coated to mask the bitter taste of the drug and to minimize the risk to healthcare personnel from potential direct contact with an antineoplastic drug. Safety and efficacy of crushed or cut Xeloda tablets have not been established; therefore, there are no recommendations for use of the product outside of the approved dosage form. Additionally, healthcare professionals handling Xeloda tablets in a dosage form outside of the package insert should exercise caution. Xeloda Administration Via Nasogastric Tube No studies have been conducted on Xeloda in a setting where the tablets were crushed, made into an extemporaneous preparation, and administered via a nasogastric tube. The published literature revealed 1 anecdotal report from an ongoing Phase III study that mentioned that Xeloda may be administered orally in a suspension or via feeding tube for patients with dysphagia. 7 No additional information was provided by the investigators.

6 Page 6 of 6 Extemporaneous Preparation References 1. Xeloda [package insert]. Genentech USA, Inc.; South San Francisco, CA 2. Chaigneau L, Royer B, Montange D, et al. Influence of capecitabine absorption on its metabolites pharmacokinetics: a bioequivalence study. Ann Oncol 2008;19: Judson IR, Beale PJ, Trigo JM, et al. A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug. Invest New Drugs 1999;17: Cassidy J, Twelves C, Cameron D, et al. Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients. Cancer Chemother Pharmacol 1999;44: Reigner B, Clive S, Cassidy J, et al. Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients. Cancer Chemother Pharmacol 1999;43: Twelves C, Glynne-Jones R, Cassidy J, et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1999;5: Sumpter KA, Harpe-Wynne C, Cunningham D. Randomized, multicenter phase III study comparing capecitabine with fluorouracil and oxalipaltin with cisplatin in patients with advanced oesophagogastric cancer: confirmation of dose escalation. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois; May 31-June 3, ASCO Poster #1031.