HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Gemcitabine Injection is supplied as follows: NDC Gemcitabine Injection (38 mg per mL) Package Factor 25021-239-05 200 mg per 5.26 mL Single-Use Vial 1 vial per carton 25021-239-26 1 gram per 26.3 mL Single-Use Vial 1 vial per carton 25021-239-52 2 grams per 52.6 mL Single-Use Vial 1 vial per carton 16.2 Storage and Handling Unopened vials of Gemcitabine Injection are stable until the expiration date indicated on the package. Store refrigerated between 2 and 8C (36 and 46F). [See Dosage and Administration (2.6 and 2.7)]. Do not freeze. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Gemcitabine Injection is a clear and colorless to light straw-colored solution available in sterile single-use vials containing: 200 mg per 5.26 mL (38 mg per mL) 1 gram per 26.3 mL (38 mg per mL) 2 grams per 52.6 mL (38 mg per mL) Gemcitabine Injection: 200 mg per 5.26 mL injection vial (3) 1 gram per 26.3 mL injection vial (3) 2 grams per 52.6 mL injection vial (3)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label NDC 25021-239-05 Rx only Gemcitabine Injection 200 mg per 5.26 mL (38 mg per mL) For Intravenous Infusion Only Must Be Diluted Before Use Single-Use Vial Discard unused portion.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label Schedule-dependent Toxicity [see Warnings and Precautions (5.1)] Myelosuppression [see Warnings and Precautions (5.2)] Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.3)] Hemolytic-Uremic Syndrome [see Warnings and Precautions (5.4)] Hepatic Toxicity [see Warnings and Precautions (5.5)] Embryo-fetal Toxicity [see Warnings and Precautions (5.6), Use in Specific Populations (8.1), and Nonclinical Toxicology (13.1)] Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions (5.7)] Capillary Leak Syndrome [see Warnings and Precautions (5.8)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.9)] The most common adverse reactions for the single-agent (20%) are nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 clinical practice. Single-Agent Use The data described below reflect exposure to gemcitabine as a single-agent administered at doses between 800 mg/m2 to 1,250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema. Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent gemcitabine across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table. Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent Gemcitabinea a Grade based on criteria from the World Health Organization (WHO). b N=699 to 974; all patients with laboratory or non-laboratory data. c Regardless of causality. d For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. All Patients b All Grades Grade 3 Grade 4 Laboratory c 68 7 1 Hematologic Anemia Neutropenia 63 19 6 Thrombocytopenia 24 4 1 Hepatic 68 8 2 Increased ALT Increased AST 67 6 2 Increased Alkaline Phosphatase Hyperbilirubinemia 55 13 7 2 2 90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine plus cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Table 6: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial of Gemcitabine plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of 5% (All Grades) or 2% (Grades 3-4)]a a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading. b N=217 to 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. c N=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. f Non-laboratory events were graded only if assessed to be possibly drug-related. Gemcitabine plus Cisplatin b Cisplatin c All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory d Hematologic Anemia 89 22 3 67 6 1 RBC Transfusione 39 13 Neutropenia 79 22 35 20 3 1 Thrombocytopenia 85 25 25 13 3 1 Platelet Transfusionse 21 <1 Lymphopenia 75 25 18 51 12 5 Hepatic Increased Transaminase 22 2 1 10 1 0 Increased Alkaline Phosphatase 19 1 0 13 0 0 Renal Proteinuria 23 0 0 18 0 0 Hematuria 15 0 0 13 0 0 Elevated creatinine 38 4 <1 31 2 <1 Other Laboratory Hyperglycemia 30 4 0 23 3 0 Hypomagnesemia 30 4 3 17 2 0 Hypocalcemia 18 2 0 7 0 <1 Non-laboratory f Nausea 93 25 2 87 20 <1 Vomiting 78 11 12 71 10 9 Alopecia 53 1 0 33 0 0 Neuro Motor 35 12 0 15 3 0 Diarrhea 24 2 2 13 0 0 Neuro Sensory 23 1 0 18 1 0 Infection 18 3 2 12 1 0 Fever 16 0 0 5 0 0 Neuro Cortical 16 3 1 9 1 0 Neuro Mood 16 1 0 10 1 0 Local 15 0 0 6 0 0 Neuro Headache 14 0 0 7 0 0 Stomatitis 14 1 0 5 0 0 Hemorrhage 14 1 0 4 0 0 Hypotension 12 1 0 7 1 0 Rash 11 0 0 3 0 0 Table 7 presents the incidence of selected adverse reactions, occurring in 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in a randomized trial of gemcitabine plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)]. A listing of clinically significant adverse reactions is provided following the table. Patients in the gemcitabine cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the gemcitabine/cisplatin arm. Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemcitabine plus Cisplatin versus Etoposide plus Cisplatin in Patients with NSCLCa a Grade based on criteria from the World Health Organization (WHO). b N=67 to 69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days. c N=57 to 63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events. f Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. g Flu-like syndrome and edema were not graded. Gemcitabine plus Cisplatin b Etoposide plus Cisplatin c All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory d 88 22 0 77 13 2 Hematologic Anemia RBC Transfusionse 29 - - 21 - - Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 - 16 - 45 8 - 5 - Platelet Transfusionse 3 8 Hepatic 6 0 0 12 0 0 Increased ALT Increased AST 3 0 0 11 0 0 Increased Alkaline Phosphatase 16 0 0 11 0 0 Bilirubin 0 0 0 0 0 0 Renal 12 0 0 5 0 0 Proteinuria Hematuria 22 0 0 10 0 0 BUN 6 0 0 4 0 0 Creatinine 2 0 0 2 0 0 Non-laboratory f 96 35 4 86 19 7 Nausea and Vomiting Fever 6 0 0 3 0 0 Rash 10 0 0 3 0 0 Dyspnea 1 0 1 3 0 0 Diarrhea 14 1 1 13 0 2 Hemorrhage 9 0 3 3 0 3 Infection 28 3 1 21 8 0 Alopecia 77 13 0 92 51 0 Stomatitis 20 4 0 18 2 0 Somnolence 3 0 0 3 2 0 Paresthesias 38 0 0 16 2 0 Flu-like syndromeg 3 - - 0 - - Edemag 12 - - 2 - - Breast Cancer Table 8 presents the incidence of selected adverse reactions, occurring in 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus paclitaxel arm, reported in a randomized trial of gemcitabine plus paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)]. The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. Table 8: Per-Patient Incidence of Selected Adverse Reactions from Comparative Trial of Gemcitabine plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of 5% (All Grades) or 2% (Grades 3-4)] a Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0. b Regardless of causality. c Non-laboratory events were graded only if assessed to be possibly drug-related. Gemcitabine plus Paclitaxel (N=262) Paclitaxel (N=259) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hematologic Anemia Neutropenia Thrombocytopenia 69 69 26 6 31 5 1 17 <1 51 31 7 3 4 <1 <1 7 <1 Hepatobiliary 18 5 <1 6 <1 0 Increased ALT Increased AST 16 2 0 5 <1 0 Non-laboratory c 90 14 4 92 19 3 Alopecia Neuropathy-sensory 64 5 <1 58 3 0 Nausea 50 1 0 31 2 0 Fatigue 40 6 <1 28 1 <1 Vomiting 29 2 0 15 2 0 Diarrhea 20 3 0 13 2 0 Anorexia 17 0 0 12 <1 0 Neuropathy-motor 15 2 <1 10 <1 0 Stomatitis/pharyngitis 13 1 <1 8 <1 0 Fever 13 <1 0 3 0 0 Rash/desquamation 11 <1 <1 5 0 0 Febrile neutropenia 6 5 <1 2 1 0 Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the Gemcitabine plus paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). Ovarian Cancer Table 9 presents the incidence of selected adverse reactions, occurring in 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus carboplatin arm, reported in a randomized trial of gemcitabine plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following Table 9. The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for gemcitabine occurred in 10.4% of patients and gemcitabine dose was omitted in 13.7% of patients in the gemcitabine/carboplatin arm. Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of 5% (All Grades) or 2% (Grades 3-4)] a Grade based on Common Toxicity Criteria (CTC) Version 2.0. b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. Gemcitabine plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hematologic Neutropenia Anemia Thrombocytopenia RBC Transfusionsc Platelet Transfusionsc 90 86 78 38 9 42 22 30 29 6 5 58 75 57 15 3 11 9 10 1 2 1 Non-laboratory b 69 6 0 61 3 0 Nausea Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constipation 42 6 1 37 3 0 Fatigue 40 3 <1 32 5 0 Diarrhea 25 3 0 14 <1 0 Stomatitis/pharyngitis 22 <1 0 13 0 0 Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%). The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine plus carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of gemcitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular - Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias. Vascular Disorders - Peripheral vasculitis, gangrene and capillary leak syndrome [see Warnings and Precautions (5.8)]. Skin - Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions. Hepatic - Hepatic failure, hepatic veno-occlusive disease. Pulmonary - Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS). Nervous System - Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.9)].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Gemcitabine Injection is a nucleoside metabolic inhibitor indicated: in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. (1.1) in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. (1.2) in combination with cisplatin for the treatment of non-small cell lung cancer. (1.3) as a single-agent for the treatment of pancreatic cancer. (1.4) 1.1 Ovarian Cancer Gemcitabine Injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. 1.2 Breast Cancer Gemcitabine Injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. 1.3 Non-Small Cell Lung Cancer Gemcitabine Injection is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer. 1.4 Pancreatic Cancer Gemcitabine Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine Injection is indicated for patients previously treated with 5-FU.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Gemcitabine injection is for intravenous use only. Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.1) Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2) Non-small cell lung cancer: 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.3) Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one-week rest, then once weekly for 3 weeks of each 28-day cycle. (2.4) 2.1 Ovarian Cancer Recommended Dose and Schedule The recommended dose of gemcitabine injection is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information. Dose Modifications Recommended gemcitabine injection dose modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions. Table 1: Dosage Reduction Guidelines for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Day Absolute granulocyte count (x 10 6 /L) Platelet count (x 10 6 /L) % of full dose Day 1 1500 75,000 100% 1000 to 1199 or 50,000 to 75,000 75% 700 to 999 and 50,000 50% <700 or <50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule Every 4-week schedule The recommended dose of gemcitabine injection is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine injection. Every 3-week schedule The recommended dose of gemcitabine injection is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine injection. Dose Modifications Recommended dose modifications for gemcitabine injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine injection recommendations for non-hematologic adverse reactions. 2.4 Pancreatic Cancer Recommended Dose and Schedule The recommended dose of gemcitabine injection is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule is as follows: Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest. After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles. Dose Modifications Recommended dose modifications for Gemcitabine Injection for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions. Patients receiving gemcitabine injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4. Table 4: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute granulocyte count (x 10 6 /L) Platelet count (x 10 6 /L) % of full dose 1000 And 100,000 100% 500 to 999 Or 50,000 to 99,999 75% <500 Or <50,000 Hold 2.5 Dose Modifications for Non-Hematologic Adverse Reactions Permanently discontinue gemcitabine injection for any of the following: Unexplained dyspnea or other evidence of severe pulmonary toxicity Severe hepatic toxicity Hemolytic-uremic syndrome Capillary leak syndrome Posterior reversible encephalopathy syndrome Withhold gemcitabine injection or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting. 2.6 Preparation and Administration Precautions Exercise caution and wear gloves when preparing gemcitabine solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine go to OSHA Hazardous Drugs (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 2.7 Preparation for Intravenous Infusion Administration Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives. Each vial contains a gemcitabine concentration of 38 mg per mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 gram, or 2 grams of gemcitabine, respectively. Prior to administration, the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg per mL. Reconstituted gemcitabine injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20 to 25C (68 to 77F). Do not refrigerate as crystallization can occur. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

DESCRIPTION SECTION.


11 DESCRIPTION Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2-deoxy-2,2-difluorocytidine monohydrochloride (-isomer). The structural formula is as follows: The empirical formula for gemcitabine HCl is C9H11F2N3O4 HCl. It has a molecular weight of 299.66. Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. The clinical formulation is supplied as a sterile solution for intravenous single vial use only. Vials of Gemcitabine Injection contain either 200 mg, 1 gram, or 2 grams of gemcitabine HCl (expressed as free base). Each mL contains equivalent of 38 mg of gemcitabine in Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

OVERDOSAGE SECTION.


10 OVERDOSAGE Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Schedule-dependent toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly. (5.1) Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. (5.2, 5.7) Pulmonary Toxicity and Respiratory Failure: Discontinue gemcitabine immediately for unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity. (5.3) Hemolytic-Uremic Syndrome (HUS): Monitor renal function prior to initiation and during therapy. Discontinue gemcitabine for HUS or severe renal impairment. (5.4) Hepatic Toxicity: Monitor hepatic function prior to initiation and during therapy. Discontinue gemcitabine for severe hepatic toxicity. (5.5) Embryo-fetal Toxicity: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within 7 days of radiation therapy. (5.7) Capillary Leak Syndrome: Discontinue gemcitabine. (5.8) Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue gemcitabine. (5.9) 5.1 Schedule-dependent Toxicity In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)]. 5.2 Myelosuppression Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia, occurs with gemcitabine as a single-agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent gemcitabine. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving gemcitabine in combination with another drug. 5.3 Pulmonary Toxicity and Respiratory Failure Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine. Discontinue gemcitabine in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)]. 5.4 Hemolytic-Uremic Syndrome Hemolytic-uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with gemcitabine. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Assess renal function prior to initiation of gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN) [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy. 5.5 Hepatic Toxicity Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic function prior to initiation of gemcitabine and periodically during treatment. Discontinue gemcitabine in patients that develop severe liver injury. 5.6 Embryo-fetal Toxicity Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of gemcitabine [see Use in Specific Populations (8.1) and (8.3)]. 5.7 Exacerbation of Radiation Therapy Toxicity Gemcitabine is not indicated for use in combination with radiation therapy. Concurrent (given together or 7 days apart) - Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. Non-concurrent (given >7 days apart) - Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received gemcitabine after prior radiation. 5.8 Capillary Leak Syndrome Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single-agent or in combination with other chemotherapeutic agents. Discontinue gemcitabine if CLS develops during therapy. 5.9 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single-agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue gemcitabine if PRES develops during therapy.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS No specific drug interaction studies have been conducted.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits [see Data]. Advise pregnant women of the potential risk to a fetus. 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 Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. 8.2 Lactation There are no data on the presence of gemcitabine in human milk, or the effects of gemcitabine on the breastfed infant or milk production. Because of the potential for serious adverse reactions in nursing infants from gemcitabine, advise a lactating woman not to breastfeed during treatment with gemcitabine and for one week after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose [see Use in Specific Populations (8.1)]. Males Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of gemcitabine [see Nonclinical Toxicology (13.1)]. Infertility Males Based on animal studies, gemcitabine may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of gemcitabine has not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine was evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m2/min for 360 minutes weekly for three weeks followed by a one-week rest period. The safety and activity of gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes weekly for three weeks followed by a one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial. 8.5 Geriatric Use In clinical studies of gemcitabine, enrolling 979 patients with various cancers who received gemcitabine as a single-agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received gemcitabine plus carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Gemcitabine clearance is affected by age, however there are no recommended dose adjustments based on patients' age [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No clinical studies have been conducted with gemcitabine in patients with decreased renal function. 8.7 Hepatic Impairment No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. 8.8 Gender Gemcitabine clearance is affected by gender [see Clinical Pharmacology (12.3)]. In single-agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise patients of the risk of low blood cell counts and the potential need for blood transfusions and increased susceptibility to infections. Instruct patients to immediately contact their healthcare provider for development of signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or shortness of breath [see Warnings and Precautions (5.2)]. Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough [see Warnings and Precautions (5.3)]. Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding [see Warnings and Precautions (5.4)]. Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant [see Warnings and Precautions (5.5)]. SAGENT Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Made in India 2018 Sagent Pharmaceuticals, Inc. April 2018 SAGENT Pharmaceuticals

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS Gemcitabine injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Patients with a known hypersensitivity to gemcitabine. (4)

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Ovarian Cancer The safety and efficacy of gemcitabine was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine infusion on Day 1 of each cycle (n = 178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n = 178) . The primary efficacy outcome measure was progression free survival (PFS). Patient characteristics are shown in Table 11. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms. Table 11: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Baseline Demographics and Clinical Characteristics a 5 patients on the gemcitabine plus carboplatin arm and 4 patients on the carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status. b 2 on the gemcitabine plus carboplatin arm and 1 on the carboplatin arm had a platinum-free interval of less than 6 months. Gemcitabine/Carboplatin Carboplatin Number of randomized patients 178 178 Median age, years Range 59 36 to 78 58 21 to 81 Baseline ECOG performance status 0 to 1a 94% 95% Disease Status Evaluable Bidimensionally measurable 8% 92% 3% 96% Platinum-free intervalb 6 to 12 months >12 months 40% 59% 40% 60% First-line therapy Platinum-taxane combination Platinum-non-taxane combination Platinum monotherapy 70% 29% 1% 71% 28% 1% Table 12: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Efficacy Outcomes a CI=confidence interval. b Log rank, unadjusted. c Chi square. d CR=Complete response. e PR plus PRNM=Partial response plus partial response, non-measurable disease. f Independently reviewed cohort - Gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam. Gemcitabine/Carboplatin (N=178) Carboplatin (N=178) Progression free Survival Median (95% CIa) months Hazard Ratio (95% CI) 8.6 (8.0, 9.7) 5.8 (5.2, 7.1) 0.72 (0.57, 0.90) p=valueb Overall Survival Median (95% CI) months Hazard Ratio (95% CI) p=valueb Investigator Reviewed Overall Response Rate p=0.0038 18.0 (16.2, 20.3) 17.3 (15.2, 19.3) 0.98 (0.78, 1.24) p=0.8977 47.2% 30.9% p=valuec p=0.0016 CRd PR+PRNMe 14.6% 6.2% 32.6% 24.7% Independently Reviewed Overall Response Ratef 46.3% 35.6% p=valuec p=0.11 CRd 9.1% 4.0% PR+PRNMe 37.2% 31.7% Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer (N=356) 14.2 Breast Cancer The safety and efficacy of gemcitabine were evaluated in a multinational, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive gemcitabine 1250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to gemcitabine on Day 1 of each cycle (n = 267). Single-agent paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n = 262). The primary efficacy outcome measure was time to documented disease progression. A total of 529 patients were enrolled; 267 were randomized to gemcitabine and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are presented in Table 13 and Figure 2. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival. Table 13: Randomized Trial of Gemcitabine plus Paclitaxel versus Paclitaxel in Breast Cancer a Karnofsky Performance Status. b These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm. c Based on the ITT population. Gemcitabine/Paclitaxel Paclitaxel Number of patients 267 262 Demographic/Entry Characteristics Median age, years 53 52 Range 26 to 83 26 to 75 Metastatic disease 97% 97% Baseline KPSa 90 70% 74% Number of tumor sites 1 to 2 57% 59% 3 43% 41% Visceral disease 73% 73% Prior anthracycline 97% 96% Efficacy Outcomes Time to Documented Disease Progressionb Median in months (95% CI) 5.2 (4.2, 5.6) 2.9 (2.6, 3.7) Hazard Ratio (95% CI) 0.650 (0.524, 0.805) p-value p<0.0001 Overall Survivalc Median Survival in months (95% CI) 18.6 (16.5, 20.7) 15.8 (14.1, 17.3) Hazard Ratio (95% CI) 0.86 (0.71, 1.04) p-value Not significant Overall Response Ratec (95% CI) 40.8% (34.9, 46.7) 22.1% (17.1, 27.2) p-value p<0.0001 Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529) 14.3 Non-Small Cell Lung Cancer (NSCLC) The safety and efficacy of gemcitabine was evaluated in two randomized, multicenter trials. 28-Day Schedule A multinational, randomized trial compared gemcitabine plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive gemcitabine 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival. 21-Day Schedule A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle. There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see Table 14). The median survival was 8.7 months for the gemcitabine plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the gemcitabine plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided). Figure 3: Kaplan-Meier Survival Curve in Gemcitabine plus Cisplatin versus Cisplatin NSCLC Study (N=522) Table 14: Randomized Trials of Gemcitabine plus Cisplatin in Patients with NSCLC a 28-day schedule Gemcitabine plus cisplatin: Gemcitabine 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days. b 21-day schedule Gemcitabine plus cisplatin: Gemcitabine 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days. c N/A Not applicable. d Karnofsky Performance Status. e CI=confidence intervals. f p-value two-sided Fisher's Exact test for difference in binomial proportions; log rank test for time-to-event analyses. Trial 28-day Schedule a 21-day Schedule b Treatment Arm Gemcitabine plus Cisplatin Cisplatin Gemcitabine plus Cisplatin Etoposide plus Cisplatin Number of patients 260 262 69 66 Demographic/Entry Characteristics Male 70% 71% 93% 92% Median age, years 62 63 58 60 Range 36 to 88 35 to 79 33 to 76 35 to 75 Stage IIIA 7% 7% N/Ac N/Ac Stage IIIB 26% 23% 48% 52% Stage IV 67% 70% 52% 49% Baseline KPSd 70 to 80 41% 44% 45% 52% Baseline KPSd 90 to 100 57% 55% 55% 49% Efficacy Outcomes Survival Median, months 9.0 7.6 8.7 7.0 (95% CIe) months 8.2, 11.0 6.6, 8.8 7.8, 10.1 6.0, 9.7 p-valuef p=0.008 p=0.18 Time to Disease Progression Median in months 5.2 3.7 5.0 4.1 (95% CIe) months 4.2, 5.7 3.0, 4.3 4.2, 6.4 2.4, 4.5 p-valuef p=0.009 p=0.015 Tumor Response 26% 10% 33% 14% p-valuef p<0.0001 p=0.01 14.4 Pancreatic Cancer The safety and efficacy of gemcitabine was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles. The primary efficacy outcome measure in both trials was clinical benefit response. A patient was considered to have had a clinical benefit response if either of the following occurred: The patient achieved a 50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (7% increase maintained for 4 weeks) not due to fluid accumulation. The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 15). The efficacy outcome results are shown in Table 15 and for overall survival in Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm. Table 15: Randomized Trial of Gemcitabine versus 5-Fluorouracil in Pancreatic Cancer a Karnofsky Performance Status. b p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test. Gemcitabine 5-FU Number of patients 63 63 Demographic/Entry Characteristics Male 54% 54% Median age 62 years 61 years Range 37 to 79 36 to 77 Stage IV disease 71% 76% Baseline KPSa 70 70% 68% Efficacy Outcomes Clinical benefit response 22.2% 4.8% p-valueb p=0.004 Survival Median (95% CI) 5.7 months (4.7, 6.9) 4.2 months (3.1, 5.1) p-valueb p=0.0009 Time to Disease Progression Median (95% CI) 2.1 months (1.9, 3.4) 0.9 months (0.9, 1.1) p-valueb p=0.0013 Figure 4: Kaplan-Meier Survival Curve

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands which eventually results in the initiation of apoptotic cell death. 12.3 Pharmacokinetics Absorption and Distribution The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total gemcitabine dose varied from 500 to 3600 mg/m2. The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2. Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible. Metabolism Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2-deoxy-2,2- difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma. The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. Elimination Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. Table 10: Gemcitabine Clearance and Half-Life for the Typical Patient a Half-life for patients receiving <70 minute infusion. Age Clearance Men (L/hr/m 2 ) Clearance Women (L/hr/m 2 ) Half-Life a Men (min) Half-Life a Women (min) 29 92.2 69.4 42 49 45 75.7 57.0 48 57 65 55.1 41.5 61 73 79 40.7 30.7 79 94 Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. Drug Interactions When gemcitabine (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.