GEMCITABINE

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications ( 4 )] 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 )] 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, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800- 551-7176 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 practice. Single Agent The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m 2 to 1,250 mg/m 2 intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (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, increased 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 reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema. Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6 . Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine a a Grade based on criteria from the World Health Organization (WHO). b For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related. c N=699-974; all patients with laboratory or non-laboratory data. Adverse Reactions b Gemcitabine c All Grades (%) Grade 3 (%) Grade 4 (%) Nausea and Vomiting 69 13 1 Fever 41 2 0 Rash 30 <1 0 Dyspnea 23 3 <1 Diarrhea 19 1 0 Hemorrhage 17 <1 <1 Infection 16 1 <1 Alopecia 15 <1 0 Stomatitis 11 <1 0 Somnolence 11 <1 <1 Paresthesias 10 <1 0 Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine a a Grade based on criteria from the WHO. b Regardless of causality. c N=699-974; all patients with laboratory or non-laboratory data. Laboratory Abnormality b Gemcitabine c All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia 68 7 1 Neutropenia 63 19 6 Thrombocytopenia 24 4 1 Hepatic Increased ALT 68 8 2 Increased AST 67 6 2 Increased Alkaline Phosphatase 55 7 2 Hyperbilirubinemia 13 2 <1 Renal Proteinuria 45 <1 0 Hematuria 35 <1 0 Increased BUN 16 0 0 Increased Creatinine 8 <1 0 Additional adverse reactions include the following: Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%) Edema: Edema (13%), peripheral edema (20%), generalized edema (<1%) Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating and/or malaise (19%) Infection: Sepsis (<1%) Extravasation: Injection-site reactions (4%) Allergic: Bronchospasm (<2%); anaphylactoid reactions Ovarian Cancer Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with 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 <10% of patients, are provided following Table 8 . 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 adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm. Table 7: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1 a a Grade based on National Cancer Institute CTC Version 2.0. b Regardless of causality. Adverse Reactions b Gemcitabine/Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Nausea 69 6 0 61 3 0 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 Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1 a a Grade based on National Cancer Institute 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. Laboratory Abnormality b Gemcitabine/Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Thrombocytopenia 78 30 5 57 10 1 RBC Transfusions c 38 - - 15 - - Platelet Transfusions c 9 - - 3 - - Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis- stimulating agent (7% and 3.9%). The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with 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). Breast Cancer Tables 9 and 10 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with 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 )]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 10 . 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 adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2 a a Grade based on National Cancer Institute CTC Version 2.0. b Non-laboratory events were graded only if assessed to be possibly drug-related. Adverse Reactions b Gemcitabine /Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Alopecia 90 14 4 92 19 3 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 Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2 a a Grade based on National Cancer Institute CTC Version 2.0. b Regardless of causality. Laboratory Abnormality b Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia 69 6 1 51 3 <1 Neutropenia 69 31 17 31 4 7 Thrombocytopenia 26 5 <1 7 <1 <1 Hepatobiliary Increased ALT 18 5 <1 6 <1 0 Increased AST 16 2 0 5 <1 0 Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). Non-Small Cell Lung Cancer Tables 11 and 12 presents the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies ( 14.3 )]. Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>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 with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus <1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine with 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 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3 a a Grade based on National Cancer Institute Common Toxicity Criteria (CTC). b Non-laboratory events were graded only if assessed to be possibly drug-related. c N=217-253; all Gemcitabine/cisplatin patients with laboratory or non-laboratory data d N=213-248; all cisplatin patients with laboratory or non-laboratory data Adverse Reactions b Gemcitabine/Cisplatin c Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) 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 1 0 Hemorrhage 14 1 0 4 0 0 Hypotension 12 1 0 7 1 0 Rash 11 0 0 3 0 0 Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3 a a Grade based on National Cancer Institute CTC. b Regardless of causality. c N=217- 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data d N=213- 248; all cisplatin patients with laboratory or non-laboratory data e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. Laboratory Abnormality b Gemcitabine/Cisplatin c Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia 89 22 3 67 6 1 Thrombocytopenia 85 25 25 13 3 1 Neutropenia 79 22 35 20 3 1 Lymphopenia 75 25 18 51 12 5 RBC Transfusions e 39 - - 13 - - Platelet Transfusions e 21 - - <1 - - Hepatic Increased Transaminases 22 2 1 10 1 0 Increased Alkaline Phosphatase 19 1 0 13 0 0 Renal Increased Creatinine 38 4 <1 31 2 <1 Proteinuria 23 0 0 18 0 0 Hematuria 15 0 0 13 0 0 Other Laboratory Hyperglycemia 30 4 0 23 3 0 Hypomagnesemia 30 4 3 17 2 0 Hypocalcemia 18 2 0 7 0 <1 Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies ( 14.3 )]. Additional clinically significant adverse reactions are provided following Table 14 . 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 adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were 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 GC arm. Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4 a a Grade based on criteria from the WHO. b Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. c N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data. e Flu-like syndrome and edema were not graded. Adverse Reactions b Gemcitabine/Cisplatin c Etoposide/Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Nausea and Vomiting 96 35 4 86 19 7 Alopecia 77 13 0 92 51 0 Paresthesias 38 0 0 16 2 0 Infection 28 3 1 21 8 0 Stomatitis 20 4 0 18 2 0 Diarrhea 14 1 1 13 0 2 Edema e 12 - - 2 - - Rash 10 0 0 3 0 0 Hemorrhage 9 0 3 3 0 3 Fever 6 0 0 3 0 0 Somnolence 3 0 0 3 2 0 Flu-like Syndrome e 3 - - 0 - - Dyspnea 1 0 1 3 0 0 Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4 a a Grade based on criteria from the WHO. b Regardless of causality. c N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data e WHO grading scale not applicable to proportion of patients with transfusions. Laboratory Abnormality b Gemcitabine/Cisplatin c Etoposide/Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia 88 22 0 77 13 2 Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 16 45 8 5 RBC Transfusions c 29 - - 21 - - Platelet Transfusions e 3 - - 8 - - Hepatic Increased Alkaline Phosphatase 16 0 0 11 0 0 Increased ALT 6 0 0 12 0 0 Increased AST 3 0 0 11 0 0 Renal Hematuria 22 0 0 10 0 0 Proteinuria 12 0 0 5 0 0 Increased BUN 6 0 0 4 0 0 Increased Creatinine 2 0 0 2 0 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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. Blood and lymphatic system: Thrombotic microangiopathy (TMA) Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Vascular : Peripheral vasculitis, gangrene, capillary leak syndrome 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, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia Nervous System: Posterior reversible encephalopathy syndrome (PRES)

4 CONTRAINDICATIONS Gemcitabine for Injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis [see Adverse Reactions ( 6.1 )]. Patients with a known hypersensitivity to gemcitabine. ( 4 )

11 DESCRIPTION Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine hydrochloride is 2′-deoxy-2′, 2′-difluorocytidine monohydrochloride (β-isomer) with the following structural formula: The empirical formula for gemcitabine hydrochloride is C 9 H 11 F 2 N 3 O 4 • HCl. It has a molecular weight of 299.66 g/mol. Gemcitabine hydrochloride is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder and available as 200 mg, 1 g and 2 g single-dose vials for intravenous use only. Each 200 mg vial contains 200 mg gemcitabine (equivalent to 227.7 mg gemcitabine hydrochloride), 200 mg mannitol and 12.5 mg sodium acetate. Each 1 g vial contains 1 g gemcitabine (equivalent to 1.139 g gemcitabine hydrochloride), 1 g mannitol, and 62.5 mg sodium acetate. Each 2 g vial contains 2 g gemcitabine (equivalent to 2.276 g gemcitabine hydrochloride), 2 g mannitol, and 125 mg sodium acetate. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Structural Formula

2 DOSAGE AND ADMINISTRATION Gemcitabine for Injection is for intravenous use only. Ovarian Cancer: 1,000 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.1 ) Breast Cancer: 1,250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.2 ) Non-Small Cell Lung Cancer: 1,000 mg/m 2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1,250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.3 ) Pancreatic Cancer: 1,000 mg/m 2 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 dosage of Gemcitabine for Injection is 1,000 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with carboplatin AUC 4 administered intravenously on Day 1 after Gemcitabine for Injection administration. Refer to carboplatin prescribing information for additional information. Dosage Modifications Recommended Gemcitabine for Injection dosage modifications for myelosuppression are described in Tables 1 and 2 [see Warnings and Precautions ( 5.2 )] . Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration ( 2.5 )]. Table 1: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Day Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Day 1 Greater than or equal to 1,500 And Greater than or equal to 100,000 None Less than1,500 Or Less than 100,000 Delay Treatment Cycle Day 8 Greater than or equal to 1,500 And Greater than or equal to 100,000 None 1,000 to 1,499 Or 75,000 to 99,999 50% of full dose Less than1,000 Or Less than 75,000 Hold Table 2: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dosage Modification Initial Occurrence Absolute neutrophil count less than 500 x 10 6 /L for more than 5 days or Absolute neutrophil count less than 100 x 10 6 /L for more than 3 days or Febrile neutropenia or Platelets less than 25,000x10 6 /L or Cycle delay for more than one week due to toxicity Permanently reduce Gemcitabine for Injection 800 mg/m 2 on Days 1 and 8 Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction Permanently reduce Gemcitabine for Injection to 800 mg/m 2 on Day 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine for Injection is 1,250 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m 2 administered as a 3-hour intravenous infusion on Day 1 before Gemcitabine for Injection administration. Refer to paclitaxel prescribing information for additional information. Dosage Modifications Recommended Gemcitabine for Injection dosage modifications for myelosuppression are described in Table 3 [see Warnings and Precautions ( 5.2 )]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration ( 2.5 )]. Table 3: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Day 1 Greater than or equal to 1,500 And Greater than or equal to 100,000 None Less than 1,500 Or Less than 100,000 Hold Day 8 Greater than or equal to 1,200 And Greater than 75,000 None 1,000 to 1,199 Or 50,000 to 75,000 75% of full dose 700 to 999 And Greater than or equal to 50,000 50% of full dose Less than 700 Or Less than 50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule 28-day schedule The recommended dosage of Gemcitabine for Injection is 1,000 mg/m 2 intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m 2 administered intravenously on Day 1 after Gemcitabine for Injection administration. 21-day schedule The recommended dosage of Gemcitabine for Injection is 1,250 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m 2 administered intravenously on Day 1 after Gemcitabine for Injection administration. Refer to cisplatin prescribing information for additional information. Dosage Modifications Recommended dosage modifications for Gemcitabine for Injection myelosuppression are described in Table 4 [see Warnings and Precautions ( 5.2 )]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration ( 2.5 )]. 2.4 Pancreatic Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine for Injection is 1,000 mg/m 2 intravenously over 30 minutes. 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 each 28-day cycle. Dosage Modifications Recommended dosage modifications for Gemcitabine for Injection for myelosuppression are described in Table 4 [see Warnings and Precautions ( 5.2 )] . Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration ( 2.5 )] . Table 4: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Greater than or equal to 1,000 And Greater than or equal to 100,000 None 500 to 999 Or 50,000 to 99,999 75 % of full dose Less than 500 Or Less than 50,000 Hold 2.5 Dosage Modifications for Non-Hematologic Adverse Reactions Permanently discontinue Gemcitabine for Injection for any of the following: Unexplained dyspnea or evidence of severe pulmonary toxicity [see Warnings and Precautions ( 5.3 )] Hemolyticuremic syndrome (HUS) or severe renal impairment [see Warnings and Precautions ( 5.4 )] Severe hepatic toxicity [see Warnings and Precautions ( 5.5 )] Capillary leak syndrome (CLS) [see Warnings and Precautions ( 5.8 )] Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions ( 5.9 )] Withhold Gemcitabine for Injection or reduce dose by 50% for other Grade 3 or 4 non-hematological adverse reactions until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting. 2.6 Preparation Gemcitabine for Injection vials contain no antimicrobial preservatives and are intended for single use only. Gemcitabine for Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Exercise caution and wear gloves when preparing Gemcitabine for Injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine for Injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. Reconstitute the 200 mg vial with 5 mL, 1 g vial with 25 mL and 2 g vial with 50 mL of 0.9% Sodium Chloride Injection, USP to yield a gemcitabine concentration of 38 mg/mL. Reconstituted Gemcitabine for Injection is a clear, colorless to light straw-colored solution. Visually inspect reconstituted product for particulate matter and discoloration. Discard if particulate matter or discoloration is observed. Withdraw the calculated dose from the vial and discard any unused portion. Prior to administration, dilute the reconstituted solution with 0.9% Sodium Chloride Injection, USP to a minimum final concentration of at least 0.1 mg/mL. Store Gemcitabine for Injection solutions (reconstituted and diluted) at controlled room temperature of 20°C to 25°C (68°F to 77°F). Do not refrigerate as crystallization can occur. Discard Gemcitabine for Injection solutions if not used within 24 hours after reconstitution. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

1 INDICATIONS AND USAGE Gemcitabine for 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 for 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 for 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 for Injection in combination with cisplatin is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC). 1.4 Pancreatic Cancer Gemcitabine for 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 for Injection is indicated for patients previously treated with fluorouracil.

10 OVERDOSAGE There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5,700 mg/m 2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.

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 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 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 mg/m 2 to 3,600 mg/m 2 . Distribution The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m 2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m 2 . 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 sex. Gemcitabine plasma protein binding is negligible. Elimination Metabolism 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. Excretion Gemcitabine disposition was studied in 5 patients who received a single 1,000 mg/m 2 of radiolabeled drug as a 30-minute infusion. Within one 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. Specific Populations Geriatric Patients Clearance of gemcitabine was affected by age. The lower clearance in geriatric patients 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 15 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and sex. Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient a Half-life for patients receiving a <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 for long infusions varied from 245 to 638 minutes, depending on age and sex, reflecting a greatly increased volume of distribution with longer infusions. Male and Female Patients Females have lower clearance and longer half-lives than male patients as described in Table 15 . Patients with Renal Impairment No clinical studies have been conducted with gemcitabine in patients with decreased renal function. Patients with Hepatic Impairment No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. Drug Interaction Studies When gemcitabine (1,250 mg/m 2 on Days 1 and 8) and cisplatin (75 mg/m 2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m 2 and on Day 8 was 107 L/hr/m 2 . Data from patients with NSCLC 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. Data from metastatic breast cancer patients shows that 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.

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 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 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 mg/m 2 to 3,600 mg/m 2 . Distribution The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m 2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m 2 . 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 sex. Gemcitabine plasma protein binding is negligible. Elimination Metabolism 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. Excretion Gemcitabine disposition was studied in 5 patients who received a single 1,000 mg/m 2 of radiolabeled drug as a 30-minute infusion. Within one 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. Specific Populations Geriatric Patients Clearance of gemcitabine was affected by age. The lower clearance in geriatric patients 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 15 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and sex. Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient a Half-life for patients receiving a <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 for long infusions varied from 245 to 638 minutes, depending on age and sex, reflecting a greatly increased volume of distribution with longer infusions. Male and Female Patients Females have lower clearance and longer half-lives than male patients as described in Table 15 . Patients with Renal Impairment No clinical studies have been conducted with gemcitabine in patients with decreased renal function. Patients with Hepatic Impairment No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. Drug Interaction Studies When gemcitabine (1,250 mg/m 2 on Days 1 and 8) and cisplatin (75 mg/m 2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m 2 and on Day 8 was 107 L/hr/m 2 . Data from patients with NSCLC 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. Data from metastatic breast cancer patients shows that 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.

20200204

18

3 DOSAGE FORMS AND STRENGTHS For injection: 200 mg gemcitabine, 1 g gemcitabine or 2 g gemcitabine as a sterile white to off-white lyophilized powder in a single-dose vial for reconstitution. For injection: 200 mg, 1 g or 2 g lyophilized powder or cake in single-dose vials for reconstitution. ( 3 )

GEMCITABINE GEMCITABINE MANNITOL SODIUM ACETATE SODIUM HYDROXIDE HYDROCHLORIC ACID GEMCITABINE HYDROCHLORIDE GEMCITABINE GEMCITABINE GEMCITABINE MANNITOL SODIUM ACETATE SODIUM HYDROXIDE HYDROCHLORIC ACID GEMCITABINE HYDROCHLORIDE GEMCITABINE GEMCITABINE GEMCITABINE MANNITOL SODIUM ACETATE SODIUM HYDROXIDE HYDROCHLORIC ACID GEMCITABINE HYDROCHLORIDE GEMCITABINE

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 intraperitoneal doses of 0.5 mg/kg/day [about 1/700 the 1,000 mg/m 2 clinical dose based on body surface area (BSA)] in male mice resulted in 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 1,000 mg/m 2 clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1,300 the 1,000 mg/m 2 clinical dose based on BSA).

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 intraperitoneal doses of 0.5 mg/kg/day [about 1/700 the 1,000 mg/m 2 clinical dose based on body surface area (BSA)] in male mice resulted in 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 1,000 mg/m 2 clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1,300 the 1,000 mg/m 2 clinical dose based on BSA).

ANDA090799

GEMCITABINE

GEMCITABINE

63323-126

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Gemcitabine 200mg-Vial Carton NDC: 63323-102-13 FK101210 GEMCITABINE FOR INJECTION, USP 200 mg per vial For Intravenous use only Must Be Diluted DO NOT REFRIGERATE Cytotoxic Agent Rx only Single-Dose Vial PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Gemcitabine 200 mg- Vial Label NDC: 63323-102-13 FK101210 GEMCITABINE FOR INJECTION, USP 200 mg per vial For Intravenous use only Must Be Diluted Rx only Single-Dose Vial 200mg vial-200mg

Warnings and Precautions, Hemolytic Uremic Syndrome ( 5.4 ) 5/2019

17 PATIENT COUNSELING INFORMATION Myelosuppression Advise patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider should any signs or symptoms of infection, including fever, or if bleeding or signs of anemia, occur [see Warnings and Precautions ( 5.2 )]. Pulmonary Toxicity 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 )]. Hemolytic-Uremic Syndrome and Renal Failure 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 )]. Hepatic Toxicity 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 )]. Embryo-Fetal Toxicity Advise females and males of reproductive potential that gemcitabine can cause fetal harm. 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 treatment with gemcitabine and for 3 months after the final dose [see Warnings and Precaution ( 5.6 ), Use in Specific Populations ( 8.1 , 8.3 )]. Lactation Advise women not to breastfeed during treatment with gemcitabine and for at least one week after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility Advise males of reproductive potential of the potential for reduced fertility with gemcitabine [see Use in Specific Populations ( 8.3 ), Nonclinical Toxicology ( 13.1 )]. Lake Zurich, IL 60047 For Product Inquiry: 1-800-551-7176 or www.fresenius-kabi.com/us 451258E/Revised: September 2019 Fresenius Kabi Logo

14 CLINICAL STUDIES 14.1 Ovarian Cancer The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in 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 1,000 mg/m 2 on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n=178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n=178). The major efficacy outcome measure was progression-free survival (PFS). A total of 356 patients were enrolled. Demographics and baseline characteristics are shown in Table 16 . Efficacy results are presented in Table 17 and Figure 1 . The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate. 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 16: Baseline Demographics and Clinical Characteristics for Study 1 Gemcitabine/Carboplatin (N=178) Carboplatin (N=178) Median age, years 59 58 Range 36 to 78 21 to 81 Baseline ECOG performance status 0-1 a 94% 95% Disease Status Evaluable 8% 3% Bidimensionally measurable 92% 96% Platinum-free interval b 6-12 months 40% 40% >12 months 59% 60% First-line therapy Platinum-taxane combination 70% 71% Platinum-non-taxane combination 29% 28% Platinum monotherapy 1% 1% a 5 patients on Gemcitabine with carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status. b 2 patients on Gemcitabine with carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months. Table 17: Efficacy Results in Study 1 a CI=confidence interval. b Log rank, unadjusted. c Chi square. d CR=Complete response. e PR with PRNM=Partial response with 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. Efficacy Parameter Gemcitabine/Carboplatin (N=178) Carboplatin (N=178) Progression-Free Survival Median (95% CI a ) in months 8.6 (8.0, 9.7) 5.8 (5.2, 7.1) Hazard Ratio (95% CI) 0.72 (0.57, 0.90) p-value b p=0.0038 Overall Survival Median (95% CI) in months 18.0 (16.2, 20.3) 17.3 (15.2, 19.3) Hazard Ratio (95% CI) 0.98 (0.78, 1.24) p-value b p=0.8977 Overall Response Rate by Investigator Review 47.2% 30.9% p-value c p=0.0016 CR d 14.6% 6.2% PR with PRNM e 32.6% 24.7% Overall Response Rate f by Independent Review 46.3% 35.6% p-value c p=0.11 CR d 9.1% 4.0% PR with PRNM e 37.2% 31.7% Figure 1: Kaplan-Meier Curves for Progression-Free Survival in Study 1 Figure 1 14.2 Breast Cancer The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive either gemcitabine 1,250 mg/m 2 on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m 2 administered on Day 1 before gemcitabine administration (n=267) or paclitaxel 175 mg/m 2 on Day 1 of each 21-day cycle (n=262). The major efficacy outcome measure was time to documented disease progression. A total of 529 patients were enrolled. Demographic and baseline characteristics were similar between treatment arms ( Table 18 ). Efficacy results are presented in Table 19 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 18: Baseline Demographics and Clinical Characteristics for Study 2 a Karnofsky Performance Status. Gemcitabine/Paclitaxel (N=267) Paclitaxel (N=262) Median age (years) 53 52 Range 26 to 83 26 to 75 Metastatic disease 97% 97% Baseline KPS a ≥90 70% 74% Number of tumor sites 1 -2 57% 59% ≥3 43% 41% Visceral disease 73% 73% Prior anthracycline 97% 96% Table 19: Efficacy Results in Study 2 a These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm. b Based on the ITT population. Efficacy Parameter Gemcitabine/Paclitaxel (N=267) Paclitaxel (N=262) Time to Documented Disease Progression a Median (95% CI) in months 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 Survival b Median (95% CI) in months 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 Rate 40.8% 22.1% (95% CI) (34.9, 46.7) (17.1, 27.2) p-value p<0.0001 Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2 Figure 2 14.3 Non-Small Cell Lung Cancer The efficacy of gemcitabine was evaluated in two randomized, multicenter trials. Study 3: 28-Day Schedule A multinational, randomized trial (Study 3) compared gemcitabine with 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 either gemcitabine 1,000 mg/m 2 on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m 2 on Day 1 after gemcitabine administration (N=260) or cisplatin 100 mg/m 2 on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival. A total of 522 patients were enrolled. Demographics and baseline characteristics ( Table 20 ) 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 with cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 21 and Figure 3 . Study 4: 21-Day Schedule A randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive either gemcitabine 1,250 mg/m 2 on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m 2 on Day 1 after gemcitabine administration or etoposide 100 mg/m 2 intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m 2 on Day 1 of each 21-day cycle. The major efficacy outcome measure was response rate. A total of 135 patients were enrolled. Demographics and baseline characteristics are summarized in Table 20 . Efficacy results are presented in Table 21 . There was no significant difference in survival between the two treatment arms. The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide with cisplatin arm (Fisher's Exact p=0.01, two-sided). Table 20: Baseline Demographics and Clinical Characteristics for Studies 3 and 4 a N/A Not applicable. b Karnofsky Performance Status. Trial 28-day Schedule (Study 3) 21-day Schedule (Study 4) Gemcitabine/Cisplatin (N=260) Cisplatin (N=262) Gemcitabine/Cisplatin (N=69) Etoposide/Cisplatin (N=66) 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/A a N/A a Stage IIIB 26% 23% 48% 52% Stage IV 67% 70% 52% 49% Baseline KPS b 70 to 80 41% 44% 45% 52% Baseline KPS b 90 to100 57% 55% 55% 49% Table 21: Efficacy Results for Studies 3 and 4 a CI=confidence intervals. b 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 (Study 3) 21-day Schedule (Study 4) Efficacy Parameter Gemcitabine /Cisplatin (N=260) Cisplatin (N=262) Gemcitabine/ Cisplatin (N=69) Etoposide/Cisplatin (N=66) Survival Median (95% CI a ) in months 9.0 (8.2, 11.0) 7.6 (6.6, 8.8) 8.7 (7.8, 10.1) 7.0 (6.0, 9.7) p-value b p=0.008 p=0.18 Time to Disease Progression Median (95% CI a ) in months 5.2 (4.2, 5.7) 3.7 (3.0, 4.3) 5.0 (4.2, 6.4) 4.1 (2.4, 4.5) p-value b p=0.009 p=0.015 Tumor Response 26% 10% 33% 14% p-value b p<0.0001 p=0.01 Figure 3: Kaplan-Meier Curves for Overall Survival in Study 3 Figure 3 14.4 Pancreatic Cancer The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5)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 (Study 6)conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1,000 mg/m 2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m 2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1,000 mg/m 2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles. The major 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. Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms ( Table 22 ). The efficacy results are shown in Table 23 and 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 fluorouracil. No confirmed objective tumor responses were observed in either treatment arm. Table 22: Baseline Demographics and Clinical Characteristics for Study 5 Gemcitabine (N=63) Fluorouracil (N=63) Male 54% 54% Median age, years 62 61 Range 37 to 79 36 to 77 Stage IV disease 71% 76% Baseline KPS a ≤70 70% 68% a Karnofsky Performance Status. Table 23: Efficacy Results in Study 5 a 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. Efficacy Parameter Gemcitabine (N=63) Fluorouracil (N=63) Clinical Benefit Response 22.2% 4.8% p-value a p=0.004 Overall Survival Median (95% CI) in months 5.7 (4.7, 6.9) 4.2 (3.1, 5.1) p-value a p=0.0009 Time to Disease Progression Median (95% CI) in months 2.1 (1.9, 3.4) 0.9 (0.9, 1.1) p-value a p=0.0013 Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5 Figure 4

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

8.5 Geriatric Use In clinical studies which enrolled 979 patients with various malignancies who received single agent gemcitabine, 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 (Study 1), 175 women received gemcitabine with 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 [see Dosage and Administration ( 2.1 )]. Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients' age [see Clinical Pharmacology ( 12.3 )] .

8.4 Pediatric Use The safety and effectiveness of gemcitabine have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m 2 /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/m 2 /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 myelosuppression, febrile neutropenia, increased serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

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 [see Clinical Pharmacology ( 12.1 )]. There are no available data on the use of gemcitabine in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Special Populations ( 8.3 )]. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies 2-4% and 15-20% respectively. Data Animal Data Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [approximately 0.005 times the 1000 mg/m 2 clinical dose based on body surface area (BSA)]. Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m 2 clinical dose based on BSA).

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 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 [see Clinical Pharmacology ( 12.1 )]. There are no available data on the use of gemcitabine in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Special Populations ( 8.3 )]. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies 2-4% and 15-20% respectively. Data Animal Data Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [approximately 0.005 times the 1000 mg/m 2 clinical dose based on body surface area (BSA)]. Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m 2 clinical dose based on BSA). 8.2 Lactation Risk Summary There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or on milk production. Due to the potential for serious adverse reactions in breastfed infants from gemcitabine, advise women not to breastfeed during treatment with gemcitabine and for at least one week following the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating gemcitabine [see Use in Specific Populations ( 8.1 )]. Contraception Gemcitabine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose of gemcitabine. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose [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 )] . It is not known whether these effects on fertility are reversible. 8.4 Pediatric Use The safety and effectiveness of gemcitabine have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m 2 /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/m 2 /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 myelosuppression, febrile neutropenia, increased serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial. 8.5 Geriatric Use In clinical studies which enrolled 979 patients with various malignancies who received single agent gemcitabine, 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 (Study 1), 175 women received gemcitabine with 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 [see Dosage and Administration ( 2.1 )]. Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients' age [see Clinical Pharmacology ( 12.3 )] . 8.6 Gender Gemcitabine clearance is decreased in females [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 [see Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder available in single-dose vials individually packaged in a carton containing 200 mg, 1 g or 2 g gemcitabine: Product Code Unit of Sale Strength FK101210 NDC 63323-102-13 Individually packaged 200 mg per vial FK102550 NDC 63323-125-53 Individually packaged 1 gram per vial FK102600 NDC 63323-126-03 Individually packaged 2 grams per vial Gemcitabine for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Store at controlled room temperature 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC and 30ºC (59ºF and 86ºF) [see USP Controlled Room Temperature]. The container closure is not made with natural rubber latex.