ADVERSE REACTIONS SECTION.

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)] 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 Ingenus Pharmaceuticals, LLC at 1-877-748-1970 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in the clinical practice.Single Agent The data described below reflect exposure to gemcitabine as single agent administered at doses between 800 mg/m2to 1250 mg/m2intravenously 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 or 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 patient were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.Tables and present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 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 Gemcitabinea Grade based on criteria from the World Health Organization (WHO).b For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. N=699-974; all patients with laboratory or non-laboratory data. Gemcitabinec Adverse Reactionsb All Grades (%) Grade (%) Grade (%) Nausea and Vomiting 69 13 Fever 41 0 Rash 30 <1 Dyspnea 23 <1 Diarrhea 19 0 Hemorrhage 17 <1 <1 Infection 16 <1 Alopecia 15 <1 Stomatitis 11 <1 Somnolence 11 <1 <1 Paresthesias 10 <1 Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabinea Grade based on criteria from WHO. Regardless of causality. N=699-974; all patients with laboratory or non-laboratory data. Laboratory Abnormalityb Gemcitabinec All Grades (%) Grade (%) Grade (%) Hematologic Anemia 68 1 Neutropenia 63 19 Thrombocytopenia 24 1 Hepatic Increased ALT 68 2 Increased AST 67 2 Increased Alkaline Phosphatase 55 2 Hyperbilirubinemia 13 <1 Renal Proteinuria 45 <1 Hematuria 35 <1 Increased BUN 16 0 Increased Creatinine <1 Additional adverse reactions include the following:Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%)Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, insomnia, rhinitis, sweating, and/or malaise (19%)Infection: Sepsis (<1%).Extravasation: Injection-site reactions (4%).Allergic: Bronchospasm (<2%); anaphylactoid reactionsOvarian Cancer Tables and present the incidence of selected adverse reactions and laboratory abnormalities, occurring in >=10% of gemcitabine-treated patients and at higher incidence in the gemcitabine/carboplatin arm, reported in 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 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 1a Grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0. Regardless of causality. Adverse Reactionsb Gemcitabine/ Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Nausea 69 0 61 0 Alopecia 49 0 17 0 Vomiting 46 0 36 <1 Constipation 42 1 37 0 Fatigue 40 <1 32 0 Diarrhea 25 0 14 <1 Stomatitis/Pharyngitis 22 <1 13 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 1a Grade based on Nutional Cancer Institute CTC Version 2.0.b Regardless of causality.c Percent of patients receiving transfusion. Transfusion are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. Laboratory Abnormalityb Gemcitabine/ Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Hematologic Neutropenia 90 42 29 58 11 Anemia 86 22 75 2 Thrombocytopenia 78 30 57 10 RBC Transfusionc 38 - 15 - Platelet Transfusionc - 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 and 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 CancerTables and 10 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in >=10% of gemcitabine-treated patients and at higher incidence in the gemcitabine/paclitaxel arm, reported in 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 2a Grade based on National Cancer Institute CTC Version 2.0. Non-laboratory events were graded only if assessed to be possibly drug-related. Adverse Reactionsb Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Alopecia 90 14 92 19 Neuropathy-Sensory 64 <1 58 0 Nausea 50 0 31 0 Fatigue 40 <1 28 <1 Vomiting 29 0 15 0 Diarrhea 20 0 13 0 Anorexia 17 0 12 <1 Neuropathy-Motor 15 <1 10 <1 Stomatitis/Pharyngitis 13 <1 <1 Fever 13 <1 3 0 Rash/Desquamation 11 <1 <1 0 Febrile Neutropenia 5 <1 1 Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of >=5% (All Grades) or >=2% (Grades 3-4)] in Study 2a Grade based on National Cancer Institute CTC Version 2.0.b Regardless of causality. Laboratory Abnormalityb Gemcitabine/ Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Hematologic Anemia 69 1 51 <1 Neutropenia 69 31 17 31 7 Thrombocytopenia 26 <1 <1 <1 Hepatobiliary Increased ALT Increased AST 18 16 2 <1 6 <1 <1 0 Clinically relevant Grade or dyspnea occurred with 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 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in >=10% of gemcitabine-treated patients and at higher incidence in the gemcitabine with cisplatin arm, reported in 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 median of cycles of treatment and those randomized to cisplatin alone received median of 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 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine/cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with (1.5%) possibly treatment-related deaths, including 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 3a Grade based on National Cancer Institute CTC. Non-laboratory events were graded only if assessed to be possibly drug-related. 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 Reactionsb Gemcitabine/Cisplatinc Cisplatind All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Nausea 93 25 87 20 <1 Vomiting 78 11 12 71 10 Alopecia 53 0 33 0 Neuro Motor 35 12 15 0 Diarrhea 24 2 13 0 Neuro Sensory 23 0 18 0 Infection 18 2 12 0 Fever 16 0 0 Neuro Cortical 16 1 1 Neuro Mood 16 0 10 0 Local 15 0 0 Neuro Headache 14 0 0 Stomatitis 14 0 0 Hemorrhage 14 0 0 Hypotension 12 0 1 Rash 11 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 3a Grade based on National Cancer Institute CTC.b Regardless of causality. N=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. N=213-248; all cisplatin patients with laboratory or non-laboratory data. Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. Laboratory Abnormalityb Gemcitabine/Cisplatinc Cisplatind All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Hematologic Anemia 89 22 67 1 Thrombocytopenia 85 25 25 13 1 Neutropenia 79 22 35 20 1 Lymphopenia 75 25 18 51 12 RBC Transfusione 39 - 13 - Platelet Transfusionse 21 - <1 - Hepatic Increased Transaminase Increased Alkaline Phosphatase 22 19 1 0 10 13 0 0 Renal Increased Creatinine 38 <1 31 <1 Proteinuria 23 0 18 0 Hematuria 15 0 13 0 Other Laboratory Hyperglycemia 30 0 23 0 Hypomagnesemia 30 3 17 0 Hypocalcemia 18 0 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 higher incidence in the gemcitabine with cisplatin arm, reported in 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 median of cycles and those in the etoposide/cisplatin (EC) arm received median of 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, 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 4a Grade based on criteria from WHO. Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. N=57-63; all etoposide/cisplatin patients with laboratory or non-laboratory data. Flu-like syndrome and edema were not graded. Adverse Reactionsb Gemcitabine/Cisplatinc Etoposide/Cisplatind All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Nausea and Vomiting 96 35 86 19 Alopecia 77 13 92 51 Paresthesias 38 0 16 0 Infection 28 1 21 0 Stomatitis 20 0 18 0 Diarrhea 14 1 13 2 Edemae 12 - - Rash 10 0 0 Hemorrhage 0 3 3 Fever 0 3 0 Somnolence 0 3 0 Flu-like Syndromee - 0 - Dyspnea 0 3 0 Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4a Grade based on criteria from WHO. Regardless of causality.c N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. N=57-63; all etoposide/cisplatin patients with laboratory or non-laboratory data. Percent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions. Laboratory Abnormalityb Gemcitabine/Cisplatinc Etoposide/Cisplatind All Grades (%) Grade (%) Grade (%) All Grades (%) Grade (%) Grade (%) Hematologic Anemia 88 22 77 13 Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 16 45 5 RBC Transfusione 29 - 21 - Platelet Transfusione - 8 - Hepatic Increased Alkaline Phosphatase 16 0 11 0 Increased ALT 0 12 0 Increased AST 0 11 0 Renal Hematuria 22 0 10 0 Proteinuria 12 0 0 Increased BUN 0 4 0 Increased Creatinine 0 2 0 Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%). Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%). Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, insomnia, rhinitis, sweating, and/or malaise (19%). Infection: Sepsis (<1%).. Extravasation: Injection-site reactions (4%).. Allergic: Bronchospasm (<2%); anaphylactoid reactions. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of gemcitabine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System: TMACardiovascular: 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 diseasePulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary eosinophilia, pulmonary edema, adult respiratory distress syndrome (ARDS)Nervous System: Posterior reversible encephalopathy syndrome (PRES).

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 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/m2 to 3600 mg/m2.DistributionThe 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 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.EliminationMetabolism 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.ExcretionGemcitabine disposition was studied in patients who received single 1000 mg/m2of radiolabeled drug as 30-minute infusion. 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. 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.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 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. Table 15: Gemcitabine Clearance and Half-Life for the Typical Patient Half-life for patients receiving <70 minute infusion. Age Clearance Men (L/hr/m ) Clearance Women (L/hr/m ) Half-Life Men (min) Half-Life 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 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 StudiesWhen gemcitabine (1250 mg/m2 on Days and 8) and cisplatin (75 mg/m2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day was 128 L/hr/m2 and on Day was 107 L/hr/m2. 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 patients with metastatic breast cancer 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Ovarian Cancer. The efficacy of gemcitabine was evaluated in randomized trial (Study 1) conducted in women with advanced ovarian cancer that had relapsed at least months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m2on Days and of each 21-day cycle with carboplatin AUC on Day after gemcitabine administration (n 178) or carboplatin AUC on Day of each 21-day cycle (n 178). The major efficacy outcome measure was progression-free survival (PFS). 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 a patients on the gemcitabine/carboplatin arm and patients on the carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status. 2 patients on the gemcitabine/carboplatin arm and on the carboplatin arm had platinum-free interval 6 months. Gemcitabine/Carboplatin (N=178) Carboplatin (N=178) Median age, years Range 59 36 to 78 58 21 to 81 Baseline ECOG performance status 0-1a 94% 95% Disease Status Evaluable Bidimensionally measurable 8% 92% 3% 96% Platinum-free intervalb 6-12 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 17: Efficacy Results in Study a CI= confidence interval.b Log rank, unadjusted.c Chi square.d CR=Complete responsee PR plus PRNM=Partial response plus partial response, non-measurable diseasef 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% CIa) months 8.6 (8.0, 9.7) 5.8 (5.2, 7.1) Hazard Ratio (95% CI) 0.72 (0.57, 0.90) p=valueb Overall Survival Median (95% CI) months p=0.0038 18.0 (16.2, 20.3) 17.3 (15.2, 19.3) Hazard Ratio (95% CI) p=valueb 0.98 (0.78, 1.24) p=0.8977 Overall Response Rate by Investigator Review 47.2 30.9 p=valuec 0.0016 CRd PR+PRNMe 14.6% 32.6% 6.2% 24.7% Overall Response Rate by Independent Reviewf 46.3% 35.6% p=valuec p=0.11 CRd PR+PRNMe 9.1% 37.2% 4.0% 31.7% Figure 1: Kaplan-Meier Curve for Progression-Free Survival in Study 1. 14.2 Breast Cancer. The efficacy of gemcitabine was evaluated in multinational, randomized, open-label trial 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 gemcitabine 1250 mg/m2 on Days and of each 21-day cycle with paclitaxel 175 mg/m2 administered on Day before gemcitabine administration (n 267) or paclitaxel 175 mg/m2 on Day of each 21-day cycle (n 262). The major efficacy outcome measure was time to documented disease progression. 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 a Karnofsky Performance Status. Gemcitabine/Paclitaxel (N 267) Paclitaxel (N 262) Median age, years Range 53 26 to 83 52 26 to 75 Metastatic disease 97% 97% Baseline KPSa >=90 70% 74% Number of tumor sites 1-2 >=3 57% 43% 59% 41% Visceral disease 73% 73% Prior anthracycline 97% 96% Table 19: Efficacy Results in Study a These represent reconciliation of investigator and Independent Review Committee assessments according to predefined algorithm. Based on the ITT population. Efficacy Parameter Gemcitabine/Paclitaxel (N=267) Paclitaxel (N=262) Time to Documented Disease Progressiona 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 Survivalb 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 Rateb (95% CI) 40.8% (34.9, 46.7) 22.1% (17.1, 27.2) p-value p<0.0001 Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2. 14.3 Non-Small Cell Lung Cancer. The efficacy of gemcitabine was evaluated in two randomized, multicenter trials.Study 3: 28-Day Schedule 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 1000 mg/m2 on Days 1, 8, and 15 of 28-day cycle with cisplatin 100 mg/m2 on Day after gemcitabine administration (N=260) or cisplatin 100 mg/m2 on Day of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival. 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 randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1250 mg/m2 on Days and of each 21-day cycle with cisplatin 100 mg/m2 on Day after gemcitabine administration or etoposide 100 mg/m2 intravenously on Days 1, 2, and with cisplatin 100 mg/m2 on Day of each 21-day cycle. The major efficacy outcome measure was response rate. 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 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 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 (Fishers Exact p=0.01, two-sided).Figure 3: Kaplan-Meier Curves for Overall Survival in Study Table 20: Baseline Demographics and Clinical Characteristics for Studies and 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 Median age, years Range 70% 62 36 to 88 71% 63 35 to 79 93% 58 33 to 76 92% 60 35 to 75 Stage IIIA Stage IIIB Stage IV 7% 26% 67% 7% 23% 70% N/Aa 48% 52% N/Aa 52% 49% Baseline KPSb 70 to 80 Baseline KPSb 90 to 100 41% 57% 44% 55% 45% 55% 52% 49% Table 21: Efficacy Results for Studies and a CI=confidence intervals.b p-valiue two-side Fishers Extract 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% CIa) 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-valueb p=0.008 p=0.18 Time to Disease Progression Median (95% CIa) 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-valueb p=0.009 p=0.015 Tumor Response 26% 10% 33% 14% p-valueb P<0.0001 p=0.01 14.4 Pancreatic Cancer. The efficacy of gemcitabine was evaluated in two trials (Studies and 6), 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 single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for weeks followed by one-week rest, then once weekly for consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m2intravenously over 30 minutes once weekly for weeks followed by one-week rest, then once weekly for consecutive weeks every 28-days in subsequent cycles.The major efficacy outcome measure in both trials was clinical benefit response. patient was considered to have had clinical benefit response if either of the following occurred: The patient achieved >=50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or 20-point or greater improvement in performance status (Karnofsky Performance Status) for period of at least consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as consecutive weeks with either any increase in pain intensity or analgesic consumption or 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 marked, sustained weight gain (>=7% increase maintained for >=4 weeks) not due to fluid accumulation.Study 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 a Karnofsky Performance Status. Gemcitabine (N=63) Fluorouracil (N=63) Male Median age Range Stage IV disease Baseline KPSa <=70 54% 62 years 37 to 79 71% 70% 54% 61 years 36 to 77 76% 68% Table 23: Efficacy Results in Study 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-valuea p=0.004 Overall Survival Median (95% CI) in months 5.7 (4.7, 6.9) 4.2 (3.1, 5.1) p-valuea 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-valuea p=0.0013 Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5. Figure 1: Kaplan-Meier Curve for Progression-Free Survival in Study 1. Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2. Image 3. Image 4.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Gemcitabine Injection is for intravenous use only.Ovarian Cancer: 1000 mg/m2 over 30 minutes on Days and of each 21 -day cycle. (2.1)Breast Cancer: 1250 mg/m2 over 30 minutes on Days and 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 and of each 21-day cycle. (2.3)Pancreatic Cancer: 1000 mg/m2 over 30 minutes once weekly for the first weeks, then one-week rest, then once weekly for weeks of each 28-day cycle. (2.4). Ovarian Cancer: 1000 mg/m2 over 30 minutes on Days and of each 21 -day cycle. (2.1). Breast Cancer: 1250 mg/m2 over 30 minutes on Days and 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 and of each 21-day cycle. (2.3). Pancreatic Cancer: 1000 mg/m2 over 30 minutes once weekly for the first weeks, then one-week rest, then once weekly for weeks of each 28-day cycle. (2.4). 2.1 Ovarian Cancer. Recommended Dose and ScheduleThe recommended dosage of Gemcitabine Injection is 1000 mg/m2intravenously over 30 minutes on Days and of each 21-day cycle, in combination with carboplatin AUC administered intravenously on Day after Gemcitabine Injection administration. Refer to carboplatin prescribing information for additional information.Dosage ModificationsRecommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Tables and [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 Injection for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment day Absolute Neutrophil Count (x 106/L) Platelet Count (x 106/L) Dosage Modification Day Greater than or equal to 1500 And Greater than or equal to 100,000 None Less than 1500 Or Less than 100,000 Delay Treatment Cycle Day Greater than or equal to 1500 And Greater than or equal to 100,000 None 1000 to 1499 Or 75,000 to 99,999 50% of full dose Less than 1000 Or Less than 75,000 Hold Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dosage Modification Initial Occurrence Absolute neutrophil count less than 500 106//L for more than days or Absolute neutrophil count less than 100 106//L for more than days or Febrile neutropenia or Platelets less than 25,000 106//L Cycle delay of more than one week due to toxicity Permanently reduce Gemcitabine Injection to 800 mg/m2 on Days and Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction Permanently reduce Gemcitabine Injection dose to 800 mg/m2 on Day only 2.2 Breast Cancer. Recommended Dose and ScheduleThe recommended dosage of Gemcitabine Injection is 1250 mg/m2intravenously over 30 minutes on Days and of each 21-day cycle in combination with paclitaxel 175 mg/m2administered as 3-hour intravenous infusion on Day before Gemcitabine Injection administration. Refer to paclitaxel prescribing information for additional information.Dosage ModificationsRecommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Table [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 Injection for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute Neutrophil Count (x 106/L) Platelet Count (x 106/L) Dosage Modification Day Greater than or equal to 1500 And Greater than or equal to 100,000 None Less than 1500 Or Less than 100,000 Hold Day Greater than or equal to 1200 And Greater than 75,000 None 1000 to 1199 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 Schedule28-day scheduleThe recommended dosage of Gemcitabine Injection is 1000 mg/m2intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m2administered intravenously on Day after Gemcitabine Injection administration.21-day scheduleThe recommended dosage of Gemcitabine Injection is 1250 mg/m2intravenously over 30 minutes on Days and of each 21-day cycle in combination with cisplatin 100 mg/m2administered intravenously on Day after Gemcitabine Injection administration.Refer to cisplatin prescribing information for additional information.Dosage Modifications Recommended dosage modifications for Gemcitabine Injection myelosuppression are described in Table [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 ScheduleThe recommended dosage of Gemcitabine Injection is 1000 mg/m2 intravenously over 30 minutes. The recommended treatment schedule is as follows:Weeks to 8: weekly dosing for the first weeks followed by one-week rest.After week 8: weekly dosing on Days 1, 8, and 15 of each 28-day cycle.Dosage ModificationsRecommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Table [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 Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute Neutrophil Count (x 106/L) Platelet count (x 106/L) Dosage Modification Greater than or equal to 1000 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 Weeks to 8: weekly dosing for the first weeks followed by one-week rest.. After week 8: weekly dosing on Days 1, 8, and 15 of each 28-day cycle.. 2.5 Dosage Modifications for Non-Hematologic Adverse Reactions. Permanently discontinue Gemcitabine Injection for any of the following: Unexplained dyspnea or evidence of severe pulmonary toxicity [see Warnings and Precautions (5.3)] Hemolytic uremic 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 Injection or reduce dose by 50% for other Grade or non-hematological adverse reactions until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.. Unexplained dyspnea or evidence of severe pulmonary toxicity [see Warnings and Precautions (5.3)] Hemolytic uremic 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)] 2.6 Preparation. Gemcitabine Injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1Exercise caution and wear gloves when preparing Gemcitabine Injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine Injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.Preparation for Intravenous Infusion AdministrationWithdraw the calculated dose from the vial and discard any unused portion.Prior to administration, dilute the appropriate amount of drug with 0.9% Sodium Chloride Injection to minimum final concentration of at least 0.1 mg/mL.Store diluted Gemcitabine Injection solution for no more than 24 hours at controlled room temperature of 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Discard if not used within 24 hours after dilution.Visually inspect for particulate matter or discoloration prior to administration and discard if particulate matter or discoloration is observed.No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.. Withdraw the calculated dose from the vial and discard any unused portion.. Prior to administration, dilute the appropriate amount of drug with 0.9% Sodium Chloride Injection to minimum final concentration of at least 0.1 mg/mL.. Store diluted Gemcitabine Injection solution for no more than 24 hours at controlled room temperature of 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Discard if not used within 24 hours after dilution.. Visually inspect for particulate matter or discoloration prior to administration and discard if particulate matter or discoloration is observed.. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

PHARMACOKINETICS SECTION.

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/m2 to 3600 mg/m2.DistributionThe 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 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.EliminationMetabolism 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.ExcretionGemcitabine disposition was studied in patients who received single 1000 mg/m2of radiolabeled drug as 30-minute infusion. 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. 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.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 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. Table 15: Gemcitabine Clearance and Half-Life for the Typical Patient Half-life for patients receiving <70 minute infusion. Age Clearance Men (L/hr/m ) Clearance Women (L/hr/m ) Half-Life Men (min) Half-Life 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 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 StudiesWhen gemcitabine (1250 mg/m2 on Days and 8) and cisplatin (75 mg/m2 on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day was 128 L/hr/m2 and on Day was 107 L/hr/m2. 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 patients with metastatic breast cancer 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy. Risk SummaryBased on animal data and its mechanism of action, Gemcitabine Injection can cause fetal harm when administered to 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 fetus [see Use in Specific Populations (8.3)]. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataGemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [about 0.005 times the 1000 mg/m2clinical dose based on body surface area (BSA)]. Gemcitabine is 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 (about 0.002 times the 1000 mg/m2clinical 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, advise women not to breastfeed during treatment with Gemcitabine Injection 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 Injection [see Use in Specific Populations (8.1)]. Contraception Gemcitabine Injection can cause fetal harm when administered to 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 Injection and for months after the final dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for 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 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 one-week rest period. The safety and activity of gemcitabine were evaluated in trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at dose of 10 mg/m2/min administered over 360 minutes weekly for three weeks followed by one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive 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 higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In 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 subsequent cycle and to experience Grade 3-4 neutropenia and thrombocytopenia [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

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) Pulmonary Toxicity and Respiratory Failure: Discontinue Gemcitabine Injection for unexplained dyspnea or other evidence of severe pulmonary toxicity. (5.3) Hemolytic Uremic Syndrome (HUS): Monitor renal function prior to initiation and during treatment. Discontinue Gemcitabine Injection for HUS or severe renal impairment. (5.4) Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential to use effective contraception. (5.6, 8.1) Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within days of radiation therapy. (5.7) Capillary Leak Syndrome: Discontinue Gemcitabine Injection. (5.8) Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue Gemcitabine Injection. (5.9) 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) Pulmonary Toxicity and Respiratory Failure: Discontinue Gemcitabine Injection for unexplained dyspnea or other evidence of severe pulmonary toxicity. (5.3) Hemolytic Uremic Syndrome (HUS): Monitor renal function prior to initiation and during treatment. Discontinue Gemcitabine Injection for HUS or severe renal impairment. (5.4) Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential to use effective contraception. (5.6, 8.1) Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within days of radiation therapy. (5.7) Capillary Leak Syndrome: Discontinue Gemcitabine Injection. (5.8) Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue Gemcitabine Injection. (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)]. Refer to the recommended Gemcitabine Injection dosage [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)]. 5.2 Myelosuppression. Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia, occurs with gemcitabine as 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 the 979 patients who received 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 [see Adverse Reactions (6.1)]. Prior to each dose of Gemcitabine Injection, obtain complete blood count (CBC) with differential and platelet count. Modify the dosage as recommended [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].. 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 the discontinuation of therapy. The onset of pulmonary symptoms may occur up to weeks after the last dose of gemcitabine [see Adverse Reactions (6.1, 6.2)]. Permanently discontinue Gemcitabine Injection in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity.. 5.4 Hemolytic Uremic Syndrome. Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2429 patients. Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1)]. Serious cases of thrombotic microangiopathy (TMA) other than HUS have been reported with gemcitabine [see Adverse Reactions (6.2)]. Assess renal function prior to initiation of Gemcitabine Injection and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe thrombocytopenia; or evidence of renal failure (increased serum creatinine or BUN). Permanently discontinue Gemcitabine Injection in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the 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 with other potentially hepatotoxic drugs [see Adverse Reactions (6.1, 6.2)]. Administration of gemcitabine in patients with concurrent liver metastases or pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of Gemcitabine Injection and periodically during treatment. Permanently discontinue Gemcitabine Injection in patients who develop severe hepatic toxicity.. 5.6 Embryo-Fetal Toxicity. Based on animal data and its mechanism of action, Gemcitabine Injection can cause fetal harm when administered to pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for months following the final dose [see Use in Specific Populations (8.1, 8.3)]. 5.7 Exacerbation of Radiation Therapy Toxicity. Gemcitabine is not recommended for use in combination with radiation therapy.Concurrent (given together or <=7 days apart) Life-threatening mucositis, especially esophagitis and pneumonitis occurred in trial in which gemcitabine was administered at dose of 1000 mg/m2to patients with non-small cell lung cancer for up to consecutive weeks concurrently with thoracic radiation.Non-concurrent (given >7 days apart) Excessive toxicity has not been observed when gemcitabine is administered more than 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 single agent or in combination with other chemotherapeutic agents [see Adverse Reactions (6.2)]. Permanently discontinue Gemcitabine Injection if CLS develops during therapy.. 5.9 Posterior Reversible Encephalopathy Syndrome. Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents [see Adverse Reactions (6.2)]. 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). Permanently discontinue Gemcitabine Injection if PRES develops during therapy.