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 Hospira, Inc. at 1-800-441-4100 or ProductComplaintsPPhospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical 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 practice.. Single AgentThe data described below reflect exposure to gemcitabine as single agent administered at doses between 800 mg/m2 to 1250 mg/m2 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 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 patients 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 GemcitabineGrade based on criteria from the World Health Organization (WHO). Adverse ReactionsFor approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. GemcitabineN=699-974; all patients with laboratory or non-laboratory data. All Grades(%)Grade 3(%)Grade 4(%)Nausea and Vomiting69131Fever4120Rash30<10Dyspnea233<1Diarrhea1910Hemorrhage17<1<1Infection161<1Alopecia15<10Stomatitis11<10Somnolence11<1<1Paresthesias10<10Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent GemcitabineGrade based on criteria from WHO. Laboratory AbnormalityRegardless of causality. GemcitabineN=699-974; all patients with laboratory or non-laboratory data. All Grades(%)Grade 3(%)Grade 4(%)Hematologic Anemia6871 Neutropenia63196 Thrombocytopenia2441Hepatic Increased ALT6882 Increased AST6762 Increased Alkaline Phosphatase5572 Hyperbilirubinemia132<1Renal Proteinuria45<10 Hematuria35<10 Increased BUN1600 Increased Creatinine8<10Additional 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, insomnia, rhinitis, sweating, and/or malaise (19%)Infection: Sepsis (<1%)Extravasation: Injection-site reactions (4%)Allergic: Bronchospasm (<2%); anaphylactoid reactions. 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, insomnia, rhinitis, sweating, and/or malaise (19%). Infection: Sepsis (<1%). Extravasation: Injection-site reactions (4%). Allergic: Bronchospasm (<2%); anaphylactoid reactions. Ovarian CancerTables 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 1Grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0. Adverse ReactionsRegardless of causality. Gemcitabine/Carboplatin(N=175)Carboplatin(N=174)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Nausea69606130Alopecia49001700Vomiting4660362<1Constipation42613730Fatigue403<13250Diarrhea253014<10Stomatitis/Pharyngitis22<101300Table 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 1Grade based on National Cancer Institute CTC Version 2.0. Laboratory AbnormalityRegardless of causality. Gemcitabine/Carboplatin(N=175)Carboplatin(N=174)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Hematologic Neutropenia90422958111 Anemia862267592 Thrombocytopenia7830557101 RBC TransfusionPercent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. 38--15-- Platelet Transfusion 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 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 2Grade based on National Cancer Institute CTC Version 2.0. Adverse ReactionsNon-laboratory events were graded only if assessed to be possibly drug-related. Gemcitabine/Paclitaxel(N=262)Paclitaxel(N=259)All GradesGrade 3Grade 4All GradesGrade 3Grade 4(%)(%)(%)(%)(%)(%)Alopecia9014492193Neuropathy-Sensory645<15830Nausea50103120Fatigue406<1281<1Vomiting29201520Diarrhea20301320Anorexia170012<10Neuropathy-Motor152<110<10Stomatitis/Pharyngitis131<18<10Fever13<10300Rash/Desquamation11<1<1500Febrile Neutropenia65<1210Table 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 2Grade based on National Cancer Institute CTC Version 2.0. Laboratory AbnormalityRegardless of causality. Gemcitabine/ Paclitaxel(N=262)Paclitaxel(N=259)All GradesGrade 3Grade 4All GradesGrade 3Grade 4(%)(%)(%)(%)(%)(%)Hematologic Anemia6961513<1 Neutropenia6931173147 Thrombocytopenia265<17<1<1Hepatobiliary Increased ALT185<16<10 Increased AST16205<10Clinically 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 CancerTables 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 3Grade based on National Cancer Institute CTC. Adverse ReactionsNon-laboratory events were graded only if assessed to be possibly drug-related. Gemcitabine/CisplatinN=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. CisplatinN=213-248; all cisplatin patients with laboratory or non-laboratory data. All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Nausea932528720<1Vomiting78111271109Alopecia53103300Neuro Motor351201530Diarrhea24221300Neuro Sensory23101810Infection18321210Fever1600500Neuro Cortical1631910Neuro Mood16101010Local1500600Neuro Headache1400700Stomatitis1410500Hemorrhage1410400Hypotension1210710Rash1100300Table 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 3Grade based on National Cancer Institute CTC. Laboratory AbnormalityRegardless of causality. Gemcitabine/CisplatinN=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. CisplatinN=213-248; all cisplatin patients with laboratory or non-laboratory data. All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Hematologic Anemia892236761 Thrombocytopenia8525251331 Neutropenia7922352031 Lymphopenia75251851125 RBC TransfusionPercent of patients receiving transfusions. Percent transfusions are not CTC-graded events. 39--13-- Platelet Transfusions 21--<1--Hepatic Increased Transaminase22211010 Increased Alkaline Phosphatase19101300Renal Increased Creatinine384<1312<1 Proteinuria23001800 Hematuria15001300Other Laboratory Hyperglycemia30402330 Hypomagnesemia30431720 Hypocalcemia182070<1Tables 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 4Grade based on criteria from WHO. Adverse ReactionsNon-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. Gemcitabine/CisplatinN=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. Etoposide/CisplatinN=57-63; all etoposide/cisplatin patients with laboratory or non-laboratory data. All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Nausea and Vomiting9635486197Alopecia7713092510Paresthesias38001620Infection28312180Stomatitis20401820Diarrhea14111302EdemaFlu-like syndrome and edema were not graded. 12--2--Rash1000300Hemorrhage903303Fever600300Somnolence300320Flu-like Syndrome 3--0--Dyspnea101300Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4Grade based on criteria from WHO. Laboratory AbnormalityRegardless of causality. Gemcitabine/CisplatinN=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. Etoposide/CisplatindN=57-63; all etoposide/cisplatin patients with laboratory or non-laboratory data. All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)Hematologic Anemia8822077132 Neutropenia883628872056 Thrombocytopenia8139164585 RBC TransfusionPercent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions. 29--21-- Platelet Transfusions 3--8--Hepatic Increased Alkaline Phosphatase16001100 Increased ALT6001200 Increased AST3001100Renal Hematuria22001000 Proteinuria1200500 Increased BUN600400 Increased Creatinine200200. 6.2Postmarketing 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 arrhythmiasVascular: Peripheral vasculitis, gangrene, capillary leak syndrome Skin: Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptionsHepatic: 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.. Elimination. MetabolismThe 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/m2 of 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 PatientsClearance 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 PatientsFemales 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 PatientAgeClearance Men(L/hr/m2)Clearance Women(L/hr/m2)Half-LifeHalf-life for patients receiving <70 minute infusion. Men(min)Half-Life Women(min)2992.269.442494575.757.048576555.141.561737940.730.77994. Patients with Renal ImpairmentNo clinical studies have been conducted with gemcitabine in patients with decreased renal function.. Patients with Hepatic ImpairmentNo 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. 14.1Ovarian 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/m2 on 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 1Gemcitabine/Carboplatin(N=178)Carboplatin(N=178)Median age, years5958 Range36 to 7821 to 81Baseline ECOG performance status 0-15 patients on gemcitabine/carboplatin arm and patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status. 94%95%Disease Status Evaluable8%3% Bidimensionally measurable92%96%Platinum-free interval2 patients on gemcitabine/carboplatin arm and patient on carboplatin arm had platinum-free interval 6 months. 6-12 months40%40% >12 months59%60%First-line therapy Platinum-taxane combination70%71% Platinum-non-taxane combination29%28% Platinum monotherapy1%1%Table 17: Efficacy Results in Study 1Efficacy ParameterGemcitabine/Carboplatin (N=178)Carboplatin (N=178)Progression-Free SurvivalMedian (95% CI CI=confidence interval) in months8.6 (8.0, 9.7)5.8 (5.2, 7.1) Hazard Ratio (95% CI)0.72 (0.57, 0.90)p=valueLog rank, unadjusted p=0.0038Overall Survival Median (95% CI) in months18.0 (16.2, 20.3)17.3 (15.2, 19.3) Hazard Ratio (95% CI)0.98 (0.78, 1.24)p=value p=0.8977Overall Response Rate by Investigator Review47.2%30.9%p=valueChi square p=0.0016CRCR=Complete response 14.6%6.2% PR with PRNMPR with PRNM=Partial response with partial response, non-measurable disease 32.6%24.7%Overall Response Rate by Independent ReviewIndependently reviewed cohort gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam. 46.3%35.6%p=value p=0.11 CR 9.1%4.0% PR with PRNM 37.2%31.7%Figure 1: Kaplan-Meier Curves for Progression-Free Survival in Study 1. Figure 1. 14.2Breast 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.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 2Gemcitabine/Paclitaxel(N=267)Paclitaxel(N=262)Median age, years Range535226 to 8326 to 75Metastatic disease97%97%Baseline KPSKarnofsky Performance Status. >=9070%74%Number of tumor sites 1-257%59% >=343%41%Visceral disease73%73%Prior anthracycline97%96%Table 19: Efficacy Results in Study 2Efficacy ParameterGemcitabine/Paclitaxel(N=267)Paclitaxel(N=262)Time to Documented Disease ProgressionThese represent reconciliation of investigator and Independent Review Committee assessments according to predefined algorithm. Median (95% CI) in months5.2(4.2, 5.6)2.9(2.6, 3.7) Hazard Ratio (95% CI)0.650 (0.524, 0.805) p-valuep<0.0001Overall SurvivalBased on the ITT population. Median (95% CI) in months18.6(16.5, 20.7)15.8(14.1, 17.3) Hazard Ratio (95% CI)0.86 (0.71, 1.04) p-valueNot Significant Overall Response Rate (95% CI)40.8% (34.9, 46.7)22.1% (17.1, 27.2) p-valuep<0.0001Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2. Figure 2. 14.3Non-Small Cell Lung Cancer. The efficacy of gemcitabine was evaluated in two randomized, multicenter trials.. Study 3: 28-Day ScheduleA 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 each 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 ScheduleA 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.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 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 3Table 20: Baseline Demographics and Clinical Characteristics for Studies and 4Trial28-day Schedule (Study 3)21-day Schedule (Study 4)Gemcitabine/Cisplatin(N=260)Cisplatin(N=262)Gemcitabine/Cisplatin(N=69)Etoposide/Cisplatin(N=66)Male70%71%93%92%Median age, years62635860Range36 to 8835 to 7933 to 7635 to 75Stage IIIA7%7%N/AN/A Not applicable. N/A Stage IIIB26%23%48%52%Stage IV67%70%52%49%Baseline KPSKarnofsky Performance Status. 70 to 8041%44%45%52%Baseline KPS 90 to 10057%55%55%49%Table 21: Efficacy Results for Studies and 4Trial28-day Schedule (Study 3)21-day Schedule (Study 4)Efficacy ParameterGemcitabine/Cisplatin(N=260)Cisplatin(N=262)Gemcitabine/Cisplatin(N=69)Etoposide/Cisplatin(N=66)Survival Median (95% CICI=confidence intervals.) in months9.0 (8.2, 11.0)7.6 (6.6, 8.8)8.7 (7.8, 10.1)7.0 (6.0, 9.7) p-valuep-value two-sided Fishers Exact test for difference in binomial proportions; log rank test for time-to-event analyses. p=0.008p=0.18Time to Disease Progression Median (95% CI) in months5.2 (4.2, 5.7)3.7 (3.0, 4.3)5.0 (4.2, 6.4)4.1 (2.4, 4.5) p-value p=0.009p=0.015Tumor Response26%10%33%14% p-value p<0.0001p=0.01. Figure 3. 14.4Pancreatic 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/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. 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.ORThe 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 5Gemcitabine(N=63)Fluorouracil(N=63)Male54%54%Median age62 years61 yearsRange37 to 7936 to 77Stage IV disease71%76%Baseline KPSKarnofsky Performance Status. <=7070%68%Table 23: Efficacy Results in Study 5Efficacy ParameterGemcitabine(N=63)Fluorouracil (N=63)Clinical Benefit Response22.2%4.8% p-valuep-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. p=0.004Overall Survival Median (95% CI) in months5.7 (4.7, 6.9)4.2 (3.1, 5.1) p-value p=0.0009Time to Disease Progression Median (95% CI) in months2.1 (1.9, 3.4)0.9 (0.9, 1.1) p-value p=0.0013Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5. 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.. 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.. Figure 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). 2.1Ovarian Cancer. Recommended Dose and ScheduleThe recommended dosage of Gemcitabine Injection is 1000 mg/m2 intravenously 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 DayAbsolute Neutrophil Count (x 106/L)Platelet Count (x 106/L)Dosage ModificationDay 1Greater than or equal to 1500AndGreater than or equal to 100,000NoneLess than 1500OrLess than 100,000Delay Treatment CycleDay 8Greater than or equal to 1500AndGreater than or equal to 100,000None1000 to 1499Or75,000 to 99,99950% of full doseLess than 1000OrLess than 75,000HoldTable 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian CancerOccurrenceMyelosuppression During Treatment CycleDosage ModificationInitial OccurrenceAbsolute neutrophil count less than 500 106/L for more than days orAbsolute neutrophil count less than 100 106/L for more than days orFebrile neutropenia orPlatelets less than 25,000 106/LCycle delay for more than one week due to toxicityPermanently reduce Gemcitabine Injection to 800 mg/m2 on Days and 8Subsequent OccurrenceIf any of the above toxicities occur after the initial dose reductionPermanently reduce Gemcitabine Injection dose to 800 mg/m2 on Day only. 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 for more than one week due to toxicity. 2.2Breast Cancer. Recommended Dose and ScheduleThe recommended dosage of Gemcitabine Injection is 1250 mg/m2 intravenously over 30 minutes on Days and of each 21-day cycle in combination with paclitaxel 175 mg/m2 administered 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 CancerTreatment DayAbsolute Neutrophil Count (x 106/L)Platelet Count (x 106/L)Dosage ModificationDay 1Greater than or equal to 1500AndGreater than or equal to 100,000NoneLess than 1500OrLess than 100,000HoldDay 8Greater than or equal to 1200AndGreater than 75,000None1000 to 1199Or50,000 to 75,00075% of full dose700 to 999AndGreater than or equal to 50,00050% of full doseLess than 700OrLess than 50,000Hold. 2.3Non-Small Cell Lung Cancer. Recommended Dose and Schedule. 28-day scheduleThe recommended dosage of Gemcitabine Injection is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m2 administered intravenously on Day after Gemcitabine Injection administration.. 21-day scheduleThe recommended dosage of Gemcitabine Injection is 1250 mg/m2 intravenously over 30 minutes on Days and of each 21-day cycle in combination with cisplatin 100 mg/m2 administered intravenously on Day after Gemcitabine Injection administration.Refer to cisplatin prescribing information for additional information.. Dosage ModificationsRecommended 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)].. 2.4Pancreatic 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.. 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 CancerAbsolute Neutrophil Count (x 106/L)Platelet Count (x 106/L)Dosage ModificationGreater than or equal to 1000AndGreater than or equal to 100,000None500 to 999Or50,000 to 99,99975% of full doseLess than 500OrLess than 50,000Hold. 2.5Dosage 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)] 2.6Preparation. Gemcitabine Injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Exercise 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.. Elimination. MetabolismThe 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/m2 of 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 PatientsClearance 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 PatientsFemales 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 PatientAgeClearance Men(L/hr/m2)Clearance Women(L/hr/m2)Half-LifeHalf-life for patients receiving <70 minute infusion. Men(min)Half-Life Women(min)2992.269.442494575.757.048576555.141.561737940.730.77994. Patients with Renal ImpairmentNo clinical studies have been conducted with gemcitabine in patients with decreased renal function.. Patients with Hepatic ImpairmentNo 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.. Data. Animal 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/m2 clinical 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/m2 clinical dose based on BSA).. 8.2 Lactation. Risk SummaryThere 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 TestingVerify pregnancy status in females of reproductive potential prior to initiating Gemcitabine Injection [see Use in Specific Populations (8.1)].. ContraceptionGemcitabine Injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. FemalesBecause 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.. MalesBecause 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. MalesBased 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)].. 8.6Gender. 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). 5.1Schedule-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)].. 5.2Myelosuppression. 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)].. 5.3Pulmonary 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.. 5.4Hemolytic 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.. 5.5Hepatic 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.. 5.6Embryo-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)]. 5.7Exacerbation 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/m2 to 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.. 5.8Capillary 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.. 5.9Posterior 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.