FDA label af878c20-5af1-46a0-a855-9c3ff00e4f0e

5 WARNINGS AND PRECAUTIONS Schedule-Dependent Toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly. ( 5.1 ) Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. ( 5.2 , 5.7 ) Pulmonary Toxicity and Respiratory Failure: Discontinue gemcitabine 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 for HUS or severe renal impairment. ( 5.4 ) Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue gemcitabine 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 7 days of radiation therapy. ( 5.7 ) Capillary Leak Syndrome: Discontinue gemcitabine. ( 5.8 ) Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue gemcitabine. ( 5.9 ) 5.1 Schedule-Dependent Toxicity In clinical trials evaluating the maximum tolerated dose of Gemcitabine for Injection USP, 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 for Injection USP 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 a single agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of 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 for Injection USP in combination with another drug [see Adverse Reactions ( 6.1 )] . Prior to each dose of Gemcitabine for Injection USP, obtain a complete blood count (CBC) with a differential and a 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 2 weeks after the last dose of Gemcitabine for Injection USP [see Adverse Reactions ( 6.1 , 6.2 )] . Permanently discontinue Gemcitabine for Injection USP 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 for Injection USP. 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 other than HUS have been reported with Gemcitabine for Injection USP [see Adverse Reactions ( 6.2 )] . Assess renal function prior to initiation of Gemcitabine for Injection USP 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 renal failure (increased serum creatinine or BUN). Permanently discontinue Gemcitabine for Injection USP 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 for Injection USP alone or with other potentially hepatotoxic drugs [see Adverse Reactions ( 6.1 , 6.2 )] . Administration of Gemcitabine for Injection USP in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of Gemcitabine for Injection USP and periodically during treatment. Permanently discontinue Gemcitabine for Injection USP in patients who develop severe hepatic toxicity. 5.6 Embryo-Fetal Toxicity Based on animal data and its mechanism of action, Gemcitabine for Injection USP can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Gemcitabine for Injection USP and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Gemcitabine for Injection USP and for 3 months following the final dose [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.7 Exacerbation of Radiation Therapy Toxicity Gemcitabine for Injection USP is not recommended for use in combination with radiation therapy. Concurrent (given together or less than or equal to 7 days apart) Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which Gemcitabine for Injection USP was administered at a dose of 1000 mg/m 2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. Non-concurrent (given greater than 7 days apart) Excessive toxicity has not been observed when Gemcitabine for Injection USP is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received Gemcitabine for Injection USP after prior radiation. 5.8 Capillary Leak Syndrome Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemcitabine for Injection USP as a single agent or in combination with other chemotherapeutic agents [see Adverse Reactions ( 6.2 )] . Permanently discontinue Gemcitabine for Injection USP if CLS develops during therapy. 5.9 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemcitabine for Injection USP as a 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 for Injection USP if PRES develops during therapy.

6 ADVERSE REACTIONS The most common adverse reactions for the single agent (greater than or equal to 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 Heritage Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Single Agent The data described below reflect exposure to Gemcitabine for Injection USP as a single agent administered at doses between 800 mg/m 2 to 1250 mg/m 2 intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (greater than or equal to 20%) adverse reactions of single agent Gemcitabine for Injection USP 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 (greater than or equal to 5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting, increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemcitabine for Injection USP due to adverse reactions. Adverse reactions resulting in discontinuation of Gemcitabine for Injection USP in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemcitabine for Injection USP in less than 1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema. Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent Gemcitabine for Injection USP across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6. Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine for Injection USP a a Grade based on criteria from the World Health Organization (WHO). b For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related. c N=699-974; all patients with laboratory or non-laboratory data. Adverse Reactions b Gemcitabine for Injection USP c All Grades (%) Grade 3 (%) Grade 4 (%) Nausea and Vomiting Fever Rash Dyspnea Diarrhea Hemorrhage Infection Alopecia Stomatitis Somnolence Paresthesias 69 41 30 23 19 17 16 15 11 11 10 13 2 <1 3 1 <1 1 <1 <1 <1 <1 1 0 0 <1 0 <1 <1 0 0 <1 0 Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine for Injection USP a a Grade based on criteria from the WHO. b Regardless of causality. c N=699-974; all patients with laboratory or non-laboratory data. Laboratory Abnormality b Gemcitabine for Injection USP c All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia Neutropenia Thrombocytopenia 68 63 24 7 19 4 1 6 1 Hepatic Increased ALT Increased AST Increased Alkaline Phosphatase Hyperbilirubinemia 68 67 55 13 8 6 7 2 2 2 2 <1 Renal Proteinuria Hematuria Increased BUN Increased Creatinine 45 35 16 8 <1 <1 0 <1 0 0 0 0 Additional adverse reactions include the following: Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (less than 1%) Edema: Edema (13%), peripheral edema (20%), generalized edema (less than 1%) Flu-like symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating, and/or malaise (19%) Infection: Sepsis (less than 1%) Extravasation: Injection-site reactions (4%) Allergic: Bronchospasm (less than 2%); anaphylactoid reactions Ovarian Cancer Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies ( 14.1 )] . Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following Table 8. The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm. Table 7: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1 Grade based on National Cancer Institute CTC Version 2.0. Adverse Reactions Regardless of causality. Gemcitabine/Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Nausea Alopecia Vomiting Constipation Fatigue Diarrhea Stomatitis/Pharyngitis 69 49 46 42 40 25 22 6 0 6 6 3 3 <1 0 0 0 1 <1 0 0 61 17 36 37 32 14 13 3 0 2 3 5 <1 0 0 0 <1 0 0 0 0 Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1 Grade based on National Cancer Institute CTC Version 2.0. Laboratory Abnormality Regardless of causality. Gemcitabine/Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Neutropenia Anemia Thrombocytopenia RBC Transfusions Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. Platelet Transfusions 90 86 78 38 9 42 22 30 - - 29 6 5 - - 58 75 57 15 3 11 9 10 - - 1 2 1 - - Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%). The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). Breast Cancer Tables 9 and 10 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neoadjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies ( 14.2 )] . Additional clinically significant adverse reactions, occurring in less than 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 (less than 1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2%(Grades 3-4)] in Study 2 Grade based on National Cancer Institute CTC Version 2.0. Adverse Reactions Non-laboratory events were graded only if assessed to be possibly drug-related. Gemcitabine/ Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Alopecia Neuropathy-Sensory Nausea Fatigue Vomiting Diarrhea Anorexia Neuropathy-Motor Stomatitis/Pharyngitis Fever Rash/Desquamation Febrile Neutropenia 90 64 50 40 29 20 17 15 13 13 11 6 14 5 1 6 2 3 0 2 1 <1 <1 5 4 <1 0 <1 0 0 0 <1 <1 0 <1 <1 92 58 31 28 15 13 12 10 8 3 5 2 19 3 2 1 2 2 <1 <1 <1 0 0 1 3 0 0 <1 0 0 0 0 0 0 0 0 Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2 Grade based on National Cancer Institute CTC Version 2.0. Laboratory Abnormality Regardless of causality. Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia Neutropenia Thrombocytopenia 69 69 26 6 31 5 1 17 <1 51 31 7 3 4 <1 <1 7 <1 Hepatobiliary Increased ALT Increased AST 18 16 5 2 <1 0 6 5 <1 <1 0 0 Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). Non-Small Cell Lung Cancer Tables 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies ( 14.3 )] . Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (greater than 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 less than 1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus less than 1%) were all higher in the gemcitabine with cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment- related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Table 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin[Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3 a a Grade based on National Cancer Institute Common Toxicity Criteria (CTC). b Non-laboratory events were graded only if assessed to be possibly drug-related. c N=217-253; all Gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=213-248; all cisplatin patients with laboratory or non-laboratory data. Adverse Reactions b Gemcitabine/Cisplatin c Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Nausea Vomiting Alopecia Neuro Motor Diarrhea Neuro Sensory Infection Fever Neuro Cortical Neuro Mood Local Neuro Headache Stomatitis Hemorrhage Hypotension Rash 93 78 53 35 24 23 18 16 16 16 15 14 14 14 12 11 25 11 1 12 2 1 3 0 3 1 0 0 1 1 1 0 2 12 0 0 2 0 2 0 1 0 0 0 0 0 0 0 87 71 33 15 13 18 12 5 9 10 6 7 5 4 7 3 20 10 0 3 0 1 1 0 1 1 0 0 0 0 1 0 <1 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3 a a Grade based on National Cancer Institute CTC. b Regardless of causality. c N=217-253; all Gemcitabine /cisplatin patients with laboratory or non-laboratory data. d N=213-248; all cisplatin patients with laboratory or non-laboratory data. e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. Laboratory Abnormality b Gemcitabine/Cisplatin c Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia Thrombocytopenia Neutropenia Lymphopenia RBC Transfusions e Platelet Transfusions e 89 85 79 75 39 21 22 25 22 25 - - 3 25 35 18 - - 67 13 20 51 13 <1 6 3 3 12 - - 1 1 1 5 - - Hepatic Increased Transaminases 22 2 1 10 1 0 Increased Alkaline Phosphatase 19 1 0 13 0 0 Renal Increased Creatinine Proteinuria Hematuria 38 23 15 4 0 0 <1 0 0 31 18 13 2 0 0 <1 0 0 Other Laboratory Hyperglycemia Hypomagnesemia Hypocalcemia 30 30 18 4 4 2 0 3 0 23 17 7 3 2 0 0 0 <1 Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies ( 14.3 )] . Additional clinically significant adverse reactions are provided following Table 14. Patients in the gemcitabine/cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm. The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm. Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4 a a Grade based on criteria from the WHO. b Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. c N=67-69; all Gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data. e Flu-like syndrome and edema were not graded. Adverse Reactions b Gemcitabine/Cisplatin c Etoposide/Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Nausea and Vomiting 96 35 4 86 19 7 Alopecia Paresthesias Infection Stomatitis Diarrhea Edema e Rash Hemorrhage Fever Somnolence Flu-like Syndrome e Dyspnea 77 38 28 20 14 12 10 9 6 3 3 1 13 0 3 4 1 - 0 0 0 0 - 0 0 0 1 0 1 - 0 3 0 0 - 1 92 16 21 18 13 2 3 3 3 3 0 3 51 2 8 2 0 - 0 0 0 2 - 0 0 0 0 0 2 - 0 3 0 0 - 0 Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4 a a Grade based on criteria from the WHO. b Regardless of causality. c N=67-69; all Gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=57-63; all Etoposide/cisplatin patients with laboratory or non-laboratory data. e WHO grading scale not applicable to proportion of patients with transfusions. Laboratory Abnormality b Gemcitabine/Cisplatin c Etoposide/Cisplatin d All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia Neutropenia Thrombocytopenia RBC Transfusions e Platelet Transfusions e 88 88 81 29 3 22 36 39 - - 0 28 16 - - 77 87 45 21 8 13 20 8 - - 2 56 5 - - Hepatic Increased Alkaline Phosphatase 16 0 0 11 0 0 Increased ALT Increased AST 6 3 0 0 0 0 12 11 0 0 0 0 Renal Hematuria Proteinuria Increased BUN Increased Creatinine 22 12 6 2 0 0 0 0 0 0 0 0 10 5 4 2 0 0 0 0 0 0 0 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Gemcitabine for Injection USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system: Thrombotic microangiopathy (TMA) Cardiovascular : Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome Skin: Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions Hepatic: Hepatic failure, hepatic veno-occlusive disease Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia Nervous System : Posterior reversible encephalopathy syndrome (PRES)

<table ID="ID245" width="703"><caption> Table 5: Selected Adverse Reactions Occurring in &#x2265;10% of Patients Receiving Single Agent Gemcitabine for Injection USP^a</caption><col width="229"/><col width="168"/><col width="156"/><col width="150"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^aGrade based on criteria from the World Health Organization (WHO).</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^bFor approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^cN=699-974; all patients with laboratory or non-laboratory data. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse Reactions^b</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Gemcitabine for Injection USP^c</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Grades</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 3</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 4</content> <content styleCode="bold"> (%)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea and Vomiting Fever Rash Dyspnea Diarrhea Hemorrhage Infection Alopecia Stomatitis Somnolence Paresthesias </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 69 41 30 23 19 17 16 15 11 11 10 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 2 &lt;1 3 1 &lt;1 1 &lt;1 &lt;1 &lt;1 &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 0 0 &lt;1 0 &lt;1 &lt;1 0 0 &lt;1 0 </td></tr></tbody></table>

<table ID="ID248" width="703" styleCode="Noautorules"><caption> Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine for Injection USP^a</caption><col width="229"/><col width="168"/><col width="156"/><col width="150"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^a Grade based on criteria from the WHO.</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^bRegardless of causality.</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^c N=699-974; all patients with laboratory or non-laboratory data.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Laboratory Abnormality^b</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Gemcitabine for Injection USP^c</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Grades</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 3</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 4</content> <content styleCode="bold"> (%)</content> </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Hematologic </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Anemia Neutropenia Thrombocytopenia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 68 63 24 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 19 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 6 1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Hepatic </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased ALT Increased AST Increased Alkaline Phosphatase Hyperbilirubinemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 68 67 55 13 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 6 7 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 2 2 &lt;1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Renal </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Proteinuria Hematuria Increased BUN Increased Creatinine </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45 35 16 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 &lt;1 0 &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 0 0 0 </td></tr></tbody></table>

<table ID="ID333" width="722" styleCode="Noautorules"><caption> Table 7: Adverse Reactions Occurring in &gt;10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of &#x2265;5% (All Grades) or &#x2265;2% (Grades 3-4)] in Study 1<footnote ID="ID3330"> Grade based on National Cancer Institute CTC Version 2.0.</footnote></caption><col width="187"/><col width="82"/><col width="90"/><col width="90"/><col width="92"/><col width="90"/><col width="91"/><tbody><tr><td rowspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule Botrule" align="left"><content styleCode="bold"> Adverse Reactions<footnote ID="ID3331"> Regardless of causality.</footnote></content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Gemcitabine/Carboplatin</content> <content styleCode="bold"> (N=175)</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Carboplatin</content> <content styleCode="bold"> (N=174)</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Grades</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 3</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 4</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Grades</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 3</content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 4</content> <content styleCode="bold"> (%)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea Alopecia Vomiting Constipation Fatigue Diarrhea Stomatitis/Pharyngitis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 69 49 46 42 40 25 22 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 0 6 6 3 3 &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 0 0 1 &lt;1 0 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 61 17 36 37 32 14 13 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 0 2 3 5 &lt;1 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 0 &lt;1 0 0 0 0 </td></tr></tbody></table>