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adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label Schedule-dependent Toxicity [see Warnings and Precautions (5.1)] Myelosuppression [see Warnings and Precautions (5.2)] Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.3)] Hemolytic Uremic Syndrome [see Warnings and Precautions (5.4)] Hepatic Toxicity [see Warnings and Precautions (5.5)] Embryofetal Toxicity [see Warnings and Precautions (5.6), Use in Specific Populations (8.1), and Nonclinical Toxicology (13.1)] Exacerbation of Radiation Toxicity [see Warnings and Precautions (5.7)] Capillary Leak Syndrome [see Warnings and Precautions (5.8)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.9)] The most common adverse reactions for the single agent (≥ 20%) are nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact X-Gen Pharmaceuticals, Inc. at 1-866-390-4411 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised 04/2016 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Single-Agent Use: The data described below reflect exposure to gemcitabine for injection as a single agent administered at doses between 800 mg/m 2 to 1250 mg/m 2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥ 20%) adverse reactions of single-agent gemcitabine for injection are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine for injection due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine for injection in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine for injection in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema. Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent gemcitabine for injection across 5 clinical trials. Table 5 includes all clinical adverse reactions reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table. Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent Gemcitabine for Injection a All Patients b All Grades Grade 3 Grade 4 Laboratory c Hematologic Anemia 68 7 1 Neutropenia 63 19 6 Thrombocytopenia 24 4 1 Hepatic Increased ALT 68 8 2 Increased AST 67 6 2 Increased Alkaline Phosphatase 55 7 2 Hyperbilirubinemia 13 2 < 1 Renal Proteinuria 45 < 1 0 Hematuria 35 < 1 0 Increased BUN 16 0 0 Increased Creatinine 8 < 1 0 Non-laboratory d Nausea and Vomiting 69 13 1 Fever 41 2 0 Rash 30 < 1 0 Dyspnea 23 3 < 1 Diarrhea 19 1 0 Hemorrhage 17 < 1 < 1 Infection 16 1 < 1 Alopecia 15 < 1 0 Stomatitis 11 < 1 0 Somnolence 11 < 1 < 1 Paresthesias 10 < 1 0 a Grade based on criteria from the World Health Organization (WHO). b N=699 to 974; all patients with laboratory or non-laboratory data. c Regardless of causality. d For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (< 1%) Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms. Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm. Edema — Edema (13%), peripheral edema (20%), and generalized edema (< 1%); < 1% of patients discontinued gemcitabine for injection due to edema. Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating, and/or malaise (19%); < 1% of patients discontinued gemcitabine for injection due to flu-like symptoms Infection — Sepsis (< 1%) Extravasation — Injection-site reactions (4%) Allergic — Bronchospasm (< 2%); anaphylactoid reactions [see Contraindications (4)] . Non-Small Cell Lung Cancer: Table 6 presents the incidence of selected adverse reactions, occurring in ≥ 10% of gemcitabine for injection -treated patients and at a higher incidence in the gemcitabine for injection plus cisplatin arm, reported in a randomized trial of gemcitabine for injection plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)] . Patients randomized to gemcitabine for injection plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (> 90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine for injection plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus < 1%) were all higher in the gemcitabine for injection plus cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Table 6: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial of Gemcitabine for Injection plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemcitabine for Injection-Treated Patients [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 to 4)] a Gemcitabine for Injection plus Cisplatin b Cisplatin c All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory d Hematologic Anemia 89 22 3 67 6 1 RBC Transfusion e 39 13 Neutropenia 79 22 35 20 3 1 Thrombocytopenia 85 25 25 13 3 1 Platelet Transfusions e 21 < 1 Lymphopenia 75 25 18 51 12 5 Hepatic Increased Transaminases 22 2 1 10 1 0 Increased Alkaline Phosphatase 19 1 0 13 0 0 Renal Proteinuria 23 0 0 18 0 0 Hematuria 15 0 0 13 0 0 Elevated Creatinine 38 4 < 1 31 2 < 1 Other Laboratory Hyperglycemia 30 4 0 23 3 0 Hypomagnesemia 30 4 3 17 2 0 Hypocalcemia 18 2 0 7 0 < 1 Non-laboratory f Nausea 93 25 2 87 20 < 1 Vomiting 78 11 12 71 10 9 Alopecia 53 1 0 33 0 0 Neuro Motor 35 12 0 15 3 0 Diarrhea 24 2 2 13 0 0 Neuro Sensory 23 1 0 18 1 0 Infection 18 3 2 12 1 0 Fever 16 0 0 5 0 0 Neuro Cortical 16 3 1 9 1 0 Neuro Mood 16 1 0 10 1 0 Local 15 0 0 6 0 0 Neuro Headache 14 0 0 7 0 0 Stomatitis 14 1 0 5 0 0 Hemorrhage 14 1 0 4 0 0 Hypotension 12 1 0 7 1 0 Rash 11 0 0 3 0 0 a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading. b N=271 to 253; all gemcitabine for injection plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine for injection at 1000 mg/m 2 on Days 1, 8, and 15 and cisplatin at 100 mg/m 2 on Day 1 every 28 days. c N=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m 2 on Day 1 every 28 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. f Non-laboratory events were graded only if assessed to be possibly drug-related. Table 7 presents the incidence of selected adverse reactions, occurring in ≥ 10% of gemcitabine for injection -treated patients and at a higher incidence in the gemcitabine for injection plus cisplatin arm, reported in a randomized trial of gemcitabine for injection plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)] . A listing of clinically significant adverse reactions is provided following the table. Patients in the gemcitabine for injection cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the gemcitabine for injection cisplatin arm. Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemcitabine for Injection plus Cisplatin versus Etoposide plus Cisplatin in Patients with NSCLC a Gemcitabine for injection plus Cisplatin b Etoposide plus Cisplatin c All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory d Hematologic Anemia 88 22 0 77 13 2 RBC Transfusions e 29 - - 21 - - Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 16 45 8 5 Platelet Transfusions e 3 - - 8 - - Hepatic Increased ALT 6 0 0 12 0 0 Increased AST 3 0 0 11 0 0 Increased Alkaline Phosphatase 16 0 0 11 0 0 Bilirubin 0 0 0 0 0 0 Renal Proteinuria 12 0 0 5 0 0 Hematuria 22 0 0 10 0 0 BUN 6 0 0 4 0 0 Creatinine 2 0 0 2 0 0 Non-laboratory f Nausea and Vomiting 96 35 4 86 19 7 Fever 6 0 0 3 0 0 Rash 10 0 0 3 0 0 Dyspnea 1 0 1 3 0 0 Diarrhea 14 1 1 13 0 2 Hemorrhage 9 0 3 3 0 3 Infection 28 3 1 21 8 0 Alopecia 77 13 0 92 51 0 Stomatitis 20 4 0 18 2 0 Somnolence 3 0 0 3 2 0 Paresthesias 38 0 0 16 2 0 Flu-like syndrome g 3 - - 0 - - Edema g 12 - - 2 - - a Grade based on criteria from the World Health Organization (WHO). b N=67 to 69; all gemcitabine for injection plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine for injection at 1250 mg/m 2 on Days 1 and 8 and cisplatin at 100 mg/m 2 on Day 1 every 21 days. c N=57 to 63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m 2 on Day 1 and intravenous etoposide at 100 mg/m 2 on Days 1, 2, and 3 every 21 days. d Regardless of causality. e WHO grading scale not applicable to proportion of patients with transfusions. f Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. g Flu-like syndrome and edema are not graded. Breast Cancer Table 8 presents the incidence of selected adverse reactions, occurring in ≥ 10% of gemcitabine for injection -treated patients and at a higher incidence in the gemcitabine for injection plus paclitaxel arm, reported in a randomized trial of gemcitabine for injection plus paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)] . The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine for injection/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (< 1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. Table 8: Per-Patient Incidence of Selected Adverse Reactions from Comparative Trial of Gemcitabine for Injection plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancer a Occurring at Higher Incidence in Gemcitabine for Injection-Treated Patients [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 to 4)] Gemcitabine for injection plus Paclitaxel (N=262) Paclitaxel (N=259) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hemtologic Anemia 69 6 1 51 3 < 1 Neutropenia 69 31 17 31 4 7 Thrombocytopenia 26 5 < 1 7 < 1 < 1 Hepatobiliary Increased ALT 18 5 < 1 6 < 1 0 Increased AST 16 2 0 5 < 1 0 Non-laboratory c Alopecia 90 14 4 92 19 3 Neuropathy-sensory 64 5 < 1 58 3 0 Nausea 50 1 0 31 2 0 Fatigue 40 6 < 1 28 1 < 1 Vomiting 29 2 0 15 2 0 Diarrhea 20 3 0 13 2 0 Anorexia 17 0 0 12 < 1 0 Neuropathy-motor 15 2 < 1 10 < 1 0 Stomatitis/pharyngitis 13 1 < 1 8 < 1 0 Fever 13 < 1 0 3 0 0 Rash/desquamation 11 < 1 < 1 5 0 0 Febrile neutropenia 6 5 < 1 2 1 0 a Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) version 2.0. b Regardless of causality. c Non-laboratory events were graded only if assessed to be possibly drug-related. Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine for injection plus paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). Ovarian Cancer Table 9 presents the incidence of selected adverse reactions, occurring in ≥ 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine for injection plus carboplatin arm, reported in a randomized trial of gemcitabine for injection plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)] . Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following Table 9. The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for gemcitabine for injection occurred in 10.4% of patients and gemcitabine for injection dose was omitted in 13.7% of patients in the gemcitabine for injection /carboplatin arm. Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemcitabine for Injection plus Carboplatin versus Carboplatin in Ovarian Cancer a Occurring at Higher Incidence in Gemcitabine for Injection-Treated Patients [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 to 4)] Gemcitabine for injection plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Thrombocytopenia 78 30 5 57 10 1 RBC Transfusions c 38 15 Platelet Transfusions c 9 3 Non-laboratory b Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 < 1 Constipation 42 6 1 37 3 0 Fatigue 40 3 < 1 32 5 0 Diarrhea 25 3 0 14 < 1 0 Stomatitis/pharyngitis 22 < 1 0 13 0 0 a Grade based on Common Toxicity Criteria (CTC) Version 2.0. b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. Hematopoietic growth factors were administered more frequently in the gemcitabine for injection -containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%). The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine for injection plus carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of gemcitabine for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular — Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Vascular Disorders — Peripheral vasculitis, gangrene, and capillary leak syndrome [see Warnings and Precautions (5.8)] Skin — Cellulitis, severe skin reactions, including desquamation and bullous skin eruptions Hepatic — Hepatic failure, hepatic veno-occlusive disease Pulmonary — Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS) Nervous System — Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.9)]