Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated: •in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. (1.1) •in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. (1.2) •in combination with cisplatin for the treatment of non-small cell lung cancer. (1.3) •as a single-agent for the treatment of pancreatic cancer. (1.4) 1.1 Ovarian Cancer Gemcitabine injection in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. 1.2 Breast Cancer Gemcitabine injection in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. 1.3 Non-Small Cell Lung Cancer Gemcitabine injection is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer. 1.4 Pancreatic Cancer Gemcitabine injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine injection is indicated for patients previously treated with 5-FU.

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Advisory information

contraindications
4 CONTRAINDICATIONS Gemcitabine injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Patients with a known hypersensitivity to gemcitabine. (4)
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 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, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Single-Agent Use The data described below reflect exposure to gemcitabine as a single-agent administered at doses between 800 mg/m2 to 1,250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent gemcitabine 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 due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine 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 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 Gemcitabinea All Patientsb All Grades Grade 3 Grade 4 Laboratoryc 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-laboratoryd 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 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 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-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in a randomized trial of gemcitabine 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 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 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 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 plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]a Gemcitabine plus Cisplatinb Cisplatinc All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryd Hematologic Anemia 89 22 3 67 6 1 RBC Transfusione 39 13 Neutropenia 79 22 35 20 3 1 Thrombocytopenia 85 25 25 13 3 1 Platelet Transfusionse 21 <1 Lymphopenia 75 25 18 51 12 5 Hepatic Increased Transaminase 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-laboratoryf 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=217 to 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1,000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. c N=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 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-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in arandomized trial of gemcitabine plus cisplatin (n=69) administered in 21-day cycles as compared toetoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced ormetastatic NSCLC [see Clinical Studies (14.3)]. A listing of clinically significant adverse reactions isprovided following the table. 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 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/cisplatin arm. Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemcitabine plus Cisplatin versus Etoposide plus Cisplatin in Patients with NSCLCa Gemcitabine plus Cisplatinb Etoposide plus Cisplatinc All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryd Hematologic Anemia 88 22 0 77 13 2 RBC Transfusione 29 - - 21 - - Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 16 45 8 5 Platelet Transfusionse 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 12 0 0 2 0 0 Non-laboratoryf 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 syndromeg 3 - - 0 - - Edemag 12 - - 2 - - a Grade based on criteria from the World Health Organization (WHO). b N=67 to 69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1,250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 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/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events. 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 were not graded. Breast Cancer Table 8 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus paclitaxel arm, reported in arandomized trial of gemcitabine 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-containingchemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [seeClinical Studies (14.2)]. 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 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 plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)] Gemcitabine plus Paclitaxel (N=262) Paclitaxel (N=259) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryb Hematologic Anemia 69 6 1 51 3 <1 Neutropenia 69 31 17 31 4 7 Thrombocytopenia 26 5 <1 7 <1 <1 Hepatobiliary Increased ALT 18 5 <1 6 <1 0 Increased AST 16 2 0 5 <1 0 Non-laboratoryc 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 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 plus carboplatin arm, reported in a randomized trial of gemcitabine 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 occurred in 10.4% of patients and gemcitabine dose was omitted in 13.7% of patients in the gemcitabine/carboplatin arm. Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)] Gemcitabine plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratoryb Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Thrombocytopenia 78 30 5 57 10 1 RBC Transfusionsc 38 15 Platelet Transfusionsc 9 3 Non-laboratoryb 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-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 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. 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, pseudocellulitis, 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)]

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. •Ovarian cancer: 1,000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.1) •Breast cancer: 1,250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2) •Non-small cell lung cancer: 1,000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1,250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.3) •Pancreatic cancer: 1,000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one-week rest, then once weekly for 3 weeks of each 28-day cycle. (2.4) 2.1 Ovarian Cancer Recommended Dose and Schedule The recommended dose of gemcitabine injection is 1,000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information. Dose Modifications Recommended gemcitabine injection dose modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions. Table 1: Dosage Reduction Guidelines for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Day Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose Day 1 ≥1,500 and ≥100,000 100% <1,500 or <100,000 Delay Treatment Cycle Day 8 ≥1,500 and ≥100,000 100% 1,000 to 1,499 or 75,000 to 99,999 50% <1,000 or <75,000 Hold Table 2: Gemcitabine Injection Dose Modification for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dose Modification Initial Occurrence Absolute granulocyte count less than 500 x 106/L for more than 5 days Absolute granulocyte count less than 100 x 106/L for more than 3 days Febrile neutropenia Platelets less than 25,000 x 106/L Cycle delay of more than one week due to toxicity Permanently reduce gemcitabine injection to 800 mg/m2 on Days 1 and 8 Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction Permanently reduce gemcitabine injection dose to 800 mg/m2 on Day 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dose of gemcitabine injection is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine injection administration. Dose Modifications Recommended dose modifications for gemcitabine injection for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions. Table 3: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose Day 1 ≥1,500 and ≥100,000 100% less than 1,500 or less than 100,000 Hold Day 8 ≥1,200 and >75,000 100% 1,000 to 1,199 or 50,000 to 75,000 75% 700 to 999 and ≥50,000 50% <700 or <50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule Every 4-week schedule The recommended dose of gemcitabine injection is 1,000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine injection. Every 3-week schedule The recommended dose of gemcitabine injection is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine injection. Dose Modifications Recommended dose modifications for gemcitabine injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine injection recommendations for non-hematologic adverse reactions. 2.4 Pancreatic Cancer Recommended Dose and Schedule The recommended dose of gemcitabine injection is 1,000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule is as follows: •Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest. •After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles. Dose Modifications Recommended dose modifications for gemcitabine injection for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions. Patients receiving gemcitabine injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4. Table 4: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose ≥1,000 And ≥100,000 100% 500 to 999 Or 50,000 to 99,999 75% <500 Or <50,000 Hold 2.5 Dose Modifications for Non-Hematologic Adverse Reactions Permanently discontinue gemcitabine injection for any of the following: •Unexplained dyspnea or other evidence of severe pulmonary toxicity •Severe hepatic toxicity •Hemolytic-uremic syndrome •Capillary leak syndrome •Posterior reversible encephalopathy syndrome Withhold gemcitabine injection or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting. 2.6 Preparation and Administration Precautions Exercise caution and wear gloves when preparing gemcitabine solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks includingOSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 2.7 Preparation for Intravenous Infusion Administration Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives. Each vial contains a gemcitabine concentration of 38 mg/mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 g, or 2 g of gemcitabine, respectively. Prior to administration, the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. Reconstituted gemcitabine injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine injection is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits [see Data]. Advise pregnant women of the potential risk to a fetus In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. 8.2 Lactation There are no data on the presence of gemcitabine in human milk, or the effects of gemcitabine on the breastfed infant or milk production. Because of the potential for serious adverse reactions in nursing infants from gemcitabine injection, advise a lactating woman not to breastfeed during treatment with gemcitabine injection and for one week after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Advise females of reproductive potential to use effective contraception during treatment with gemcitabine injection and for 6 months after the final dose [see Use in Specific Populations (8.1)]. Males Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of gemcitabine injection [see Nonclinical Toxicology (13.1)]. Infertility Males Based on animal studies, gemcitabine injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of gemcitabine has not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine was evaluated in a 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 a one-week rest period. The safety and activity of gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes weekly for three weeks followed by a one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial. 8.5 Geriatric Use In clinical studies of gemcitabine, enrolling 979 patients with various cancers who received gemcitabine as a single-agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3 to 4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received gemcitabine plus 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. Gemcitabine clearance is affected by age, however there are no recommended dose adjustments based on patients' age [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No clinical studies have been conducted with gemcitabine in patients with decreased renal function. 8.7 Hepatic Impairment No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. 8.8 Gender Gemcitabine clearance is affected by gender [see Clinical Pharmacology (12.3)]. In single-agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia.

Interactions

7 DRUG INTERACTIONS No specific drug interaction studies have been conducted.

More information

Category Value
Authorisation number ANDA205242
Agency product number U347PV74IL
Orphan designation No
Product NDC 67457-616,67457-617,67457-618
Date Last Revised 27-04-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1720975
Marketing authorisation holder Mylan Institutional LLC