Gemcitabine

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 ) Severe Cutaneous Adverse Reactions (SCARs) Permanently discontinue gemcitabine injection if SCARs occur. ( 5.3 ) Pulmonary Toxicity and Respiratory Failure: Discontinue gemcitabine injection for unexplained dyspnea or other evidence of severe pulmonary toxicity. ( 5.4 ) Hemolytic Uremic Syndrome (HUS): Monitor renal function prior to initiation and during treatment. Discontinue gemcitabine for HUS or severe renal impairment. ( 5.5 ) Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue gemcitabine for severe hepatic toxicity. ( 5.6 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential to use effective contraception. ( 5.7 , 8.1 ) Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within 7 days of radiation therapy. ( 5.8 ) Capillary Leak Syndrome: Discontinue gemcitabine. ( 5.9 ) Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue gemcitabine. ( 5.10 ) 5.1 Schedule-Dependent Toxicity In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology ( 12.3 )] . Refer to the recommended gemcitabine 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 in combination with another drug [see Adverse Reactions ( 6.1 )] . Prior to each dose of gemcitabine, 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 Severe Cutaneous Adverse Reactions (SCARs) SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with gemcitabine treatment [see Adverse Reactions ( 6.2 )] . Monitor patients for signs and symptoms of severe cutaneous adverse reactions. Permanently discontinue gemcitabine in patients who develop SCARs. 5.4 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 [see Adverse Reactions ( 6.1 , 6.2 )] . Permanently discontinue gemcitabine in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity. 5.5 Hemolytic Uremic Syndrome Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2,429 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 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 in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy. 5.6 Hepatic Toxicity Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or with other potentially hepatotoxic drugs [see Adverse Reactions ( 6.1 , 6.2 )]. Administration of gemcitabine in patients with concurrent liver metastases or 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 and periodically during treatment. Permanently discontinue gemcitabine in patients who develop severe hepatic toxicity. 5.7 Embryo-Fetal Toxicity Based on animal data and its mechanism of action, gemcitabine 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 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 and for 3 months following the final dose [see Use in Specific Populations ( 8.1 , 8.3 )]. 5.8 Exacerbation of Radiation Therapy Toxicity Gemcitabine is not recommended for use in combination with radiation therapy. Concurrent (given together or ≤7 days apart) Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1,000 mg/m 2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. Non-Concurrent (given >7 days apart) Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received gemcitabine after prior radiation. 5.9 Capillary Leak Syndrome Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents [see Adverse Reactions ( 6.2 )] . Permanently discontinue gemcitabine if CLS develops during therapy. 5.10 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine 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 if PRES develops during therapy.

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 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.3 )] Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions ( 5.4 )] Hemolytic Uremic Syndrome [see Warnings and Precautions ( 5.5 )] Hepatic Toxicity [see Warnings and Precautions ( 5.6 )] Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions ( 5.8 )] Capillary Leak Syndrome [see Warnings and Precautions ( 5.9 )] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions ( 5.10 )] 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 Sagent Pharmaceuticals at 1-866-625-1618 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 practice. Single Agent The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m 2 to 1,250 mg/m 2 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 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 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 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine 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 a a Grade based on criteria from the World Health Organization (WHO). b For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. c N=699 to 974; all patients with laboratory or non-laboratory data. Adverse Reactions b Gemcitabine c All Grades (%) Grade 3 (%) Grade 4 (%) 69 13 1 Nausea and Vomiting 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 Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine a a Grade based on criteria from WHO. b Regardless of causality. c N=699 to 974; all patients with laboratory or non-laboratory data. Laboratory Abnormality b Gemcitabine c All Grades (%) Grade 3 (%) Grade 4 (%) 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 Additional 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 Ovarian Cancer Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine/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 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 a a Grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0. b Regardless of causality. Adverse Reactions b Gemcitabine/Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) 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 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 a a Grade based on National Cancer Institute 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. Laboratory Abnormality b Gemcitabine/Carboplatin (N=175) Carboplatin (N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Thrombocytopenia 78 30 5 57 10 1 RBC Transfusion c 38 – – 15 – – Platelet Transfusion c 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 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 ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine/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/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 2 a a Grade based on National Cancer Institute CTC Version 2.0. b Non-laboratory events were graded only if assessed to be possibly drug-related. Adverse Reactions b Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) 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 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 a a Grade based on National Cancer Institute CTC Version 2.0. b Regardless of causality. Laboratory Abnormality b Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) 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 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 3 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 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 CTC. b Non-laboratory events were graded only if assessed to be possibly drug-related. c N=217 to 253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=213 to 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 93 25 2 87 20 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 to 253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=213 to 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 89 22 3 67 6 1 Thrombocytopenia 85 25 25 13 3 1 Neutropenia 79 22 35 20 3 1 Lymphopenia 75 25 18 51 12 5 RBC Transfusion e 39 – – 13 – – Platelet Transfusions e 21 – – <1 – – Hepatic Increased Transaminase 22 2 1 10 1 0 Increased Alkaline Phosphatase 19 1 0 13 0 0 Renal Increased Creatinine 38 4 <1 31 2 <1 Proteinuria 23 0 0 18 0 0 Hematuria 15 0 0 13 0 0 Other Laboratory Hyperglycemia 30 4 0 23 3 0 Hypomagnesemia 30 4 3 17 2 0 Hypocalcemia 18 2 0 7 0 <1 Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at 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 WHO. b Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected. c N=67 to 69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=57 to 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 77 13 0 92 51 0 Paresthesias 38 0 0 16 2 0 Infection 28 3 1 21 8 0 Stomatitis 20 4 0 18 2 0 Diarrhea 14 1 1 13 0 2 Edema e 12 – – 2 – – Rash 10 0 0 3 0 0 Hemorrhage 9 0 3 3 0 3 Fever 6 0 0 3 0 0 Somnolence 3 0 0 3 2 0 Flu-like Syndrome e 3 – – 0 – – Dyspnea 1 0 1 3 0 0 Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4 a a Grade based on criteria from WHO. b Regardless of causality. c N=67 to 69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data. d N=57 to 63; all etoposide/cisplatin patients with laboratory or non-laboratory data. e Percent of patients receiving transfusions. WHO Grading scale not applicable to proportion 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 88 22 0 77 13 2 Neutropenia 88 36 28 87 20 56 Thrombocytopenia 81 39 16 45 8 5 RBC Transfusion e 29 – – 21 – – Platelet Transfusion e 3 – – 8 – – Hepatic Increased Alkaline Phosphatase 16 0 0 11 0 0 Increased ALT 6 0 0 12 0 0 Increased AST 3 0 0 11 0 0 Renal Hematuria 22 0 0 10 0 0 Proteinuria 12 0 0 5 0 0 Increased BUN 6 0 0 4 0 0 Increased Creatinine 2 0 0 2 0 0 6.2 Postmarketing 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. Blood and Lymphatic System: TMA Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome Skin: Cellulitis, pseudocellulitis, severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP); desquamation and bullous skin eruptions Hepatic: Hepatic failure, hepatic veno-occlusive disease Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary eosinophilia, pulmonary edema, adult respiratory distress syndrome (ARDS) Nervous System: Posterior reversible encephalopathy syndrome (PRES)

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 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 [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 a 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 to 4% and 15 to 20%, respectively. Data Animal Data Gemcitabine 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 1,000 mg/m 2 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 1,000 mg/m 2 clinical dose based on BSA). 8.2 Lactation Risk Summary There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or on milk production. Due to the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with gemcitabine and for at least one week following the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating gemcitabine [see Use in Specific Populations ( 8.1 )] . Contraception Gemcitabine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the final dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Males Based on animal studies, gemcitabine may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )]. It is not known whether these effects on fertility are reversible. 8.4 Pediatric Use The safety and effectiveness of gemcitabine have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m 2 /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/m 2 /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 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 a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer (Study 1), 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3-4 neutropenia in women 65 years of age or older [see Dosage and Administration ( 2.1 )] . Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients’ age [see Clinical Pharmacology ( 12.3 )] . 8.6 Gender Gemcitabine clearance is decreased in females [see Clinical Pharmacology ( 12.3 )]. In single agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3-4 neutropenia and thrombocytopenia [see Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 )] .