GEMCITABINE

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 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 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 in combination with cisplatin is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC). 1.4 Pancreatic Cancer Gemcitabine 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 is indicated for patients previously treated with fluorouracil.

2 DOSAGE AND ADMINISTRATION Gemcitabine for injection, USP is for intravenous use only. • Ovarian Cancer: 1,000 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.1 ) • Breast Cancer: 1,250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.2 ) • Non-Small Cell Lung Cancer: 1,000 mg/m 2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1,250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.3 ) • Pancreatic Cancer: 1,000 mg/m 2 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 dosage of gemcitabine is 1,000 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with carboplatin AUC 4 administered intravenously on Day 1 after gemcitabine administration. Refer to carboplatin prescribing information for additional information. Dosage Modifications Recommended gemcitabine dosage modifications for myelosuppression are described in Tables 1 and 2 [see Warnings and Precautions (5.2) ] . Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ] . Table 1: Recommended Dosage Modifications for Gemcitabine for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Day Absolute Neutrophil Count (× 10 6 /L) Platelet Count (× 10 6 /L) Dosage Modification Day 1 Greater than or equal to 1,500 And Greater than or equal to 100,000 None Less than 1,500 Or Less than 100,000 Delay Treatment Cycle Day 8 Greater than or equal to 1,500 And Greater than or equal to 100,000 None 1,000 to 1,499 Or 75,000 to 99,999 50% of full dose Less than 1,000 Or Less than 75,000 Hold Table 2: Recommended Dosage Modifications for Gemcitabine for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dosage Modification Initial Occurrence • Absolute neutrophil count less than 500 × 10 6 /L for more than 5 days or • Absolute neutrophil count less than 100 × 10 6 /L for more than 3 days or • Febrile neutropenia or • Platelets less than 25,000 × 10 6 /L or • Cycle delay for more than one week due to toxicity Permanently reduce gemcitabine to 800 mg/m 2 on Days 1 and 8 Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction: Permanently reduce gemcitabine to 800 mg/m 2 on Day 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dosage of gemcitabine is 1,250 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m 2 administered as a 3-hour intravenous infusion on Day 1 before gemcitabine administration. Refer to paclitaxel prescribing information for additional information. Dosage Modifications Recommended gemcitabine dosage modifications for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2) ]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ] . Table 3: Recommended Dosage Modifications for Gemcitabine for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute Neutrophil Count (× 10 6 /L) Platelet Count (× 10 6 /L) Dosage Modification Day 1 Greater than or equal to 1,500 And Greater than or equal to 100,000 None Less than 1,500 Or Less than 100,000 Hold Day 8 Greater than or equal to 1,200 And Greater than 75,000 None 1,000 to 1,199 Or 50,000 to 75,000 75% of full dose 700 to 999 And Greater than or equal to 50,000 50% of full dose Less than 700 Or Less than 50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule 28-day schedule The recommended dosage of gemcitabine is 1,000 mg/m 2 intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m 2 administered intravenously on Day 1 after gemcitabine administration. 21-day schedu…

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 , 5.8 ) • Severe Cutaneous Adverse Reactions (SCARs): Permanently discontinue gemcitabine injection if SCARs occur. ( 5.3 ) • Pulmonary Toxicity and Respiratory Failure: Discontinue gemcitabine for 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 injection for HUS or severe renal impairment. ( 5.5 ) • Hepatic Toxicity: Monitor hepatic function prior to initiation and during treatment. Discontinue gemcitabine for injection 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 for injection. ( 5.9 ) • Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue gemcitabine for injection. ( 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), includin…

4 CONTRAINDICATIONS Gemcitabine is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis [see Adverse Reactions (6.1) ] . Patients with a known hypersensitivity to gemcitabine. ( 4 )

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 Special Populations (8.3) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2–4% and 15–20% respectively. Data Animal Data Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [approximately 0.005 times the 1,000 mg/m 2 clinical dose based on body surface area (BSA)]. Gemcitabine was 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 (approximately 0.002 times the 1,000 mg/m 2 clinical dose based on BSA).

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 Hospira, Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or https://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 Grade based on criteria from the World Health Organization (WHO). Adverse Reactions For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related. Gemcitabine N=699–974; all patients with laboratory or non-laboratory data. All Grades (%) Grade 3 (%) Grade 4 (%) 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 Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine Grade based on criteria from the WHO. Laboratory Abnormality Regardless of causality. Gemcitabine N=699–974; all patients with laboratory or non-laboratory data. …