Gemcitabine

12.1 Mechanism of Action Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands which eventually results in the initiation of apoptotic cell death.

1 INDICATIONS AND USAGE Gemcitabine Injection 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 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 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 fluorouracil.

2 DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. • Ovarian Cancer: 1000 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.1 ) • Breast Cancer: 1250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.2 ) • Non-Small Cell Lung Cancer: 1000 mg/m 2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.3 ) • Pancreatic Cancer: 1000 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 Injection is 1000 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 Injection administration. Refer to carboplatin prescribing information for additional information. Dosage Modifications Recommended dosage modifications for Gemcitabine Injection 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 Injection for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Day Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Day 1 Greater than or equal to 1500 And Greater than or equal to 100,000 None Less than 1500 Or Less than 100,000 Delay Treatment Cycle Day 8 Greater than or equal to 1500 And Greater than or equal to 100,000 None 1000 to 1499 Or 75,000 to 99,999 50% of full dose Less than 1000 Or Less than 75,000 Hold Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dosage Modification Initial Occurrence • Absolute neutrophil count less than 500 x 10 6 /L for more than 5 days or • Absolute neutrophil count less than 100 x 10 6 /L for more than 3 days or • Febrile neutropenia or • Platelets less than 25,000 x 10 6 /L • Cycle delay for more than one week due to toxicity Permanently reduce Gemcitabine Injection 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 Injection dose to 800 mg/m 2 on Day 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine Injection is 1250 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 Injection administration. Refer to paclitaxel prescribing information for additional information. Dosage Modifications Recommended dosage modifications for Gemcitabine Injection 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 Injection for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Day 1 Greater than or equal to 1500 And Greater than or equal to 100,000 None Less than 1500 Or Less than 100,000 Hold Day 8 Greater than or equal to 1200 And Greater than 75,000 None 1000 to 1199 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 Injection is 1000 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 Injection administration. 21-day schedule The recommended dosage of Gemcitabine Injection is 1250 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m 2 administered intravenously on Day 1 after Gemcitabine Injection administration. Refer to cisplatin prescribing information for additional information. Dosage Modifications Recommended dosage modifications for Gemcitabine Injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2) ] . Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ] . 2.4 Pancreatic Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine Injection is 1000 mg/m 2 intravenously over 30 minutes. The recommended treatment schedule is as follows: • Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest.

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 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 practice. Single Agent The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m 2 to 1250 mg/m 2 intravenously over 30 minutes once weekly, in 979 patients with various malignancies. The most common (≥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 events were graded only if assessed to be possibly drug-related. Gemcitabine N=699 to 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 WHO. Gemcitabine N=699 to 974; all patients with laboratory or non-laboratory data. Laboratory Abnormality Regardless of causality. 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/ca