AVGEMSI

1 INDICATIONS AND USAGE AVGEMSI 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 AVGEMSI 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 AVGEMSI 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 AVGEMSI 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 AVGEMSI 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. AVGEMSI is indicated for patients previously treated with fluorouracil.

2 DOSAGE AND ADMINISTRATION AVGEMSI 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 AVGEMSI 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 AVGEMSI administration. Refer to carboplatin prescribing information for additional information. Dosage Modifications Recommended dosage modifications for AVGEMSI 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 AVGEMSI 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 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 AVGEMSI 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 AVGEMSI 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 AVGEMSI to 800 mg/m 2 on Days 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dosage of AVGEMSI 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 on Day 1 before AVGEMSI administration. Refer to paclitaxel prescribing information for additional information. Dosage Modifications Recommended dosage modifications for AVGEMSI 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 AVGEMSI 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 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 AVGEMSI 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 AVGEMSI administration. 21-day schedule The recommended dosage of AVGEMSI is 1,250 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination …

3 DOSAGE FORMS AND STRENGTHS Injection: 200 mg/5.26 mL (38 mg/mL), 1 g/26.3 mL (38 mg/mL), and 2 g/52.6 mL (38 mg/mL) as a clear and colorless to light straw-colored solution in a multiple-dose vial. Injection: 200 mg/5.26 mL,1 g/26.3 mL, and 2 g/52.6 mL(38 mg/mL) in a multiple-dose vial. ( 3 )

4 CONTRAINDICATIONS AVGEMSI 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 )

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 Avyxa Pharma, LLC at 1-888-520-0954 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 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 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 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 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 10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Ag …

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, AVGEMSI 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 2-4% and 15-20% respectively. Data Animal Data Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal 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 1000 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 from gemcitabine, advise women not to breastfeed during treatment with AVGEMSI and for at least one week following the last dose. 8.3 Females and Males of Reproductive Potential AVGEMSI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating AVGEMSI [see Use in Specific Populations (8.1) ] . Contraception Females Because of the potential for genotoxicity and embryo-fetal toxicity, advise females of reproductive potential to use effective contraception during treatment with AVGEMSI and for 6 months after the final dose of AVGEMSI. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with AVGEMSI and for 3 months after the final dose [see Nonclinical Toxicology (13.1) ] . Infertility Males Based on animal studies, AVGEMSI 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 betwe …

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 (selfpotentiation). 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.

11 DESCRIPTION Gemcitabine is a nucleoside metabolic inhibitor. The chemical name of gemcitabine hydrochloride, is 2'-deoxy-2',2 ́-difluorocytidine monohydrochloride (β-isomer). The structural formula is as follows: Gemcitabine hydrochloride, USP is a white to off-white solid with a molecular formula of C 9 H 11 F 2 N 3 O 4 • HCl and a molecular weight of 299.66 g/mol. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. AVGEMSI is a sterile solution in multiple-dose vials for intravenous use. Each vial contains 200 mg, 1 g, or 2 g of gemcitabine equivalent to 227.57 mg, 1.137 g, or 2.275 g of gemcitabine hydrochloride, USP. Each mL contains 38 mg of gemcitabine-free base in water for injection equivalent to 43.26 mg of gemcitabine hydrochloride, USP. Sodium hydroxide is used for pH adjustment. structure

10 OVERDOSAGE There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m 2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.

16 HOW SUPPLIED/STORAGE AND HANDLING AVGEMSI TM Injection, is a clear and colorless to light straw-colored solution available in sterile multiple-dose vials individually packaged in a carton as follows: 200 mg/5.26 mL (38 mg/mL), NDC 83831-122-01 1 g/26.3 mL (38 mg/mL), NDC 83831-123-01 2 g/52.6 mL (38 mg/mL), NDC 83831-124-01 Store unopened multiple-dose vials at 2° to 8°C (36° to 46°F). Do not freeze. AVGEMSI is a hazardous drug. Follow applicable special handling and disposal procedures .1