Nelarabine

12.1 Mechanism of Action Nelarabine is a prodrug of the deoxyguanosine analogue 9-β- D -arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5’-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.

1 INDICATIONS AND USAGE Nelarabine injection is indicated for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in adult and pediatric patients age 1 year and older whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. Nelarabine injection is a nucleoside metabolic inhibitor indicated for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in adult and pediatric patients age 1 year and older whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. (1)

2 DOSAGE AND ADMINISTRATION Adult Dose : 1,500 mg/m² administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. ( 2.1 ) Pediatric Dose : 650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. ( 2.1 ) Discontinue treatment for neurologic reactions greater than or equal to Grade 2. ( 2.2 ) Dosage may be delayed for hematologic reactions. ( 2.2 ) Take measures to prevent hyperuricemia. ( 2.4 ) 2.1 Recommended Dosage This product is for intravenous use only. Adult Dosage : The recommended adult dose of nelarabine injection is 1,500 mg/m² administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Administer nelarabine injection undiluted. Pediatric Dosage : The recommended pediatric dose of nelarabine injection is 650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. Administer nelarabine injection undiluted. The recommended duration of treatment for adult and pediatric patients has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for hematopoietic stem cell transplantation (HSCT), or the patient no longer continued to benefit from treatment. 2.2 Dosage Modification Discontinue nelarabine injection if the patient develops a neurologic adverse reaction of NCI CTCAE Grade 2 or greater. Dosage may be delayed for other toxicity, including hematologic toxicity [see Boxed Warning, Warnings and Precautions ( 5.1 , 5.2 )]. 2.3 Dosage in Special Populations Nelarabine injection has not been studied in patients with renal or hepatic dysfunction [see Use in Specific Populations ( 8.6 , 8.7 )] . No dose adjustment is recommended for patients with a creatinine clearance (CLCr) greater than or equal to 50 mL/min [see Clinical Pharmacology ( 12.3 )] . There are insufficient data to support a dose recommendation for patients with a CLCr less than 50 mL/min. 2.4 Prevention of Hyperuricemia Take precautions against hyperuricemia (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) [see Warnings and Precautions ( 5.4 )] . 2.5 Instructions for Handling, Preparation, and Administration Handling : Nelarabine injection is a cytotoxic agent. Caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. Proper aseptic technique should be used. Guidelines for proper handling and disposal of anticancer drugs have been published. 1 Preparation and Administration : Administer nelarabine injection undiluted. Transfer the appropriate dose of nelarabine injection into polyvinylchloride (PVC) infusion bags or glass containers and administer as a 2-hour infusion in adult patients and as a 1-hour infusion in pediatric patients. Prior to administration, inspect the drug product visually for particulate matter and discoloration. Discard unused portion. Stability: Nelarabine Injection is stable in PVC infusion bags and glass containers for up to 8 hours at up to 30°C.

6 ADVERSE REACTIONS The following clinically-significant adverse reactions are discussed in greater detail in other sections of the label: Neurologic [see Boxed Warning, Warnings and Precautions ( 5.1 )] Hematologic [see Warnings and Precautions ( 5.2 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] Effects on Ability to Drive and Use Machines [see Warnings and Precautions ( 5.6 )] The most common (≥ 20%) adverse reactions were: Adult: anemia, thrombocytopenia, neutropenia, nausea, diarrhea, vomiting, constipation, fatigue, pyrexia, cough, and dyspnea ( 6.1 ) Pediatric: anemia, neutropenia, thrombocytopenia, and leukopenia ( 6.1 ) The most common (> 10%) neurological adverse reactions were: Adult: somnolence, dizziness, peripheral neurologic disorders, hypoesthesia, headache, and paresthesia ( 6.1 ) Pediatric: headache and peripheral neurologic disorders ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory T-ALL and T-LBL Nelarabine injection was studied in 459 patients in Phase I and Phase II clinical trials. Adult Patient: The safety profile of nelarabine injection is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) trial and an adult chronic lymphocytic leukemia trial. The most common adverse reactions in adults were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia. The most common adverse reactions in adults by Body System, including severe or life-threatening adverse reactions (NCI CTCAE Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 1. Table 1. Most Commonly Reported (≥ 5% Overall) Adverse Reactions in Adult Patients Treated With ,500 mg/m 2 of Nelarabine Injection Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days Percentage of Patients (N = 103) Body System Adverse Reaction Toxicity Grade Grade 3 % Grades 4 and 5 a % All Grades % Blood and Lymphatic System Disorders Anemia 20 14 99 Thrombocytopenia 37 22 86 Neutropenia 14 49 81 Febrile neutropenia 9 1 12 Cardiac Disorders Sinus tachycardia 1 0 8 Gastrointestinal Disorders Nausea 0 0 41 Diarrhea 1 0 22 Vomiting 1 0 22 Constipation 1 0 21 Abdominal pain 1 0 9 Stomatitis 1 0 8 Abdominal distension 0 0 6 General Disorders and Administration Site Conditions Fatigue 10 2 50 Pyrexia 5 0 23 Asthenia 0 1 17 Edema, peripheral 0 0 15 Edema 0 0 11 Pain 3 0 11 Rigors 0 0 8 Gait, abnormal 0 0 6 Chest pain 0 0 5 Noncardiac chest pain 0 1 5 Infections Infection 2 1 9 Pneumonia 4 1 8 Sinusitis 1 0 7 Hepatobiliary Disorders AST increased 1 1 6 Metabolism and Nutrition Disorders Anorexia 0 0 9 Dehydration 3 1 7 Hyperglycemia 1 0 6 Musculoskeletal and Connective Tissue Disorders Myalgia 1 0 13 Arthralgia 1 0 9 Back pain 0 0 8 Muscular weakness 5 0 8 Pain in extremity 1 0 7 Nervous System Disorders (see Table 2) Psychiatric Disorders Confusional state 2 0 8 Insomnia 0 0 7 Depression 1 0 6 Respiratory, Thoracic, and Mediastinal Disorders Cough 0 0 25 Dyspnea 4 2 20 Pleural effusion 5 1 10 Epistaxis 0 0 8 Dyspnea, exertional 0 0 7 Wheezing 0 0 5 Vascular Disorders Petechiae 2 0 12 Hypotension 1 1 8 Abbreviation: AST, aspartate transaminase. a Five patients had a fatal adverse reaction. Fatal adverse reactions included hypotension (n = 1), respiratory arrest (n = 1), pleural effusion/pneumothorax (n = 1), pneumonia (n = 1), and cerebral hemorrhage/coma/leukoencephalopathy (n = 1). Other Adverse Reactions: Blurred vision was also reported in 4% of adult patients. There was a single report of biopsy-confirmed progressive multifocal leukoencephalopathy in the adult patient population. Neurologic Adverse Reactions: Nervous system adverse reactions, were reported for 76% of adult patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥ 2%) in adult patients including all grades (NCI CTCAE) are shown in Table 2. Table 2. Neurologic Adverse Reactions (≥ 2%) in Adult Patients Treated With 1,500 mg/m 2 of Nelarabine Injection Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days Nervous System Disorders Adverse Reaction Percentage of Patients (N =103) Grade 1 % Grade 2 % Grade 3 % Grade 4 % All Grades % Somnolence 20 3 0 0 23 Dizziness 14 8 0 0 21 Peripheral neurologic disorders

7 DRUG INTERACTIONS Administration of nelarabine injection in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended [see Clinical Pharmacology (12.3)] . Administration in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended. ( 7 , 12.3 )