NELARABINE

Product Type: HUMAN PRESCRIPTION DRUG

Route: INTRAVENOUS

Dosage Form:

NDC: 72205-154

Application: ANDA216948

Effective: 20230516

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 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.

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 Adjustment of Dose 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. Stability : Nelarabine Injection is stable in polyvinylchloride (PVC) infusion bags and glass containers for up to 8 hours at up to 30°C. Discard unused portion.

4 CONTRAINDICATIONS None. None

Not available.

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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 was studied in 459 patients in Phase I and Phase II clinical trials. Adult Patient : The safety profile of nelarabine 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 1,500 mg/m 2 of Nelarabine Administered Intravenously over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days Body System Adverse Reaction Percentage of Patients (N = 103) 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 1 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 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, any adverse reaction 8 12 2 0 21 Neuropathy 0 4 0 0 4 Peripheral neuropathy 2 2 1 0 5 Peripheral motor neuropathy 3 3 1 0 7 Peripheral sensory neuropathy 7 6 0 0 13 Hypoesthesia 5 10 2 0 17 Headache 11 3 1 0 15 Paresthesia 11 4 0 0 15 Ataxia 1 6 2 0 9 Depressed level of consciousness 4 1 0 1 6 Tremor 2 3 0 0 5 Amnesia 2 1 0 0 3 Dysgeusia 2 1 0 0 3 Balance disorder 1 1 0 0 2 Sensory loss 0 2 0 0 2 One patient had a fatal neurologic adverse reaction, cerebral hemorrhage/coma/leukoencephalopathy. Most nervous system adverse reactions in the adult patients were evaluated as Grade 1 or 2. The additional Grade 3 adverse reactions in adult patients, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%). The other neurologic adverse reactions reported as Grade 1, 2, or unknown in adult patients were abnormal coordination, burning sensation, disturbance in attention, dysarthria, hyporeflexia, neuropathic pain, nystagmus, peroneal nerve palsy, sciatica, sensory disturbance, sinus headache, and speech disorder, each reported in one patient (1%). Pediatric Patient : The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-ALL/T-LBL treatment trial. The most common adverse reactions in pediatric patients were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non-hematologic adverse reactions in pediatric patients, the most frequent adverse reactions reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting. The most common adverse reactions in pediatric patients by System Organ Class including severe or life threatening adverse reactions (NCI CTCAE Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 3. Table 3. Most Commonly Reported (≥ 5% Overall) Adverse Reactions in Pediatric Patients Treated With 650 mg/m 2 of Nelarabine Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days Body System Adverse Reaction Percentage of Patients (N = 84) Toxicity Grade Grade 3 % Grade 4 and 5 a % All Grades % Blood and Lymphatic System Disorders Anemia 45 10 95 Neutropenia 17 62 94 Thrombocytopenia 27 32 88 Leukopenia 14 7 38 Hepatobiliary Disorders Transaminases increased 4 0 12 Blood albumin decreased 5 1 10 Blood bilirubin increased 7 2 10 Metabolic/Laboratory Blood potassium decreased 4 2 11 Blood calcium decreased 1 1 8 Blood creatinine increased 0 0 6 Blood glucose decreased 4 0 6 Blood magnesium decreased 2 0 6 Nervous System Disorders (see Table 4) Gastrointestinal Disorders Vomiting 0 0 10 General Disorders & Administration Site Conditions Asthenia 1 0 6 Infections & Infestations Infection 2 1 5 a Three patients had a fatal adverse reaction. Fatal adverse reactions included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1). Neurologic Adverse Reactions: Nervous system adverse reactions were reported for 42% of pediatric patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥ 2%) in pediatric patients including all grades (NCI CTCAE) are shown in Table 4. Table 4. Neurologic Adverse Reactions (≥ 2%) in Pediatric Patients Treated With 650 mg/m 2 of Nelarabine Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days Nervous System Disorders Adverse Reaction Percentage of Patients (N = 84) Grade 1 % Grade 2 % Grade 3 % Grade 4 and 5 a % All Grades % Headache 8 2 4 2 17 Peripheral neurologic disorders, any adverse reaction 1 4 7 0 12 Peripheral neuropathy 0 4 2 0 6 Peripheral motor neuropathy 1 0 2 0 4 Peripheral sensory neuropathy 0 0 6 0 6 Somnolence 1 4 1 1 7 Hypoesthesia 1 1 4 0 6 Seizures 0 0 0 6 6 Convulsions 0 0 0 3 4 Grand mal convulsions 0 0 0 1 1 Status epilepticus 0 0 0 1 1 Motor dysfunction 1 1 1 0 4 Nervous system disorder 1 2 0 0 4 Paresthesia 0 2 1 0 4 Tremor 1 2 0 0 4 Ataxia 1 0 1 0 2 a One (1) patient had a fatal neurologic adverse reaction, status epilepticus. The other Grade 3 neurologic adverse reaction in pediatric patients was hypertonia reported in 1 patient (1%). The additional Grade 4 neurologic adverse reactions, were 3 rd nerve paralysis, and 6 th nerve paralysis, each reported in 1 patient (1%). The other neurologic adverse reactions reported as Grade 1, 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in 1 patient (1%). Nelarabine in Combination with Multi-Agent Chemotherapy in T-ALL and T-LBL Nelarabine was studied in combination with multi-agent chemotherapy in a randomized clinical trial [NCT00408005]. The safety population in this trial included 804 patients with newly-diagnosed T-ALL (85%) or T-LBL (15%) treated with (n = 411) or without (n =393) nelarabine in combination with the augmented Berlin-Frankfurt-Münster chemotherapy regimen (aBFM) after initial induction therapy. Patients assigned to nelarabine received 650 mg/m 2 intravenously over 1 hour daily for 5 consecutive days, during consolidation days 1 to 5 and 43 to 47, delayed intensification days 29 to 33, and during the initial 3 courses of maintenance days 29 to 33. The median age on enrollment was 9.5 years (range, 1-29), the majority of patients were male (73%) and white (69%). Sixty-five percent of patients assigned to the nelarabine arms received at least 85% of the planned dose through the third course of maintenance therapy compared to 79% of patients on the control arms who received 3 courses of maintenance therapy. There was one fatal neurological adverse reaction in the nelarabine arm. The incidence of the following grades 3 and 4 adverse reactions were higher in the nelarabine treated arms compared to the control arms: abnormal transaminases, motor and sensory neuropathy, nausea and vomiting, and dehydration. The incidence of seizures of any grade was 3% (14 of 411). Rhabdomyolysis was diagnosed in 2% (7 of 411) of nelarabine treated patients and occurred after the first course of nelarabine during the consolidation phase of therapy. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of nelarabine. 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. Infections and Infestations : Fatal opportunistic infections. Metabolism and Nutrition Disorders : Tumor lysis syndrome. Nervous System Disorders : Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome. Musculoskeletal and Connective Disorders : Rhabdomyolysis, blood creatine phosphokinase increased.