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 2 chemotherapy regimens. Nelarabine is a nucleoside metabolic inhibitor indicated for the treatment of patients with 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Adult Dose : 1,500 mg/m 2 administered by intravenous infusion over 2 hours on Days 1, 3, and 5 repeated every 21 days. ( 2.1 ) Pediatric Dose : 650 mg/m 2 administered by intravenous infusion 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/m 2 administered by intravenous infusion 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/m 2 administered by intravenous infusion 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 hazardous drug. 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.

5 WARNINGS AND PRECAUTIONS Neurologic Adverse Reactions : Severe neurologic reactions have been reported. Monitor for signs and symptoms of neurologic toxicity. ( 5.1 ) Hematologic Reactions : Complete blood counts including platelets should be monitored regularly. ( 5.2 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception; and advise males to use condoms. ( 5.3 , 8.1 , 8.3 ) Effects on Ability to Drive and Use Machines : Somnolence may occur. Advise patients to refrain from these activities until somnolence has resolved. ( 5.6 ) 5.1 Neurologic Adverse Reactions Nervous system adverse reactions of any grade were reported for 223 (76%) adult patients across the Phase I and Phase II trials, and Grade 3 or higher (severe, life-threatening, or fatal) adverse reactions were reported for 55 (19%) patients following initiation of nelarabine therapy [see Adverse Reactions (6.1) ] . Based on patients with complete data, the median time to onset of first event is 5 days from start of first infusion (range: 1 to 166), and the median duration is 6 days (range: 1 to 393 days). Nervous system adverse reactions of any grade were reported for 69 (42%) pediatric patients across the Phase I and Phase II trials, and Grade 3 or higher (severe, life-threatening, or fatal) adverse reactions were reported for 25 (15%) patients following initiation of nelarabine therapy [see Adverse Reactions (6.1) ] . Based on patients with complete data, the median time to onset of first event is 8 days from start of first infusion (range: 1 to 269), and the median duration is 2 days (range: 1 to 82 days). Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, headache, paresthesia and dysesthesia, dizziness, neuropathy (sensory and motor), cerebellar disturbances and tremor. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome. Full recovery from these adverse reactions has not always occurred with cessation of therapy with nelarabine. Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events. Monitor patients frequently for signs and symptoms of neurologic toxicity during and for at least 24 hours after completion of treatment with nelarabine. Discontinue nelarabine for neurologic adverse reactions of NCI CTCAE Grade 2 or greater and provide supportive care [see Dosage and Administration (2.2) , Adverse Reactions (6.1) ] . 5.2 Hematologic Adverse Reactions Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia, have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly [see Dosage and Administration (2.2) , Adverse Reactions (6.1) ] . 5.3 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animal studies, nelarabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . In animal reproduction studies, intravenous administration of nelarabine to pregnant rabbits during the period of organogenesis resulted in teratogenicity at maternal doses below the recommended human adult dose of 1,500 mg/m 2 /day (see Data) . Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with nelarabine. Advise males with female partners of reproductive potential to use condoms during treatment with nelarabine and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) , Nonclinical Toxicology (13.1) ] . 5.4 Tumor Lysis Syndrome Patients receiving nelarabine should receive intravenous hydration according to standard medical practice for the management of hyperuricemia…

4 CONTRAINDICATIONS None. None. ( 4 )

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

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animal studies, nelarabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Limited available data with nelarabine use in pregnant women are insufficient to determine a drug-associated risk for major birth defects, miscarriage or adverse maternal, or fetal outcomes. There are risks to the pregnant woman associated with untreated leukemia or lymphoma (see Clinical Considerations) . In animal reproduction studies, intravenous administration of nelarabine to pregnant rabbits during the period of organogenesis resulted in teratogenicity at maternal doses below the recommended human adult dose of 1,500 mg/m 2 /day (see Data) . Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk There are risks to the mother from untreated leukemia or lymphoma, including anemia, thrombocytopenia, and death. Data Animal Data In an embryo-fetal development study in which pregnant rabbits were administered daily doses of nelarabine during organogenesis, increased incidences of fetal malformations, anomalies, and variations were observed at doses greater than or equal to 360 mg/m 2 /day (8-hour IV infusion; approximately 25% of the recommended human adult dose compared on a mg/m 2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,600 mg/m 2 /day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given greater than or equal to 1,200 mg/m 2 /day (approximately 75% of the recommended adult dose), while absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification was seen at all doses. Maternal body weight gain and fetal body weights were reduced in rabbits given 3,600 mg/m 2 /day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Nelarabine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Verify the pregnancy status of females of reproductive potential prior to starting treatment with nelarabine. Contraception Females Nelarabine can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3) , Use in Specific Populations (8.1) ] . Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with nelarabine. Males Because of the potential for genotoxicity, advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with nelarabine and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] .

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 Amneal Pharmaceuticals LLC at 1-877-835-5472 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-ALL/T-cell T-LBL trial and an adult chronic lymphocytic leukemia trial. The most common adverse reactions in adults were fatigue; gastrointestinal 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 by Intravenous Infusion 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 5a% 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 (5) 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 …