Arranon

1 INDICATIONS AND USAGE ARRANON 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. ARRANON 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 ARRANON is 1,500 mg/m 2 administered by intravenous infusion over 2 hours on Days 1, 3, and 5 repeated every 21 days. Administer ARRANON undiluted. Pediatric Dosage : The recommended pediatric dose of ARRANON is 650 mg/m 2 administered by intravenous infusion over 1 hour daily for 5 consecutive days repeated every 21 days. Administer ARRANON 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 ARRANON 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 ARRANON 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 : ARRANON 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 ARRANON undiluted. Transfer the appropriate dose of ARRANON 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: ARRANON Injection is stable in PVC infusion bags and glass containers for up to 8 hours at up to 30oC.

3 DOSAGE FORMS AND STRENGTHS ARRANON Injection 250 mg/50 mL (5 mg/mL) is supplied as a clear, colorless, sterile solution in Type I, clear glass single-dose vials with a gray bromobutyl rubber stopper (not made with natural rubber latex) and an aluminum seal with a snap-off cap. Injection: 250 mg/50 mL (5 mg/mL) single-dose vial. ( 3 )

4 CONTRAINDICATIONS None. None. (4)

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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 ARRANON was studied in 459 patients in Phase I and Phase II clinical trials. Adult Patient : The safety profile of ARRANON 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 ARRANON Administered by Intravenous Infusion Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days Percentage of Patients (N = 103) Toxicity Grade Body System Grade 3 Grades 4 and 5 a All Grades Adverse Reaction % % % 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) …

7 DRUG INTERACTIONS Administration of ARRANON 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 USE IN SPECIFIC POPULATIONS • Lactation : Advise not to breastfeed. ( 8.2 ) • Renal Impairment : Closely monitor patients with moderate or severe renal impairment for toxicities. ( 8.6 ) • Hepatic Impairment : Closely monitor patients with severe hepatic impairment for toxicities. ( 8.7 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animal studies, ARRANON can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . Limited available data with ARRANON 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 3600 mg/m 2 /day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given greater than or equal to 1200 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 3600 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. 8.2 Lactation Risk Summary There are no data on the presence of nelarabine or ara-G in human or animal milk, the effect on the breastfed child, or the effect on milk production. Because of the potential for serious adverse reactions in the breastfed child from ARRANON, such as severe neurological reactions, advise women not to breastfeed during treatment with ARRANON. 8.3 Females and Males of Reproductive Potential Pregnancy Testing ARRANON 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 ARRANON. Contraception Females ARRANON 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 ARRANON. 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 ARRANON and for 3 months after the last dose [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use The safety and effectiveness of ARRANON for relapsed or …

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 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.

11 DESCRIPTION ARRANON (nelarabine) is a prodrug of the cytotoxic deoxyguanosine analogue, 9-β- D -arabinofuranosylguanine (ara-G). The chemical name for nelarabine is 2-amino-9-β- D -arabinofuranosyl-6-methoxy-9 H -purine. It has the molecular formula C 11 H 15 N 5 O 5 and a molecular weight of 297.27. Nelarabine has the following structural formula: Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209oC and 217oC. ARRANON (nelarabine) injection is supplied as a clear, colorless, sterile solution in glass single-dose vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in Water for Injection, USP. ARRANON is intended for intravenous infusion. Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0. The following structural formula for nelarabine is 2-amino-9-b-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27.

10 OVERDOSAGE There is no known antidote for overdoses of ARRANON. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death. In the event of overdose, supportive care consistent with good clinical practice should be provided. At a dose of 2200 mg/m 2 given on Days 1, 3, and 5 every 21 days, 2 patients developed a significant Grade 3 ascending sensory neuropathy. Magnetic resonance imaging evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.

16 HOW SUPPLIED/STORAGE AND HANDLING ARRANON (nelarabine) injection is supplied as a clear, colorless, sterile solution in Type I, clear glass single-dose vials with a gray bromobutyl rubber stopper (not made with natural rubber latex) and an aluminum seal with a snap-off cap. Single-dose Vials are available in 250 mg/50 mL (5 mg/mL) strength and the following carton sizes: NDC 0078-0683-61 (package of 1). Discard Unused Portion. NDC 0078-0683-06 (package of 6). Discard Unused Portion. Store ARRANON (nelarabine) Injection between 20°C and 25°C (68°F and 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.