Nelarabine

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 )

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 )

None. None. (4)

• 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 ARRANON 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: 1-166), and the median duration is 6 days (range: 1-393 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 ARRANON 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: 1-269), and the median duration is 2 days (range: 1-82 days). Common signs and symptoms of ARRANON-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 ARRANON. 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 ARRANON. Discontinue ARRANON 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 ARRANON 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, ARRANON 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 ARRANON. Advise males with female partners of reproductive potential to use condoms during treatment with ARRANON 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 ARRANON should receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumor lysis syndrome. Consideration should be given to the use of allopurinol in patients at risk of hyperuricemia [see Dosage and Administration ( 2.4 )] .

5.5 Vaccinations Avoid the administration of live vaccines to immunocompromised patients.

5.6 Effects on Ability to Drive and Use Machines Patients treated with ARRANON may experience somnolence during and for several days after treatment [see Adverse Reactions (6.1)] . Advise patients to refrain from driving or engaging in hazardous occupations or activities until somnolence has resolved.

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 Sandoz Inc. at 1-800-525-8747 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 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 hemorrhage/coma/leukoencephalopathy (n = 1). 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 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 ARRANON Administered by Intravenous Infusion Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days Percentage of Patients (N =103) Nervous System Disorders Grade 1 Grade 2 Grade 3 Grade 4 All Grades Adverse Reaction % % % % % 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 ARRANON Administered by Intravenous Infusion Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days a Three (3) 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). […]

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 )

• 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 refractory T-ALL and T-LBL has been established in pediatric patients age 1 year and older. The effectiveness of ARRANON in pediatric patients is supported by one single-arm clinical trial, and safety has been asssessed in 165 pediatric patients age 1 year and older across multiple Phase I and Phase II trials. The trial establishing efficacy included 84 patients age 21 years and younger, who had relapsed or refractory T-ALL or T-LBL. The most frequent adverse reactions of any grade occurring on treatment in this study were hematologic laboratory abnormalities. Hematologic toxicity observed in the pediatric population was higher than that seen in the adult population [see Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Studies (14.2)] . Nervous system adverse reactions have been reported for 42% of pediatric patients across the Phase I and Phase II trials. The incidence of nervous system adverse reactions was less in the pediatric population than that seen in adult patients with relapsed/refractory T-ALL/T-LBL [see Adverse Reactions (6.1)] . In a phase III study of ARRANON in combination with multi-agent chemotherapy as first-line therapy, there were 411 patients with T-ALL or T-LBL treated with ARRANON. The safety profile in the 357 patients age 1 to 16 years was consistent with that seen in older patients in the study [see Adverse Reactions (6.1)] . Due to lack of long-term follow up data, a determination of the impact of ARRANON on the growth and pubertal development of pediatric patients cannot be made.

8.5 Geriatric Use Clinical studies of ARRANON did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. In an exploratory analysis, increasing age, especially age 65 years and older, appeared to be associated with increased rates of neurologic adverse reactions. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection [see Use in Specific Populations (8.6)] .

8.6 Renal Impairment Ara-G clearance decreased as renal function decreased [see Clinical Pharmacology (12.3)] . Because the risk of adverse reactions to this drug may be greater in patients with moderate (CLCr 30 to 50 mL/min) or severe (CLCr less than 30 mL/min) renal impairment, these patients should be closely monitored for toxicities when treated with ARRANON [see Dosage and Administration (2.3)] .

8.7 Hepatic Impairment The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated. Because the risk of adverse reactions to this drug may be greater in patients with severe hepatic impairment (total bilirubin greater than 3 times upper limit of normal), these patients should be closely monitored for toxicities when treated with ARRANON.

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.