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NELARABINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nelarabine is a pro-drug of 9-beta-D-arabinofuranosylguanine (ara-G), a cytotoxic purine nucleoside analogue used for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in patients who are refractory to treatment with at least two chemotherapy regimens or who have relapsed following treatment with at least two chemotherapy regimens.

Specific Substances

    1) 2-Amino-9-beta-D-arabinofuranosyl-6-methoxy-9H-purine
    2) 9-beta-D-arabinofuranosylguanine (ara-G)
    3) Arabinosylguanine (ara-G)
    4) Ara-G
    5) Nelzarabine
    6) MAY
    7) GW-506U
    8) GW-506U78
    9) 506U
    10) 506U78
    11) 3011155 (PubChem)
    12) CAS 121032-29-9
    1.2.1) MOLECULAR FORMULA
    1) C11-H15-N5-O5 (Sweetman, 2005)

Available Forms Sources

    A) FORMS
    1) Nelarabine is available in the United States as a clear, colorless, sterile solution containing 250 mg nelarabine (5 mg/mL) for intravenous administration (Prod Info ARRANON(R) intravenous injection, 2014).
    B) SOURCES
    1) Nelarabine is manufactured by GlaxoSmithKline, Research Triangle Park, NC (Prod Info ARRANON(R) intravenous injection, 2014).
    C) USES
    1) Nelarabine is indicated for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in patients who are refractory to treatment with at least two chemotherapy regimens or who have relapsed following treatment with at least two chemotherapy regimens (Prod Info ARRANON(R) intravenous injection, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nelarabine, a nucleoside metabolic inhibitor, is used for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least 2 chemotherapy regimens.
    B) PHARMACOLOGY: Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). It is demethylated by adenosine deaminase to ara-G, phosphorylated by mitochondrial deoxyguanosine kinase and deoxycytidine kinase, and converted to the active 5' -triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for its incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death.
    C) EPIDEMIOLOGY: Exposure is not common.
    D) WITH THERAPEUTIC USE
    1) SUMMARY: The dose-limiting toxicity in both adult and pediatric patients is neurotoxicity.
    2) ADULT: The most common adverse effects in adult patients, following therapeutic administration of nelarabine, include myelosuppression (anemia, neutropenia, thrombocytopenia), gastrointestinal distress (nausea, vomiting, diarrhea), fatigue, somnolence, headache, peripheral neuropathy, paresthesias, dyspnea, and cough.
    3) PEDIATRIC: The most common adverse effects in pediatric patients, following therapeutic administration of nelarabine, include myelosuppression (anemia, neutropenia, leukopenia, and thrombocytopenia), headache, vomiting, and elevated hepatic enzyme and serum bilirubin levels.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Nelarabine overdose information is limited. It is anticipated that nelarabine overdosage would result in myelosuppression, vomiting, severe neurotoxicity, including paralysis and coma, and possibly death.
    2) During clinical trials, two patients developed significant grade 3 ascending sensory neuropathy following intravenous administration of nelarabine at a dose of 2,200 mg/m(2) on days 1,3, and 5 repeated every 21 days.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hyperthermia has been frequently reported following therapeutic administration of nelarabine.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Severe neurological events have been reported following therapeutic administration of nelarabine. These events have included altered mental states including severe somnolence, central nervous system effects including seizures, and peripheral neuropathy ranging from numbness and paresthesias to motor weakness and paralysis.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Myelosuppression (anemia, thrombocytopenia, and neutropenia) is a common occurrence in both the adult and pediatric population following therapeutic administration of nelarabine.
    0.2.20) REPRODUCTIVE
    A) Nelarabine is classified as FDA pregnancy category D. Nelarabine can cause fetal harm when administered to pregnant women. Advise women of reproductive potential to avoid becoming pregnant while receiving therapy with nelarabine.

Laboratory Monitoring

    A) Monitor neuro status closely; neurotoxicity is the dose-limiting toxicity of nelarabine therapy.
    B) Monitor CBC including differential and platelets for several weeks after overdose; delayed bone marrow suppression may develop.
    C) Monitor electrolytes, fluid status, liver enzymes and renal function as clinically indicated following exposure.
    D) Monitor for signs/symptoms of infection or sepsis in severely immunocompromised patients.
    E) Nerve conduction studies may be useful in patients with symptoms of peripheral neuropathy.
    F) Serum nelarabine levels are not clinically useful in guiding management following overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Nelarabine is administered intravenously. Treatment of nelarabine poisoning is symptomatic and supportive. There is no specific antidote.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive; there is no known antidote. Neurotoxicity is the dose-limiting toxicity of nelarabine therapy. Monitor neuro status closely following exposure. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for neutropenia. Initially treat seizure activity with benzodiazepines and/or barbiturates. HYPOTENSION: Begin with adequate fluid resuscitation, if hypotension persists treat with intravenous normal saline 10 to 20 mL/kg, dopamine or norepinephrine. Stomatitis may develop with exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor neuro status closely. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is unlikely to be necessary because nelarabine is administered intravenously.
    2) HOSPITAL: Gastrointestinal decontamination is unlikely to be necessary because nelarabine is administered intravenously. Wash exposed skin and irrigate exposed eyes with warm water as needed.
    D) AIRWAY MANAGEMENT
    1) Airway management may not be needed following a mild exposure; however, monitor patient closely and intubate if the patient becomes neurologically unstable or develops respiratory dysfunction.
    E) ANTIDOTE
    1) There is no antidote for nelarabine overdose.
    F) NEUROTOXICITY
    1) Neurotoxicity is the dose-limiting toxicity of nelarabine. Treatment is symptomatic. Common events associated with toxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Potentially severe toxicity can produce coma, status epilepticus, craniospinal demyelination, ascending neuropathy (may appear similar to Guillain-Barre syndrome).
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day subQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia 7 days or more, unstable, significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia less than 7 days, clinically stable, no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Based on limited data, nausea and vomiting following a nelarabine overdose is likely to be mild to moderate. Symptoms may be controlled with a combination of antiemetic agents as needed. If severe nausea and vomiting occurs with nelarabine therapy, treat with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    K) STOMATITIS
    1) Mild stomatitis has been reported infrequently in patients receiving nelarabine therapy. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a nelarabine overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) INTRATHECAL INJECTION
    1) No clinical reports available; information derived from experience with other antineoplastics. Nelarabine is extremely neurotoxic, severe toxicity should be anticipated after inadvertent intrathecal injection; rapid treatment is imperative. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Fresh frozen plasma (25 mL FFP/liter NS or LR) or albumin 5% have also been used for perfusion. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    M) ENHANCED ELIMINATION
    1) Nelarabine is extensively distributed throughout the body; hemodialysis is unlikely to be beneficial.
    N) PHARMACOKINETICS
    1) Following a 1500 mg/m(2) dose of nelarabine infused over 2 hours in adult patients, the mean peak plasma drug concentrations for nelarabine and ara-G (its active metabolite) were 5 +/- 3 mcg/mL and 31.4 +/- 5.6 mcg/mL, respectively. It is less than 25% bound to plasma proteins. Nelarabine and ara-G are extensively distributed throughout the body, and is primarily and rapidly metabolized by O-demethylation to form ara-G, which undergoes hydrolysis to form guanine. Nelarabine and ara-G are partially eliminated by the kidneys. Following a 1500 mg/m(2) dose in adult patients, nelarabine is rapidly eliminated from plasma with a half-life of approximately 30 minutes.
    O) PATIENT DISPOSITION
    1) HOME CRITERIA: There are no data to support home management.
    2) ADMISSION CRITERIA: Patients with a large overdose should be closely monitored in an inpatient setting, with frequent monitoring of vital signs and neuro status, daily monitoring of CBC with differential and platelet count, clinical assessment and evaluation to determine the need for prophylactic therapies (ie, antibiotics, growth factors).
    3) CONSULT CRITERIA: Consult an oncologist, hematologist, medical toxicologist, infectious disease physician and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: A patient with a large overdose may benefit from early transfer to a cancer treatment or bone marrow transplant center

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established. OVERDOSE: Limited overdose data. FATALITIES: ADULT: Patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days resulted in 5 fatal cases. Fatal events included hypotension (n=1), respiratory arrest (n=1), pleural effusion/pnuemothorax (n=1), pneumonia (n=1), and cerebral hemorrhage/coma/leukoencephalopathy (n=1). PEDIATRIC: Children (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days resulted in 3 fatal cases. Fatal events included neutropenia and pyrexia (n=1), status epilepticus/seizure (n=1), and fungal pneumonia (n=1). SURVIVAL: ADULT: Two adults developed grade 3 ascending sensory neuropathy following administration of nelarabine 2,200 mg/m(2) given on days 1, 3, and 5 every 21 days. PEDIATRIC: At doses greater than 900 mg/m(2), 5 of 18 (28%) pediatric patients had grade 3 or 4 neurological adverse events.
    B) THERAPEUTIC DOSE: ADULT: 1500 mg/m(2) IV over 2 hours on days 1, 3 and 5, repeated every 21 days. PEDIATRIC: 650 mg/m(2) IV over 1 hr daily for 5 consecutive days repeated every 21 days.

Clinical Effects

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Severe neurological events have been reported following therapeutic administration of nelarabine. These events have included altered mental states including severe somnolence, central nervous system effects including seizures, and peripheral neuropathy ranging from numbness and paresthesias to motor weakness and paralysis.
    3.7.2) CLINICAL EFFECTS
    A) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) A study of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days resulted in one fatal case involving coma, cerebral hemorrhage, and leukoencephalopathy (Prod Info ARRANON(R) intravenous injection, 2014)
    B) COMA
    1) WITH THERAPEUTIC USE
    a) ADULT: A study of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days resulted in one fatal case involving coma, cerebral hemorrhage, and leukoencephalopathy (Prod Info ARRANON(R) intravenous injection, 2014)
    b) PEDIATRIC: A 6-year-old child, given 75 mg/kg/day of nelarabine during a phase I clinical trial, developed severe seizures, myoclonic jerks, ascending paralysis, and coma approximately 12 days after beginning therapy. The patient required mechanical ventilation for 2 weeks. Although the patient subsequently improved enough to breathe without assistance, the child never completely regained consciousness and ultimately died of progressive leukemia approximately 3 months after beginning nelarabine therapy (Kurtzberg et al, 2005).
    C) STATUS EPILEPTICUS
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: A study of pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days resulted in one fatal case of status epilepticus on day 4 of therapy in a patient with a previous seizure history (Prod Info ARRANON(R) intravenous injection, 2014).
    D) SEIZURE
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC
    1) Grade 4/5 seizures were reported with an incidence of 6% in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    2) CASE REPORT: A 6-year-old child, given 75 mg/kg/day of nelarabine during a phase I clinical trial, developed severe seizures, myoclonic jerks, ascending paralysis, and coma approximately 12 days after beginning therapy. The patient required mechanical ventilation for 2 weeks. Although the patient subsequently improved enough to breathe without assistance, the child never completely regained consciousness and ultimately died of progressive leukemia approximately 3 months after beginning nelarabine therapy (Kurtzberg et al, 2005).
    b) In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, there was one grade 3 seizure reported (Prod Info ARRANON(R) intravenous injection, 2014).
    E) DEMYELINATING DISEASE OF CENTRAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) There have been reports following the administration of nelarabine of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barre syndrome (Prod Info ARRANON(R) intravenous injection, 2014; Berg et al, 2005).
    b) PEDIATRIC: A 6-year-old child, given 75 mg/kg/day of nelarabine during a phase I clinical trial, developed severe seizures, myoclonic jerks, ascending paralysis, and coma approximately 12 days after beginning therapy. The patient required mechanical ventilation for 2 weeks. Although the patient subsequently improved enough to breathe without assistance, the child never completely regained consciousness and ultimately died of progressive leukemia approximately 3 months after beginning nelarabine therapy (Kurtzberg et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) Grade 3 ascending sensory neuropathy was reported in 2 patients who received 2,200 mg/m(2) of nelarabine on days 1, 3, and 5 every 21 days. MRI findings in both patients showed the occurrence of a demyelinating process in the cervical spine (Prod Info ARRANON(R) intravenous injection, 2014).
    F) LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) In an adult patient population there was a single report of biopsy confirmed progressive multifocal leukoencephalopathy (Prod Info ARRANON(R) intravenous injection, 2014).
    G) APHASIA
    1) WITH THERAPEUTIC USE
    a) In an adult patient population receiving nelarabine, there was a single report of grade 3 aphasia (DeAngelo et al, 2007).
    H) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, peripheral neuropathy disorders were reported at 21% for all grades. Grade 3 peripheral neuropathy disorders in adults were reported at a rate of 2% and there were no grade 4/5 events reported (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: Peripheral neuropathies, both motor and sensory, were reported with an incidence of 12% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 peripheral neuropathy disorders were reported in pediatric patients at a rate of 7% and there were no grade 4/5 events reported (Prod Info ARRANON(R) intravenous injection, 2014).
    c) CONCURRENT INTRATHECAL CHEMOTHERAPY: A 37-year-old woman with a T-cell lymphoblastic lymphoma was being treated for relapsed disease. She was started on nelarabine 1500 mg/m(2) on days 1,3, and 5 with a dose of intrathecal cytarabine 100 mg on day 2 for CNS prophylaxis. She tolerated the procedure well and went into complete remission. One month later, a second cycle of nelarabine was administered without additional intrathecal prophylaxis to maintain her remission until a suitable donor was found for allogenic transplant. Within a week the patient developed significant numbness in her lower extremities that began in her feet and eventually reached her distal upper extremities. A MRI showed changes subacute degeneration from C2 to C6. Her symptoms were associated with nelarabine neurotoxicity. Following aggressive physical therapy, she was able to undergo another reduced intensity allogenic transplant. However, her postoperative course was complicated by cytomegalovirus and neutropenic fever. She continued to undergo aggressive physical therapy and was showing noticeable improvement, in particular, her lower extremities. By week 10, there was evidence of relapse and she was no longer a candidate for additional chemotherapy. The patient was started on conservative care and palliative radiotherapy. Based on limited experience, it was suggested that neurotoxicity was increased with concurrent intrathecal therapy and high dose systemic nelarabine chemotherapy. In this case, a single dose of intrathecal cytarabine had an additive effect on producing neurotoxicity based on the close timing of administration with nelarabine (ie, able to penetrate the blood brain barrier and potentiate severe neurotoxicity) (Ngo et al, 2015).
    I) ATAXIA
    1) WITH THERAPEUTIC USE
    a) ADULT: A study of adult patients (n=103) treated with nelarabine 1500 mg/m(2) intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days reported a 9% overall incidence of ataxia (Prod Info ARRANON(R) intravenous injection, 2014). A phase II study in adults reported ataxia in 2/18 (11%) of patients (Czuczman et al, 2007).
    b) PEDIATRIC: A study of pediatric patients (n=84) receiving nelarabine 650 mg/m(2) intravenously over 1 hour daily for 5 consecutive days repeated every 21 days reported a 2% overall incidence of ataxia (Prod Info ARRANON(R) intravenous injection, 2014).
    J) HEADACHE DISORDER
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC - Headache was reported with an incidence of 17% for all grades in pediatric patients (n=84) taking nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 and grade 4/5 headache were reported in pediatric patients at rates of 4% and 2%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    b) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, headache was reported at 15% for all grades. Grade 3 headache in adults was reported at a rate of 1% (Prod Info ARRANON(R) intravenous injection, 2014).
    K) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ADULT: Dizziness was reported in 21% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    L) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, paresthesia was reported at 15% for all grades (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: Paresthesia was reported with an incidence of 4% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 paresthesia was reported in pediatric patients at a rate of 1% (Prod Info ARRANON(R) intravenous injection, 2014).
    M) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) ADULT: Asthenia was reported in 17% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, with 1% of the occurrences being grade 4/5 (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: In pediatric patients taking nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days, asthenia was reported in 6% of patients (Prod Info ARRANON(R) intravenous injection, 2014).
    N) DROWSY
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: Somnolence was reported with an incidence of 7% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 and grade 4/5 somnolence were reported in pediatric patients at a rate of 1% for each (Prod Info ARRANON(R) intravenous injection, 2014).
    b) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, grade 1 and grade 2 somnolence were reported at rates of 20% and 3%, respectively. No grade 3 or grade 4/5 somnolence were reported in adults (Prod Info ARRANON(R) intravenous injection, 2014).
    O) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in 7% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 41% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014)
    b) In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, vomiting was reported in 22% of patients. Grade 3 vomiting was reported in 1% of patients (Prod Info ARRANON(R) intravenous injection, 2014).
    c) PEDIATRIC: Vomiting occurred in 10% of pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 22% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Grade 3 diarrhea was reported in 1% of patients (Prod Info ARRANON(R) intravenous injection, 2014).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 21% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Grade 3 constipation was reported in 1% of patients (Prod Info ARRANON(R) intravenous injection, 2014).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain (9%) and distention (6%) were reported in adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    E) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis occurred in 8% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Grade 3 stomatitis was reported in 1% of patients (Prod Info ARRANON(R) intravenous injection, 2014).
    F) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia occurred in 9% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ADULT: AST was increased in 6% of adult patients treated with 1,500 mg/m(2) of nelarabine administered IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: Hepatic transaminase levels were elevated in 12% of pediatric patients (n=84) following treatment with nelarabine 650 mg/m(2) IV administered over 1 hour daily for 5 consecutive days repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    B) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: Elevated bilirubin levels were reported in 10% of pediatric patients (n=84) following treatment with nelarabine 650 mg/m(2) IV administered 1 hour daily for 5 consecutive days repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Summary Of Exposure

    A) USES: Nelarabine, a nucleoside metabolic inhibitor, is used for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least 2 chemotherapy regimens.
    B) PHARMACOLOGY: Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). It is demethylated by adenosine deaminase to ara-G, phosphorylated by mitochondrial deoxyguanosine kinase and deoxycytidine kinase, and converted to the active 5' -triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for its incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death.
    C) EPIDEMIOLOGY: Exposure is not common.
    D) WITH THERAPEUTIC USE
    1) SUMMARY: The dose-limiting toxicity in both adult and pediatric patients is neurotoxicity.
    2) ADULT: The most common adverse effects in adult patients, following therapeutic administration of nelarabine, include myelosuppression (anemia, neutropenia, thrombocytopenia), gastrointestinal distress (nausea, vomiting, diarrhea), fatigue, somnolence, headache, peripheral neuropathy, paresthesias, dyspnea, and cough.
    3) PEDIATRIC: The most common adverse effects in pediatric patients, following therapeutic administration of nelarabine, include myelosuppression (anemia, neutropenia, leukopenia, and thrombocytopenia), headache, vomiting, and elevated hepatic enzyme and serum bilirubin levels.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Nelarabine overdose information is limited. It is anticipated that nelarabine overdosage would result in myelosuppression, vomiting, severe neurotoxicity, including paralysis and coma, and possibly death.
    2) During clinical trials, two patients developed significant grade 3 ascending sensory neuropathy following intravenous administration of nelarabine at a dose of 2,200 mg/m(2) on days 1,3, and 5 repeated every 21 days.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hyperthermia has been frequently reported following therapeutic administration of nelarabine.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Hyperthermia was reported in 23% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Grade 3 hyperthermia occurred in 5% of adults (Prod Info ARRANON(R) intravenous injection, 2014).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision was reported in 4% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Epistaxis was reported in 8% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    2) Sinusitis was reported in 7% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension was reported in 8% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain (5%) and noncardiac chest pain (5%) were reported in adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    C) SINUS TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Sinus tachycardia was reported in 8% of adult patients (n=103) treated with 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    D) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema was reported in 11% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Peripheral edema also occurred in 15% of adult patients (Prod Info ARRANON(R) intravenous injection, 2014).
    E) DEEP VENOUS THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Deep venous thrombosis developed in one patient following treatment with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 (Alvarado et al, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) ADULT: Pneumonia occurred in 8% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Grade 3 and grade 4/5 pneumonia in adults were reported at rates of 4% and 1%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: A study of pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days reported one case of fatal fungal pneumonia (Prod Info ARRANON(R) intravenous injection, 2014).
    B) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, pleural effusion was reported at 10% for all grades. Grade 3 and grade 4/5 pleural effusion in adults were reported at rates of 5% and 1%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea occurred in 20% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days. Grade 3 and grade 4/5 dyspnea in adults were reported at rates of 4% and 2%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    D) WHEEZING
    1) WITH THERAPEUTIC USE
    a) Wheezing was reported in 5% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    E) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough was reported in 25% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: An increase in serum creatinine was reported with an incidence of 6% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Myelosuppression (anemia, thrombocytopenia, and neutropenia) is a common occurrence in both the adult and pediatric population following therapeutic administration of nelarabine.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, anemia was reported at 99% for all grades. Grade 3 and grade 4/5 anemia in adults were reported at rates of 20% and 14%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: Anemia was reported with an incidence of 95% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 and grade 4/5 anemia were reported in pediatric patients at rates of 45% and 10%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, neutropenia was reported at 81% for all grades. Grade 3 and grade 4/5 neutropenia in adults were reported at rates of 14% and 49%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    b) PEDIATRIC: Neutropenia was reported with an incidence of 94% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 and grade 4/5 neutropenia were reported in pediatric patients at rates of 17% and 62%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) ADULT: In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, thrombocytopenia was reported at 86% for all grades. Grade 3 and grade 4/5 thrombocytopenia in adults were reported at rates of 37% and 22%, respectively (Prod Info ARRANON(R) intravenous injection, 2014). In another study, life-threatening platelet adverse events were present in 3/18 (17%) of patients (Czuczman et al, 2007).
    b) PEDIATRIC: Thrombocytopenia was reported with an incidence of 88% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 and grade 4/5 thrombocytopenia were reported in pediatric patients at rates of 27% and 32%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) PEDIATRIC: Leukopenia was reported with an incidence of 38% for all grades in pediatric patients (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days. Grade 3 and grade 4/5 leukopenia were reported in pediatric patients at rates of 14% and 7%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).
    E) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days, febrile neutropenia was reported at 12% for all grades. Grade 3 and grade 4/5 febrile neutropenia in adults were reported at rates of 9% and 1%, respectively (Prod Info ARRANON(R) intravenous injection, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PETECHIAE
    1) WITH THERAPEUTIC USE
    a) Petechiae was reported in 12% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia was reported in 9% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 13% of adult patients (n=103) treated with 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia was reported in 6% of adult patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Nelarabine is classified as FDA pregnancy category D. Nelarabine can cause fetal harm when administered to pregnant women. Advise women of reproductive potential to avoid becoming pregnant while receiving therapy with nelarabine.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) An increased incidence of fetal malformations, anomalies, and variations occurred in animals following administration of nelarabine during the period of organogenesis at doses approximately one-quarter the adult dose. Cleft palate occurred in animals who received approximately 2-fold the adult dose, and absent digits occurred at doses approximately three-quarters the adult dose. Absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification occurred at all doses (Prod Info ARRANON(R) intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified nelarabine as FDA pregnancy category D (Prod Info ARRANON(R) intravenous injection, 2014).
    B) RISK SUMMARY
    1) Nelarabine can cause fetal harm when administered to pregnant women. Advise women of reproductive potential to avoid becoming pregnant while receiving therapy with nelarabine (Prod Info ARRANON(R) intravenous injection, 2014).
    C) ANIMAL STUDIES
    1) Maternal body weight gain and fetal body weights were reduced in animals who were administered approximately 2-fold the adult dose (Prod Info ARRANON(R) intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether nelarabine or ara-G (the active metabolite) is excreted in human breast milk. Nursing should be discontinued in women who are receiving therapy with nelarabine (Prod Info ARRANON(R) intravenous injection, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS121032-29-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Genotoxicity

    A) In vitro, nelarabine was mutagenic in L5178Y/TK mouse lymphoma cells with and without metabolic activation (Prod Info ARRANON(R) intravenous injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor neuro status closely; neurotoxicity is the dose-limiting toxicity of nelarabine therapy.
    B) Monitor CBC including differential and platelets for several weeks after overdose; delayed bone marrow suppression may develop.
    C) Monitor electrolytes, fluid status, liver enzymes and renal function as clinically indicated following exposure.
    D) Monitor for signs/symptoms of infection or sepsis in severely immunocompromised patients.
    E) Nerve conduction studies may be useful in patients with symptoms of peripheral neuropathy.
    F) Serum nelarabine levels are not clinically useful in guiding management following overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with a large overdose should be closely monitored in an inpatient setting, with frequent monitoring of vital signs and neuro status, daily monitoring of CBC with differential and platelet count, clinical assessment and evaluation to determine the need for prophylactic therapies (ie, antibiotics, growth factors).
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There are no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, hematologist, medical toxicologist, infectious disease physician and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) A patient with a large overdose may benefit from early transfer to a cancer treatment or bone marrow transplant center

Monitoring

    A) Monitor neuro status closely; neurotoxicity is the dose-limiting toxicity of nelarabine therapy.
    B) Monitor CBC including differential and platelets for several weeks after overdose; delayed bone marrow suppression may develop.
    C) Monitor electrolytes, fluid status, liver enzymes and renal function as clinically indicated following exposure.
    D) Monitor for signs/symptoms of infection or sepsis in severely immunocompromised patients.
    E) Nerve conduction studies may be useful in patients with symptoms of peripheral neuropathy.
    F) Serum nelarabine levels are not clinically useful in guiding management following overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is unlikely to be necessary because nelarabine is administered intravenously.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Nelarabine is extensively distributed throughout the body (Prod Info ARRANON(R) intravenous injection, 2014); hemodialysis is unlikely to be beneficial.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established. OVERDOSE: Limited overdose data. FATALITIES: ADULT: Patients (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days resulted in 5 fatal cases. Fatal events included hypotension (n=1), respiratory arrest (n=1), pleural effusion/pnuemothorax (n=1), pneumonia (n=1), and cerebral hemorrhage/coma/leukoencephalopathy (n=1). PEDIATRIC: Children (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days resulted in 3 fatal cases. Fatal events included neutropenia and pyrexia (n=1), status epilepticus/seizure (n=1), and fungal pneumonia (n=1). SURVIVAL: ADULT: Two adults developed grade 3 ascending sensory neuropathy following administration of nelarabine 2,200 mg/m(2) given on days 1, 3, and 5 every 21 days. PEDIATRIC: At doses greater than 900 mg/m(2), 5 of 18 (28%) pediatric patients had grade 3 or 4 neurological adverse events.
    B) THERAPEUTIC DOSE: ADULT: 1500 mg/m(2) IV over 2 hours on days 1, 3 and 5, repeated every 21 days. PEDIATRIC: 650 mg/m(2) IV over 1 hr daily for 5 consecutive days repeated every 21 days.

Therapeutic Dose

    7.2.1) ADULT
    A) T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA; T-CELL LYMPHOBLASTIC LYMPHOMA
    1) Recommended dose is 1,500 mg/m(2) IV over 2 hours on days 1, 3, and 5; repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).
    7.2.2) PEDIATRIC
    A) T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA; T-CELL LYMPHOBLASTIC LYMPHOMA
    1) Recommended dose is 650 mg/m(2) IV over 1 hour daily for 5 consecutive days; repeated every 21 days (Prod Info ARRANON(R) intravenous injection, 2014).

Minimum Lethal Exposure

    A) SUMMARY: A specific minimum toxic dose has not been established.
    B) ADULT: A study of adults (n=103) treated with nelarabine 1500 mg/m(2) IV over 2 hours on days 1, 3, and 5 repeated every 21 days resulted in 5 fatal cases. Fatal events included hypotension (n=1), respiratory arrest (n=1), pleural effusion/pnuemothorax (n=1), pneumonia (n=1), and cerebral hemorrhage/coma/leukoencephalopathy (n=1) (Prod Info ARRANON(R) intravenous injection, 2014)
    C) PEDIATRIC: A study of children (n=84) receiving nelarabine 650 mg/m(2) IV over 1 hour daily for 5 consecutive days repeated every 21 days resulted in 3 fatal cases. Fatal events included neutropenia and pyrexia (n=1), status epilepticus/seizure (n=1), and fungal pneumonia (n=1) (Prod Info ARRANON(R) intravenous injection, 2014).

Maximum Tolerated Exposure

    A) ADULT: Grade 3 ascending neuropathy was reported in two patients following nelarabine administration of 2,200 mg/m(2) given on days 1, 3, and 5 every 21 days. MRI evaluations of the two patients showed the occurrence of a demyelinating process in the cervical spine (Prod Info ARRANON(R) intravenous injection, 2014).
    B) PEDIATRIC: At doses greater than 900 mg/m(2), 5 of 18 (28%) pediatric patients had grade 3 or 4 neurological adverse events (Berg et al, 2005).

Workplace Standards

    A) ACGIH TLV Values for CAS121032-29-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS121032-29-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS121032-29-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS121032-29-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G). Nelarabine is 10-times more water-soluble than ara-G (Czuczman et al, 2007). Nelarabine is demethylated by adenosine deaminase to ara-G, phosphorylated by mitochondrial deoxyguanosine kinase and deoxycytidine kinase, and converted to the active 5' -triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for its incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms probably contribute to the cytotoxicity and systemic toxicity of nelarabine (Prod Info ARRANON(R) IV injection, 2006; Cohen et al, 2006). Accumulation of ara-GTP is greater in T-cells than B-cells (Kisor, 2005). Ara-G is relatively resistant to phosphorolysis by purine nucleoside phosphorylase (PNP), and Ara-GTP accumulates in T-lymphoblasts in a dose-dependent manner in patients with T-cell acute lymphoblastic leukemia and T-lymphoid blast crisis (Gandhi et al, 1998).

Physicochemical

Molecular Weight

    A) 297.3 (Sweetman, 2005)

References

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