Nelarabine

Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2-Amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine
Molecular Formula: C11H15N5O5
CAS Number: 121032-29-9
Brands: Arranon

Warning(s)

  • Neurotoxicity
  • Severe, possibly irreversible, neurologic events (e.g., somnolence, confusion, seizures, peripheral neuropathy).1 2 3 5 Craniospinal demyelination and ascending peripheral neuropathy (similar in presentation to Guillain-Barré syndrome) reported.1 (See Neurotoxicity under Cautions.)

  • Closely monitor for adverse neurologic effects; discontinue therapy for neurologic events of NCI Common Toxicity Criteria grade ≥2.1

  • Experience of Supervising Clinician
  • For IV use only; administer only under the supervision of qualified clinicians experienced in the use of cancer chemotherapeutic agents.a

Introduction

Antimetabolite antineoplastic agent.1 2 5

Uses for Nelarabine

Acute Lymphocytic Leukemia (ALL)

Treatment of acute T-cell lymphocytic (lymphoblastic) leukemia (ALL) and T-cell lymphoblastic lymphoma in patients whose disease is refractory to or has relapsed after ≥2 prior chemotherapy regimens (designated an orphan drug by FDA for these conditions).1 2 4 6

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Nelarabine Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

  • Appropriate measures (e.g., administration of IV fluids, allopurinol, and alkalinization of urine) should be taken to prevent hyperuricemia of tumor lysis syndrome.1 (See Tumor Lysis Syndrome under Cautions.)

Administration

IV Administration

Administer by IV infusion.1

Nelarabine injection should not be diluted prior to administration.1

Withdraw appropriate dose from the required number of vials and transfer into empty PVC infusion bags or glass containers prior to administration.1

Rate of Administration

Adults: Administer by IV infusion over 2 hours.1

Pediatric patients: Administer by IV infusion over 1 hour.1

Dosage

Pediatric Patients

Acute Lymphocytic Leukemia
Relapsed or Refractory T-cell ALL or T-cell Lymphoblastic Lymphoma
IV

650 mg/m2 daily for 5 consecutive days; repeat every 21 days.1 2

Optimal duration of treatment not established.1 In clinical studies, treatment was continued until evidence of disease progression, unacceptable toxicity, bone marrow transplantation, or lack of clinical benefit was observed.1

Adults

Acute Lymphocytic Leukemia
Relapsed or Refractory T-cell ALL or T-cell Lymphoblastic Lymphoma
IV

1500 mg/m2 on days 1, 3, and 5; repeat every 21 days.1 2

Optimal duration of treatment not established.1 In clinical studies, treatment was continued until evidence of disease progression, unacceptable toxicity, bone marrow transplantation, or lack of clinical benefit was observed.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

No dosage adjustment required in patients with mild renal impairment (Clcr ≥50 mL/minute); not studied in patients with moderate to severe renal impairment.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Nelarabine

Contraindications

  • Known hypersensitivity to nelarabine or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Adequate Patient Monitoring and Evaluation

Administer only under the supervision of qualified clinicians experienced in the use of cancer chemotherapy agents.1

Neurotoxicity

Potentially irreversible and dose-limiting neurotoxicity, usually manifested by somnolence, confusion, seizures, and peripheral neuropathy (ranging from numbness to motor weakness and paralysis).1 2 3 5 Coma, status epilepticus, craniospinal demyelination, and ascending peripheral neuropathy (similar in presentation to Guillain-Barré syndrome) reported.1

Increased risk of neurotoxicity in patients who have received prior or concomitant intrathecal chemotherapy or prior craniospinal irradiation; discontinue therapy in patients experiencing neurologic events of NCI Common Toxicity Criteria grade ≥2.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.1 Avoid pregnancy during therapy; if used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

General Precautions

Hematologic Effects

Leukopenia, thrombocytopenia, anemia, and neutropenia reported.1 Perform CBC, including platelet count, regularly while patient is receiving the drug.1

Tumor Lysis Syndrome

May occur as a result of nelarabine therapy; consider measures (e.g., hydration, urinary alkalinization, allopurinol) to prevent hyperuricemia in patients at risk for tumor lysis syndrome.1

Immunization

Avoid administration of live virus vaccines during therapy.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether nelarabine or ara-G is distributed into milk; discontinue nursing because of potential risk to nursing infants.1

Pediatric Use

Safety and efficacy established in patients 2.5–21 years of age.1

Geriatric Use

Possible inreased incidence of neurologic effects compared with younger adults.1 (See Neurotoxicity under Cautions.)

Hepatic Impairment

Not studied in patients with hepatic impairment; possible increased risk of adverse reactions in patients with severe hepatic impairment (serum bilirubin >3 mg/dL).1

Renal Impairment

Possible increased risk of adverse reactions in patients with severe renal impairment (Clcr <30 mL/minute).1

Common Adverse Effects

In adults: Myelosuppresion,1 2 somnolence,1 2 dizziness,1 peripheral neurologic disorders,1 hypoesthesia,1 2 headache,1 2 paresthesia,1 fatigue,1 pyrexia,1 asthenia,1 edema,1 pain,1 myalgia,1 nausea,1 diarrhea,1 vomiting,1 constipation,1 cough,1 dyspnea,1 pleural effusion,1 petechiae.1

In pediatric patients: Myelosuppression,1 2 headache,1 2 peripheral neurologic disorders,1 elevated serum transaminase concentrations,1 hyperbilirubinemia,1 hypokalemia,1 hypoalbuminemia,1 vomiting.1

Interactions for Nelarabine

Does not appear to inhibit CYP isoenzymes, including 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro.1

Specific Drugs

Drug

Interaction

Comments

Adenosine deaminase inhibitors (i.e., pentostatin)

Possible decrease in nelarabine efficacy and/or change in adverse effect profile for either druga

Concomitant use not recommendeda

Fludarabine

Pharmacokinetics of nelarabine not altered1

Nelarabine Pharmacokinetics

Distribution

Extent

Extensively distributed throughout the body.1

Not known whether nelarabine crosses the placenta or is distributed into milk.a

Plasma Protein Binding

<25%.a

Elimination

Metabolism

Metabolized to ara-G, principally via O-demethylation by adenosine deaminase; ara-G undergoes further hydrolysis to guanine.a

Elimination Route

Nelarabine and ara-G are partially eliminated by the kidneys.a

Half-life

Nelarabine: 0.5 hour.a

Ara-G: 3 hours.a

Special Populations

In pediatric patients, clearance of nelarabine is increased by 30%; ara-G clearance is comparable to that in adults.a

Renal impairment may reduce clearance.a

In white patients, clearance and volume of distribution of nelarabine increased by 10%; clearance and volume of distribution of ara-G decreased by 15–20% when compared with black patients.a

Stability

Storage

Parenteral

Solution

25°C (may be exposed to 15–30°C).a

Stable in PVC bags and glass containers at ≤30°C for up to 8 hours.a

Actions

  • Prodrug of the deoxyguanosine analog ara-G, which is subsequently converted to the active 5′-triphosphate, ara-GTP.1 2 5

  • Ara-GTP accumulates in leukemic blasts and incorporates into DNA, inducing fragmentation and apoptosis.1 2 5

Advice to Patients

  • Risk of neurotoxicity; importance of informing clinician immediately if any changes in mental status, signs and symptoms of peripheral neuropathy (e.g., tingling or numbness in extremities, unsteadiness while walking, difficulty with fine motor coordination, increased tripping, weakness when rising from a low chair or climbing stairs), or seizures occur.a

  • Risk of sleepiness; avoid driving or operating machinery.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy; advise pregnant women of risk to the fetus.1 a

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Nelarabine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

5 mg/mL (250 mg)

Arranon

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Arranon (nelarabine) injection prescribing information. Research Triangle Park, NC; 2005 Oct.

2. Anon. Nelarabine (Arranon) for T-cell acute lymphoblastic leukemia. Med Lett Drugs Ther. 2006; 48:14-5.

3. Berg SL, Blaney SM, Devidas M et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. J Clin Oncol. 2005; 23:3376-82. [PubMed 15908649]

4. Childhood acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2006 Feb 17.

5. Kisor DF. Nelarabine: a nucleoside analog with efficacy in T-cell and other leukemias. Ann Pharmacother. 2005; 39:1056-63. [PubMed 15870141]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2006 Mar 21. From FDA website (). Accessed 2006 Apr 3.

7. GlaxoSmith Kline, Research Triangle Park, NC: Personal communication

a. GlaxoSmithKline. Arranon (nelarabine) injection prescribing information. Research Triangle Park, NC; 2006 July.

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