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Nelarabine

Pronunciation

(nel AY re been)

Index Terms

  • 2-Amino-6-Methoxypurine Arabinoside
  • 506U78
  • GW506U78

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Arranon: 5 mg/mL (50 mL)

Brand Names: U.S.

  • Arranon

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Purine Analog)

Pharmacology

Nelarabine, a prodrug of ara-G, is demethylated by adenosine deaminase to ara-G and then converted to ara-GTP. Ara-GTP is incorporated into the DNA of the leukemic blasts, leading to inhibition of DNA synthesis and inducing apoptosis. Ara-GTP appears to accumulate at higher levels in T-cells, which correlates to clinical response.

Distribution

Vss:

Nelarabine: Children: ~213 L/m2; Adults: ~197 L/m2

Ara-G: Children: ~33 L/m2; Adults: ~50 L/m2

Metabolism

Hepatic; demethylated by adenosine deaminase to form ara-G (active); also hydrolyzed to form methylguanine. Both ara-G and methylguanine metabolized to guanine. Guanine is deaminated into xanthine, which is further oxidized to form uric acid, which is then oxidized to form allantoin.

Excretion

Urine (nelarabine 5% to 10%, ara-G 20% to 30%)

Time to Peak

Adults: 3 to 25 hours (of day 1)

Half-Life Elimination

Children: Nelarabine: 13 minutes, Ara-G: 2 hours; Adults: Nelarabine: 18 minutes, Ara-G: 3 hours

Protein Binding

Nelarabine and ara-G: <25%

Special Populations: Renal Function Impairment

Cl reduced 15% in patients with mild renal impairment (CrCl 50 to 80 mL/min) and 40% in patients with moderate renal impairment(CrCl less than 50 mL/min).

Special Populations: Elderly

Reduced renal function in elderly patients may reduce ara-G Cl.

Special Populations: Children

Mean Cl of nelarabine is approximately 30% higher in children.

Special Populations: Race

Mean Cl and Vd values tended to be higher in white patients than in black patients (by approximately 10%). The opposite is true for ara-G; mean apparent Cl and Vd values tended to be lower in white patients than in black patients (by approximately 15% to 20%).

Use: Labeled Indications

T-cell acute lymphoblastic leukemia/lymphoma: Treatment of relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma following at least 2 chemotherapy regimens.

Contraindications

There are no contraindications listed in the US labeling.

Canadian labeling: Hypersensitivity to nelarabine or any component of the formulation.

Dosage

T-cell acute lymphoblastic leukemia/lymphoma:

Pediatrics: IV: 650 mg/m2/dose on days 1 through 5; repeat every 21 days until a transplant candidate, disease progression, or unacceptable toxicity

Adults: IV: 1,500 mg/m2/dose on days 1, 3, and 5; repeat every 21 days until a transplant candidate, disease progression, or unacceptable toxicity

Dosage adjustment for toxicity:

Neurologic toxicity ≥ grade 2: Discontinue treatment.

Hematologic or other (non-neurologic) toxicity: Consider treatment delay.

Dosage adjustment in renal impairment:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling, (although ARA-G clearance is decreased as renal function declines, data is insufficient for a dosing recommendation); monitor closely.

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); closely monitor with severe impairment (total bilirubin >3 times ULN)

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitution is not required; do not dilute; the appropriate dose should be added to empty plastic (PVC) bag or glass container.

Administration

Adequate IV hydration recommended to prevent tumor lysis syndrome; allopurinol may be used if hyperuricemia is anticipated.

IV:

Children: Infuse over 1 hour daily for 5 consecutive days

Adults: Infuse over 2 hours on days 1, 3, and 5

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Storage

Store unopened vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Stable in plastic (PVC) or glass containers for up to 8 hours at room temperature.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Pentostatin: May diminish the antineoplastic effect of Nelarabine. Conversion of nelarabine, a pro-drug, to its active form may be inhibited by pentostatin. Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Note: Pediatric adverse reactions fell within a range similar to adults except where noted.

>10%:

Cardiovascular: Peripheral edema (15%), edema (11%)

Central nervous system: Fatigue (50%), fever (23%), somnolence (7% to 23%; grades 2-4: 1% to 6%), dizziness (21%; grade 2: 8% adults), headache (15% to 17%; grades 2-4: 4% to 8%), hypoesthesia (6% to 17%; grades 2/3: children 5%, adults 12%), pain (11%)

Dermatologic: Petechiae (12%)

Endocrine & metabolic: Hypokalemia (11%)

Gastrointestinal: Nausea (41%), diarrhea (22%), vomiting (10% to 22%), constipation (21%)

Hematologic: Anemia (95% to 99%; grade 4: 10% to 14%), neutropenia (81% to 94%; grade 4: children 62%, adults 49%), thrombocytopenia (86% to 88%; grade 4: 22% to 32%), leukopenia (38%; grade 4: 7%), neutropenic fever (12%; grade 4: 1%)

Hepatic: Transaminases increased (12%; grade 3: 4%)

Neuromuscular & skeletal: Peripheral neuropathy (12% to 21%; grades 2/3: 11% to 14%), weakness (6% to 17%; grade 4: 1%), paresthesia (4% to 15%; grades 2/3: 3% to 4%), myalgia (13%)

Respiratory: Cough (25%), dyspnea (7% to 20%)

1% to 10%:

Cardiovascular: Hypotension (8%), sinus tachycardia (8%), chest pain (5%)

Central nervous system: Ataxia (2% to 9%; grades 2/3: children 1%, adults 8%), confusion (8%), insomnia (7%), depressed level of consciousness (6%; grades 2-4: 2%), depression (6%), seizure (grade 3: 1% adults; grade 4: 6% children), motor dysfunction (4%; grades 2/3: 2%), amnesia (3%; grade 2: 1%), balance disorder (2%; grade 2: 1%), sensory loss (1% to 2%), aphasia (grade 3: 1%), attention disturbance (1%), cerebral hemorrhage (grade 4: 1%), coma (grade 4: 1%), encephalopathy (grade 4: 1%), hemiparesis (grade 3: 1%), hydrocephalus (1%), intracranial hemorrhage (grade 4: 1%), lethargy (1%), leukoencephalopathy (grade 4: 1%), loss of consciousness (grade 3: 1%), mental impairment (1%), nerve paralysis (1%), neuropathic pain (1%), nerve palsy (1%), paralysis (1%), sciatica (1%), sensory disturbance (1%), speech disorder (1%)

Endocrine & Metabolic: Hypocalcemia (8%), dehydration (7%), hyper-/hypoglycemia (6%), hypomagnesemia (6%)

Gastrointestinal: Abdominal pain (9%), anorexia (9%), stomatitis (8%), abdominal distension (6%), taste perversion (3%)

Hepatic: Albumin decreased (10%), bilirubin increased (10%; grade 3: 7%, grade 4: 2%), AST increased (6%)

Neuromuscular & skeletal: Arthralgia (9%), back pain (8%), muscle weakness (8%), rigors (8%), limb pain (7%), abnormal gait (6%), noncardiac chest pain (5%), tremor (4% to 5%; grade 2: 2% to 3%), dysarthria (1%), hyporeflexia (1%), hypertonia (1%), incoordination (1%)

Ocular: Blurred vision (4%), nystagmus (1%)

Renal: Creatinine increased (6%)

Respiratory: Pleural effusion (10%), epistaxis (8%), pneumonia (8%), sinusitis (7%), wheezing (5%), sinus headache (1%)

Miscellaneous: Infection (5% to 9%)

<1% (Limited to important or life-threatening): Craniospinal demyelination, neuropathy (peripheral) (similar to Guillain-Barré syndrome), opportunistic infection, pneumothorax, progressive multifocal leukoencephalopathy (PML), respiratory arrest, rhabdomyolysis, tumor lysis syndrome

ALERT: U.S. Boxed Warning

Neurologic adverse reactions:

Severe neurologic reactions have been reported with the use of nelarabine. These reactions have included the following: altered mental states, including severe somnolence; CNS effects, including convulsions; and peripheral neuropathy, ranging from numbness and paresthesias to motor weakness and paralysis. There have also been reports of reactions associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.

Full recovery from these reactions has not always occurred with cessation of therapy with nelarabine. Close monitoring for neurologic reactions is strongly recommended; discontinue nelarabine for neurologic reactions of National Cancer Institute (NCI) Common Toxicity Criteria grade 2 or greater.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Leukopenia, thrombocytopenia, anemia, and neutropenia (including neutropenic fever) are associated with treatment. Monitor blood counts regularly.

• Neurotoxicity: [US Boxed Warning]: Severe neurotoxicities, including mental status changes, severe somnolence, seizures, and peripheral neuropathy (ranging from numbness and paresthesias to motor weakness and paralysis), have been reported. Observe closely for signs and symptoms of neurotoxicity; discontinue if ≥ grade 2. Adverse reactions associated with demyelination and ascending peripheral neuropathies similar to Guillain-Barré syndrome have also been reported. Neurologic toxicities may not fully return to baseline after treatment cessation. Neurologic toxicity is dose-limiting. Risk of neurotoxicity may increase in patients with concurrent or previous intrathecal chemotherapy or history of craniospinal irradiation. Fatal neurological outcomes have been reported following concurrent use of nelarabine with intrathecal chemotherapy. The Canadian labeling does not recommend concurrent use with intrathecal therapy and/or craniospinal radiation.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) may occur as a consequence of leukemia treatment. May lead to life-threatening acute renal failure; adequate hydration and prophylactic allopurinol should be instituted prior to treatment to prevent hyperuricemia and TLS; monitor closely.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; monitor closely. Risk of adverse reactions may be higher with severe hepatic dysfunction.

• Renal impairment: Use with caution in patients with renal impairment; monitor closely. Ara-G clearance may be reduced with renal dysfunction

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Vaccines: Avoid administration of live vaccines.

Monitoring Parameters

CBC with differential, liver and kidney function; monitor closely for neurologic toxicity (severe somnolence, seizure, peripheral neuropathy, confusion, ataxia, paresthesia, hypoesthesia, coma, or craniospinal demyelination); signs and symptoms of tumor lysis syndrome; hydration status

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies and nelarabine may cause fetal harm if administered during pregnancy. Women of childbearing potential should be advised to use effective contraception and avoid becoming pregnant during therapy.

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation. Specific use of nelarabine is not discussed (Peccatori 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, dizziness, nausea, constipation, diarrhea, headache, or arthralgia. Have patient report immediately to prescriber signs of infection, dyspnea, pallor, considerable edema, ecchymosis, hemorrhaging, significant asthenia, illogical thinking, abnormal gait, intolerable myalgia, difficulty with motor activity, or signs of tumor lysis syndrome (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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