Nelarabine

Pronunciation: (nel-AR-a-been)
Class: DNA demethylation agent

Trade Names

Arranon
- Injection 5 mg/mL

Pharmacology

Converted to ara-G, then activated to ara-GTP. Ara-GTP accumulates in leukemic blasts and is incorporated into DNA, leading to inhibition of DNA synthesis and cell death.

Pharmacokinetics

Absorption

C _max of ara-G generally occurs at the end of nelarabine infusion. Mean plasma nelarabine and ara-G C _max values were approximately 5 and 31.4 mcg/mL, respectively. Exposure to ara-G AUC is 37 times higher than that for nelarabine on day 1 (162 vs 4.4 mcg•h/mL, respectively). T _max for ara-GTP is within 3 to 25 hours on day 1.

Distribution

Nelarbine and ara-G are extensively distributed. Protein binding is less than 25%. Nelarabine Vd at steady state is 197 L/m ² . Ara-G Vd at steady state is 50 L/m ² .

Metabolism

Rapid and extensive conversion of nelarabine to ara-G by O-demethylation. Ara-G is hydrolyzed to guanine, which is N-deaminated to xanthine and then oxidized to uric acid.

Elimination

Rapidly eliminated from plasma. The mean Cl of nelarabine is 197 L/h/m ² and the apparent Cl of ara-G is 10.5 L/h/m ² . Partially eliminated by kidneys (6.6% nelarabine; 27% ara-G); half-life is 18 min (nelarabine) and 3.2 h (ara-G).

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).

Hepatic Function Impairment

The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated.

Elderly

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

Children

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

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%).

Indications and Usage

Treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in patients whose disease has not responded to or has relapsed following treatment with at least 2 chemotherapy regimens.

Contraindications

None well documented.

Dosage and Administration

Leukemia/Lymphoma
Adults

IV 1,500 mg/m ² over 2 h on days 1, 3, and 5; repeated every 21 days.

Children

IV 650 mg/m ² over 1 h daily for 5 consecutive days; repeated every 21 days.

Discontinuation/Delay of Therapy

Discontinue therapy for neurologic reactions grade 2 or higher. Dosage may be delayed for other toxicities, including hematologic toxicity.

Duration of Therapy

Duration of treatment has not been clearly established. Generally, treatment is continued until there is evidence of disease progression, the patient experiences unacceptable toxicity, the patient no longer continues to benefit from treatment, or the patient becomes a candidate for bone marrow transplantation.

General Advice

For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
Follow institutional procedures for handling, administration, and disposal of anticancer drugs. Wear appropriate protective equipment when preparing and administering medication.
Injection solution does not need to be diluted prior to administration. Transfer prescribed dose of nelarabine into a PVC infusion bag or glass infusion container and administer over appropriate interval.
Solution should be clear and colorless. Do not use if solution is discolored, cloudy, or contains particulate matter.
Appropriate measures (eg, hydration, prophylaxis with allopurinol, urine alkalinization) must be taken to prevent hyperuricemia.

Storage/Stability

Store unopened vials at 59° to 86°F. Nelarabine is stable in glass infusion containers and PVC infusion bags for up to 8 h if stored at room temperatures up to 86°F.

Drug Interactions

Pentostatin

Coadministration of nelarabine and pentostatin is not recommended. Administration of pentostatin, a strong inhibitor of adenosine deaminase, may result in a reduction in the conversion of the prodrug nelarabine to its active metabolite, reducing the efficacy of nelarabine and changing the adverse reaction profile of either drug.

Live vaccines

Avoid administration of live vaccines to immunocompromised patients.

Adverse Reactions

Cardiovascular

Hypotension, sinus tachycardia (8%).

CNS

Fatigue (50%); somnolence (23%); any peripheral neurologic reaction, dizziness (21%); asthenia, headache, hypoesthesia (17%); paresthesia (15%); peripheral sensory neuropathy (13%); ataxia (9%); confusion (8%); insomnia, peripheral motor neuropathy (7%); abnormal gait, convulsions, depressed level of consciousness, depression, peripheral neuropathy (6%); tremor (5%); motor dysfunction, nervous system disorder, neuropathy (4%); amnesia, dysgeusia (3%); balance disorder, sensory loss (2%); aphasia, burning sensation, cerebral hemorrhage, coma, disturbance in attention, dysarthria, encephalopathy, generalized tonic-clonic convulsions, hemiparesis, hydrocephalus, hypertonia, hyporeflexia, intracranial hemorrhage, lethargy, leukoencephalopathy, loss of consciousness, mental impairment, metabolic encephalopathy, neuropathic pain, nystagmus, paralysis, peroneal nerve palsy, sciatica, sensory disturbance, sensory loss, sixth nerve paralysis, status epilepticus, third nerve paralysis, (1%); demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome (postmarketing).

EENT

Sinusitis (5%); blurred vision (4%); sinus headache, speech disorder (1%).

GI

Nausea (41%); diarrhea, vomiting (22%); constipation (21%); abdominal pain, anorexia (9%); stomatitis (8%); abdominal distension (6%).

Hematologic-Lymphatic

Anemia (99%); neutropenia (94%); thrombocytopenia (88%); leukopenia (38%); febrile neutropenia (12%).

Lab Tests

Transaminases increased (12%); decreased potassium (11%); decreased albumin, decreased bilirubin (10%); decreased calcium (8%); decreased creatinine, decreased glucose, decreased magnesium, increased AST (6%).

Metabolic-Nutritional

Peripheral edema (15%); dehydration (7%); hyperglycemia (6%).

Musculoskeletal

Myalgia (13%); arthralgia (9%); back pain, muscular weakness, rigors (8%); pain in extremities (7%).

Respiratory

Cough (25%); dyspnea (20%); pleural effusion (10%); epistaxis, pneumonia (8%); exertional dyspnea (7%); wheezing (5%).

Miscellaneous

Pyrexia (23%); petechiae (12%); edema, pain (11%); infection (9%); chest pain, noncardiac chest pain (5%); fatal opportunistic infections, tumor lysis syndrome (postmarketing).

Precautions

Warnings

Severe neurologic reactions have been reported. Reactions included altered mental status (eg, severe somnolence), CNS effects (eg, convulsions), peripheral neuropathy ranging from numbness and paresthesias to motor weakness and paralysis, and 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. Close monitoring for neurologic reactions is strongly recommended; discontinue nelarabine for neurologic reactions grade 2 or higher.

Monitor

Closely monitor patients for neurologic reactions. Monitor CBC and platelet count regularly. Closely monitor patients with moderate or severe renal impairment or patients with severe hepatic impairment for toxicity.

Pregnancy

Category D .

Lactation

Undetermined.

Elderly

Take care in dose selection; it may be useful to monitor renal function.

Renal Function

Risk of reactions may be greater in patients with severe renal function impairment (CrCl less than 30 mL/min); closely monitor these patients for toxicity.

Hepatic Function

Risk of reactions may be greater in patients with severe hepatic impairment (bilirubin more than 3 mg/dL); closely monitor these patients for toxicity.

Hazardous Tasks

May cause somnolence.

Hematologic toxicity

Anemia, leukopenia, neutropenia, and thrombocytopenia, including febrile neutropenia, have been associated with nelarabine therapy.

Hyperuricemia

Provide appropriate measures (eg, IV hydration, prophylaxis with allopurinol, urine alkalinization) to prevent hyperuricemia in patients at risk of tumor lysis syndrome.

Neurologic effects

Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse reactions.

Overdosage

Symptoms

Myelosuppression, severe neurotoxicity (possibly including coma, paralysis), and potentially death.

Patient Information

Because patients receiving nelarabine therapy may experience somnolence, caution them about operating hazardous machinery, including automobiles.
Advise patient to immediately report any of the following to health care provider: bleeding or unusual bruising; chills, fever, or other signs of infection; difficulty breathing or unexplained shortness of breath; difficulty with fine motor coordination tasks (eg, buttoning clothing); hives; increased tripping while walking; pain, redness, or swelling at the injection site; paleness; rash; seizures; tingling or numbness in fingers, hands, toes, or feet; unsteadiness while walking; weakness in climbing stairs or arising from a chair.
Advise patient to report any of the following to health care provider: persistent appetite loss, nausea, or vomiting; persistent or worsening general body weakness.
Advise women of childbearing potential to use effective contraception to avoid becoming pregnant during therapy.
Advise lactating women to avoid breast-feeding during therapy.