ARRANON should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Neurologic Events (see boxed WARNING)
ARRANON is a potent antineoplastic agent with potentially significant toxic side effects. Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ARRANON should be closely observed for signs and symptoms of neurologic toxicity.
Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome.
Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events. See DOSAGE AND ADMINISTRATION.
Pregnancy Category D
ARRANON may cause fetal harm when administered to a pregnant woman. There are no studies of ARRANON in pregnant women. When compared to controls, nelarabine administration during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits at doses ≥360 mg/m2/day (8-hour IV infusion; approximately ¼ the adult dose compared on a mg/m2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,600 mg/m2/day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given ≥1,200 mg/m2/day (approximately ¾ the 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 3,600 mg/m2/day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
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.
Administration of live vaccines to immunocompromised patients should be avoided.
Information for Patients
Since patients receiving nelarabine therapy may experience somnolence, they should be cautioned about operating hazardous machinery, including automobiles.
Patients should be instructed to contact their physician if they experience new or worsening symptoms of peripheral neuropathy (see WARNINGS and DOSAGE AND ADMINISTRATION). These signs and symptoms include: tingling or numbness in fingers, hands, toes, or feet; difficulty with the fine motor coordination tasks such as buttoning clothing; unsteadiness while walking; weakness arising from a low chair; weakness in climbing stairs; increased tripping while walking over uneven surfaces.
Patients should be instructed that seizures have been known to occur in patients who receive nelarabine. If a seizure occurs, the physician administering ARRANON should be promptly informed.
Patients who develop fever or signs of infection while on therapy should notify their physician promptly.
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breast feeding during treatment with ARRANON.
Nelarabine and ara-G did not significantly inhibit the activities of the human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at concentrations of nelarabine and ara-G up to 100 μM.
There is in vitro evidence that pentostatin is a strong inhibitor of adenosine deaminase. This may result in a reduction in the conversion of the pro-drug nelarabine to its active moiety and consequently in a reduction in efficacy of nelarabine and/or change in adverse event profile of either drug. Administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity testing of nelarabine has not been done. However, nelarabine was mutagenic when tested in vitro in L5178Y/TK mouse lymphoma cells with and without metabolic activation. No studies have been conducted in animals to assess genotoxic potential or effects on fertility. The effect on human fertility is unknown.
Pregnancy Category D. (See WARNINGS.)
It is not known whether nelarabine or ara-G are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ARRANON, nursing should be discontinued in women who are receiving therapy with ARRANON.
(See CLINICAL STUDIES, Pediatric Clinical Study).
Clinical studies of ARRANON did not include sufficient numbers of patients aged 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 events.
Use in Renally Impaired Patients
Ara-G clearance decreased as renal function decreased (see CLINICAL PHARMACOLOGY). Because the risk of adverse reactions to this drug may be greater in patients with severe renal impairment (CLcr<30 mL/min), these patients should be closely monitored for toxicities when treated with ARRANON (see DOSAGE AND ADMINISTRATION).
Use in Hepatically Impaired Patients
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 (bilirubin >3.0 mg/dL), these patients should be closely monitored for toxicities when treated with ARRANON.