ARRANON®
(nelarabine)
Injection
FOR INTRAVENOUS USE
WARNING
ARRANON (nelarabine) Injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous use only.
Neurologic Events: Severe neurologic events have been reported with the use of ARRANON. These events have included altered mental states including severe somnolence, central nervous system effects including convulsions, and peripheral neuropathy ranging from numbness and paresthesias to motor weakness and paralysis. There have also been reports of events associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Full recovery from these events has not always occurred with cessation of therapy with ARRANON. Close monitoring for neurologic events is strongly recommended, and ARRANON should be discontinued for neurologic events of NCI Common Toxicity Criteria grade 2 or greater.
DESCRIPTION
ARRANON (nelarabine) is a pro-drug of the cytotoxic deoxyguanosine analogue, 9-β-D-arabinofuranosylguanine (ara-G).
The chemical name for nelarabine is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27. Nelarabine has the following structural formula:
Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209° and 217° C.
ARRANON Injection is supplied as a clear, colorless, sterile solution in glass vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. ARRANON is intended for intravenous infusion.
Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0.
CLINICAL PHARMACOLOGY
Mechanism of Action
Nelarabine is a pro-drug of the deoxyguanosine analogue 9-β-D-arabinofuranosylguanine (ara-G). Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5’-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.
Pharmacokinetics
Pharmacokinetic studies in adult patients with refractory leukemia or lymphoma have demonstrated that nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours, respectively, after a 1,500 mg/m2 nelarabine dose. No pharmacokinetic data are available in pediatric patients at the once daily 650 mg/m2 nelarabine dose. Plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G. Mean plasma nelarabine and ara-G Cmax values were 5.0 ± 3.0 μg/mL and 31.4 ± 5.6 μg/mL, respectively, after a 1,500 mg/m2 nelarabine dose in
