ARRANON- nelarabine injection
GlaxoSmithKline LLC
DESCRIPTION
ARRANON (nelarabine) is prodrug of the cytotoxic deoxyguanosine analogue, 9-?-D -arabinofuranosylguanine (ara-G).
The chemical name for nelarabine is 2-amino-9-?-D -arabinofuranosyl-6-methoxy-9H -purine. It has the molecular formula C11 H15 N5 O5 and molecular weight of 297.27
Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209? and 217? C.
ARRANON Injection is supplied as clear, colorless, sterile solution in glass vials. Each vial contains 250 mg of nelarabine g 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.
Mechanism of Action
Nelarabine is prodrug of the deoxyguanosine analogue 9-?-D -arabinofuranosylguanine (ara-G), nucleoside metabolic inhibitor. 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.
WARNING: NEUROLOGIC ADVERSE REACTIONS
Severe neurologic adverse reactions have been reported with the use of ARRANON?. These adverse reactions 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 adverse reactions associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barr? syndrome [see Warnings and Precautions ].
Full recovery from these adverse reactions has not always occurred with cessation of therapy with ARRANON. Close monitoring for neurologic adverse reactions is strongly recommended, and ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade or greater.
INDICATIONS AND USAGE
ARRANON is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
This product is for intravenous use only.
The recommended duration of treatment for adult and pediatric patients has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
Adult Dosage: The recommended adult dose of ARRANON is 1,500 mg/m? administered intravenously over hours on Days 1, 3, and repeated every 21 days. ARRANON is administered undiluted.
Pediatric Dosage: The recommended pediatric dose of ARRANON is 650 mg/m? administered intravenously over hour daily for consecutive days repeated every 21 days. ARRANON is administered undiluted.
2.2 Dosage Modification
Administration of ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade or greater. Dosage may be delayed for other toxicity including hematologic toxicity. [See Boxed Warning, Warnings and Precautions (5.1, 5.2).]
2.3 Adjustment of Dose in Special Populations
ARRANON has not been studied in patients with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)]. No dose adjustment is recommended for patients with creatinine clearance (CLcr ?50 mL/min [see Clinical Pharmacology (12.3)]. There are insufficient data to support dose recommendation for patients with CLcr <50 mL/min.
2.4 Prevention of Hyperuricemia
Appropriate measures (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia [see Warnings and Precautions ].
2.5 Instructions for Handling, Preparation, and Administration
Handling: ARRANON is cytotoxic agent. Caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. Proper aseptic technique should be used. Guidelines for proper handling and disposal of anticancer drugs have been published.1-4
Preparation and Administration: Do not dilute ARRANON prior to administration. The appropriate dose of ARRANON is transferred into polyvinylchloride (PVC) infusion bags or glass containers and administered as 2-hour infusion in adult patients and as 1-hour infusion in pediatric patients.
Prior to administration, inspect the drug product visually for particulate matter and discoloration.
Stability: ARRANON Injection is stable in polyvinylchloride (PVC) infusion bags and glass containers for up to hours at up to 30? C.
3 DOSAGE FORMS AND STRENGTHS
250 mg/50 mL g/mL) vial
Pregnancy
Pregnancy Category D
ARRANON can cause fetal harm when administered to pregnant woman.
Nelarabine administered during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbit
DRUG INTERACTIONS
Administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended
OVERDOSAGE
There is no known antidote for overdoses of ARRANON. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death. In the event of overdose, supportive care consistent with good clinical practice should be provided.
HOW SUPPLIED/STORAGE AND HANDLING
ARRANON Injection is supplied as clear, colorless, sterile solution in Type I, clear glass vials with gray bromobutyl rubber stopper (not made with natural rubber latex) and red snap-off aluminum seal. Each vial contains 250 mg of nelarabine g nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. Vials (NDC 0007-4401-01) are available in the following carton size:
NDC 0007-4401-06 (package of 6)
Store at 25? (77? F); excursions permitted to 15? to 30? (59? to 86? F) [see USP Controlled Room Temperature].
