Nelarabine – Arranon®

Nelarabine - Arranon®

Usual Diluents

Dilution Data

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 8 hours at up to 30° C (room temperature).

DESCRIPTION
ARRANON (nelarabine) is a pro-drug of the cytotoxic deoxyguanosine analogue, 9-β-D-arabinofuranosylguanine (ara-G).

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), a 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.

1. 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 a 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/m2 administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. ARRANON is administered undiluted.

Pediatric Dosage: The recommended pediatric dose of ARRANON is 650 mg/m2 administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. ARRANON is administered undiluted.

2.2 Dosage Modification
ARRANON administration should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria grade 2 or greater. Dosage may be delayed for other toxicity including hematologic toxicity. [See Boxed Warning and 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 a creatinine clearance (CLcr) ≥50 mL/min [see Clinical Pharmacology (12.3)]. There are insufficient data to support a dose recommendation for patients with a 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 (5.4)].

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2.5 Instructions for Handling, Preparation, and Administration
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Handling: ARRANON is a 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 a two-hour infusion in adult patients and as a one-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 8 hours at up to 30° C.

3. DOSAGE FORMS AND STRENGTHS
250 mg/50 mL (5 mg/mL) vial

4. CONTRAINDICATIONS
None.

5. WARNINGS AND PRECAUTIONS

5.1 Neurologic Adverse Reactions
Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ARRANON should be closely observed for signs and symptoms of neurologic toxicity [see Boxed Warning and Dosage and Administration (2.2)]. 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.

5.2 Hematologic Adverse Reactions
Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

5.3 Pregnancy
Pregnancy Category D

ARRANON can cause fetal harm when administered to a pregnant woman.

Nelarabine administered during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits (see Use in Specific Populations (8.1)].

There are no adequate and well-controlled studies of ARRANON in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.

5.4 Hyperuricemia
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 [see Dosage and Administration (2.4)].

5.5 Vaccinations
Administration of live vaccines to immunocompromised patients should be avoided

HOW SUPPLIED/STORAGE AND HANDLING
ARRANON Injection is supplied as a clear, colorless, sterile solution in Type I, clear glass vials with a gray butyl rubber (latex-free) stopper and a red snap-off aluminum seal. 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. Vials are available in the following carton size:

NDC 0007-4401-06 (package of 6)

Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature].

©2009, GlaxoSmithKline. All rights reserved. ARRANON is a registered trademark of GlaxoSmithKline.