Antineoplastic agents, antimetabolites, purine analogues

Nelarabine

Each ml contains 5 mg of nelarabine. Each vial contains 250 mg of nelarabine. Excipients: Each ml contains 1.725 mg (75 micromols) of sodium

Solution for infusion. Clear, colourless solution.

Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. Due to the small patient populations in these disease settings, the information to support these indications is based on limited data.

Nelarabine is for intravenous use only and must only be administered under the supervision of a physician experienced in the use of cytotoxic agents. Nelarabine is not diluted prior to administration. The appropriate dose of nelarabine is transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients.

Complete blood counts including platelets must be monitored regularly.

Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered.

Adults and adolescents (aged 16 years and older)

The recommended dose of nelarabine for adults is 1,500 mg/m² administered intravenously over two hours on days 1, 3 and 5 and repeated every 21 days.

Dose modification

Nelarabine must be discontinued at the first sign of neurological events of National Cancer Institute Common Terminology Criteria Adverse Event (NCI CTCAE) grade 2 or greater. Delaying subsequent dosing is an option for other toxicities, including haematological toxicity.

 Renal Impairment

Nelarabine has not been studied in individuals with renal impairment. Nelarabine and 9-β-D-arabinofuranosylguanine (ara-G) are partially renally excreted (see section 5.2 — Renal impairment). There are insufficient data to support a dose adjustment recommendation for patients with a renal clearance of creatinin Cl_cr less than 50 ml/min. Patients with renal impairment must be closely monitored for toxicities when treated with nelarabine.

Hepatic Impairment

Nelarabine has not been studied in patients with hepatic impairment. These patients should be treated with caution.

Children and adolescents (aged 21 years and younger)

The recommended dose of nelarabine for children is 650 mg/m² administered intravenously over one hour daily for 5 consecutive days, repeated every 21 days.

In clinical studies, the 650 mg/m² and 1,500 mg/m² dose have both been used in patients in the age range 16 to 21 years. Efficacy and safety were similar for both regimens. The prescribing physician should consider which regimen is appropriate when treating patients in this age range.

Limited clinical pharmacology data are available for patients below the age of 4 years.

Insufficient numbers of patients aged 65 years of age and older have been treated with nelarabine to determine whether they respond differently than younger patients.

Hypersensitivity to the active substance or to any of the excipients.

NEUROLOGICAL ADVERSE EVENTS

Severe neurological events have been reported with the use of nelarabine. 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 nelarabine. Therefore, close monitoring for neurological events is strongly recommended, and nelarabine must be discontinued at the first sign of neurological events of NCI CTCAE Grade 2 or greater.

Neurotoxicity is the dose-limiting toxicity of nelarabine. It is advised that patients undergoing therapy with nelarabine be closely observed for signs and symptoms of neurological toxicity.

Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paraesthesias, and hypoesthesia. Severe neurological toxicity can manifest as coma, status epilepticus, demyelination, or ascending neuropathy similar in appearance to Guillain-Barré syndrome.

Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation are potentially at increased risk for neurological adverse events and therefore concomitant intrathecal therapy and/or craniospinal irradiation is not recommended.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Leukopenia, thrombocytopenia, anaemia, and neutropenia, (including febrile neutropenia) have been associated with nelarabine therapy. Complete blood counts including platelets must be monitored regularly.

Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk of tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered.

Elderly

Clinical studies of nelarabine 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 aged 65 years and older, appeared to be associated with increased rates of neurological adverse events.

Carcinogenicity and mutagenicity

Carcinogenicity testing of nelarabine has not been performed. Nelarabine however, is known to be genotoxic to mammalian cells.

Sodium warning

This medicinal product contains 1.725 mg/ml (75 micromols) of sodium. To be taken into consideration by patients on a controlled sodium diet.

Nelarabine and ara-G did not significantly inhibit the activities of the major hepatic cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro.

Concomitant administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin is not recommended. Concomitant administration may reduce the efficacy of nelarabine and/or change the adverse event profile of either active substance.

Clinical trial data

Pivotal clinical trial data

The safety profile from pivotal clinical trials at the recommended doses of nelarabine in adults (1,500 mg/m²) and children (650 mg/m²) is based on data from 103 adults and 84 paediatric patients respectively. The most frequently occurring adverse events were fatigue; gastrointestinal disorders; haematological disorders; respiratory disorders; nervous system disorders; and pyrexia. Neurotoxicity is the dose limiting toxicity associated with nelarabine therapy.

The following convention has been utilised for the classification of frequency: Very common (1/10), Common (1/100 to <1/10), Uncommon (1/1,000 to <1/100), Rare (1/10,000 to <1/1,000) and Very rare (<1/10,000), not known (cannot be estimated from the available data)

Data from NCI studies/compassionate use programme and phase I studies

In addition to the adverse reactions seen in the pivotal clinical trials, there are also data from 875 patients from NCI studies/compassionate use programme (694 patients) and Phase I (181 patients) studies of nelarabine. The following additional adverse reactions were seen:

Neoplasms benign and malignant (including cysts and polyps)

GlaxoSmithKline

(POM)

11 August 2009