Atriance 5 mg/ml

/ Novartis

Nelarabine is for intravenous use only and must only be administered under the supervision of a physician experienced in the use of cytotoxic agents.
Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricaemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricaemia, the use of allopurinol should be considered. Complete blood counts including platelets must be monitored regularly.
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.
Paediatric population: Children and adolescents (aged 21 years and younger) The recommended dose of nelarabine for children and adolescents 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.
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.
Elderly: 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. Renal Impairment Nelarabine has not been studied in individuals with renal impairment. Nelarabine and 9-β-Darabinofuranosylguanine (ara-G) are partially renally excreted. There are insufficient data to support a dose adjustment recommendation for patients with a renal clearance of creatinine Clcr 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.
Method of administration: Nelarabine must not be diluted prior to administration. The appropriate dose of nelarabine must be transferred into polyvinylchloride (PVC) or ethyl vinyl acetate (EVA) infusion bags or glass containers and administered intravenously as a two-hour infusion in adult patients and as a one-hour infusion in paediatric patients.
See prescribing information for full details.

For the treatment of patients with T-cell acute lymphoblastic leukemia (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.

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

NEUROLOGICAL ADVERSE REACTIONS: Severe neurological reactions have been reported with the use of nelarabine. These 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 reactions associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barré Syndrome. Full recovery from these reactions has not always occurred with cessation of nelarabine. Therefore, close monitoring for neurological reactions is strongly recommended, and nelarabine must be discontinued at the first sign of neurological reactions 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 hyperuricaemia in patients at risk of tumour lysis syndrome. For patients at risk of hyperuricaemia, 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.
See prescribing information for full details.

The most frequently occurring adverse events were fatigue, GI disorders, hematological disorders, respiratory disorders, nervous system disorders, and pyrexia. Neurotoxicity is the dose limiting toxicity associated with nelarabine therapy.
See prescribing information for full details.

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.

Pregnancy: There are no or limited amount of data from the use of nelarabine in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk in humans is unknown, however, exposure during pregnancy will likely lead to anomalies and malformations of the foetus. Nelarabine should not be used during pregnancy unless clearly necessary. If a patient becomes pregnant during treatment with nelarabine, they should be informed of the possible risk to the foetus.
Breastfeeding: It is unknown whether nelarabine or its metabolites are excreted in human breast milk. A risk to ths newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment with Atriance.

No case of overdose has been reported. Nelarabine has been administered in clinical trials up to a dose of 75 mg/kg (approximately 2,250 mg/m²) daily for 5 days to a paediatric patient, up to a dose of 60 mg/kg (approximately 2,400 mg/m2) daily for 5 days to 5 adult patients and up to 2,900 mg/m2 in a further 2 adults on days 1, 3 and 5.
Symptoms and signs: It is likely that nelarabine overdose would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression and potentially death. At a dose of 2200 mg/m² given on days 1, 3 and 5 every 21 days, 2 patients developed a significant grade 3 ascending sensory neuropathy. MRI evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.
Treatment: There is no known antidote for nelarabine overdose. Supportive care consistent with good clinical practice should be provided.

Storage: Below 30°C. Atriance is stable for up to 8 hours at up to 30°C once the vial is opened.