ATRIANCE Solution for infusion Ref.[9065] Active ingredients: Nelarabine

Neurological adverse reactions

Severe neurological reactions have been reported with the use of nelarabine. These reactions have included altered mental states including severe somnolence, confusion and coma, central nervous system effects including convulsions, ataxia and status epilepticus, and peripheral neuropathy including hypoesthesia 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. (see section 4.8).

Neurotoxicity is the dose-limiting toxicity of nelarabine. 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.

Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation are potentially at increased risk for neurological adverse events (see section 4.2 – dose modification) 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 (see sections 4.2 and 4.8).

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 age 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 (see section 5.3).

Sodium warning

This medicinal product contains 1.725 mg/ml (75 micromols/ml) 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.

Contraception in males and females

Both sexually active men and women should use effective methods of contraception during treatment with nelarabine. Men with partners who are pregnant or could become pregnant should use condoms during treatment with nelarabine and for at least three months following cessation of treatment.

Pregnancy

There are no or limited amount of data from the use of nelarabine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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.

Breast-feeding

It is unknown whether nelarabine or its metabolites are excreted in human breast milk. A risk to the newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment with Atriance.

Fertility

The effect of nelarabine on fertility in humans is unknown. Based on the pharmacological action of the compound, undesirable effects on fertility are possible. Family planning should be discussed with patients as appropriate

Atriance has major influence on the ability to drive and use machines. Patients treated with nelarabine are potentially at risk of suffering from somnolence during and for several days after treatment. Patients must be cautioned that somnolence can affect performance of skilled tasks, such as driving.

Summary of the safety profile

The safety profile from pivotal clinical studies 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 (somnolence, peripheral neurological disorders [sensory and motor], dizziness, hypoaesthesia, paraesthesia, headache); and pyrexia. Neurotoxicity is the dose-limiting toxicity associated with nelarabine therapy (see section 4.4).

Tabulated list of adverse reactions

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), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Description of selected adverse reactions

Infection and infestations

There was a single additional report of biopsy confirmed progressive multifocal leukoencephalopathy in the adult population. There have been reports of sometimes fatal opportunistic infections in patients receiving nelarabine therapy.

Nervous system disorders

There have been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.

Two paediatric patients had fatal neurological events.

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

In addition to the adverse reactions seen in the pivotal clinical studies, 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): Tumour lysis syndrome – 7 cases (see sections 4.2 and 4.4).

Post–marketing data

Rhabdomyolysis and increased blood creatine phosphokinase have been identified during post-approval use of nelarabine. This includes spontaneous case reports as well as serious adverse events from ongoing studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.