ATRIANCE 5mg / ml infusion solution medication leaflet

Atriance 5 mg/ml solution for infusion

Each ml of solution contains 5 mg of nelarabine.

Each vial contains 250 mg of nelarabine.

Each ml of solution contains 1.770 mg (77 micromols) of sodium.

For the full list of excipients, see section 6.1.

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 hasrelapsed following treatment with at least two chemotherapy regimens.

Due to the small patient populations in these disease settings, the information to support theseindications is based on limited data.

Nelarabine must only be administered under the supervision of a physician experienced in the use ofcytotoxic agents.

Complete blood counts including platelets must be monitored regularly (see sections 4.4 and 4.8).

Adults and adolescents (aged 16 years and older)

The recommended dose of nelarabine for adults and adolescents aged 16 years and older is1,500 mg/m2 administered intravenously over two hours on days 1, 3 and 5 and repeated every21 days.

Children and adolescents (aged 21 years and younger)

The recommended dose of nelarabine for children and adolescents (aged 21 years and younger) is650 mg/m2 administered intravenously over one hour daily for 5 consecutive days, repeated every21 days.

In clinical studies, the 650 mg/m2 and 1,500 mg/m2 dose have both been used in patients in the agerange 16 to 21 years. Efficacy and safety were similar for both regimens. The prescribing physicianshould 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 (seesection 5.2).

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 subsequentdosing is an option for other toxicities, including haematological toxicity.

Insufficient numbers of patients aged 65 years of age and older have been treated with nelarabine todetermine whether they respond differently than younger patients (see sections 4.4 and 5.2).

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). There are insufficientdata to support a dose adjustment recommendation for patients with a renal clearance of creatinine Clcrless than 50 ml/min. Patients with renal impairment must be closely monitored for toxicities whentreated with nelarabine.

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

Nelarabine is for intravenous use only and must not be diluted prior to administration. The appropriatedose 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 adultpatients and as a one-hour infusion in paediatric patients.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

NEUROLOGICAL ADVERSE REACTIONS

Severe neurological reactions have been reported with the use of nelarabine. These reactions haveincluded altered mental states including severe somnolence, confusion and coma, central nervoussystem effects including convulsions, ataxia and status epilepticus, and peripheral neuropathyincluding hypoesthesia ranging from numbness and paresthesias to motor weakness and paralysis.

There have also been reports of reactions associated with demyelination, and ascending peripheralneuropathies 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 notalways occurred with cessation of nelarabine. Therefore, close monitoring for neurological reactionsis strongly recommended, and nelarabine must be discontinued at the first sign of neurologicalreactions of NCI CTCAE Grade 2 or greater.

Patients treated previously or concurrently with intrathecal chemotherapy or previously withcraniospinal irradiation are potentially at increased risk for neurological adverse events (seesection 4.2 - dose modification) and therefore concomitant intrathecal therapy and/or craniospinalirradiation is not recommended.

Immunisation using a live organism vaccine has the potential to cause infection inimmunocompromised hosts. Therefore, immunisations with live organism vaccines are notrecommended.

Leukopenia, thrombocytopenia, anaemia, and neutropenia, (including febrile neutropenia) have beenassociated with nelarabine therapy. Complete blood counts including platelets must be monitoredregularly (see sections 4.2 and 4.8).

Patients receiving nelarabine are recommended to receive intravenous hydration according to standardmedical 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.

Clinical studies of nelarabine did not include sufficient numbers of patients aged 65 and over todetermine 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 ofneurological adverse events.

Carcinogenicity testing of nelarabine has not been performed. Nelarabine however, is known to begenotoxic to mammalian cells (see section 5.3).

Sodium warning

This medicinal product contains 88.51 mg (3.85 mmol) sodium per vial (50 ml), equivalent to 4.4% ofthe WHO recommended maximum daily intake of 2 g sodium for an adult.

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 aspentostatin is not recommended. Concomitant administration may reduce the efficacy of nelarabineand/or change the adverse event profile of either active substance.

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

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 isunknown, however, exposure during pregnancy will likely lead to anomalies and malformations of thefoetus.

Nelarabine should not be used during pregnancy unless clearly necessary. If a patient becomespregnant during treatment with nelarabine, they should be informed of the possible risk to the foetus.

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

Atriance.

The effect of nelarabine on fertility in humans is unknown. Based on the pharmacological action of thecompound, undesirable effects on fertility are possible. Family planning should be discussed withpatients 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 forseveral days after treatment. Patients must be cautioned that somnolence can affect performance ofskilled tasks, such as driving.

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 patientsrespectively. The most frequently occurring adverse events were fatigue; gastrointestinal disorders;haematological disorders; respiratory disorders; nervous system disorders (somnolence, peripheralneurological disorders [sensory and motor], dizziness, hypoaesthesia, paraesthesia, headache); andpyrexia. Neurotoxicity is the dose-limiting toxicity associated with nelarabine therapy (seesection 4.4).

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

Adverse reactions Adults (1,500 mg/m2) Children (650 mg/m2)

N=103 N=84

Infection (including but not limited to; sepsis, Very common: 40 (39%) Very common: 13 (15%)bacteraemia, pneumonia, fungal infection)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Tumour lysis syndrome (see also data from Common: 1 (1%) N/Acompassionate use programme and non-pivotal studies)

Febrile neutropenia Very common: 12 (12%) Common: 1 (1%)

Neutropenia Very common: 83 (81%) Very common: 79 (94%)

Leukopenia Common: 3 (3%) Very common: 32 (38%)

Thrombocytopenia Very common: 89 (86%) Very common: 74 (88%)

Anaemia Very common: 102 Very common: 80 (95%)(99%)

Hypoglycaemia N/A Common: 5 (6%)

Hypocalcaemia Common: 3 (3%) Common: 7 (8%)

Hypomagnesaemia Common: 4 (4%) Common: 5 (6%)

Hypokalaemia Common: 4 (4%) Very common: 9 (11%)

Anorexia Common: 9 (9%) N/A

Confusional state Common: 8 (8%) Common: 2 (2%)

Seizures (including convulsions, grand mal Common: 1 (1%) Common: 5 (6%)convulsions, status epilepticus)

Amnesia Common: 3 (3%) N/A

Somnolence Very common: 24 (23%) Common: 6 (7%)

Peripheral neurological disorders (sensory and Very common: 22 (21%) Very common: 10 (12%)motor)

Hypoesthesia Very common: 18 (17%) Common: 5 (6%)

Paraesthesia Very common: 15 (15%) Common: 3 (4%)

Ataxia Common: 9 (9%) Common: 2 (2%)

Balance disorder Common: 2 (2%) N/A

Tremor Common: 5 (5%) Common: 3 (4%)

Dizziness Very common: 22 (21%) N/A

Headache Very common: 15 (15%) Very common: 14 (17%)

Dysgeusia Common: 3 (3%) N/A

Blurred vision Common: 4(4%) N/A

Hypotension Common: 8 (8%) N/A

Pleural effusion Common: 10 (10%) N/A

Wheezing Common: 5 (5%) N/A

Dyspnoea Very common: 21 (20%) N/A

Cough Very common: 26 (25%) N/A

Diarrhoea Very common: 23 (22%) Common: 2 (2%)

Stomatitis Common: 8 (8%) Common: 1 (1%)

Vomiting Very common: 23 (22%) Common: 8 (10%)

Abdominal pain Common: 9 (9%) N/A

Constipation Very common: 22 (21%) Common: 1 (1%)

Nausea Very common: 42 (41%) Common: 2 (2%)

Hyperbilirubinaemia Common: 3 (3%) Common: 8 (10%)

Transaminases increased N/A Very common: 10(12%)

Aspartate aminotransferase increased Common: 6 (6%) N/A

Muscle weakness Common: 8 (8%) N/A

Myalgia Very common: 13 (13%) N/A

Arthralgia Common: 9 (9%) Common: 1 (1%)

Back pain Common: 8 (8%) N/A

Pain in extremity Common: 7 (7%) Common: 2 (2%)

Rhabdomyolysis, blood creatine Rare: N/A Rare: N/Aphosphokinase increased (see “Post -marketing data”)

Blood creatinine increased Common: 2 (2%) Common: 5 (6%)

Oedema Very common: 11 (11%) N/A

Gait abnormal Common: 6 (6%) N/A

Oedema peripheral Very common: 15 (15%) N/A

Pyrexia Very common: 24 (23%) Common: 2 (2%)

Pain Very common: 11 (11%) N/A

Fatigue Very common: 51 (50%) Common: 1 (1%)

Asthenia Very common: 18 (17%) Common: 5 (6%)

Infection and infestations

There was a single additional report of biopsy confirmed progressive multifocal leukoencephalopathyin the adult population.

There have been reports of sometimes fatal opportunistic infections in patients receiving nelarabinetherapy.

There have been reports of events associated with demyelination and ascending peripheralneuropathies 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 from875 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 eventsfrom ongoing studies.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

Nelarabine has been administered in clinical studies up to a dose of 75 mg/kg (approximately2,250 mg/m2) daily for 5 days to a paediatric patient, up to a dose of 60 mg/kg (approximately2,400 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 and5 every 21 days, 2 patients developed a significant grade 3 ascending sensory neuropathy. MRIevaluations of the 2 patients demonstrated findings consistent with a demyelinating process in thecervical spine.

There is no known antidote for nelarabine overdose. Supportive care consistent with good clinicalpractice should be provided.

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, purine analogues, ATC code:

L01B B 07

Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated byadenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosinekinase and deoxycytidine kinase to its 5’-monophosphate metabolite. The monophosphate metaboliteis subsequently converted to the active 5’-triphosphate form, ara-GTP. Accumulation of ara-GTP inleukaemic blasts allows for preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA)leading to inhibition of DNA synthesis. This results in cell death. Other mechanisms may contribute tothe cytotoxic effects of nelarabine. In vitro, T-cells are more sensitive than B-cells to the cytotoxiceffects of nelarabine.

Clinical efficacy and data

Adult clinical study in relapsed or refractory T-ALL and T-LBL

In an open-label study carried out by the Cancer and Leukaemia Group B and the Southwest Oncology

Group, the safety and efficacy of nelarabine were evaluated in 39 adults with T-cell acutelymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty-eight of the39 adults had relapsed or were refractory to at least two prior induction regimens and aged between 16to 65 years of age (mean 34 years). Nelarabine at a dose of 1500 mg/m2/day was administeredintravenously over two hours on days 1, 3 and 5 of a 21 day cycle. Five of the 28 patients (18 %)[95 % CI: 6 %—37 %] treated with nelarabine achieved a complete response (bone marrow blastcounts ≤ 5 %, no other evidence of disease, and full recovery of peripheral blood counts). A total of6 patients (21 %) [95 % CI: 8 %-41 %] achieved a complete response with or without haematologicalrecovery. Time to complete response in both classifications of response ranged from 2.9 to11.7 weeks. Duration of response (in both classifications of response (n=5) ranged between 15 and195+ weeks. Median overall survival was 20.6 weeks [95 % CI: 10.4-36.4]. Survival at one year was29 % [95 % CI: 12 %-45 %].

Paediatric clinical study in relapsed or refractory T-ALL and T-LBL

In an open-label, multicenter study carried out by Childrens Oncology Group, nelarabine wasadministered intravenously over 1 hour for 5 days to 151 patients ≤ 21 years of age, 149 of whom hadrelapsed or refractory T-cell acute lymphoblastic leukaemia (T-ALL) or T-cell lymphoblasticlymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior inductionregimens and 31 whom had received one prior induction regimen, were treated with 650 mg/m2/day ofnelarabine administered intravenously over 1 hour daily for 5 consecutive days repeated every21 days.

Of the 39 patients who had received two or more prior induction regimens, 5 (13 %) [95 % CI: 4 %-27 %] achieved a complete response (bone marrow blast counts ≤ 5 %, no other evidence of disease,and full recovery of peripheral blood counts) and 9 (23 %) [95 % CI: 11 %-39 %] achieved completeresponses with or without full haematological recovery. Duration of response in both classifications ofresponse ranged between 4.7 and 36.4 weeks and median overall survival was 13.1 weeks [95 % CI:8.7-17.4] and survival at one year was 14 % [95 % CI: 3 %-26 %].

Thirteen (42 %) of the 31 patients treated with one prior induction regimen achieved a completeresponse overall. Nine of these 31 patients failed to respond to prior induction (refractory patients).

Four (44 %) of the nine refractory patients experienced a complete response to nelarabine.

This medicinal product has been authorised under “exceptional circumstances”. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated byadenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosinekinase and deoxycytidine kinase to its 5’-monophosphate metabolite. The monophosphate metaboliteis subsequently converted to the active 5’-triphosphate from, ara-GTP. Accumulation of ara-GTP inleukaemic blasts allows for preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA)leading to inhibition of DNA synthesis. This results in cell death. Other mechanisms may contribute tothe cytotoxic effects of nelarabine. In vitro, T-cells are more sensitive than B-cells to the cytotoxiceffects of nelarabine.

In a cross-study analysis using data from four Phase I studies, the pharmacokinetics of nelarabine andara-G were characterized in patients aged less than 18 years and adult patients with refractoryleukaemia or lymphoma.

Plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generallyhigher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G.

After infusion of 1,500 mg/m2 nelarabine over two hours in adult patients, mean (%CV) plasmanelarabine Cmax and AUCinf values were 13.9 µM (81 %) and 13.5 µM.h (56 %) respectively. Meanplasma ara-G Cmax and AUCinf values were 115 µM (16 %) and 571 µM.h (30 %), respectively.

Intracellular Cmax for ara-GTP appeared within 3 to 25 hours on day 1. Mean (%CV) intracellular ara-

GTP Cmax and AUC values were 95.6 µM (139 %) and 2214 µM.h (263 %) at this dose.

After infusion of 400 or 650 mg/m2 nelarabine over one hour in 6 paediatric patients, mean (%CV)plasma nelarabine Cmax and AUCinf values, adjusted to a 650 mg/m2 dose, were 45.0 µM (40 %) and38.0 µM.h (39 %), respectively. Mean plasma ara-G Cmax and AUCinf values were 60.1 µM (17 %) and212 µM.h (18 %), respectively.

Nelarabine and ara-G are extensively distributed throughout the body based on combined Phase Ipharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2. Specifically, for nelarabine, mean(%CV) VSS values were 115 l/m2 (159 %) and 89.4 l/m2 (278 %) in adult and paediatric patients,respectively. For ara-G, mean VSS/F values were 44.8 l/m2 (32 %) and 32.1 l/m2 (25 %) in adult andpaediatric patients, respectively.

Nelarabine and ara-G are not substantially bound to human plasma proteins (less than 25 %) in vitro,and binding is independent of nelarabine or ara-G concentrations up to 600 µM.

No accumulation of nelarabine or ara-G was observed in plasma after nelarabine administration oneither a daily or a day 1, 3, 5 schedule.

Intracellular ara-GTP concentrations in leukaemic blasts were quantifiable for a prolonged period afternelarabine administration. Intracellular ara-GTP accumulated with repeated administration ofnelarabine. On the day 1, 3, and 5 schedule, Cmax and AUC(0-t) values on day 3 were approximately50 % and 30 %, respectively, greater than Cmax and AUC(0-t) values on day 1.

The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to formara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolysed toform methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to formxanthine, which is further oxidized to yield uric acid.

Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutesand 3 hours, respectively. These findings were demonstrated in patients with refractory leukaemia orlymphoma given a dose of 1,500 mg/m2 nelarabine (adults) or a 650 mg/m2 (paediatrics).

Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2 indicate that mean(%CV) clearance (Cl) values for nelarabine are 138 l/h/m2 (104 %) and 125 l/h/m2 (214 %) in adultand paediatric patients, respectively, on day 1 (n = 65 adults, n = 21 paediatric patients). The apparentclearance of ara-G (Cl/F) is comparable between the two groups [9.5 l/h/m2 (35 %) in adult patientsand 10.8 l/h/m2 (36 %) in paediatric patients] on day 1.

Nelarabine and ara-G are partially eliminated by the kidneys. In 28 adult patients, 24 hours afternelarabine infusion on day 1, mean urinary excretion of nelarabine and ara-G was 5.3 % and 23.2 % ofthe administered dose, respectively. Renal clearance averaged 9.0 l/h/m2 (151 %) for nelarabine and2.6 l/h/m2 (83 %) for ara-G in 21 adult patients.

Because the timecourse of intracellular ara-GTP was prolonged, its elimination half-life could not beaccurately estimated.

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

Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2 indicate that theclearance (Cl) and Vss values for nelarabine and ara-G are comparable between the two groups.

Further data with respect to nelarabine and ara-G pharmacokinetics in the paediatric population areprovided in other subsections.

Gender has no effect on nelarabine or ara-G plasma pharmacokinetics. Intracellular ara-GTP Cmax and

AUC(0-t) values at the same dose level were 2- to 3- fold greater on average in adult female than inadult male patients.

The effect of race on nelarabine and ara-G pharmacokinetics has not been specifically studied. In apharmacokinetic/pharmacodynamic cross study analysis, race had no apparent effect on nelarabine,ara-G, or intracellular ara-GTP pharmacokinetics.

The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impairedor haemodialysed patients. Nelarabine is excreted by the kidney to a small extent (5 to 10 % of theadministered dose). Ara-G is excreted by the kidney to a greater extent (20 to 30 % of theadministered nelarabine dose). Adults and children in clinical studies were categorized into the threegroups according to renal impairment: normal with Clcr greater than 80 ml/min (n = 56), mild with Clcrequalling 50 to 80 ml/min (n = 12), and moderate with Clcr less than 50 ml/min (n = 2). The meanapparent clearance (Cl/F) of ara-G was about 7 % lower in patients with mild renal impairment than inpatients with normal renal function (see section 4.2). No data are available to provide a dose advice forpatients with Clcr less than 50 ml/min.

Age has no effect on the pharmacokinetics of nelarabine or ara-G. Decreased renal function, which ismore common in the elderly, may reduce ara-G clearance (see section 4.2).

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows: nelarabine causedhistopathological changes to the central nervous system (white matter vacuolation and degenerativechanges in cerebrum, cerebellum and spinal cord) of monkeys after daily treatment with nelarabine for23 days, at exposures below the human therapeutic exposure. Nelarabine showed in vitro cytotoxicityto monocytes and macrophages.

Carcinogenicity testing of nelarabine has not been performed.

Nelarabine was mutagenic to L5178Y/TK mouse lymphoma cells with and without metabolicactivation.

Reproduction toxicity

Compared to controls, nelarabine caused increased incidences of foetal malformations, anomalies, andvariations in rabbits when given at doses approximately 24 % of the adult human dose on a mg/m2basis during the period of organogenesis. Cleft palate was seen in rabbits given a dose approximately2-fold the adult human dose, absent pollices in rabbits given a dose approximately 79 % of the adulthuman dose while absent gall bladder, accessory lung lobes, fused or extra sternebrae and delayedossification was seen at all doses. Maternal body weight gain and foetal body weights were reduced inrabbits given a dose approximately 2-fold the adult human dose.

No studies have been conducted in animals to assess the effects of nelarabine on fertility. However, noundesirable effects were seen in the testes or ovaries of monkeys given nelarabine intravenously atdoses up to approximately 32 % of the adult human dose on a mg/m2 basis for 30 consecutive days.

Sodium chloride

Water for injections

Hydrochloric acid (to adjust the pH)

Sodium hydroxide (to adjust the pH)

Not applicable.

3 years.

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

For storage conditions after first opening of the medicinal product, see section 6.3.

Clear glass (Type I) vial with a bromobutyl rubber stopper, and an aluminium seal with a red snap-offcap.

Each vial contains 50 ml of solution. Atriance is supplied in packs of 1 vial or 6 vials.

The normal procedures for proper handling and disposal of cytotoxic anti-tumour medicinal productsshould be adopted, namely:

- Staff should be trained in how to handle and transfer the medicinal product.

- Pregnant staff should be excluded from working with this medicinal product.

- Personnel handling this medicinal product during handling/transfer should wear protectiveclothing including mask, goggles and gloves.

- All items for administration or cleaning, including gloves, should be placed in high-risk, wastedisposal bags for high-temperature incineration. Any liquid waste from the preparation of thenelarabine solution for infusion may be flushed with large amounts of water.

- Accidental contact with the skin or eyes should be treated immediately with copious amounts ofwater.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sandoz Pharmaceuticals d.d.

Verovškova ulica 571000 Ljubljana

Slovenia

EU/1/07/403/001-002

Date of first authorisation: 22 August 2007

Date of latest renewal: 16 June 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu