ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Atriance 5 mg/ml solution for infusion
2.
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.
For a full list of excipients, see section 6.1.
3.
Solution for infusion.
Clear, colourless solution.
4.
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.
Posology
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 (see section 4.4).
Adults and adolescents (aged 16 years and older)
The recommended dose of nelarabine for adults is 1,500 mg/m
2
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/m
2
administered
intravenously over one hour daily for 5 consecutive days, repeated every 21 days.
2
In clinical studies, the 650 mg/m
2
and 1,500 mg/m
2
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 (see
section 5.2).
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 (see sections 4.4 and 5.2).
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 creatinine 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.
Method of administration
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 (see sections 4.4 and 4.8).
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.
3
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 (see section 4.8).
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 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 (see section 5.3).
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.
4
Contraception in males and females
Both sexually active men and women should use effective methods of contraception during treatment
and for at least three months following cessation of treatment.
Pregnancy
There are no adequate data from the use of nelarabine in pregnant women.
Studies in animals have shown reproductive toxicity including malformations (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.
Breastfeeding
It is unknown whether nelarabine or its metabolites are excreted in human breast milk. The excretion
of nelarabine in milk has not been studied in animals. However, because of the potential for serious
adverse reactions in infants, breastfeeding should be discontinued.
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.
No studies on the effects on the ability to drive and use machines have been performed.
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.
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/m
2
) and children (650 mg/m
2
) 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 (see section 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) and Very
rare (<1/10,000), not known (cannot be estimated from the available data)
Adverse events(s)
Adults (1,500 mg/m
2
)
N=103 (%)
Children (650 mg/m
2
)
N=84 (%)
5
Adverse events(s)
Adults (1,500 mg/m
2
)
N=103 (%)
Children (650 mg/m
2
)
N=84 (%)
Infections and infestations
Infection (including but not
limited to; sepsis, bacteraemia,
pneumonia, fungal infection)
Very common: 40 (39)
Very common: 13 (15)
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.
Neoplasms benign and malignant (including cysts and polyps)
Tumour lysis syndrome (see
also Data from compassionate
use programme and non-pivotal
studies)
Common: 1 (1)
N/A
Blood and lymphatic system disorders
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 (99)
Very common: 80 (95)
Metabolism and nutrition disorders
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
Psychiatric disorders
Confusional state
Common: 8 (8)
Common: 2 (2)
Nervous system disorders
Seizures (including
convulsions, grand mal
Common: 1 (1)
Common: 5 (6)
6
Adverse events(s)
Adults (1,500 mg/m
2
)
N=103 (%)
Children (650 mg/m
2
)
N=84 (%)
convulsions, status epilepticus)
Amnesia
Common: 3 (3)
N/A
Somnolence
Very common: 24 (23)
Common: 6 (7)
Peripheral neurological
disorders (sensory and motor)
Very common: 22 (21)
Very common: 10 (12)
Hypoesthesia
Very common: 18 (17)
Common: 5 (6)
Paresthesia
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
There have also been reports of events associated with demyelination and ascending peripheral
neuropathies similar in appearance to Guillain-Barré syndrome.
One subject in the paediatric group had a fatal neurological event of status epilepticus.
Eye disorders
Blurred vision
Common: 4(4)
N/A
Vascular disorders
Hypotension
Common: 8 (8)
N/A
Respiratory, thoracic, and mediastinal disorders
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
Gastrointestinal disorders
Diarrhoea
Very common: 23 (22)
Common: 2 (2)
7
Adverse events(s)
Adults (1,500 mg/m
2
)
N=103 (%)
Children (650 mg/m
2
)
N=84 (%)
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)
Hepatobiliary disorders
Hyperbilirubinaemia
Common: 3 (3)
Common: 8 (10)
Transaminases increased
N/A
Very common: 10(12)
Aspartate aminotransferase
increased
Common: 6 (6)
N/A
Musculoskeletal and connective tissue disorders
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)
Renal and urinary disorders
Blood creatinine increased
Common: 2 (2)
Common: 5 (6)
General disorders and administrative site conditions
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)
8
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)
Tumour lysis syndrome – 7 cases (see sections 4.2 and 4.4)
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/m
2
) daily for 5 days to a paediatric patient, up to a dose of 60 mg/kg (approximately
2,400 mg/m
2
) daily for 5 days to 5 adult patients and up to 2,900 mg/m
2
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/m
2
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.
5.
5.1 Pharmacodynamic properties
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
by adenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosine
kinase and deoxycytidine kinase to its 5’-monophosphate metabolite. The monophosphate metabolite
is subsequently converted to the active 5’-triphosphate form, ara-GTP. Accumulation of ara-GTP in
leukaemic 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 to
the cytotoxic effects of nelarabine.
In vitro
, T-cells are more sensitive than B-cells to the cytotoxic
effects of nelarabine.
Clinical studies
Adult studies
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 acute
lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty–eight of the 39
9
adults had relapsed or were refractory to at least two prior induction regimens and aged between 16 to
65 years of age (mean 34 years). Nelarabine at a dose of 1500 mg/m
2
/day was administered
intravenously 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 blast
counts ≤ 5 %, no other evidence of disease, and full recovery of peripheral blood counts). A total of 6
patients (21 %) [95 % CI: 8 %–41 %] achieved a complete response with or without haematological
recovery. Time to complete response in both classifications of response ranged from 2.9 to 11.7
weeks. Duration of response (in both classifications of response (n=5) ranged between 15 and 195+
weeks. Median overall survival was 20.6 weeks [95 % CI: 10.4–36.4]. Survival at one year was 29%
[95 % CI: 12 %–45 %].
Paediatric studies
In an open-label, multicenter study carried out by Childrens Oncology Group, nelarabine was
administered intravenously over 1 hour for 5 days to 151 patients ≤ 21 years of age, 149 of whom had
relapsed or refractory T-cell acute lymphoblastic leukaemia (T-ALL) or T-cell lymphoblastic
lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction
regimens and 31 whom had received one prior induction regimen, were treated with 650 mg/m
2
/day of
nelarabine administered intravenously over 1 hour daily for 5 consecutive days repeated every 21
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 complete
responses with or without full haematological recovery. Duration of response in both classifications of
response 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 complete
response 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
to the rarity of the disease it has not been possible to obtain complete information on this medicinal
product.
The European Medicines Agency will review any new information which may become available every
year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated
by adenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosine
kinase and deoxycytidine kinase to its 5’-monophosphate metabolite. The monophosphate metabolite
is subsequently converted to the active 5’-triphosphate from, ara-GTP. Accumulation of ara-GTP in
leukaemic 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 to
the cytotoxic effects of nelarabine.
In vitro
, T-cells are more sensitive than B-cells to the cytotoxic
effects of nelarabine.
In a cross-study analysis using data from four Phase I studies, the pharmacokinetics of nelarabine and
ara-G were characterized in patients aged less than 18 years and adult patients with refractory
leukaemia or lymphoma.
Absorption
Adults
10
Plasma ara-G C
max
values generally occurred at the end of the nelarabine infusion and were generally
higher than nelarabine C
max
values, suggesting rapid and extensive conversion of nelarabine to ara-G.
After infusion of 1,500 mg/m
2
nelarabine over two hours in adult patients, mean (%CV) plasma
nelarabine C
max
and AUC
inf
values were 13.9 µM (81 %) and 13.5 µM.h (56 %) respectively. Mean
plasma ara-G C
max
and AUC
inf
values were 115 µM (16 %) and 571 µM.h (30 %), respectively.
Intracellular C
max
for ara-GTP appeared within 3 to 25 hours on day 1. Mean (%CV) intracellular ara-
GTP C
max
and AUC values were 95.6 µM (139 %) and 2214 µM.h (263 %) at this dose.
Paediatric patients
After infusion of 400 or 650 mg/m
2
nelarabine over one hour in 6 paediatric patients, mean (%CV)
plasma nelarabine C
max
and AUC
inf
values, adjusted to a 650 mg/m
2
dose, were 45.0 µM (40 %) and
38.0 µM.h (39 %), respectively. Mean plasma ara-G C
max
and AUC
inf
values were 60.1 µM (17 %) and
212 µM.h (18 %), respectively.
Distribution
Nelarabine and ara-G are extensively distributed throughout the body based on combined Phase I
pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m
2
. Specifically, for nelarabine, mean
(%CV) V
SS
values were 115 l/m
2
(159 %) and 89.4 l/m
2
(278 %) in adult and paediatric patients,
respectively. For ara-G, mean V
SS
/F values were 44.8 l/m
2
(32 %) and 32.1 l/m
2
(25 %) in adult and
paediatric 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 on
either a daily or a day 1, 3, 5 schedule.
Intracellular ara-GTP concentrations in leukaemic blasts were quantifiable for a prolonged period after
nelarabine administration. Intracellular ara-GTP accumulated with repeated administration of
nelarabine. On the day 1, 3, and 5 schedule, C
max
and AUC
(0-t)
values on day 3 were approximately
50 % and 30 %, respectively, greater than C
max
and AUC
(0-t)
values on day 1.
Metabolism
The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form
ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolysed to
form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form
xanthine, which is further oxidized to yield uric acid.
Elimination
Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes
and 3 hours, respectively. These findings were demonstrated in patients with refractory leukaemia or
lymphoma given a dose of 1,500 mg/m
2
nelarabine (adults) or a 650 mg/m
2
(paediatrics).
Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m
2
indicate that mean
(%CV) clearance (Cl) values for nelarabine are 138 l/h/m
2
(104 %) and 125 l/h/m
2
(214 %) in adult
and paediatric patients, respectively, on day 1 (n = 65 adults, n = 21 paediatric patients). The apparent
clearance of ara-G (Cl/F) is comparable between the two groups [9.5 l/h/m
2
(35 %) in adult patients
and 10.8 l/h/m
2
(36 %) in paediatric patients] on day 1.
Nelarabine and ara-G are partially eliminated by the kidneys. In 28 adult patients, 24 hours after
nelarabine infusion on day 1, mean urinary excretion of nelarabine and ara-G was 5.3 % and 23.2 % of
11
the administered dose, respectively. Renal clearance averaged 9.0 l/h/m
2
(151 %) for nelarabine and
2.6 l/h/m
2
(83%) for ara-G in 21 adult patients.
Because the timecourse of intracellular ara-GTP was prolonged, its elimination half-life could not be
accurately estimated.
Children
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/m
2
indicate that the
clearance (Cl) and V
ss
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 are
provided in other subsections.
Gender
Gender has no effect on nelarabine or ara-G plasma pharmacokinetics. Intracellular ara-GTP C
max
and
AUC
(0–t)
values at the same dose level were 2– to 3– fold greater on average in adult female than in
adult male patients.
Race
The effect of race on nelarabine and ara-G pharmacokinetics has not been specifically studied. In a
pharmacokinetic/pharmacodynamic cross study analysis, race had no apparent effect on nelarabine,
ara-G, or intracellular ara-GTP pharmacokinetics.
Renal Impairment
The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired
or haemodialysed patients. Nelarabine is excreted by the kidney to a small extent (5 to 10 % of the
administered dose). Ara-G is excreted by the kidney to a greater extent (20 to 30 % of the
administered nelarabine dose). Adults and children in clinical studies were categorized into the three
groups according to renal impairment: normal with Cl
cr
greater than 80 ml/min (n = 56), mild with Cl
cr
equalling 50 to 80 ml/min (n = 12), and moderate with Cl
cr
less than 50 ml/min (n = 2). The mean
apparent clearance (Cl/F) of ara-G was about 7 % lower in patients with mild renal impairment than in
patients with normal renal function (see section 4.2). No data are available to provide a dose advice for
patients with Cl
cr
less than 50 ml/min.
Elderly
Age has no effect on the pharmacokinetics of nelarabine or ara-G. Decreased renal function, which is
more common in the elderly, may reduce ara-G clearance (see section 4.2).
5.3 Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to
clinical exposure levels and with possible relevance to clinical use were as follows: nelarabine caused
histopathological changes to the central nervous system (white matter) vacuolation and degenerative
changes in cerebrum, cerebellum and spinal cord of monkeys after treatment with nelarabine daily
during 23 days, at exposures below the human therapeutic exposure. Nelarabine showed
in vitro
cytotoxicity to monocytes and macrophages.
Carcinogenicity
Carcinogenicity testing of nelarabine has not been performed.
12
Mutagenicity
Nelarabine was mutagenic to L5178Y/TK mouse lymphoma cells with and without metabolic
activation.
Reproduction toxicity
Compared to controls, nelarabine caused increased incidences of foetal malformations, anomalies, and
variations in rabbits when given at doses approximately 24 % of the adult human dose on a mg/m
2
basis during the period of organogenesis. Cleft palate was seen in rabbits given a dose approximately
2-fold the adult human dose, absent pollices in rabbits given a dose approximately 79 % of the adult
human dose while absent gall bladder, accessory lung lobes, fused or extra sternebrae and delayed
ossification was seen at all doses. Maternal body weight gain and foetal body weights were reduced in
rabbits given a dose approximately 2-fold the adult human dose.
Fertility
No studies have been conducted in animals to assess the effects of nelarabine on fertility. However, no
undesirable effects were seen in the testes or ovaries of monkeys given nelarabine intravenously at
doses up to approximately 32 % of the adult human dose on a mg/m
2
basis for 30 consecutive days.
6.
6.1 List of excipients
Sodium chloride
Water for injections
Hydrochloric acid (to adjust the pH)
Sodium hydroxide (to adjust the pH)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
Atriance is stable for up to 8 hours at up to 30°C once the vial is opened.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Clear glass (Type I) vials with a non-latex bromobutyl rubber stopper, sealed with an aluminium cap.
Each vial contains 50 ml. Atriance is supplied in packs of 6 vials.
6.6 Special precautions for disposal
The normal procedures for proper handling and disposal of anti-tumour medicinal products should be
adopted, namely:
— Staff should be trained in how to handle and transfer the medicinal product.
13
— Pregnant staff should be excluded from working with this medicinal product.
— Personnel handling this medicinal product during handling/transfer should wear protective clothing
including mask, goggles and gloves.
— All items for administration or cleaning, including gloves, should be placed in high-risk, waste
disposal bags for high-temperature incineration. Liquid waste may be flushed with large amounts of
water.
— Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
8.
EU/1/07/403/001
9.
22/08/2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
14
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
C.
15
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Glaxo Operations UK Ltd.
Harmire Road
Barnard Castle
Durham, DL12 8DT
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.2 presented in
Module 1.8.1. of the Marketing Authorisation, is in place and functioning before and whilst the
product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
Clinical aspects
16
1.
The Applicant has committed to provide data from an on-going COG study AALL0434. Final
data will be submitted when available (anticipated 2016).
2.
The Applicant has committed to provide data from a Post-Marketing Surveillance Study for
Atriance in the indicated patient population under 21 years of age receiving the 650mg/m
2
dose
of nelarabine. Annual reports will be submitted as part of annual reassessment of the Marketing
Authorisation issued under exceptional circumstances. A study synopsis will be submitted
within 6 months of study completion (anticipated 2012).
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Atriance 5 mg/ml solution for infusion
Nelarabine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 5 mg of nelarabine.
3.
LIST OF EXCIPIENTS
Excipients: Sodium chloride, water for injections, hydrochloric acid/sodium hydroxide.
4.
Solution for infusion
6 x 50 ml vials
250 mg/50 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
20
9.
SPECIAL STORAGE CONDITIONS
Stable for up to 8 hours at up to 30ºC once the vial is opened.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.
EU/1/07/403/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
21
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL LABEL
1.
Atriance 5 mg/ml solution for infusion
Nelarabine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 5 mg of nelarabine.
3.
LIST OF EXCIPIENTS
Excipients: Sodium chloride, water for injections, hydrochloric acid/sodium hydroxide.
4.
Solution for infusion
250 mg/50 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
22
Stable for up to 8 hours at up to 30ºC once the vial is opened.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.
EU/1/07/403/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
23
B. PACKAGE LEAFLET
24
PACKAGE LEAFLET: INFORMATION FOR THE USER
Atriance 5 mg/ml solution for infusion
Nelarabine
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Atriance is and what it is used for
2. Before you are given Atriance
3. How Atriance is given
4. Possible side effects
5.
How to store Atriance
6.
Further information
1.
WHAT ATRIANCE IS AND WHAT IT IS USED FOR
Atriance belongs to a group of medicines used to treat some types of cancer.
Atriance is used to treat patients with:
•
a type of leukaemia, called T-cell acute lymphoblastic leukaemia. Leukaemia causes an
abnormal increase in the number of white blood cells in the body, and sometimes also the blood.
The type of leukaemia relates to the type of white blood cell mainly involved. In this case, its
cells called lymphoblasts.
•
a type of lymphoma, called T-cell lymphoblastic lymphoma. This lymphoma is caused by a
mass of lymphoblasts, a type of white blood cell.
If you have any questions about your illness, talk to your doctor.
2.
BEFORE YOU ARE GIVEN ATRIANCE
You (or your child, if he/she is being treated) must not receive Atriance
•
if you (or your child, if he/she is being treated) are allergic (hypersensitive) to nelarabine or any
of the other ingredients of Atriance.
Take special care with Atriance
Severe neurological side effects have been reported with the use of Atriance. Symptoms have included
altered mental states (e.g. tiredness), effects on your nervous system (e.g. convulsions, feelings of
numbness or tingling, weakness and paralysis).
Your doctor will check for these symptoms
regularly (see also “Possible side effects").
Your doctor also needs to know the following before you are given this medicine:
•
if you (or your child, if he/she is being treated) have any kidney or liver problems
. Your
dose of Atriance may need to be adjusted
25
•
if you (or your child, if he/she is being treated) have recently been, or plan to be vaccinated
with a live vaccine (for example Polio, Varicella, Typhoid)
Tell your doctor if any of these apply to you.
Using other medicines
Tell your doctor if you are taking any other medicines
, or have recently taken any. This includes
any herbal products or medicines you have bought without a prescription
Remember to tell your doctor if you start to take any other medicines while you are on Atriance.
Pregnancy and breast-feeding
Atriance is not recommended for pregnant women. It may harm a baby if conceived before, during or
soon after treatment. Consideration to appropriate birth control is recommended to be discussed with
your doctor. Do not try and become pregnant/father a child until your doctor advises you it is safe to
do so.
Male patients, who may wish to father a child, should ask their doctor for family planning advice or
treatment. If pregnancy occurs during treatment with Atriance, you must tell your doctor immediately.
It is not known whether Atriance is passed on through breast milk. Breast-feeding must be
discontinued while you are taking Atriance. Ask your doctor for advice before taking any medicine.
See "Take special Care with Atriance".
Driving and using machines
Atriance can make people feel drowsy or sleepy, both during and for some days after treatment. If you
feel tired or weak, do not drive, and do not use any tools or machines.
Important information about some of the ingredients of Atriance
This medicine contains at least 23 mg sodium per dose. To be taken into consideration by patients on a
controlled sodium diet.
3.
HOW ATRIANCE IS GIVEN
The dose of Atriance you are given will be based on:
•
your/your child's (if he/she is being treated) body surface area
(which will be calculated by
your doctor based on your height and weight).
•
the results of blood tests
carried out before treatment
Adults and adolescents (aged 16 years and older)
The usual dose
is 1,500 mg/m
2
of body surface area per day.
A doctor or nurse
will give you a suitable dose of Atriance as an infusion (a drip). It is usually
dripped into your arm over a period of about 2 hours.
You will have an infusion (a drip) once a day on days 1, 3 and 5 of treatment
. This pattern of
treatment will normally be repeated every three weeks. This treatment may vary, depending on the
results of your regular blood tests.
Children and adolescents (aged 21 years and younger)
The usual dose
is 650 mg/m
2
of body surface area per day.
26
A doctor or nurse
will give you/your child (if he/she is being treated) a suitable dose of Atriance as
an
infusion
(a drip). It is usually dripped into your arm over a period of about 1 hour.
You/your child (if he/she is being treated) will have an infusion (a drip) once a day for 5 days
.
This pattern of treatment will normally be repeated every three weeks. This treatment may vary,
depending on the results of regular blood tests.
Stopping treatment with Atriance
Your doctor will decide when to stop the treatment.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Atriance can cause side effects, although not everybody gets them.
The majority of side effects reported with Atriance were seen in adults, children and adolescents.
Some of the side effects were reported more often in adult patients. There is no known reason for this.
If you have any concerns, discuss them with your doctor.
Very Common side effects
These may affect
more than 1 in 10 people
treated with Atriance.
•
Signs of infection
. Atriance may reduce the number of white blood cells and lower your
resistance to infection (including pneumonia). This can even be life threatening. Signs of an
infection include:
- fever
- serious deterioration of your general condition
- local symptoms such as sore throat, sore mouth or urinary problems (for example, a burning
sensation when urinating, which may be a urinary infection)
Tell your doctor immediately
if you get any of these. A blood test will be taken to check possible
reduction of white blood cells.
Other very common side effects
•
Changes in the sense of feeling in hands or feet, muscle weakness appearing as difficulty getting
up from a chair, or difficulty walking (
peripheral neuropathy
); reduced sensitivity to light
touch, or pain; abnormal sensations such as burning and, prickling, a sensation of something
crawling on the skin.
•
Feeling generally weak and tired (
temporary anaemia
). In some cases you may need a blood
transfusion.
•
Unusual bruising or bleeding, caused by a decrease in the number of clotting cells in the blood.
This can lead to severe bleeding from relatively small injuries such as a small cut. Rarely, it can
lead to even more severe bleeding (
haemorrhage
). Talk to your doctor for advice on how to
minimize the risk of bleeding.
•
Feeling drowsy and sleepy; headache; dizziness.
•
shortness of breath, difficult or laboured breathing; cough.
•
Feeling of an upset stomach (
nausea
); being sick/throwing up (
vomiting
); diarrhoea;
constipation
•
Muscle pain.
•
Swelling of parts of the body due to accumulation of abnormal amounts of fluid (
oedema
).
•
High body temperature (
fever
); tiredness; feeling weak/loss of strength.
27
Tell a doctor
if any of these becomes troublesome.
Common side effects
These may affect
up to 1 in 10 people
treated with Atriance:
•
Violent, uncontrollable muscular contractions often accompanied by unconsciousness that can
be due to an epileptic attack (
seizures
).
•
Clumsiness and lack of coordination affecting balance, walking, limb or eye movements, or
speech.
•
Unintentional rhythmic shaking of one or more limbs (
tremors
).
•
Muscle weakness (possibly associated with
peripheral neuropathy
– see above), joint pain, back
pain; pains in hands and feet including a sensation of pins and needles sensation and numbness.
•
Lowered blood pressure.
•
Weight loss and loss of appetite (
anorexia
); stomach pains; sore mouth, mouth ulcers or
inflammation.
•
Problems with memory, feeling disoriented; blurred vision; altered or loss of sense of taste
(
dysgeusia
).
•
Build up of fluid around the lungs leading to chest pain and difficulty in breathing (
pleural
effusion
); wheezing
•
Increased amounts of bilirubin in your blood, which may cause yellowing of the skin and may
make you feel lethargic.
•
Increases in blood levels of liver enzymes.
•
Increases in blood creatinine levels (a sign of kidney problems, which might lead less frequent
urination).
•
The release of tumour cell contents (
tumour lysis syndrome
), which may put extra stress on your
body. Initial symptoms including nausea and vomiting, shortness of breath, an irregular
heartbeat, clouding of urine, lethargy and/or joint discomfort. If this does occur, it is most likely
to occur at the first dose. Your doctor will take appropriate precautions to minimise the risk of
this.
•
Low blood levels of some substances:
— low calcium levels, which may cause muscle cramps, abdominal cramps or spasms
— low magnesium levels, which may cause muscle weakness, confusion, "jerky" movements,
high blood pressure, irregular heart rhythms and decreased reflexes with severely low blood
magnesium levels.
— low potassium levels may cause a feeling of weakness
— low glucose levels, which may cause nausea, sweating, weakness, faintness, confusion or
hallucinations.
Tell a doctor
if any of these becomes troublesome.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ATRIANCE
Keep out of the reach and sight of children.
Do not use Atriance after the expiry date which is stated on carton and vial.
This medicinal product does not require any special storage conditions.
Atriance is stable for up to 8 hours at up to 30°C once the vial is opened.
28
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Atriance contains
•
The active substance of Atriance is nelarabine. Each ml of Atriance solution for infusion
contains 5 mg of nelarabine. Each vial contains 250 mg of nelarabine.
•
The other ingredients are sodium chloride, water for injections, hydrochloric acid/sodium
hydroxide
What Atriance looks like and contents of the pack
Atriance solution for infusion is a clear, colourless solution. It is provided in clear glass vials with a
non-latex containing rubber stopper and sealed with an aluminium cap.
Each vial contains 50 ml.
Atriance is supplied in packs of 6 vials.
Marketing Authorisation Holder
Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.
Manufacturer
Glaxo Operations UK Limited (trading as Glaxo Wellcome Operations): Harmire Road, Barnard
Castle, County Durham DL12 8DT, United Kingdom.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
info@glaxosmithkline.dk
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
29
Eesti
GlaxoSmithKline Eesti OU
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z.o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos
Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Tel: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline (Cyprus) Ltd
Τηλ: + 357 22 89 95 01
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)31 67 09 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
{MM/YYYY}
This medicine has been authorised under “exceptional circumstances”.
30
This means that because of the rarity of this disease it has been impossible to get complete information
on this medicine.
The European Medicines Agency will review any new information on the medicine every year and
this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
. There are also links to other websites about rare diseases and treatments.
The following information is intended for medical or healthcare professionals only:
INSTRUCTIONS ON HOW TO STORE AND DISPOSE OF ATRIANCE
Storage of Atriance solution for infusion
This medicinal product does not require any special storage conditions.
Atriance is stable for up to 8 hours at up to 30ºC once the vial is opened.
Instructions for handling and disposal of Atriance
The normal procedures for proper handling and disposal of anti-tumour medicinal products should 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 protective
clothing including mask, goggles and gloves.
•
All items for administration or cleaning, including gloves, should be placed in high-risk, waste
disposal bags for high-temperature incineration. Liquid waste may be flushed with large
amounts of water.
•
Accidental contact with the skin or eyes should be treated immediately with copious amounts of
water.
31
Source: European Medicines Agency
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