ATRIANCE 5 MGML

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
NELARABINE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
L01BB
Pharmaceutical form:
SOLUTION FOR INFUSION
Composition:
NELARABINE 5 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
GLAXO OPERATIONS (UK) LIMITED
Therapeutic group:
PURINE ANALOGUES
Therapeutic indications:
Atriance 5 mg/ml 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.
Authorization number:
137 71 31525 00
Authorization date:
2012-12-31

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

:

30.05.2013

םש

רישכת

תילגנאב

רפסמו

םושירה

:

Atriance 5mg/ml (137-71-31525)

םש

לעב

םושירה

GlaxoSmithKline (ISRAEL) Ltd

:

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

אפורל ןולעב אפורל ןולעב תורמחהה

תושקובמה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Adverse events

------

Post – Marketing Data

Rare: Rhabdomyolysis, blood creatine

phosphokinase increased

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

םודאב

.

םייוניש

םניאש

רדגב

תורמחה

ונמוס

)ןולעב( עבצב

.קורי רבעוה

ראודב

ינורטקלא

ךיראתב

30.05.2013

Atriance

®

5 mg/ml

1.

NAME OF THE MEDICINAL PRODUCT

Atriance

®

5 mg/ml

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 5 mg of nelarabine.

Each vial contains 250 mg of nelarabine.

Excipient with known effect

Each ml of solution contains 1.725 mg (75 micromols) of sodium.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for infusion.

Clear, colourless solution.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Atriance 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.

4.2 Posology and method of administration

Nelarabine must only be administered under the supervision of a

physician experienced in the use of cytotoxic agents.

Posology

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 is 1,500 mg/m

administered intravenously over two

hours on days 1, 3 and 5 and repeated every 21 days.

Children and adolescents (aged 21 years and younger)

The recommended dose of nelarabine for children and adolescents

(aged 21 years and younger) is 650 mg/m

administered intravenously

over one hour daily for 5 consecutive days, repeated every 21 days.

In clinical studies, the 650 mg/m

and 1,500 mg/m

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.

Special populations

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). There are insufficient data to support

a dose adjustment recommendation for patients with a renal clearance

of creatinine Cl

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 for intravenous use only and 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

listed in section 6.1.

4.4 Special warnings and precautions for use

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.

4.5 Interaction with other medicinal products and other

forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile

The safety profile from pivotal clinical studies at the recommended doses

of nelarabine in adults (1,500 mg/m

) and children (650 mg/m

) 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)

Adverse reactions

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%)

Neoplasms benign, malignant and unspecified (including cysts

and polyps)

Tumour lysis

syndrome (see

also data from

compassionate use

programme and

non-pivotal studies)

Common: 1 (1%)

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

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%)

Psychiatric disorders

Confusional state

Common: 8 (8%)

Common: 2 (2%)

Nervous system disorders

Seizures (including

convulsions, grand

mal convulsions,

status epilepticus)

Common: 1 (1%)

Common: 5 (6%)

Amnesia

Common: 3 (3%)

Adverse reactions

Adults

(1,500 mg/m

2

)

N=103

Children

(650 mg/m

2

)

N=84

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%)

Paraesthesia

Very common: 15

(15%)

Common: 3 (4%)

Ataxia

Common: 9 (9%)

Common: 2 (2%)

Balance disorder

Common: 2 (2%)

Tremor

Common: 5 (5%)

Common: 3 (4%)

Dizziness

Very common: 22

(21%)

Headache

Very common: 15

(15%)

Very common: 14

(17%)

Dysgeusia

Common: 3 (3%)

Eye disorders

Blurred vision

Common: 4 (4%)

Vascular disorders

Hypotension

Common: 8 (8%)

Respiratory, thoracic and mediastinal disorders

Pleural effusion

Common: 10 (10%)

Wheezing

Common: 5 (5%)

Dyspnoea

Very common: 21

(20%)

Cough

Very common: 26

(25%)

Gastrointestinal disorders

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%)

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

Very common: 10

(12%)

Aspartate

aminotransferase

increased

Common: 6 (6%)

Musculoskeletal and connective tissue disorders

Muscle weakness

Common: 8 (8%)

Myalgia

Very common: 13

(13%)

Arthralgia

Common: 9 (9%)

Common: 1 (1%)

Back pain

Common: 8 (8%)

Pain in extremity

Common: 7 (7%)

Common: 2 (2%)

Rhabdomyolysis,

blood creatine

phosphokinase

increased (see

“Post-marketing

data”)

Rare: N/A

Rare: N/A

Renal and urinary disorders

Blood creatinine

increased

Common: 2 (2%)

Common: 5 (6%)

Atriance - ATR API 30MAR20 - P4

Adverse reactions

Adults

(1,500 mg/m

2

)

N=103

Children

(650 mg/m

2

)

N=84

General disorders and administration site conditions

Oedema

Very common: 11

(11%)

Gait abnormal

Common: 6 (6%)

Oedema peripheral

Very common: 15

(15%)

Pyrexia

Very common: 24

(23%)

Common: 2 (2%)

Pain

Very common: 11

(11%)

Fatigue

Very common: 51

(50%)

Common: 1 (1%)

Asthenia

Very common: 18

(17%)

Common: 5 (6%)

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 suspected adverse reactions after authorisation of the

medicinal product is important. It allows continued monitoring of the

benefit/risk balance of the medicinal product. Any suspected adverse

events should be reported to the Ministry of Health according to the

National Regulation by using an online form

(https://sideeffects.health.gov.il/).

4.9 Overdose

No case of overdose has been reported.

Nelarabine has been administered in clinical studies up to a dose of

75 mg/kg (approximately 2,250 mg/m

) daily for 5 days to a paediatric

patient, up to a dose of 60 mg/kg (approximately 2,400 mg/m

) daily for

5 days to 5 adult patients and up to 2,900 mg/m

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

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.

PHARMACOLOGICAL PROPERTIES

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 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 acute lymphoblastic

leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty-eight

of the 39 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

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

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

/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.

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 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.

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

Plasma ara-G C

values generally occurred at the end of the nelarabine

infusion and were generally higher than nelarabine C

values,

suggesting rapid and extensive conversion of nelarabine to ara-G.

After infusion of 1,500 mg/m

nelarabine over two hours in adult patients,

mean (%CV) plasma nelarabine C

and AUC

values were 13.9 µM

(81%) and 13.5 µM.h (56%) respectively. Mean plasma ara-G C

values were 115 µM (16%) and 571 µM.h (30%), respectively.

Intracellular C

for ara-GTP appeared within 3 to 25 hours on day 1.

Mean (%CV) intracellular ara-GTP C

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

nelarabine over one hour in 6

paediatric patients, mean (%CV) plasma nelarabine C

and AUC

values, adjusted to a 650 mg/m

dose, were 45.0 µM (40%) and 38.0

µM.h (39%), respectively. Mean plasma ara-G C

and AUC

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

. Specifically, for nelarabine, mean (%CV) V

values were 115 l/m

(159%) and 89.4 l/m

(278%) in adult and paediatric

patients, respectively. For ara-G, mean V

/F values were 44.8 l/m

(32%) and 32.1 l/m

(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

and AUC

(0-t)

values on day 3

were approximately 50% and 30%, respectively, greater than C

(0-t)

values on day 1.

Biotransformation

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

nelarabine (adults) or a 650

mg/m

(paediatrics).

Combined Phase 1 pharmacokinetic data at nelarabine doses of 104

to 2,900 mg/m

indicate that mean (%CV) clearance (Cl) values for

nelarabine are 138 l/h/m

(104%) and 125 l/h/m

(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

(35%) in adult patients and 10.8 l/h/m

(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 the

administered dose, respectively. Renal clearance averaged 9.0 l/h/m

(151%) for nelarabine and 2.6 l/h/m

(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.

Paediatric population

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

indicate that the clearance (Cl) and V

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

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

greater than 80 ml/min (n = 56), mild with

equalling 50 to 80 ml/min (n = 12), and moderate with Cl

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

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 daily treatment with nelarabine for

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.

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

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

basis

for 30 consecutive days.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Water for injection

Hydrochloric acid (to adjust pH)

Sodium hydroxide (to adjust pH)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The expiry date of the product is indicated on the label and packaging.

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

6.4 Special precautions for storage

Store below 30°C. For storage conditions after first opening of the

medicinal product see section 6.3.

6.5 Nature and contents of container

Clear glass (Type I) vial with a rubber stopper, sealed with a cap.

Each vial contains 50 ml of solution. Atriance is supplied in packs of

6 vials.

6.6 Special precautions for disposal and other handling

The normal procedures for proper handling and disposal of cytotoxic

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. Any liquid waste from the preparation of the nelarabine

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 of water.

Any unused medicinal product or waste material should be disposed

of in accordance with local requirements.

7.

MANUFACTURER

Glaxo Operations (UK) Limited

Barnard Castle, UK

8.

REGISTRATION HOLDER

Novartis Israel Ltd.

36 Shacham St., Petach-Tikva.

9.

REGISTRATION NUMBER

137 71 31525

This leaflet format has been determined by the Ministry of Health and

the content thereof has been checked and approved in May 2013 and

was updated according to the guidelines of the Ministry of Health in

December 2019

ATR API 30MAR20

.מ"עב לארשי סיטרבונ

P.O.B 7126

ביבא לת ,

:ןופלט

03-9201111

:סקפ

03-9229230

Page 1 of 2

Novartis Israel Ltd.

P.O.B 7126, TEL AVIV

Tel: 972-3-9201111 Fax: 972-3-9229230

רבמצד

2019

/דבכנ ה/אפור חקור ,ה

/

,ה/דבכנ ת

ןודנה

mg/ml, Solution for infusion

5

triance

A

תה ושר ןודנבש רישכ

יוותהל לארשיב תו

אבה תו

Atriance 5 mg/ml 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.

:ליעפה ביכרמה

5 mg/ml

Nelarabine

לע םכעידוהל וננוצרב

ה ןוכדיע רישכתה לש אפורל ןולע

ןודנב

:

עדימ

ףסוותהש

שגדומ

וקב

ותחת

עדימ

קחמנש

ןמוסמ

וקב

הצוח

תורמחה

בוהצב תושגדומ

קרפ ןוכדע

Fertility, pregnancy and lactation

.מ"עב לארשי סיטרבונ

P.O.B 7126

ביבא לת ,

:ןופלט

03-9201111

:סקפ

03-9229230

Page 2 of 2

Novartis Israel Ltd.

P.O.B 7126, TEL AVIV

Tel: 972-3-9201111 Fax: 972-3-9229230

................

קרפ ןוכדע

ffects on ability to drive and use machines

קרפ ןוכדע

ndesirable effects

................

................

ולעה

אפורל

ללוכ

ייוניש םיפסונ םייוניש / הכירע

.תורמחה םניאש

ולעה

חלשנ

לבקל ןתינו ,תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל

ספדומ

לע

לעבל הינפ ידי

םושירה

,הכרבב

שולא ידע

הנוממ תחקור

Similar products

Search alerts related to this product

View documents history

Share this information