Atriance 5 mg/ml solution for infusion

Inserted PF number in Title

7.       MARKETING AUTHORISATION HOLDER

Atriance 5 mg/ml solution for infusion

EMEA/H/C/752/IAIN/20 - to add black triangle

Summary of changes for the SUMMARY OF PRODUCT CHARACTERISTICS

Addition of the black triangle at the top of the SPC:

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Addition of the following paragraph to section 4.8:

Reporting of suspected adverse reactions

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

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Summary of changes the for PACKAGE LEAFLET

An update to the following paragraph in section 4. Possible side effects

Addition of the black triangle at the top of the SPC:

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Update to the opening paragraph:

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

-              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 only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

-              If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effect not listed in this leaflet. See section 4.

Addition of the following paragraph to section 4:

Reporting of side effects

If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below).  By reporting side effects you can help provide more information on the safety of this medicine.

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6767836

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

SPC updates:

Update to Section 7. MARKETING AUTHORISATION HOLDER

From:

Glaxo Group Limited,

Berkeley Avenue,

Greenford,

Middlesex

UB6 0NN,

United Kingdom

To:

Glaxo Group Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 5 mg of nelarabine.

Each vial contains 250 mg of nelarabine.

Excipient(s) with known effect:

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

4.2         Posology and method of administration

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

Method of administration

Nelarabine is must not be diluted prior to administration. The appropriate dose of nelarabine is 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.

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

4.4     Special warnings and precautions for use

4.8         Undesirable effects

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.

One subject in the paediatric group had a fatal neurological event of status epilepticus.

6.5     Nature and contents of container

Clear glass (Type I) vials with a non-latex bromobutyl rubber stopper, sealed with an aluminium cap.

6.6     Special precautions for disposal and other handling

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

1.         NAME OF THE MEDICINAL PRODUCT

Atriance 5 mg/ml solution for infusion

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4.         CLINICAL PARTICULARS

4.2                  Posology and method of administration

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 hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered (see section 4.4).

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). Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, 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/m² administered intravenously over two hours on days 1, 3 and 5 and repeated every 21 days.

Paediatric population

Children and adolescents (aged 21 years and younger)

The recommended dose of nelarabine for children is 650 mg/m² administered intravenously over one hour daily for 5 consecutive days, repeated every 21 days.

In clinical studies, the 650 mg/m² and 1,500 mg/m² dose have both been used in patients in the age range 16 to 21 years. Efficacy and safety were similar for both regimens. The prescribing physician should consider which regimen is appropriate when treating patients in this age range. Limited clinical pharmacology data are available for patients below the age of 4 years (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 creatinin 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).

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4.4                  Special warnings and precautions for use

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.

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4.6                  Fertility, Ppregnancy and lactation

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

Both sexually active men and women should use effective methods of contraception during treatment and for at least three months following cessation of treatment.

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.

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.

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4.8                  Undesirable effects

Clinical trial data

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5.         PHARMACOLOGICAL PROPERTIES

5.1                  Pharmacodynamic properties

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 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/m²/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%].

The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

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10.       DATE OF REVISION OF THE TEXT

19 November 200829 November 2010

Detailed information on this medicinal product is available on the website of the European Medicine Agency (EMEA) http://www.emea.europa.eu/

4.2              Posology and method of administration

The following text has been added: 

Nelaarbine 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.