PACKAGE LEAFLET: INFORMATION FOR HEALTHCARE PROFESSIONAL

1    NAME OF THE MEDICINAL PRODUCT

METASTRON 37 MBq/ml solution for injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Strontium-89 chloride: 37 MBq/ml

A solution of the active ingredient strontium-89 chloride (150 MBq) in 4ml water.

Strontium-89 is a pure beta emitter with an energy of 1.492 MeV and a half-life of 50.5 days.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metastron is indicated as an adjunct to and as an alternative to external beam radiotherapy for the palliation of pain from bone metastases secondary to prostatic carcinoma at the stage of hormone therapy failure.

4.2    Posology and method of administration

Posology

Adults

Metastron is an aqueous solution for intravenous injection and should be used without dilution. The recommended dose is 150 MBq (4 mCi) per injection, based on the average patient weight of 70kg. Alternatively in particularly heavy or light framed patients a dose of 2 MBq (55 pCi)/kg 'fat-free' body weight may be used. This dosage is suitable for the elderly. Repeat administrations should not be performed within 3 months of the previous Metastron injection. Further administrations are not indicated in patients who have not responded to a previous administration of Metastron.

Elderly Population

No dose adjustment is recommended based on age.

Renal impairment

Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients.

Paediatric population

The product is not for administration to children.

Method of administration

Metastron is for single use only. (For repeat use after several weeks see section 4.4)

The instructions for preparation of radiopharmaceuticals are given in section 12.

For patient preparation, see section 4.4.

4.3    Contraindications

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

Code Reads

Metastron should not be used as a primary treatment for cord compression secondary to spinal metastases where more rapid treatment may be necessary.

Use of the product in patients with evidence of seriously compromised bone marrow, particularly low neutrophil and platelet counts, is not recommended unless the potential benefit of the treatment is considered to outweigh the risk.

4.4 Special warnings and precautions for use Individual benefit/risk justification:

For each patient, exposure to ionising radiation must be justifiable on the basis of likely benefit. The activity administered must be such that the resulting radiation dose is as low as reasonably achievable bearing in mind the need to obtain the intended therapeutic result.

Renal impairment:

Careful consideration of the benefit risk ratio in patients with renal impairment is required since an increased radiation exposure is possible.

Paediatric population:

For information on the use in paediatric population, see section 4.2.

Patient preparation:

The patient should be well hydrated before the start of the examination and urged to void as often as possible during the first hours after the examination in order to reduce radiation. Special precautions, such as urinary catheterisation, should be taken following administration of Metastron to patients who are significantly incontinent to minimise risks of radioactive contamination. International guidelines for disposal of radioactive waste must be followed.

Specific warnings:

Use of the product in patients with evidence of seriously compromised bone marrow, particularly low neutrophil and platelet counts, is not recommended unless the potential benefit of the treatment is considered to outweigh the risk. The following values can be considered in general: Leukocytes >3000/pl, platelets >100,000/pl and haemoglobin (Hb) >90 g/l.

It is recommended that the haematology of patients should be monitored. In considering repeat administration of Metastron the patient's haematological response to his initial dose, current platelet levels and any other evidence of marrow depletion should all be carefully considered.

A cytotoxic agent may be administered to a patient who has previously received Metastron provided that haematological parameters are stable and within the normal range. An interval of 12 weeks is recommended between administrations of the two therapies.

Therapy with Metastron is inappropriate for patients with a life expectancy less than 4 weeks. Considering the latency in the onset of the palliative effect, is more beneficial in patients with a relatively long life expectancy.

It should be taken into account in patient management that the expected time of onset of pain relief is 10 to 20 days following Metastron administration. Retention of 89Sr in metastatic bone lesions is probably 90 days or more and thus significantly prolonged compared with retention in normal bone tissue. Care should be exercised in the pre-treatment assessment of the haematological status of patients who, for the same cause, have previously received extensive bone radiation and/or another injectable bone-seeking isotope.

It is important that information concerning this treatment and the associated safety precautions are given to the patient, relatives and hospital staff.

For precautions with respect to environmental hazard see section 6.6.

A calcium-like flushing sensation has been observed in patients following a rapid (less than 30 second injection) administration.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free.

4.5    Interactions with other medicinal products and other forms of interaction

Calcium therapy should be discontinued at least two weeks before Metastron administration.

4.6    Fertility, pregnancy and lactation

Not relevant due to indication.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8    Undesirable effects

The frequencies of undesirable effects are defined as follows:

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)

Blood and lymphatic system disorders

Very common: Bone marrow depression, including serious thrombocytopenia, serious leukopenia, reduced haemoglobin or low red blood cell count (see section 4.4).

Vascular disorders

Common: Flushing.

General disorders and administration site conditions

Very common: Pain exacerbated (transient).

Adverse effects may include an exacerbation of pain within the first few days of administration. In clinical trials this effect was temporary and controlled with analgesics. Some degree of haematological toxicity, including thrombocytopenia and leucopenia, is to be expected following administration of Metastron. Typically platelets will be depressed by about 30% (95% confidence limits 10-55%) compared to pre-administration levels. Because of the natural progress of their disease, more severe depression of platelet levels may be observed in some patients.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects.

The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations.

In all cases it is necessary to ensure that the risks of the radiation are less than from the disease itself. The effective dose is 465 mSv when the maximal recommended activity of 150 MBq is administered.

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:

United Kingdom:

Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

Kunpo^/ Cyprus

OappaKEUTLKeq Ynripeareq YnoupYsro YYeraq CY-1475 AeuKwora Oa^: + 357 22608649 laTOTonoq: www.moh.gov.cy/phs

Ceska republika

Statni ustav pro kontrolu leciv Srobarova 48 100 41 Praha 10

Webove stranky: www.sukl.cz/nahlasit-nezadouci-ucinek Magyarorszag/ Hungary :

Orszagos Gyogyszereszeti es Elelmezes-egeszsegugyi Intezet Postafiok 450 H-1372 Budapest Honlap: www.ogyei.gov.hu

EXXaSa/ Greece:

EGvLKoq OpYavrapoq OappaKwv MeaoYsrwv 284 GR-15562 XoXapYoq, A0r|va TqX: + 30 21 32040380/337 Oa^: + 30 21 06549585 laTOTonoq: http://www.eof.gr

Norge/ Norway:

Statens legemiddelverk

Nettside:http://www. legemiddelverket.no/meldeskjema Romania/ Romania:

Agentia Nationala a Medicamentului §i a Dispozitivelor Medicale

Str. Aviator Sanatescu nr. 48, sector 1

Bucurejti 011478- RO

Tel: + 4 0757 117 259

Fax: +4 0213 163 497

e-mail: adr@anm.ro

Slovenska republika

Statny ustav pre kontrolu lieciv

Sekcia klinickeho skusania liekov a farmakovigilancie

Kvetna 11

SK-825 08 Bratislava 26 Tel: + 421 2 507 01 206 Fax: + 421 2 507 01 237

internetova stranka: http://www.sukl.sk/sk/bezpecnost-liekov e-mail: neziaduce.ucinky@sukl.sk

4.9 Overdose

Not applicable.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: therapeutic radiopharmaceuticals, pain palliation (bone seeking agents) strontium (⁸⁹Sr) chloride ATC code: V10BX01

- Measure bar should be 150mm at 100% scale -

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Metastron - SMS2P - Technical Leaflet

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The chemical properties of strontium enable it to imitate calcium in vivo, rapidly localising in proliferating bone. Strontium-89 is a beta emitter (100%), with a physical half-life of 50.5 days. The range of B-particles in tissue is 0.8 cm.

5.2    Pharmacokinetic properties Distribution

The extent of uptake and retention of strontium-89 will depend on the metastatic involvement of the skeleton.

Organ uptake

The longer retention of strontium-89 in metastatic lesions enables the isotope to deliver a larger radiation dose to metastases whilst delivering a relatively small dose to bone marrow.

Elimination

Strontium which is not localised in the skeleton is excreted mainly via the urine with a small amount via the faeces.

Half-life

Strontium is retained in lesions with a long biological half life compared to the physical half-life of strontium-89, whilst strontium taken up into normal bone exhibits a half life of about 14 days.

Renal/hepatic impairment

The pharmacokinetics in patients with renal or hepatic impairment has not been characterised.

5.3    Preclinical safety data

The chemical toxicity of non-radioactive strontium chloride is well documented and of little consequence, particularly in terms of the risk/benefit to the patient for whom this product is intended.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Strontium chloride Water for injections Ph.Eur.

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life

The shelf life of the product is 28 days post the radioactivity reference date.

6.4    Special precautions for storage

Store below 25^oC. Do not refrigerate or freeze.

Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials.

6.5    Nature and contents of container

The product is supplied in a neutral glass vial as an aqueous solution. The vial is sealed with a PTFE coated rubber closure and metal overseal and is individually packed. Each vial is packed within a radiation shielding container of lead metal.

Pack size: a single 150 MBq vial.

6.6    Special precautions for disposal and other handling General warning

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage,

use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

If at any time in the preparation of this product the integrity of the container is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

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

7 MARKETING AUTHORISATION HOLDER

GE Healthcare Limited

Amersham Place, Little Chalfont, Buckinghamshire HP7 9NA United Kingdom

8 MARKETING AUTHORISATION NUMBERs

UK:    PL 00221/0127

Norway:

Greece:

Czech Republic:

Hungary:

Slovakia:

Cyprus:

Romania:

Mexico:

Israel:

Japan:

Malaysia:

Panama:

Colombia:

MTnr. 8358

16905/16-9-93

88/028/93-C

OGYI-T-9495/01

88/0061/04-S

S00438

8755/2016/01

0155R98

100-18-28395-00

21900AMG00003

MAL 20051389AZ

81195

2009M-013079-R1

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 DATE OF REVISION OF THE TEXT

July 2016

11 DOSIMETRY

The estimated radiation doses that would be received by normal healthy adults from the intravenous administration of 1 MBq of strontium-89 are given in the table below. Data are taken from Publication 53 of the ICRP (International Commission on Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals, Pergamon Press 1987).

GE Healthcare

Radiation doses to normal adults from the intravenous injection of strontium-89

When osseous metastases are present significantly enhanced localisation of the radiopharmaceutical will occur with correspondingly higher doses to the metastases relative to other organs.

The absorbed dose to vertebral metastases has been measured in a group of 10 patients with widely varying extends of disease*. The minimum, maximum and mean doses in this group are listed below.

Radiation dose to vertebral metastases from intravenous injection of strontium-89

*Blake, G M et al Strontium-89 therapy: Measurement of absorbed dose to skeletal metastases. J Nucl Med 1988; 29(4), 549-557.

The Effective Dose for strontium-89 is 465 mSv per 150 MBq (ICRP 80, 1998).

12    INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Metastron is an aqueous solution for intravenous injection and should be used without dilution. See section 4.2.

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

13    OTHER INFORMATION Manufacturer

GE Healthcare Limited The Grove Centre White Lion Road Amersham

Buckinghamshire HP7 9LL United Kingdom

Metastron is a trademark of GE Healthcare.

GE and the GE Monogram are trademarks of General Electric Company.

IIIIIIIIH Code Reads

HEATHCARE PROFESSIONAL INFORMATION

Metastron

37 MBq/ml solution for injection Strontium-89 chloride SMS2P

9 9 9 9 9 9 9

L/6330/01

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Measure bar should be 150mm at 100% scale

►

ۥ

Multi

Packaging

Solutions

artwork.leicester@multipkg.com

Clearly mark any amendments on one proof and return to MPS

Approval

Signature

Warning! We cannot accept responsibility for any errors in this proof after approval. Whilst we take extreme care at all times to ensure accuracy to our client’s brief, the final responsibility must be taken by our client.

IF YOU SIGN THIS PROOF YOU ARE SIGNIFYING FULL APPROVAL OF DESIGN AND TEXT.

Customer

Description

Item Code

Profile

Size

Min. Point Size

Market

Language

Proof By

Proof No.

Date

GE Healthcare

Colours Used

Metastron - SMS2P - Technical Leaflet

Process Black

L/6330/01

Keylines (does not print)

N/A

190 x 400mm

8 pt

UK/ROW

English

niall.mcateer-lee

4

06/07/2016

Pharma    -7

Code ¹²¹⁷