Document: document 1 change

• document 0
• document 1

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Stabilised Ceretec 500 micrograms kit for radiopharmaceutical preparation

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains exametazime 500 micrograms.

The product before reconstitution contains:

Sodium: 1.77 mg/vial. This needs to be taken into consideration for patients on a controlled sodium diet.

For a full list of excipients, see section 6.1.

Stabilised Ceretec is reconstituted with Sodium Pertechnetate (^99mTc) Injection Ph.Eur. (not included in this kit) to prepare stabilised Technetium (^99mTc) Exametazime Injection.

3    PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation.

White powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Technetium-99m exametazime injection is indicated for brain scintigraphy. The product is to be used for the diagnosis of abnormalities of regional cerebral blood flow, such as those occurring following stroke and other cerebrovascular disease, epilepsy, Alzheimer’s Disease and other forms of dementia, transient ischaemic attack, migraine and tumours of the brain.

4.2 Posology and method of administration

Dose for adults and the elderly:

350-500 MBq by direct intravenous injection.

Normally a once-only diagnostic procedure.

Technetium-99m exametazime is not recommended for administration to children.

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4    Special warnings and precautions for use

The possibility of hypersensitivity including serious signs and symptoms of anaphylaxis should always be considered. Advanced life support facilities should be readily available.

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 diagnostic result.

According to the time of conditioning injection for the patient, the content of sodium may in some cases be greater than 1 mmol. This should be taken into account in patients on low sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed and no drug interactions have been reported to date.

4.6 Pregnancy and lactation

Pregnancy:

No data are available on the use of this product in human pregnancy. Animal reproduction studies have not been performed.

When it is necessary to administer radioactive medicinal products to women of childbearing potential, information should always be sought about pregnancy. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. Where uncertainty exists it is important that radiation exposure should be the minimum consistent with achieving the desired clinical information. Alternative techniques which do not involve ionising radiation should be considered.

Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus. Only imperative investigations should be carried out during pregnancy, when the likely benefit exceeds the risk incurred by the mother and the foetus.

Breast-feeding:

Before administering a radioactive medicinal product to a mother who is breastfeeding consideration should be given as to whether the investigation could be reasonably delayed until after the mother has ceased breast-feeding and as to whether the most appropriate choice of radiopharmaceutical has been made, bearing in mind the secretion of activity in breast milk.

If the administration is considered necessary, breast feeding should be interrupted for 12 hours and the expressed feeds discarded.

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)

Immune system disorders

Not known: Hypersensitivity including rash, erythema, urticaria, angiooedema, pruritus

Nervous system disorders

Not known: Headache, dizziness, paraesthesia

Vascular disorders

Not known: Flushing

Gastrointestinal disorders

Not known: Nausea, vomiting

General disorders and administration site conditions

Not known: Asthenic conditions (e.g., malaise, fatigue)

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 5.2mSv when the maximal recommended activity of 555 MBq is administered these adverse events are expected to occur with a low probability.

4.9. Overdose

In the event of the administration of a radiation overdose frequent micturition and defecation should be encouraged in order to minimise the absorbed dose to patient.

5    Pharmacological properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: diagnostic radiopharmaceutical for central nervous system, technetium (99m Tc) exametazine, ATC Code: V09AA01

At the chemical concentrations and activities used for diagnostic procedures technetium-99m exametazime does not appear to exert any pharmacodynamic effects.

5.2    Pharmacokinetic properties

The technetium-99m complex of the active ingredient is uncharged, lipophilic and of sufficiently low molecular weight to cross the blood-brain barrier. It is rapidly cleared from the blood after intravenous injection. Uptake in the brain reaches a maximum of 3.5-7.0% of the injected dose within one minute of injection. Up to 15% of the cerebral activity washes out of the brain 2 minutes post injection after which there is little loss of activity for the following 24 hours except by physical decay of technetium-99m. The activity not associated with the brain is widely distributed throughout the body particularly in muscle and soft tissue. About 20% of the injected dose is removed by the liver immediately after injection and excreted through the hepatobiliary system. About 40% of the injected dose is excreted through the kidneys and urine over the 48 hours after injection resulting in a reduction in general muscle and soft tissue background.

In vitro stabilisation of technetium-99m exametazime injection with cobalt (II) chloride does not appear to affect the in vivo pharmacokinetics of the complex.

5.3    Preclinical safety data

There are no additional preclinical safety data of relevance concerning exametazime for the prescriber in recognising the safety profile of the product used for the authorised indication.

There are no indications that the gross toxicity profile of the stabilised formulation of technetium-99m exametazime is significantly different from that of the non-stabilised formulation.

In vitro mutagenicity studies indicate that the stabilised formulation of technetium-99m exametazime is weakly mutagenic in the Ames (bacterial mutation) test, human lymphocyte chromosome aberration assay and mouse lymphoma

thymidine kinase assay. The stabilised formulation is found not to be mutagenic in two in vivo assays (rat bone marrow micronucleus and rat liver micronucleus).

At quantities such as those encountered in stabilised technetium-99m exametazime preparations, cobalt (II) ions or complexed forms of cobalt have no known adverse effects and are rapidly eliminated from the circulation by urinary excretion.

6 Pharmaceutical particulars

6.1    List of excipients

The finished product contains the following excipients:

Ceretec component:

•    Sodium chloride Ph. Eur.

•    Stannous chloride dihydrate Ph. Eur.

Cobalt stabiliser solution:

•    Cobalt (II) chloride 6-hydrate

•    Water for injections Ph. Eur.

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 12.

6.3    Shelf life

26 weeks from the day of manufacture. The stabilised product must be injected between 30 minutes and 5 hours after preparation.

The stabilised reconstituted product should be stored below 25^oC. Do not freeze.

6.4    Special precautions for storage

Store below 25^oC. Do not freeze.

Storage should be in accordance with national regulations for radioactive materials. For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

The freeze-dried component of the product is supplied in a glass vial sealed with a chlorobutyl rubber closure and aluminium overseal and blue flip off cap. The cobalt stabiliser solution is supplied in a glass vial with a chlorobutyl rubber closure and metal overseal.

Pack sizes: each kit contains 2 or 5 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Normal safety precautions for handling radioactive materials should be observed. After use, all materials associated with the preparation and administration of radiopharmaceuticals, including any unused product and its container, should be decontaminated or treated as radioactive waste and disposed of in accordance with the conditions specified by the local competent authority. Contaminated material must be disposed of as radioactive waste via an authorised route.

7. MARKETING AUTHORISATION HOLDER

GE Healthcare Limited Amersham Place Little Chalfont Buckinghamshire HP7 9NA United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 00221/0136

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 09 September 1998 Date of last renewal: 29 November 2003

31/01/2014

The radiopharmaceutical may 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 local competent official organisations (see section 6.6).

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

Normal safety precautions for the handling of radioactive materials should be observed in addition to the use of aseptic technique to maintain sterility of the vial contents.

Procedure for preparation of cobalt stabilised technetium-99m exametazime for intravenous injection:

Use aseptic technique throughout.

Place the exametazime vial in a shielding container and swab the closure with the sanitising swab provided.

Using a 10ml syringe, inject into the shielded vial 5ml of sterile eluate from a

technetium-99m generator (see notes 1 - 6). Before withdrawing the syringe from the vial withdraw 5ml of gas from the space above the solution to normalise the pressure in the vial. Shake the shielded vial for 10 seconds to ensure complete dissolution of the powder.

Between 1 and 5 minutes after reconstitution, inject 2ml of cobalt stabiliser solution into the shielded vial using a 3ml syringe. Before withdrawing the syringe from the vial, withdraw 2ml of gas from the space above the solution to normalise the pressure in the vial. Shake the shielded vial for 10 seconds to ensure complete mixing.

Assay the total radioactivity and calculate the volume to be injected.

Complete the label provided and attach to the vial.

Use the stabilised product between 30 minutes and 5 hours after preparation.

Individual patient doses may be stored aseptically in a capped syringe if required (see note 7).

Discard any unused material.

Note:

(1) For the highest radiochemical purity reconstitute with freshly eluted technetium-99m generator eluate.

The technetium-99m generator eluate must be used within 4 hours of elution from a generator that has already been eluted within the previous 24 hours.

0.37 - 1.11 GBq technetium-99m may be added to the vial.

Before reconstitution the generator eluate may be adjusted to the correct radioactive concentration (0.37 - 1.11 GBq in 5 ml) by dilution with sodium chloride for injection.

[^99mTc]pertechnetate complying with the specifications prescribed by the USP and

BP/Ph.Eur. monographs on Sodium Pertechnetate (^99mTc) Injection should be used.

The cobalt stabilised technetium-99m exametazime is a pale straw-coloured solution and the pH is in the range 5.0 - 8.0.

When Stabilised Ceretec preparations are transferred to individual patient syringes, a small volume of the headspace gas must be withdrawn from the vial into the syringe after solution transfer to ensure that no solution remains in contact with the syringe needle prior to administration to the patient.

The shelf life of the reconstituted Ceretec component without the addition of the cobalt stabiliser is only 30 minutes.

Radiochemical purity measurement

Three potential radiochemical impurities may be present in prepared Technetium (^99mTc) Exametazime Injection. These are a secondary ^99mTc-exametazime complex, free [^99mTc]pertechnetate and reduced-hydrolysed-technetium-99m. A combination of two chromatographic systems is necessary for the determination of the radiochemical purity of the injection.

Test samples are applied by needle approximately 2.5cm from the bottom of two Glass Microfiber Chromatography Paper impregnated with Silicic Acid (GMCP-SA) strips (2cm (+ 2 mm) x 20cm). The strips are then immediately placed in prepared ascending chromatography development tanks, one containing butan-2-one and the other 0.9% sodium chloride (1cm depth fresh solvent). After a 15cm elution the strips are removed, solvent fronts marked, the strips dried and the distribution of activity determined using suitable equipment.

Interpretation of chromatograms

System 1 (GMCP-SA:butan-2-one(methyl ethyl ketone))

Secondary ^99mTc-exametazime complex and reduced-hydrolysed-technetium-99m remain at the origin.

Lipophilic ^99mTc-exametazime complex and [^99mTc]pertechnetate migrate at R_f 0.8-1.0.

System 2 (GMCP-SA:0.9% sodium chloride)

Lipophilic ^99mTc-exametazime complex, secondary ^99mTc-exametazime complex and reduced-hydrolysed-technetium-99m remain at the origin.

[^99mTc]pertechnetate migrates at R_f 0.8-1.0.

I.    Calculate the percentage of activity due to both secondary ^99mTc exametazime complex and reduced-hydrolysed-technetium-99m from System 1 (A%). Calculate the percentage of activity due to [^99mTc]pertechnetate from System 2 (B%).

II.    The radiochemical purity (as percentage lipophilic technetium-99m exametazime complex) is given by:

100-(A%+B%) where:

A% represents the level of secondary technetium-99m exametazime complex plus reduced-hydrolysed technetium-99m.

B% represents the level of [^99mTc]pertechnetate.

A radiochemical purity of at least 80% may be expected provided the test samples have been taken and analysed within 5 hours of the preparation of the stabilised product.