CERETEC FREEZE DRIED

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
EXAMETAZIME
Available from:
GE Healthcare Limited
ATC code:
V09AA01
INN (International Name):
EXAMETAZIME
Dosage:
500 Microgram
Pharmaceutical form:
Kit for radiopharmaceutical preparation
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
technetium (99mTc) exametazime
Authorization status:
Marketed
Authorization number:
PA0240/004/001
Authorization date:
1988-04-19

In more serious cases reactions may include:

passing out (unconsciousness), feeling dizzy or

lightheaded.

If any of the side effects above happen after you

leave the hospital or clinic, you should go or be

taken straight to the casualty department of your

nearest hospital.

Other side effects include (frequency not known)

itchy lumpy rash

headache

feeling dizzy

fl ushing

feeling sick (nausea)

being sick (vomiting)

general feeling of being unwell, weak or tired

unusual feelings of numbness, tingling, prickling

burning or creeping on skin.

This radiopharmaceutical will deliver low amounts

of ionising radiation with the least risk of cancer

and hereditary abnormalities.

Reporting of side effects

If you notice any side effects, or if you notice any

side effects not listed in this leafl et, please tell

your Nuclear medicine doctor who supervises the

procedure.

You can also report side effects directly to:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

By reporting side effects, you can help provide

more information on the safety of this medicine.

5. How Ceretec is stored

You will not have to store this medicine. This

medicine is stored under the responsibility of the

specialist in appropriate premises. Storage of

After injection, you will be offered a drink and

asked to urinate immediately preceding the test.

Ceretec will always be used in a hospital or clinic.

Ceretec will be given to you by a specially trained

and qualifi ed person. They will provide you with

the necessary information on the procedure.

Duration of the procedure

Your nuclear medicine doctor will inform you

about the usual duration of the procedure.

After administration of Ceretec you should:

urinate frequently in order to eliminate the

product from your body

The nuclear medicine doctor will inform you if

you need to take any special precautions after

receiving this medicine. Contact your nuclear

medicine doctor if you have any questions.

If you have been given more Ceretec than you

should

An overdose is unlikely because you will only

receive a single dose of Ceretec precisely

controlled by the nuclear medicine doctor

supervising the procedure. However, in the case

of an overdose, you will be encouraged to urinate

and defecate frequently in order to minimise the

absorbed dose.

Should you have any further question on the use

of Ceretec, please ask the nuclear medicine doctor

who supervises the procedure.

4. Possible side effects

Like all medicines, this medicine can cause side

effects, although not everybody gets them.

Allergic reactions

Tell your doctor straight away if you have an

allergic reaction when you are in hospital or a

clinic having the scan. The signs may include:

skin rash or itching or fl ushing

swelling of the face

diffi culty in breathing.

radiopharmaceuticals will be in accordance with

national regulation on radioactive materials.

Hospital staff will ensure that the product is stored

and disposed of correctly and not used after the

expiry date stated on the label.

The following information is intended for

healthcare or medical professionals only:

Keep this medicine Ceretec is kept out of the

reach and sight and reach of children.

Ceretec must not be used after the expiry date

which is stated on the label after ‘EXP’. The

expiry date refers to the last day of that month.

Ceretec must not be used if it is noticed that

there are visible signs of discolouration or

particulate matter

Before reconstitution: Store below 25°C. Do not

freeze.

Store the reconstituted product below 25°C. Do

not freeze or refrigerate.

The labelled product must be injected within 30

minutes of reconstitution.

6. Contents of the pack and other

information

What Ceretec contains

The active ingredient is exametazime. Each

vial of Ceretec contains 500 micrograms of

exametazime.

The other ingredients are stannous chloride

dihydrate and sodium chloride.

What Ceretec looks like and contents of the

pack

Ceretec is a white powder.

Ceretec is supplied as a kit for radio-pharmaceutical

preparation. The kit contains two or fi ve vials. Not all

pack sizes may be marketed.

Each vial contains 500 micrograms of

exametazime.

Marketing

Authorisation

Holder

GE Healthcare Limited

Amersham Place

Little Chalfont

Buckinghamshire

HP7 9NA

United Kingdom

Manufacturer

GE Healthcare AS

Nycoveien 1-2

0401 OSLO

Norway

This leafl et was last

revised in August

2016

Marketing

Authorisation

Ireland: PA 240/4/1

Ceretec is a

trademark of GE

Healthcare.

GE and the GE

Monogram are

trademarks of General

Electric Company.

PATIENT

INFORMATION

Ceretec

TM

500 micrograms kit for

radiopharmaceutical

preparation

Exametazime

1189060 IRL

GE Healthcare

1189060

Document: 1189060 IRL Version: 2 Draft: 3

important to know after a stroke, if you have

fi ts or epilepsy, Alzheimer’s disease or a similar

type of dementia. It may also be used in people

who have migraine (headaches) or a brain

tumour.

The scan can help your doctor investigate fever

when the reason for the fever is not known.

The scan can also help your doctor investigate

sites of infection, such as in your abdomen

(the area around your stomach).

Some other people are given this medicine to

see swelling (infl ammation) in the bowel.

Your nuclear medicine doctor will explain

which part of your body will be scanned.

The use of Ceretec does involve exposure to

small amounts of radioactivity. Your doctor and

the nuclear medicine doctor have considered

that the clinical benefi t of this procedure with the

radiopharmaceutical outweighs the risk of being

exposed to these small amounts of radiation.

Ask your nuclear medicine doctor if you have any

questions.

2. What you need to know before Ceretec is

used

Ceretec must not be used:

If you are allergic (hypersensitive) to the active

ingredient or any other ingredients of this

medicine (listed in Section 6).

Warnings and precautions

Talk to your nuclear medicine doctor before using

Ceretec

if the person who will be given this medicine is

a child.

if you are pregnant or think you may be

pregnant.

if you are breast-feeding.

if you are on a low sodium diet.

Children and adolescents

Ceretec is not recommended for administration to

children.

Package leafl et: Information for the patient

Ceretec 500 micrograms kit for

radiopharmaceutical preparation

Exametazime

(called Ceretec in this leafl et)

Read all of this leafl et carefully before you

are given this medicine because it contains

important information for you.

Keep this leafl et. You may need to read it again.

If you have any further questions, ask your

nuclear medicine doctor.

If you get any side effects, talk to your nuclear

medicine doctor. This includes any possible side

effects not listed in this leafl et. See section 4.

What is in this leafl et:

1. What Ceretec is and what it is used for

2. What you need to know before Ceretec is used

3. How Ceretec is used

4. Possible side effects

5. How Ceretec is stored

6. Contents of the pack and other information

1. What Ceretec is and what it is used for

Ceretec is a radiopharmaceutical product for

diagnostic use only. It is used only to help identify

illness.

Ceretec is given before a scan and helps a special

camera see inside a part of your body.

It contains an active ingredient called

‘exametazime’. This is mixed with another

ingredient called technetium’ before it is used.

Once injected it can be seen from outside your

body by a special camera used in the scan.

The scan can help your doctor see how much

blood is fl owing through the brain. This may be

Other medicines and Ceretec

Tell your nuclear medicine doctor who will

supervise the procedure if you are taking, have

recently taken or might take any other medicines,

since they may affect the way Ceretec works.

No medicines have been reported that affect

the way Ceretec works. But it is still best to tell

your doctor or nurse if you are taking any other

medicines.

Pregnancy and breast-feeding

You must tell your nuclear medicine doctor before

you are given Ceretec if there is a possibility you

might be pregnant, if you have missed your period

or if you are breast-feeding. When in doubt, it is

important to consult your nuclear medicine doctor

who will supervise the procedure.

If you are pregnant

The nuclear medicine doctor will only give this

medicine during pregnancy if a benefi t is expected

which would outweigh the risk.

If you are breast-feeding

Do not breast-feed if you are given Ceretec. This is

because small amounts of ‘radioactivity’ may pass

into the mother’s milk. If you are breast-feeding,

your nuclear medicine doctor may wait until you

have fi nished breast-feeding before using Ceretec.

If it is not possible to wait your nuclear medicine

doctor may ask you to:

stop breast-feeding for 12 hours, and

use formula feed for your child, and

express (remove) breast milk and throw away

the milk.

Your nuclear medicine doctor will let you know

when you can start breast-feeding again.

Driving and using machines

It is considered unlikely that Ceretec will affect

your ability to drive or to use machines. Ask your

nuclear medicine doctor if you can drive or use

machines after you have been given Ceretec.

Important information about some of the

ingredients of Ceretec

Ceretec contains sodium 1.77 mg per vial. This

may need to be considered for people on a low

sodium diet.

3. How Ceretec is used

There are strict laws on the use, handling and

disposal of radiopharmaceutical products. Ceretec

will only be used in special controlled areas. This

product will only be handled and given to you

by people who are trained and qualifi ed to use

it safely. These persons will take special care for

the safe use of this product and will keep you

informed of their actions.

The nuclear medicine doctor supervising the

procedure will decide on the amount of Ceretec

to be used in your case. It will be the smallest

quantity necessary to get the desired information.

The quantity to be administered usually

recommended for an adult ranges from 350 to

500 MBq for brain scintigraphy and 200 MBq for

in vivo localisation of technetium-99m-labelled

leucocytes. Megabecquerel (MBq) is the unit used

to express radioactivity.

Use in children and adolescents

Ceretec is not recommended for use in children.

Administration of Ceretec and conduct of the

procedure

Samples that will be required before you have

Ceretec

A sample of your blood may be taken.

If a sample of your blood has been taken it will be

mixed with a solution (containing Ceretec and the

ingredient called ‘technetium’) which will then be

given to you as an injection.

Ceretec is administered by intravenous injection.

One injection is suffi cient to carry out the scan

that your doctor needs

turn over ➤

Document: 1189060 IRL Version: 2 Draft: 3

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

<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

known:

Hypersensitivity

including

rash,

erythema,

urticaria,

angiooedema, pruritus

Re-injected Ceretec labelled leukocytes only

Know:

Hypersensitivity

including

rash,

erythema,

urticaria,

angiooedema, pruritus, anaphylactoid reaction or anaphylactoid shock

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 5.2 mSv when the maximal recommended activity of 555 MBq is

administered these adverse events are expected to occur with a low

probability.

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal product is important. It allows continued monitoring of the

benefit/risk balance of the medicinal product. Healthcare professionals

asked

report

suspected

adverse

reactions

HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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 radiopharmaceuticals, central

nervous system, ATC code: V09AA01

Pharmacotherapeutic

group:

diagnostic

radiopharmaceuticals,

inflammation and infection detection, ATC code: V09HA02

chemical

concentrations

activities

used

diagnostic

procedures

technetium-99m

exametazime

technetium-99m-

labelled

leucocytes

appear

exert

pharmacodynamic

effects.

5.2 Pharmacokinetic properties

Direct intravenous injection

The technetium-99m complex of the active ingredient is uncharged,

lipophilic

sufficiently

molecular

weight

cross

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.

Injection of labelled leucocytes

Technetium-99m-labelled

leucocytes

distribute

between

marginating pools of the liver (within 5 minutes) and spleen (within about

minutes),

circulating

pool,

(the

latter

represents

approximately 50% of the leucocyte pool). Approximately 37% of the

cell associated technetium-99m is recoverable from the circulating pool

40 minutes after injection. Technetium-99m activity is slowly eluted from

the cells and is excreted partly by the kidneys and partly via the liver into

the gall bladder. This results in increasing amounts of activity being seen

in the intestines.

5.3 Preclinical safety data

There

additional

preclinical

safety

data

relevance

prescriber in recognising the safety profile of the product used for the

authorised indications.

6

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Stannous chloride dihydrate

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products

except those mentioned in section 12.

6.3 Shelf life

1 year from the day of manufacture.

Store the reconstituted product below 25°C. Do not freeze or refrigerate.

The labelled product must be injected within 30 minutes of reconstitution.

6.4 Special precautions for storage

Before reconstitution: Store below 25°C. Do not freeze.

After reconstitution: For storage conditions after reconstitution of the

medicinal product, see section 6.3.

Storage

should

accordance

with

national

regulations

radioactive materials.

6.5 Nature and contents of container

10ml Type I Ph.Eur., clear, colourless, borosilicate glass vial sealed with

a chlorobutyl rubber closure and oversealed with an aluminium overseal

with a blue flip off cap.

Pack sizes: kit contains 2 or 5 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

General warning

Radiopharmaceuticals

should

received,

used

administered

only by authorised persons in designated clinical settings. Its 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

pharmaceutical

quality

requirements.

Appropriate aseptic precautions should be taken.

Contents of the vial are intended only for use in the preparation of

technetium (

Tc) exametazime injection and are not to be administered

directly to the patient without first undergoing the preparative procedure.

instructions

reconstitution

medicinal

product

before

administration, see section 12.

After

reconstitution

with

Sodium

Pertechnetate

Injection,

product is indicated in adults for:

Technetium

Exametazime

Injection

indicated

brain

scintigraphy.

product

used

diagnosis

abnormalities

regional

cerebral

blood

flow,

such

those

occurring

following

stroke

other

cerebrovascular

disease,

epilepsy,

Alzheimer’s

Disease

other

forms

dementia,

transient ischaemic attack, migraine and tumours of the brain.

Technetium

Exametazime

Injection

also

indicated

in vitro technetium-99m leucocyte labelling, the labelled leucocytes

subsequently

being

re-injected

scintigraphy

carried

image the sites of localisation. This procedure may be used in the

detection of sites of focal infection (e.g. abdominal abscess), in the

investigation of pyrexia of unknown origin and in the evaluation

of inflammatory conditions not associated with infection such as

inflammatory bowel disease.

4.2 Posology and method of administration

The route of administration is direct intravenous injection for brain

scintigraphy studies and intravenous injection of labelled leucocytes post

labelling in vitro.

Posology

Adults and the elderly population

for brain scintigraphy, 350-500 MBq

vivo

localisation

technetium-99m-labelled

leucocytes,

200 MBq

Normally a once-only diagnostic procedure.

Paediatric population

Technetium-99m exametazime and technetium-99m-labelled leucocytes

are not recommended for administration to children.

Method of administration

This medicinal product should be reconstituted before administration to

the patient.

instructions

reconstitution

medicinal

product

before

administration, see 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.

4.4 Special warnings and precautions for use

Potential for hypersensitivity or anaphylactic reactions

The possibility of hypersensitivity including anaphylactic/anaphylactoid

reactions should always be considered. If hypersensitivity or anaphylactic

reactions

occur,

administration

medicinal

product

must

discontinued

immediately

intravenous

treatment

initiated,

necessary. To enable immediate action in emergencies, the necessary

medicinal

products

equipment

such

endotracheal

tube

ventilator must be immediately available.

Re-injected Ceretec labelled leukocytes only.

When

preparing

technetium-99m-labelled

leucocytes

essential

that cells are washed free of sedimentation agents before they are

re-injected into the patient as materials used in cell separation may

cause hypersensitivity reactions.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely

benefit. The activity administered should in every case be as low as

reasonably achievable to obtain the required diagnostic information.

Renal impairment and hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required

since an increased radiation exposure is possible.

Paediatric population

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.

Specific warnings

Depending on the time when you administer the injection, the content of

sodium given to the patient may in some cases be greater than 1 mmol.

This should be taken into account in patients on low sodium diet.

Precautions with respect to environmental hazard see section 6.6.

4.5 Interaction with other medicinal products and other forms of

interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Women with childbearing potential:

When

administration

radiopharmaceuticals

woman

childbearing potential is intended, it is important to determine whether

or not she is pregnant. Any woman who has missed a period should be

assumed to be pregnant until proven otherwise. If in doubt about her

potential pregnancy (if the woman has missed a period, if the period is

very irregular, etc.), alternative techniques not using ionising radiation

(if there are any) should be offered to the patient.

Pregnancy:

No data are available on the use of this product in human pregnancy.

Animal reproduction studies have not been performed. Radionuclide

procedures carried out on pregnant women also involve radiation doses

to the fœtus. Only imperative investigations should be carried out during

pregnancy, when the likely benefit exceeds the risk incurred by the

mother and the fœtus.

Breast-feeding:

Before administering a radioactive medicinal product to a mother who is

breast-feeding

consideration

should

given

whether

investigation could be reasonably delayed until after the mother has

If at any time in the preparation of this product the integrity of this

vial 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 content of the kit before reconstitution is not radioactive. However,

after sodium pertechnetate (

Tc), Ph. Eur. is added, adequate shielding

of the final preparation must be maintained.

administration

radiopharmaceuticals

creates

risks

other

persons from external radiation or contamination from spill of urine,

vomiting

etc.

Radiation

protection

precautions

accordance

with

national regulations must therefore be taken.

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 local requirements.

7.

MARKETING AUTHORISATION HOLDER

GE Healthcare Limited

Amersham Place

Little Chalfont

Buckinghamshire HP7 9NA

United Kingdom

8.

MARKETING AUTHORISATION NUMBER

Ireland: PA 240/4/1

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation

Date of last renewal

Ireland

19 April 1988

19 April 2008

10. DATE OF REVISION OF THE TEXT

August 2016

11

DOSIMETRY

Technetium (

Tc) is produced by means of a (

Tc) generator and

decays with the emission of gamma radiation with a mean energy of

140 keV and a half-life of 6.02 hours to technetium (

Tc) which, in view

of its long half-life of 2.13 x 10

years can be regarded as quasi stable.

Brain scinitigraphy

The table below shows the dosimetry as calculated according to the

Publication 62 of the ICRP (International Commission on Radiological

Protection

Biomedical

Research,

Pergamon

Press

1991)

following

administration of

Tc-exametazime to adults.

Organ

Absorbed dose per unit activity administered

(mGy/MBq) Adult

Adrenals

Bladder

Bone surfaces

Brain

Breast

Gall bladder

GI tract

Stomach

Heart

Kidneys

Liver

Lungs

Muscles

Oesophagus

Ovaries

Pancreas

Red marrow

Skin

Spleen

Testes

Thymus

Thyroid

Uterus

Remaining organs

5.3E-03

2.3E-02

5.1E-03

6.8E-03

2.0E-03

1.8E-02

6.4E-03

1.2E-02

1.8E-02

1.5E-02

3.7E-03

3.4E-02

8.6E-03

1.1E-02

2.8E-03

2.6E-03

6.6E-03

5.1E-03

3.4E-03

1.6E-03

4.3E-03

2.4E-03

2.6E-03

2.6E-02

6.6E-03

3.2E-03

Effective dose

(mSv/MBq)

9.3E-03

Effective Dose is 4.7 mSv/500 MBq (70 kg individual).

In vivo localisation of technetium-99m-labelled leucocytes

The table below shows the dosimetry as calculated according to the

Publication 80 of the ICRP (International Commission on Radiological

Protection,

Radiation

Dose

Patients

from

Radiopharmaceuticals,

Pergamon Press 1998).

Organ

Absorbed dose per unit activity

administered (mGy/MBq)

Adrenals

Bladder

Bone surfaces

Brain

Breast

Gall bladder

GI-tract

Stomach

Colon

Heart

Kidneys

Liver

Lungs

Muscles

Oesophagus

Ovaries

Pancreas

Red marrow

Skin

Spleen

Testes

Thymus

Thyroid

Uterus

Remaining organs

Adult

1.0E-02

2.6E-03

1.6E-02

2.3E-03

2.4E-03

8.4E-03

8.1E-03

4.6E-03

4.3E-03

4.7E-03

3.7E-03

9.4E-03

1.2E-02

2.0E-02

7.8E-03

3.3E-03

3.5E-03

3.9E-03

1.3E-02

2.3E-02

1.8E-03

1.5E-01

1.6E-03

3.5E-03

2.9E-03

3.4E-03

3.4E-03

15 years

1.2E-02

3.5E-03

2.1E-02

2.9E-03

2.9E-03

1.0E-02

9.6E-03

5.7E-03

5.4E-03

5.9E-03

4.8E-03

1.2E-02

1.4E-02

2.6E-02

9.9E-03

4.1E-03

4.2E-03

5.0E-03

1.6E-02

2.5E-02

2.1E-03

2.1E-01

2.1E-03

4.2E-03

3.7E-03

4.3E-03

4.2E-03

10 years

1.8E-02

5.2E-03

3.4E-02

4.4E-03

4.9E-03

1.6E-02

1.4E-02

8.7E-03

8.4E-03

9.3E-03

7.3E-03

1.7E-02

2.2E-02

3.8E-02

1.5E-02

6.0E-03

5.8E-03

7.2E-03

2.3E-02

4.0E-02

3.4E-03

3.1E-01

3.2E-03

5.8E-03

5.8E-03

6.5E-03

6.3E-03

5 years

2.6E-02

7.8E-03

6.1E-02

7.0E-03

7.6E-03

2.5E-02

2.0E-02

1.3E-02

1.2E-02

1.4E-02

1.0E-02

2.5E-02

3.2E-02

5.4E-02

2.3E-02

8.9E-03

8.6E-03

1.1E-02

3.4E-02

7.1E-02

5.5E-03

4.8E-01

5.1E-03

8.6E-03

9.3E-03

9.7E-03

9.5E-03

1 year

4.3E-02

1.4E-02

1.5E-01

1.3E-02

1.3E-02

3.6E-02

3.2E-02

2.1E-02

2.1E-02

2.3E-02

1.8E-02

4.4E-02

5.4E-02

9.7E-02

4.1E-02

1.6E-02

1.5E-02

1.8E-02

5.3E-02

1.4E-01

1.0E-02

8.5E-01

9.2E-03

1.5E-02

1.7E-02

1.6E-02

1.6E-02

Effective dose

(mSv/MBq)

1.1E-02

1.4E-02

2.2E-02

3.4E-02

6.2E-02

Effective Dose is 2.2 mSv/200 MBq (70 kg individual).

PACKAGE LEAFLET: INFORMATION FOR HEALTHCARE PROFESSIONAL

1.

NAME OF THE MEDICINAL PRODUCT

Ceretec 500 micrograms kit for radiopharmaceutical preparation.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains exametazime 500 micrograms.

Ceretec is reconstituted with Sodium Pertechnetate (

Tc) Injection (not

included in this kit) to prepare Technetium (

Tc) Exametazime Injection.

Excipients with known effect

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.

3.

PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation.

A white powder.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

12

INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

The technetium-99m exametazime is clear, colourless liquid, essentially

particle-free solution.

Withdrawals should be performed under aseptic conditions. The vials

must not be opened before disinfecting the stopper, the solution should

be withdrawn via the stopper using a single dose syringe fitted with

suitable protective shielding and a disposable sterile needle or using an

authorised automated application system. If the integrity of this vial is

compromised, the product should not be used.

Method of preparation of technetium-99m exametazime for

intravenous injection or in vitro leucocyte labelling:

Use aseptic technique throughout.

Place the 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

technetium-99m

generator

(see

notes

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.

Assay the total activity and calculate the volume to be injected or

used for in vitro technetium-99m-leucocyte labelling.

Complete the label provided and attach to the vial.

Use within a maximum of 30 minutes after reconstitution. Discard

any unused material.

Note:

For the highest radiochemical purity reconstitute with freshly eluted

technetium-99m generator eluate.

Use only eluate which was eluted less than 2 hours previously from

a generator which was eluted within 24 hours.

0.37-1.11 GBq (10-30 mCi) 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.

Pertechnetate complying with the specifications prescribed by the

USP and BP/Ph.Eur. monographs on Sodium Pertechnetate (

Injection should be used.

The pH of the prepared injection/labelling agent is in the range

9.0-9.8.

Procedure for separation of leucocytes and subsequent in vitro labelling

with technetium-99m exametazime

Use aseptic technique throughout.

Draw 9 ml of acid-citrate-dextrose (ACD) (see note a) into each of

two 60 ml plastic non-heparinized syringes.

Withdraw 51ml of patient’s blood into each syringe, using a 19G

Butterfly needle infusion set. Close the syringes with sterile hubs.

Dispense

sedimentation

agent

(see

note

into

each

5 Universal containers or tubes.

Without

attaching

needle

syringes

dispense

blood into each of the 5 Universal tubes containing sedimentation

agent. Dispense the remaining 20ml of blood into a tube without

sedimentation agent.

TIP: To avoid bubbles and frothing run the blood gently down the sides

of the tubes.

Mix the blood and sedimentation agent with one gentle inversion.

Remove the cap of the Universal tube and burst the bubble formed

at the top using a sterile needle. Replace the cap and allow the tubes

to stand for 30-60 minutes for erythrocyte sedimentation to take

place.

TIP: The period of time for erythrocyte sedimentation depends on the

patient’s condition. As a guideline it should be stopped when the blood

has sedimented to give approximately half the volume as sedimented

red cells.

Meanwhile centrifuge the tube containing 20 ml of blood and no

sedimentation

agent

2000g

minutes.

This

will

yield

supernatant cell-free plasma (CFP) containing ACD which is retained,

at room temperature, for use as a cell labelling and re-injection

medium.

When sufficient red cell sedimentation has taken place [see (5)]

carefully

transfer

aliquots

cloudy

straw-coloured

supernatant

into

clean

Universal

tubes.

Take

care

avoid

withdrawing

sedimented

erythrocytes.

supernatant

leucocyte-rich, platelet-rich plasma [LRPRP].

TIP: Do not use needles on sampling syringes to avoid unnecessary cell

damage.

Centrifuge the LRPRP at 150g for 5 minutes to give supernatant,

platelet-rich plasma (PRP) and a pellet of “mixed” leucocytes.

Remove

much

possible

into

clean

Universal

tubes and further centrifuge at 2000g for 10 minutes to give more

supernatant, CFP containing sedimentation agent. This will be used

to wash the cells after labelling.

(10) Meanwhile loosen the pellets of “mixed” leucocytes by very gently

tapping and swirling the Universal tubes. Using a syringe, without

an attached needle, pool all the cells into one tube then, using the

same syringe, add 1ml of cell-free plasma containing ACD (from 6)

and gently swirl to resuspend.

(11) Reconstitute a vial of Ceretec with 5 ml of technetium-99m generator

eluate containing approximately 500 MBq (13.5 mCi) of

(using the procedure described above).

(12)

Immediately

following

reconstitution

resulting

technetium-99m exametazime solution to the “mixed” leucocytes in

CFP (from 10).

(13) Gently swirl to mix and incubate for 10 minutes at room temperature.

(14) If

required,

immediately

spot

chromatography

strips

assessment

radiochemical

purity

technetium-99m

exametazime, as instructed overleaf.

(15) On completion of incubation carefully add 10ml of CFP containing

sedimentation agent (from 9) to the cells, in order to stop labelling.

Gently invert the cells to mix.

(16) Centrifuge at 150g for 5 minutes.

(17) Remove and retain all of the supernatant.

TIP:

critical

that

supernatant

which

contains

unbound

technetium-99m exametazime is removed at this stage. This can be best

achieved using a syringe with a wide-bore [19G] needle.

(18) Gently

resuspend

technetium-99m

labelled

mixed

leucocyte

preparation in 5-10 ml of CFP containing ACD from (6). Gently swirl

to mix.

(19) Measure the radioactivity in the cells and in the supernatant from

(17). Calculate the labelling efficiency [LE] which is defined as the

activity in the cells as a percentage of the sum of the activity in the

cells and the activity in the supernatant.

TIP Labelling efficiency depends on the patient’s leucocyte count and will

vary according to the volume of the initial blood sample. Using the

volumes in (2), a LE of about 55% might be expected.

(20) Without attaching a needle, carefully draw up the labelled cells into

a plastic, non-heparinised syringe and close it with a sterile hub.

Measure the radioactivity.

(21)

Labelled

cells

ready

re-injection.

This

should

performed without delay.

Document: 1189061 IRL Version: 2 Draft: 4

Note:

Acid-citrate-dextrose (ACD) should be made up as follows:

NIH Formula A. For 1 litre add 22g trisodium citrate, 8g citric acid,

22.4g dextrose and make up to 1 litre with Water for injections

Ph.Eur.

product

should

manufactured

under

aseptic

condition. Commercial preparations of the product are also available.

The product should be stored under the conditions recommended

by the manufacturer and should be used only up to the expiry date

given by the manufacturer.

hydroxyethyl

starch

should

manufactured

under

aseptic

conditions. Commercial preparations of the product are available.

The product should be stored under the conditions recommended

by the manufacturer and should be used only up to the expiry date

given by the manufacturer

Quality control

Three potential radiochemical impurities may be present in the prepared

exametazime

injection.

These

secondary

exametazime

complex, free 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

applied

needle

approximately

2.5cm

from

bottom of two Glass Microfi ber 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% aq.

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

exametazime

complex

reduced-hydrolysed-

technetium remain at the origin.

Lipophilic

Tc exametazime complex and pertechnetate migrate at

Rf 0.8-1.0.

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

Lipophilic

Tc exametazime complex, secondary

Tc exametazime

complex and reduced-hydrolysed-Tc remain at the origin.

Pertechnetate migrates at Rf 0.8-1.0.

Calculate the percentage of activity due to both secondary

exametazime

complex

reduced-hydrolysed-technetium-99m

from System 1 (A%). Calculate the percentage of activity due to

pertechnetate from System 2 (B%).

radiochemical

purity

percentage

lipophilic

Tc exametazime complex) is given by:

100-(A%+B%) where:

A% represents the level of secondary 99mTc exametazime complex plus

reduced-hydrolysed technetium-99m

B% represents the level of pertechnetate.

A radiochemical purity of at least 80% may be expected provided the

test

samples

have

been

taken

analysed

within

minutes

reconstitution.

13

OTHER INFORMATION

Manufacturer

GE Healthcare AS

Nycoveien 1-2

0401 OSLO

Norway

Ceretec is a trademark of GE Healthcare.

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

GE Healthcare

1189061 IRL

HEALTHCARE PROFESSIONAL

INFORMATION

Ceretec™

500 micrograms kit for

radiopharmaceutical

preparation.

Exametazime

1189061

Document: 1189061 IRL Version: 2 Draft: 4

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ceretec 500 micrograms kit for radiopharmaceutical preparation.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains exametazime 500 micrograms.

Ceretec is reconstituted with Sodium Pertechnetate (

Tc) Injection (not included in this kit) to prepare Technetium

Tc) Exametazime Injection.

Excipients with known effect

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.

3 PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation.

A white powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.

After reconstitution with Sodium Pertechnetate (

Tc) Injection, the product is indicated in adults for:

Technetium (

Tc) 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.

Technetium (

Tc) Exametazime Injection is also indicated for in vitro technetium-99m leucocyte labelling,

the labelled leucocytes subsequently being re-injected and scintigraphy carried out to image the sites of localisation.

This procedure may be used in the detection of sites of focal infection (e.g. abdominal abscess), in the investigation of

pyrexia of unknown origin and in the evaluation of inflammatory conditions not associated with infection such as

inflammatory bowel disease.

4.2 Posology and method of administration

The route of administration is direct intravenous injection for brain scintigraphy studies and intravenous injection of

labelled leucocytes post labelling in vitro.

Posology

Adults and the elderly population

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for brain scintigraphy, 350-500 MBq

for in vivo localisation of technetium-99m-labelled leucocytes, 200 MBq

Normally a once-only diagnostic procedure.

Paediatric population

Technetium-99m exametazime and technetium-99m-labelled leucocytes are not recommended for administration to

children.

Method of administration

This medicinal product should be reconstituted before administration to the patient.

For instructions on reconstitution of the medicinal product before administration, see 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.

4.4 Special warnings and precautions for use

Potential for hypersensitivity or anaphylactic reactions

The possibility of hypersensitivity including anaphylactic/anaphylactoid reactions should always be considered. If

hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued

immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the

necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

Re-injected Ceretec labelled leucocytes only.

When preparing technetium-99m-labelled leucocytes it is essential that cells are washed free of sedimentation agents

before they are re-injected into the patient as materials used in cell separation may cause hypersensitivity reactions.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in

every case be as low as reasonably achievable to obtain the required diagnostic information.

Renal impairment and hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is

possible.

Paediatric population

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.

Specific warnings

Depending on the time when you administer the injection, the content of sodium given to the patient may in some cases

be greater than 1 mmol. This should be taken into account in patients on low sodium diet.

Precautions with respect to environmental hazard see section 6.6.

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.

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4.6 Fertility, pregnancy and lactation

Women with childbearing potential:

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to

determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until

proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very

irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient.

Pregnancy:

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

performed. 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 breast-feeding 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, angioedema, pruritus

Re-injected Ceretec labelled leukocytes only

Not known: Hypersensitivity including rash, erythema, urticaria, angioedema, pruritus, anaphylactoid reaction or

anaphylactoid shock.

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 developing hereditary defects. As the

effective dose is 5.2 mSv when the maximal recommended activity of 555 MBq is administered, these adverse events

are expected to occur with a low probability.

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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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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

Pharmaceutical group: diagnostic radiopharmaceuticals, central nervous system, ATC code: V09A A01

Pharmaceutical group: diagnostic radiopharmaceuticals, inflammation and infection detection, ATC code: V09H A02

At the chemical concentrations and activities used for diagnostic procedures technetium -99m exametazime and

technetium-99m-labelled leucocytes do not appear to exert any pharmacodynamic effects.

5.2 Pharmacokinetic properties

Direct intravenous injection

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.

Injection of labelled leucocytes

Technetium-99m-labelled leucocytes distribute between the marginating pools of the liver (within 5 minutes) and

spleen (within about 40 minutes), and the circulating pool, (the latter represents approximately 50% of the leucocyte

pool). Approximately 37% of the cell associated technetium-99m is recoverable from the circulating pool 40 minutes

after injection. Technetium-99m activity is slowly eluted from the cells and is excreted partly by the kidneys and partly

via the liver into the gall bladder.

This results in increasing amounts of activity being seen in the intestines.

5.3 Preclinical safety data

There is no additional preclinical safety data of relevance for the prescriber in recognising the safety profile of the

product used for the authorised indications.

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6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Stannous chloride dihydrate

6.2 Incompatibilities

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

6.3 Shelf life

1 year from the day of manufacture.

Store the reconstituted product below 25°C.

Do not freeze or refrigerate. The labelled product must be injected within

30 minutes of reconstitution.

6.4 Special precautions for storage

Before reconstitution:

Store below 25°C. Do not freeze.

After reconstitution:

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Storage should be in accordance with national regulations for radioactive materials.

6.5 Nature and contents of container

10ml Type I Ph. Eur., clear, colourless, borosilicate glass vial sealed with a chlorobutyl rubber closure and oversealed

with an aluminium overseal with a blue flip off cap.

Pack sizes: kit contains 2 or 5 vials

Not all pack sizes may be marketed.

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.

Its 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.

Contents of the vial are intended only for use in the preparation of technetium (

Tc) exametazime injection and are

not to be administered directly to the patient without first undergoing the preparative procedure.

For instructions on reconstitution of the medicinal product before administration, see section 12.

If at any time in the preparation of this product the integrity of this vial 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.

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The content of the kit before reconstitution is not radioactive. However, after sodium pertechnetate (

Tc), Ph. Eur. is

added, adequate shielding of the final preparation must be maintained.

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.

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 local requirements.

7 MARKETING AUTHORISATION HOLDER

GE Healthcare Limited

Amersham Place

Little Chalfont

Buckinghamshire

HP7 9NA

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA0240/004/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 April 1988

Date of last renewal: 19 April 2008

10 DATE OF REVISION OF THE TEXT

August 2017

11 DOSIMETRY

Technetium (

Tc) is produced by means of a (

Tc) generator and decays with the emission of gamma

radiation with a mean energy of 140 keV and a half-life of 6.02 hours to technetium (

Tc) which, in view of its long

half-life of 2.13 x 10

years can be regarded as quasi stable.

Brain scintigraphy

The table below shows the dosimetry as calculated according to the Publication 62 of the ICRP (International

Commission on Radiological Protection in Biomedical Research, Pergamon Press 1991) following administration of

Tc-exametazime to adults.

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Effective Dose is 4.7 mSv/500 MBq (70 kg individual).

In vivo localisation of technetium-99m-labelled leucocytes

The table below shows the dosimetry as calculated according to the Publication 80 of the ICRP (International

Commission on Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals, Pergamon Press

1998).

Organ

Absorbed dose per unit activity administered

(mGy/MBq) Adult

Adrenals

5.3E - 03

Bladder

2.3E - 02

Bone surfaces

5.1E -03

Brain

6.8E - 03

Breast

2.0E - 03

Gall bladder

1.8E - 02

GI tract

Stomach

6.4E - 03

1.2E - 02

1.8E – 02

1.5E - 02

Heart

3.7E - 03

Kidneys

3.4E - 02

Liver

8.6E - 03

Lungs

1.1E – 02

Muscles

2.8E -03

Oesophagus

2.6E - 03

Ovaries

6.6E - 03

Pancreas

5.1E - 03

Red marrow

3.4E - 03

Skin

1.6E - 03

Spleen

4.3E - 03

Testes

2.4E -03

Thymus

2.6E - 03

Thyroid

2.6E - 02

Uterus

6.6E - 03

Remaining organs

3.2E - 03

Effective dose

(mSv/MBq)

9.3E - 03

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Effective Dose is 2.2 mSv/200 MBq (70 kg individual).

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

The technetium-99m exametazime is clear, colourless liquid, essentially particle-free solutionWithdrawals should be

performed under aseptic conditions. The vials must not be opened before disinfecting the stopper, the solution should

be withdrawn via the stopper using a single dose syringe fitted with suitable protective shielding and a disposable

sterile needle or using an authorised automated application system. If the integrity of this vial is compromised, the

product should not be used.

Method of preparation of technetium-99m exametazime for intravenous injection or in vitro leucocyte labelling:

Use aseptic technique throughout.

Place the 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.

Assay the total activity and calculate the volume to be injected or used for in vitro technetium¬99m-leucocyte

Organ

Absorbed dose per unit activity administered (mGy/MBq)

Adult

15 years

10 years

5 years

1 year

Adrenals

1.0E-02

1.2E-02

1.8E-02

2.6E-02

4.3E-02

Bladder

2.6E-03

3.5E-03

5.2E-03

7.8E-03

1.4E-02

Bone surfaces

1.6E-02

2.1E-02

3.4E-02

6.1E-02

1.5E-01

Brain

2.3E-03

2.9E-03

4.4E-03

7.0E-03

1.3E-02

Breast

2.4E-03

2.9E-03

4.9E-03

7.6E-03

1.3E-02

Gall bladder

8.4E-03

1.0E-02

1.6E-02

2.5E-02

3.6E-02

GI-tract

Stomach

8.1E-03

9.6E-03

1.4E-02

2.0E-02

3.2E-02

4.6E-03

5.7E-03

8.7E-03

1.3E-02

2.1E-02

Colon

4.3E-03

5.4E-03

8.4E-03

1.2E-02

2.1E-02

4.7E-03

5.9E-03

9.3E-03

1.4E-02

2.3E-02

3.7E-03

4.8E-03

7.3E-03

1.0E-02

1.8E-02

Heart

9.4E-03

1.2E-02

1.7E-02

2.5E-02

4.4E-02

Kidneys

1.2E-02

1.4E-02

2.2E-02

3.2E-02

5.4E-02

Liver

2.0E-02

2.6E-02

3.8E-02

5.4E-02

9.7E-02

Lungs

7.8E-03

9.9E-03

1.5E-02

2.3E-02

4.1E-02

Muscles

3.3E-03

4.1E-03

6.0E-03

8.9E-03

1.6E-02

Oesophagus

3.5E-03

4.2E-03

5.8E-03

8.6E-03

1.5E-02

Ovaries

3.9E-03

5.0E-03

7.2E-03

1.1E-02

1.8E-02

Pancreas

1.3E-02

1.6E-02

2.3E-02

3.4E-02

5.3E-02

Red marrow

2.3E-02

2.5E-02

4.0E-02

7.1E-02

1.4E-01

Skin

1.8E-03

2.1E-03

3.4E-03

5.5E-03

1.0E-02

Spleen

1.5E-01

2.1E-01

3.1E-01

4.8E-01

8.5E-01

Testes

1.6E-03

2.1E-03

3.2E-03

5.1E-03

9.2E-03

Thymus

3.5E-03

4.2E-03

5.8E-03

8.6E-03

1.5E-02

Thyroid

2.9E-03

3.7E-03

5.8E-03

9.3E-03

1.7E-02

Uterus

3.4E-03

4.3E-03

6.5E-03

9.7E-03

1.6E-02

Remaining organs

3.4E-03

4.2E-03

6.3E-03

9.5E-03

1.6E-02

Effective dose

(mSv/MBq)

1.1E-02

1.4E-02

2.2E-02

3.4E-02

6.2E-02

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labelling

Complete the label provided and attach to the vial.

Use within a maximum of 30 minutes after reconstitution. Discard any unused material.

Note:

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

Use only eluate which was eluted less than 2 hours previously from a generator which was eluted within 24

hours.

0.37-1.11 GBq (10-30 mCi) 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.

Pertechnetate complying with the specifications prescribed by the USP and BP/Ph.Eur. Monographs on

Sodium Pertechnetate (

Tc) Injection should be used.

The pH of the prepared injection/labelling agent is in the range 9.0-9.8.

Procedure for separation of leucocytes and subsequent in vitro labelling with technetium-99m exametazime

Use aseptic technique throughout.

Draw 9 ml of acid-citrate-dextrose (ACD) (see note a) into each of two 60 ml plastic non-heparinized syringes.

Withdraw 51ml of patient's blood into each syringe, using a 19G Butterfly needle infusion set. Close the

syringes with sterile hubs.

Dispense 2ml sedimentation agent (see note b) into each of 5 Universal containers or tubes.

Without attaching a needle to the syringes dispense 20 ml of blood into each of the 5 Universal tubes

containing sedimentation agent. Dispense the remaining 20ml of blood into a tube without sedimentation agent.

TIP:

To avoid bubbles and frothing run the blood gently down the sides of the tubes.

Mix the blood and sedimentation agent with one gentle inversion. Remove the cap of the Universal tube and

burst the bubble formed at the top using a sterile needle.

Replace the cap and allow the tubes to stand for 30-60

minutes for erythrocyte sedimentation to take place.

TIP:

The period of time for erythrocyte sedimentation depends on the patient's condition. As a guideline it should be

stopped when the blood has sedimented to give approximately half the volume as sedimented red cells.

Meanwhile centrifuge the tube containing 20 ml of blood and no sedimentation agent at 2000g for 10 minutes.

This will yield supernatant cell-free plasma (CFP) containing ACD which is retained, at room temperature, for use as a

cell labelling and re-injection medium.

When sufficient red cell sedimentation has taken place [see (5)] carefully transfer 15 ml aliquots of the cloudy

straw-coloured supernatant into clean Universal tubes.

Take care to avoid withdrawing any sedimented erythrocytes.

The supernatant is leucocyte-rich, platelet-rich plasma [LRPRP].

TIP:

Do not use needles on sampling syringes to avoid unnecessary cell damage.

Centrifuge the LRPRP at 150g for 5 minutes to give supernatant, platelet-rich plasma (PRP) and a pellet of

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"mixed" leucocytes.

Remove as much of the PRP as possible into clean Universal tubes and further centrifuge at 2000g for 10

minutes to give more supernatant, CFP containing sedimentation agent. This will be used to wash the cells after

labelling.

(10)

Meanwhile loosen the pellets of "mixed" leucocytes by very gently tapping and swirling the Universal tubes.

Using a syringe, without an attached needle, pool all the cells into one tube then, using the same syringe, add 1ml of

cell-free plasma containing ACD (from 6) and gently swirl to resuspend.

(11)

Reconstitute a vial of Ceretec with 5 ml of technetium-99m generator eluate containing approximately 500

MBq (13.5 mCi) of 99mTcO4 (using the procedure described above)

(12)

Immediately following reconstitution adds 4 ml of the resulting technetium-99m exametazime solution to the

"mixed" leucocytes in CFP (from 10).

(13)

Gently swirl to mix and incubate for 10 minutes at room temperature.

(14)

If required, immediately spot the chromatography strips for assessment of radiochemical purity of the

technetium-99m exametazime, as instructed overleaf.

(15)

On completion of incubation carefully add 10ml of CFP containing sedimentation agent (from 9) to the cells, in

order to stop labelling. Gently invert the cells to mix.

(16)

Centrifuge at 150g for 5 minutes.

(17)

Remove and retain all of the supernatant.

TIP: It is critical that all the supernatant which contains unbound technetium-99m exametazime is removed at this

stage. This can be best achieved using a syringe with a wide-bore [19G] needle.

(18)

Gently resuspend the technetium-99m labelled mixed leucocyte preparation in 5-10 ml of CFP containing ACD

from (6). Gently swirl to mix.

(19)

Measure the radioactivity in the cells and in the supernatant from (17).

Calculate the labelling efficiency [LE]

which is defined as the activity in the cells as a percentage of the sum of the activity in the cells and the activity in the

supernatant.

TIP:

Labelling efficiency depends on the patient’s leucocyte count and will vary according to the volume of the

initial blood sample. Using the volumes in (2), a LE of about 55% might be expected

(20)

Without attaching a needle, carefully draw up the labelled cells into a plastic, non-heparinised syringe and

close it with a sterile hub. Measure the radioactivity.

(21)

Labelled cells are now ready for re-injection. This should be performed without delay.

Note:

Acid-citrate-dextrose (ACD) should be made up as follows:

NIH Formula A.

For 1 litre add 22g trisodium citrate, 8g citric acid, 22.4g dextrose and make up to 1 litre with Water

for injections. The product should be manufactured under aseptic condition.

Commercial preparations of the product

are also available. The product should be stored under the conditions recommended by the manufacturer and should be

used only up to the expiry date given by the manufacturer.

6% hydroxyethyl starch should be manufactured under aseptic conditions. Commercial preparations of the

product are available. The product should be stored under the conditions recommended by the manufacturer and should

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0

be used only up to the expiry date given by the manufacturer.

Quality control

Three potential radiochemical impurities may be present in the prepared exametazime injection. These are a secondary

Tc exametazime complex, free pertechnetate and educed-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 (2 cm (± 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% aq.

sodium chloride (1cm depth fresh solvent). After a 14cm 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

Tc exametazime complex and reduced-hydrolysed-technetium remain at the origin.

Lipophilic

Tc exametazime complex and pertechnetate migrate at Rf 0.8-1.0.

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

Lipophilic

Tc exametazime complex, secondary

Tc exametazime complex and reduced-hydrolysed-Tc remain at

the origin.

Pertechnetate migrates at Rf 0.8-1.0.

Calculate the percentage of activity due to both secondary

Tc exametazime complex and reduced-

hydrolysed-technetium-99m from System 1 (A%). Calculate the percentage of activity due to pertechnetate from

System 2 (B%).

The radiochemical purity (as percentage lipophilic

Tc exametazime complex) is given by:

100-(A%+B%) where:

A% represents the level of secondary

Tc exametazime complex plus reduced-hydrolysed technetium-99m

B% represents the level of pertechnetate.

A radiochemical purity of at least 80% may be expected provided the test samples have been taken and analysed within

30 minutes of reconstitution.

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