Consumer medicine information

Ceretec

Exametazime

BRAND INFORMATION

Brand name

Ceretec

Active ingredient

Exametazime

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ceretec.

What is in this leaflet

This leaflet answers some common questions about CERETEC. It does not contain all the available information, nor does it take the place of talking to your doctor or treatment provider.

All medicines and diagnostic preparations have risks and benefits. Your doctor has weighed the risks of you being treated with CERETEC against the expected benefits.

If you have any concerns about being given this preparation, ask your doctor, or treatment provider.

Keep this leaflet. You may need to read it again.

What CERETEC is used for

CERETEC is used in the preparation of a radiopharmaceutical which is a medicinal product containing a small amount of radioactivity.

Such radiopharmaceuticals are given in small amounts to find or rule out a disease. The radiation your body receives is very low and is considered safe. After the radioactive liquid is given to you, it is taken up by the organs of interest or just passes through your body. The radiation is taken up by a special camera and pictures are prepared. These pictures allow the nuclear medicine doctor to detect any problems.

In particular, CERETEC is used to produce images of the brain of patients who have fits or seizures. They occur when the brain's electrical currents become disordered from time to time in some people. This disease is called epilepsy. There is a number of different types of epilepsy. CERETEC is used particularly for the imaging of patients with epilepsy which originates in the parts of the brain just centre and slightly behind the ears.

CERETEC is used to help find or rule out a diagnosis only. It is not used to treat or cure epilepsy.

Your doctor may have prescribed CERETEC for another reason.

CERETEC is not recommended normally for use in children because studies have not been performed on the use of CERETEC in children. Nevertheless, your doctor may have decided to still use it and will have weighed up the risks and benefits.

Ask your doctor if you have any questions about why CERETEC has been prescribed for you.

Before you are given CERETEC

When you must not be given it

You must not be given CERETEC if you are allergic to it, or:

  • any of the ingredients listed at the end of this leaflet or,
  • have had a previous allergic reaction in a diagnostic procedure with the same or similar preparation.

Before you are given CERETEC

Your doctor must know about all of the following before you are given CERETEC. Tell your doctor if you:

  1. have allergies to:
    - any other medicines, particularly those containing technetium or other imaging agents
    - any other substances, such as foods, preservatives (substances to maintain food quality or freshness) or dyes (colourants)
    - any of the ingredients of CERETEC listed at the end of this leaflet or to technetium (as CERETEC will be made up in a solution of Technetium and sodium chloride for injection).
  2. are pregnant or intend to become pregnant in the near future.
    CERETEC is to be avoided during pregnancy as adequate testing has not been performed. Your doctor may decide that the benefit may outweigh the risk. Radiopharmaceuticals are not usually given to pregnant women to avoid exposing the foetus to radiation. However, some radiopharmaceuticals may be used for diagnostic tests in pregnant women, so it is important to inform your doctor if you are pregnant.
  3. are breastfeeding.
    Components of CERETEC may be excreted in the breast milk. Therefore, you should stop breastfeeding and substitute formula feeds for at least 24 hours after you are given CERETEC or longer if your doctor tells you to.
  4. have, or have had any other medical conditions.
  5. you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you are given CERETEC.

Taking other medicines

Tell your doctor if you are taking any other medicines including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Your doctor or treatment provider has more information on medicines to be careful with or to avoid when you are given CERETEC.

If you have not told your doctor about any of the above, tell them before you are given any CERETEC.

How CERETEC is given

Your doctor may have special instructions for you to follow to get ready for your procedure.

CERETEC is given as an injection into a vein. CERETEC must only be given by a doctor or nuclear medicine technologist.

Your doctor is qualified in nuclear medicine and will decide what dose of CERETEC you will receive, depending on your condition and other factors, such as your weight. In any case, the amount of radioactivity in the injection will not be big.

CERETEC is usually given as a single dose and within minutes after it is given diagnostic images will be taken.

If you have any questions about taking CERETEC or about the diagnostic procedure, ask your doctor.

After being given CERETEC

CERETEC breaks down quickly after it is given and is virtually removed from the body after about 48 hours.

After completion of the examination, however, the doctor may ask you to go to the toilet to reduce the radiation dose to your bladder and the surrounding organs. You may also be asked to drink water to help with this process.

If you have any questions or concerns, be sure to discuss these with your doctor.

Side effects

The following side effects have been reported after use of CERETEC:

  • rash
  • symptoms of allergy/sensitivity
  • red skin
  • swelling of the face
  • fever
  • brief increase in blood pressure

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of side effects. You may not experience any of them.

Overdose

The dose of CERETEC you will receive will be calculated by a qualified nuclear medicine doctor and given to you in a highly specialised setting. Therefore the possibility of overdose is minimal.

Storage

CERETEC will be stored by the hospital or clinic.

The hospital or clinic will make sure that CERETEC is not used if the expiry date (EXP) printed on the pack has passed.

Further information

This is not all the information that is available on CERETEC. If you have any more questions or are not sure about anything, ask your doctor or nuclear medicine technologist.

Product description

Ingredients

Each vial contains:

active ingredient -
exametazime 0.5mg

other ingredients -

  • sodium chloride
  • stannous chloride dihydrate
  • nitrogen gas in the headspace

Australian Registration Number: AUST R 10018

Sponsor

CERETEC is made in England and supplied in Australia by:
GE Healthcare Australia Pty Ltd
ABN 32 001 408 402
32 Phillip St
Parramatta NSW 2150

PO Box 5079
Parramatta NSW 2150
Tel 1300 887 764
Fax 1300 434 232

This leaflet was prepared in December 2014.

Ceretec is a trademark of GE Healthcare.

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

Published by MIMS April 2015

BRAND INFORMATION

Brand name

Ceretec

Active ingredient

Exametazime

Schedule

Unscheduled

 

Name of the medicine

Exametazime (formerly known as hexamethylpropylene amine oxime (HM-PAO)).

Excipients.

Stannous chloride dihydrate 7.6 microgram (minimum stannous tin 0.6 microgram, maximum total stannous and stannic tin 4.4 microgram per vial), sodium chloride 4.5 mg. The product contains no antimicrobial preservative.

Description

Chemical name: [(RR,SS)-4,8-diaza- 3,6,6,9-tetramethylundecane- 2,10-dione bisoxime]. The Ceretec kit is supplied as packs of two or five single dose vial units for use in the preparation of a technetium (99m Tc)-exametazime intravenous injection. Each vial is sealed under nitrogen atmosphere at a pressure just below atmospheric, with a rubber closure.
When sterile pyrogen free sodium pertechnetate (99m Tc) in isotonic saline is added to the vial, a (99m Tc) complex of exametazime is formed.
Administration is by intravenous injection for diagnostic use.
Each single dose vial unit contains a predispensed sterile, nonpyrogenic, lyophilized mixture of 0.5 mg exametazime.

Physical characteristics.

Technetium-99m decays by isomeric transition with a physical half-life of 6 hours. Photons associated with this transition which are useful for detection and imaging studies are listed in Tables 1 and 2.

External radiation.

The specific gamma ray constant for 99m Tc is 0.19 mGy per MBq-h at 1 cm.
The half value thickness of lead (Pb) for 99m Tc is 0.2 mm. Attenuation by lead is given in Table 3.

Pharmacology

Pharmacodynamic properties.

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

Pharmacokinetic properties.

When sodium pertechnetate (99m Tc) is added to exametazime in the presence of stannous reductant, a lipophilic technetium-99m complex is formed. This lipophilic complex is the active moiety. It converts with time to a secondary complex which is less lipophilic. When the secondary complex is isolated from the lipophilic species, it has been shown to be unable to cross the blood-brain barrier. A consequence of the conversion of lipophilic to secondary complex is that the useful life of the reconstituted agent is restricted to 30 minutes.
Studies in normal volunteers have shown that the technetium-99m complex of the RR,SS(d,l) diastereoisomer of exametazime is rapidly cleared from the blood after intravenous injection. Blood activity falls to 15%, 10% and 4% of the administered dose at 5 minutes, 1 hour and 24 hours respectively. 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 activity is eliminated from the brain by 2 minutes postinjection, after which little activity is lost 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 30% of the injected dose is found in the gastrointestinal tract immediately after injection and about 50% of this is excreted through the intestinal tract over 48 hours. 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.

Indications

Technetium [99m Tc]-exametazime scintigraphy is indicated for scintigraphic localisation of seizure foci in patients with temporal lobe epilepsy in institutions with appropriate expertise and facilities.

Contraindications

None known.

Precautions

As part of the manufacture, the vial of freeze dried product is filled with an inert nitrogen atmosphere to a pressure just below atmospheric before being sealed with the rubber closure. The product does not contain an antimicrobial preservative. Technetium [99m Tc]-exametazime should not be mixed with any substance other than those recommended for reconstitution.
This product is a component for use in the preparation of a radioactive product intended for pharmaceutical use. Because of the small mass of chemical substances present, there is negligible risk to persons handling or administering the material, other than that from the radioactive nature of the reconstituted product.
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. Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic nuclear medicine investigations the current evidence suggests that these adverse effects will occur with negligible frequency because of the low radiation dose incurred.
For most diagnostic investigations involving a nuclear medicine procedure, the effective dose (E) to the patient is less than 20 mSv. The activity administered must not be greater than is necessary to provide the intended diagnostic information.
The use of (99m Tc)-exametazime and the interpretation of images in patients with temporal lobe epilepsy requires considerable experience. In order to avoid false positive interpretations, the findings of (99m Tc)-exametazime scintigraphy may be accepted if concordant with EEG and neurophysiological assessment. (99m Tc)-exametazime scintigraphy findings should not over-ride apparently discrepant EEG results. EEG should be continuously monitored immediately prior to and during injection of the radiopharmaceutical.
In the event of scintigraphy being performed in close proximity to a seizure, it is essential to record injection time in relation to the cessation of the fit for accurate interpretation of the study.
Each dose vial is expressly intended for single patient use. Any deviation from the Ceretec intended usage, including the preparation of multiple doses from the single dose vial supplied, may result in misdiagnosis.
The contents of the Ceretec vial are not radioactive. However, after the sodium pertechnetate (99m Tc) is added, adequate shielding of the final preparation must be maintained.
The contents of the Ceretec vial are intended only for use in preparation of technetium (99m Tc)-exametazime injection and are not to be administered directly to the patient.
A thorough knowledge of the normal distribution of intravenously administered technetium (99m Tc)-exametazime injection is essential in order to interpret pathologic studies accurately.
The technetium (99m Tc) labelling reaction involved in preparing technetium (99m Tc)-exametazime injection depends on maintaining tin in the divalent (reduced) state. Any oxidant present in the sodium pertechnetate (99m Tc) employed may adversely affect the quality of the preparation. Sodium pertechnetate (99m Tc) containing oxidants should not be used for the preparation of the labelled product. To meet the last requirement, a generator must be eluted within 24 hours prior to obtaining any eluate for reconstitution with the Ceretec kit. The eluate for reconstitution should not have been eluted more than two hours prior to use.
Sodium Chloride Injection BP must be used as the diluent. Do not use bacteriostatic sodium chloride as a diluent for sodium pertechnetate (99m Tc) injection because it will increase the oxidation products and adversely affect the biological distribution of Ceretec.
The contents of the Ceretec vial are sterile and pyrogen free. The vial contains no antimicrobial preservative. It is essential that the user follow the directions carefully and adhere to strict aseptic procedures which comply with the requirements of Good Manufacturing Practice for Pharmaceuticals, during preparation of the radiopharmaceutical.
Technetium (99m Tc)-exametazime injection, like other radioactive drugs, must be handled with care and appropriate safety measures should be used to minimise radiation exposure to clinical personnel. Care should also be taken to minimise radiation exposure to the patient consistent with proper patient management.
Radiopharmaceuticals should be used only by or under the control of physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorised to license the use of radionuclides.
To minimise radiation dose to the bladder, the patient should be encouraged to void when the examination is completed and as often, thereafter, as possible. Adequate hydration should be encouraged to permit frequent voiding.
The disposal of all radioactive wastes should be carried out in accordance with the NH&MRC "code of practice for the disposal of radioactive wastes by the user (1985)".

Carcinogenesis, mutagenesis, impairment of fertility.

No long-term animal studies have been performed to evaluate carcinogenic potential or whether technetium (99m Tc)-exametazime affects fertility in males or females. Studies in rats did not demonstrate mutagenic potential following intraperitoneal administration at doses of 70, 140 and 280 mg/kg.

Use in pregnancy.

(Category C)
Since adequate reproduction studies with technetium (99m Tc)-exametazime have not been performed in animals to determine whether this drug affects fertility in males and females, has teratogenic potential or has other adverse effects on the foetus, this radiopharmaceutical preparation should not be administered to pregnant or nursing women unless it is considered that the benefits to be gained outweigh the potential hazards to the foetus and safer alternative procedures are not available. Administration of technetium [99m Tc]-exametazime at a dose of 500 MBq results in an absorbed dose to the uterus of 3.6 mGy: administration of technetium-99m labelled leucocytes at a dose of 200 MBq results in an absorbed dose to the uterus of 3.6 mGy. A radiation dose above 0.5 mGy (equivalent to that exposure from annual background radiation) would be regarded as a potential risk to the foetus.
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 minimum consistent with achieving the desired clinical information. Alternative techniques which do not involve ionising radiation should be considered.

Use in lactation.

Technetium (99m Tc) is excreted in human milk during lactation. It is not known whether exametazime is excreted in human milk.
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 the mother has ceased breastfeeding and as to whether the most appropriate choice of radiopharmaceutical has been made bearing in mind the secretion of activity in breast milk. If administration is considered necessary, breastfeeding should be interrupted and the expressed feeds discarded. Therefore formula feeding should be substituted for breastfeeding.
Breastfeeding can be restarted when the level of radioactivity in the milk will not result in an effective dose to the child of greater than 1 mSv. In practice it is preferable to use a dose constraint of 0.3 mSv rather than the dose limit of 1 mSv, as this will ensure that the sum of both internal and external irradiation will be below the dose limit.

Paediatric use.

Safety and effectiveness in children and adolescents have not been established.

Interactions

No drug interactions have been reported to date.

Adverse Effects

A very few cases of mild hypersensitivity evidenced by the development of an urticarial rash with generalised erythema, facial oedema and fever has been reported. A transient increase in blood pressure was seen in 8% of patients. A very few cases have also been reported of possible vascular spasm following administration of the reconstituted product.
In case of side effects following administration of radiopharmaceuticals, users should ensure the availability of appropriate medical treatment at the time of administration of any radiopharmaceutical to the patient.

Dosage and Administration

Normally a once only diagnostic procedure.
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.
The user should wear waterproof gloves and use shielding at all times when handling the vial and syringes.
The recommended dose range for i.v. administration, after reconstitution with sodium pertechnetate (99m Tc), to be used in the average adult (70 kg) is 350-500 MBq.
Do not use the final radiopharmaceutical preparation more than 30 minutes after the time of reconstitution. Dispose of any unused material (and its container) via an authorised route.
Dynamic imaging may be performed between 0 to 10 minutes following injection. Static imaging may be performed from 15 minutes up to 6 hours after injection.
Although gross abnormalities may be visualised by planar imaging, it is strongly recommended that SPECT imaging is carried out to maximise the value of the study.

Radiation dosimetry.

Based on human data*, the absorbed radiation dose to humans resulting from intravenous injection of technetium (99m Tc)-exametazime is estimated in Table 4. The values are listed as mGy per 500 MBq maximum dose with urinary bladder voiding every 3.5 hours.
* Soundy RG, Tyrrell DA, Pickett RD and Stabin M, "The Radiation Dosimetry of Technetium-99m Exametazime", Nuclear Medicine Communications, 1990, vol 11, pp 791-799.

Animal toxicology summary.

Acute toxicity studies have been performed on intravenously administered Ceretec in male and female rats and rabbits. No adverse reactions or mortality were observed at a dose equivalent to the single injection of 1200 times the maximum human equivalent dose. Fourteen day repeat dose studies in rats and rabbits at a cumulative dose of up to 14,000 times the maximum human equivalent dose did not reveal adverse reactions, abnormalities, or mortality. At termination, histopathology, haematology and blood chemistry revealed no abnormalities.

Procedure for the preparation of technetium (99m Tc) exametazime injection.

Use aseptic technique throughout.
1. Place one of the vials in a suitable shielding container and swab the rubber septum with the sanitising swab provided.
2. Using a 10 mL syringe, inject into the shielded vial 5 mL of sterile eluate from a technetium (99m Tc) generator (see notes 1-8). Before withdrawing the syringe from the vial withdraw 5 mL 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.
3. Assay the total activity and calculate the volume to be injected.
4. Complete the label provided and attach to the vial shield. The technetium (99m Tc)-exametazime injection is ready for quality control.
5. Maintain adequate shielding of the radioactive preparation.
6. Do not use the preparation more than 30 minutes after time of formulation. Dispose of any unused material (and its container) via an authorised route.
7. Visually inspect the reconstituted material at a safe distance behind leaded glass, and do not use if there is evidence of foreign matter.

Cautionary notes.

1. 0.37-1.11 GBq technetium (99m Tc) may be added to the vial.
2. Before reconstitution, the generator eluate may be adjusted to the correct radioactive concentration (0.37-1.11 GBq in 5 mL) by dilution with preservative free, nonbacteriostatic sodium chloride for injection.
3. Generator eluate more than 2 hours old should not be used. For the highest radiochemical purity reconstitute with freshly eluted technetium (99m Tc) generator eluate.
4. Do not use eluate from a technetium (99m Tc) generator when more than 24 hours has elapsed since the previous elution. Do not use ‘Instant Pertechnetate’.
5. The pH of the prepared injection is in the range 9.0-9.8.
6. Radiochemical purity testing must be performed. A radiochemical purity greater than 80% with the content of pertechnate (99m Tc) not greater than 10% is necessary for product acceptance.
7. The use of pertechnetate complying with the specifications prescribed by the USP and BP/Ph Eur monographs on Sodium Pertechnetate (99m Tc) Injection will yield a preparation of an appropriate quality.
8. A single reconstitution volume of 5 mL is recommended at all times since exametazime has limited solubility and only this reconstitution volume is clinically supported.
For details of the storage, elution, handling and disposal of the Technetium-99m Sterile Generator used as the source of Sodium Pertechnetate (99m Tc) Injection required for reconstitution of Ceretec, the user is referred to the Instructions for Use supplied with the Generator by the manufacturer.

Quality control.

Radiochemical purity determination should be performed, as far as possible, before administration to the patient. Three potential radiochemical impurities may be present in the prepared injection of the lipophilic complex technetium (99m Tc)-exametazime. These are a secondary technetium (99m Tc)-exametazime complex, free pertechnetate, and reduced hydrolysed technetium (99m Tc). A combination of 2 chromatographic systems is necessary for the complete definition of the radiochemical composition of the injection.
Test samples are applied by needle approximately 2.5 cm from the bottom of two GMCP-SA strips (2 cm (± 2 mm) x 20 cm). 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 (1 cm depth fresh solvent). After a 14 cm 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: MEK (butan-2-one)).
Secondary technetium (99m Tc)-exametazime complex and reduced hydrolysed (99m Tc) remain at the origin.
Lipophilic (99m Tc)-exametazime complex and pertechnetate migrate at Rf = 0.8-1.0.
System 2 (GMCP SA: 0.9% sodium chloride).
Lipophilic technetium (99m Tc)-exametazime complex, secondary technetium (99m Tc)-exametazime complex and reduced hydrolysed technetium (99m Tc) remain at the origin.
Pertechnetate migrates at Rf = 0.8-1.0.
(i) Calculate the percentage of activity due to both secondary technetium [99m Tc]-exametazime complex and reduced hydrolysed technetium [99m Tc] from system 1 (A%).
Calculate the percentage of activity due to pertechnetate from system 2 (B%).
(ii) The radiochemical purity (as percentage lipophilic technetium [99m Tc]-exametazime complex) is given by: 100 - (A% + B%) where: A represents the level of secondary technetium [99m Tc]-exametazime complex plus reduced hydrolysed technetium-99.
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. The content of pertechnate [99m Tc] impurity should not be greater than 10%.

Overdosage

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 the patient.

Presentation

Powder for injection, 0.5 mg (predispensed, sterile, nonpyrogenic, freeze dried lyophilised mixture, preservative free): 2's, 5's (single dose vial unit supplied with a user label and sanitising swab).

Storage

Store below 25°C. Do not freeze.
Store the reconstituted injection at 15°C-25°C and use within 30 minutes following reconstitution.

Expiry.

The expiry date is stated on the label and will normally be not less than 10 weeks after the date of dispatch. The product must not be used after the expiry date.

Poison Schedule

Unscheduled.