1 Name of Medicine
Tetrofosmin.
2 Qualitative and Quantitative Composition
Myoview consists of a freeze dried formulation contained within a 10 mL, neutral glass vial and sealed with a chlorobutyl closure and an aluminium overseal.
Each vial contains:
Tetrofosmin (active ingredient) 0.23 mg;
Stannous chloride dihydrate 0.03 mg;
Disodium sulphosalicylate 0.32 mg;
Sodium D-gluconate 1.0 mg;
Sodium bicarbonate 1.8 mg;
Nitrogen gas to 80% atmospheric pressure.
Nuclear data for technetium-99m.
Sodium Pertechnetate [99mTc] Injection Ph.Eur is produced by a [99Mo/99Tc] generator. Technetium-99m disintegrates with the emission of gamma radiation (energy 141 keV, 88.5%; 43 keV, 0.03%) and a half-life of 6.02 hours).
To correct for the physical decay of this radionuclide, the fractions that remain at selected intervals relative to the time of calibration are shown in Table 1.
The specific gamma ray constant for 99mTc is 0.19 mGy per MBq-hour at 1 cm. The first half-value thickness of lead for 99mTc is 0.2 mm. Attenuation by lead is given in Table 2.
These data are useful for radiation protection purposes. The dose rate at 0.5 m from a vial containing 1.11 GBq technetium-99m will be reduced to less than 2.5 microSv/h by shielding with 2 mm lead.3 Pharmaceutical Form
See Section 2 Qualitative and Quantitative Composition.
4.1 Therapeutic Indications
Myoview is indicated as an adjunct in the diagnosis of ischaemic heart disease.
4.2 Dose and Method of Administration
For the diagnosis and localization of myocardial ischaemia the recommended procedure involves two intravenous injections of 99mTc-tetrofosmin. For adults and the elderly 185-250 MBq is given at peak exercise, followed by 500-750 MBq given at rest approximately 4 hours later. The activity administered should be restricted to 1000 MBq in any one day. As an adjunct in the diagnosis and localization of old myocardial infarction, one injection of 99mTc-tetrofosmin (185-250 MBq) at rest is sufficient.
Patients should be requested to fast overnight or to have only a light breakfast on the morning of the procedure.
Planar, or preferably SPECT, imaging should begin no earlier than 15 minutes post-injection. There is no evidence for significant changes in myocardial concentration or redistribution of 99mTc-tetrofosmin, therefore, images may be acquired up to at least four hours post-injection. For planar imaging, the standard views (anterior, LAO 40°-45°, LAO 65°-70° and/or left lateral) should be acquired.
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.
Procedure for the preparation of 99mTc-tetrofosmin injection.
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.
Use aseptic technique throughout.
1. Place the vial in a suitable shielding container and sanitise the rubber septum with the swab provided.
2. Insert a sterile needle (the venting needle, see Note 1) through the rubber septum. Using a shielded, 10 mL sterile syringe, inject the required activity of Sodium Pertechnetate [99mTc] Injection Ph.Eur. (appropriately diluted with 0.9% Sodium Chloride Injection B.P.) into the shielded vial (see Notes 2 to 4). Before removing the syringe from the vial, withdraw 5 mL of gas from above the solution. (See Note 5). Remove the venting needle. Shake the vial to ensure complete dissolution of the powder.
3. Incubate at room temperature for 15 minutes.
4. During this time assay the total activity, complete the user label provided and attach it to the vial.
5. The reconstituted product should be stored below 25°C. Do not freeze and use within 12 hours of preparation. Dispose of any unused material and its container via an authorised route.
Notes.
1. A needle of size 19G to 26G may be used.
2. The Sodium Pertechnetate [99mTc] Injection Ph.Eur. used for reconstitution should contain less than 5 ppm aluminium.
3. The volume of diluted Sodium Pertechnetate [99mTc] Injection Ph.Eur. added to the vial must be in the range 4-8 mL.
4. The radioactive concentration of the diluted Sodium Pertechnetate [99mTc] Injection Ph.Eur. must not exceed 1.5 GBq/mL when it is added to the vial.
5. The pH of the prepared injection is in the range 7.5-9.0.
6. Studies have demonstrated that satisfactory radiochemical purity is achieved when Myoview is reconstituted with Sodium Pertechnetate [99mTc] Injection Ph.Eur. eluted up to 6 hours previously, from a generator last eluted within 72 hours.
7. For preparation volumes of more than 6 mL, the remaining vial headspace is less than the 5 mL added air volume. In these cases, the withdrawal of a 5 mL volume of gas ensures that all of the vial headspace is replaced by air.
Radiation dosimetry data.
The estimated absorbed radiation dose for an average adult patient (70 kg), from intravenous injections of 99mTc-tetrofosmin, are listed in Table 3. Effective dose values were calculated in accordance with ICRP Publication 128 (International Commission of Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals; A Compendium of Current Information Related to Frequently Used Substances Ann ICRP 2015). The values are calculated assuming urinary bladder emptying at 3.5 hour intervals. The highest absorbed doses only are given.
Frequent bladder emptying should be encouraged after dosing to minimise radiation exposure.
The effective dose (ED) resulting from the administration of doses of reconstituted Myoview of 250 MBq after exercise and 750 MBq at rest is 1.73 mSv after exercise and 6.00 mSv at rest (per 70 kg individual). If doses are calculated on the basis of the previously used effective dose equivalent (EDE), values are 2.15 mSv and 8.38 mSv, respectively.
Radiochemical purity measurement.
Radiochemical purity may be checked using the following procedures:
Method 1. Equipment and eluent.
(1) GMCP-SA TLC strip (2 cm x 20 cm). Do not heat activate.
(2) Ascending chromatography tank and cover.
(3) 65:35% v/v mixture of acetone and dichloromethane (prepared freshly).
(4) 1 mL syringe with 22-25G needle.
(5) Suitable counting equipment.
Method. (1) Pour the 65:35% v/v acetone:dichloromethane mixture into the chromatography tank to a depth of 1 cm and cover the tank to allow the solvent vapour to equilibrate.
(2) Mark a GMCP-SA TLC strip with a pencil line at 3 cm from the bottom and, using an ink marker pen, at 15 cm from the pencil line. The pencil line indicates the origin where the sample is to be applied and movement of colour from the ink line will indicate the position of the solvent front when upward elution should be stopped.
(3) Cutting positions at 3.75 cm and 12 cm above the origin (Rf's 0.25 and 0.8 respectively) should also be marked in pencil.
(4) Using a 1 mL syringe and needle, apply a 10 microL sample of the prepared injection at the origin of the strip. Do not allow the spot to dry. Place the strip in the chromatography tank immediately and replace the cover. Ensure that the strip is not adhering to the walls of the tank.
Note.
A 10 microL sample will produce a spot with a diameter of approximately 10 mm. Different sample volumes have been shown to give unreliable radiochemical purity values.
(5) When the solvent reaches the ink line, remove the strip from the tank and allow it to dry.
(6) Cut the strip into 3 pieces at the marked cutting positions and measure the activity on each using suitable counting equipment. Try to ensure similar counting geometry for each piece and minimize equipment dead time losses.
(7) Calculate the radiochemical purity, see Equation 1:
Note.
Free (99mTc) pertechnetate runs to the top piece of the strip. Tetrofosmin (99mTc) runs to the centre piece of the strip. Reduced hydrolysed 99mTc and any hydrophilic complex impurities remain at the origin in the bottom piece of the strip.
Do not use material if the radiochemical purity is less than 90%.
Simplified chromatographic procedure for rapid quality control.
Method 2. Equipment and eluent.
(1) Solid Phase Extraction (SPE) C18 cartridge (360 mg Sorbent, 55 - 105 microM particle size, e.g. Waters Sep-Pak or equivalent).
(2) 3 x 10 mL vials and caps, Labelled "A", "B" and C.
(3) Lead pots.
(4) 0.9% Sodium chloride.
(5) Ethanol.
(6) Dose calibrator.
Method. Note.
All loading steps (sample and solvents) must be performed using a slow flow rate (i.e. drop by drop application of the mobile phase). If the flow is too high, components may not interact sufficiently with the stationary phase which will give an inaccurate result for radiochemical purity.
1. Place the cartridge in the correct orientation (short end facing upwards) in a clamp stand and place behind a suitable lead shield.
2. Place the vial labelled 'A' under the cartridge as a collection vial.
3. Condition the stationary phase by flushing with 2 mL 0.9% sodium chloride collecting in vial 'A'.
4. Carefully load 25 - 50 microL of the preparation onto the cartridge.
5. Elute the cartridge with 2 mL 0.9% sodium chloride, collecting the eluate in vial 'A'.
6. Cap vial 'A' and place in a shielded container. Cap and retain for measurement.
7. Place vial 'B' under the cartridge as a collection vial.
8. Elute the cartridge with 5 mL ethanol, collecting the eluate in vial 'B'.
9. Cap vial 'B' and place in a shielded container. Cap and retain for measurement.
10. Remove the SPE cartridge using tweezers and place into vial 'C' and place in a shielded container. Cap and retain for measurement.
11. Measure the activity of each of the vials labelled A to C using a dose calibrator. Under the test conditions employed:
Free 99mTc O4- (pertechnetate) is eluted from the cartridge with 2 mL 0.9% Sodium Chloride (Vial A).
99mTc-tetrofosmin is retained on the stationary phase and is eluted with 5 mL ethanol (Vial B).
Reduced hydrolysed 99mTc (RHT) and hydrophilic impurities remain on the cartridge (Vial C).
12. Calculate the % 99mTc-tetrofosmin, see Equation 2:
13. Do not use material if the radiochemical purity is less than 90%.4.3 Contraindications
Myoview is contraindicated in pregnancy and in patients with known hypersensitivity to tetrofosmin or any of the excipients.
4.4 Special Warnings and Precautions for Use
This product is not to be administered directly to the patient. The contents of the vial are intended only for use in the preparation of a radioactive technetium-99m labelled injection, using the procedures described in this pack leaflet.
Radiopharmaceutical agents should only be used by qualified personnel with the appropriate government authorisation for the use and manipulation of radionuclides. They may be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use transfer and disposal are subject to the regulations and/or appropriate licenses of the local competent official organisations.
Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken, complying with the requirements of Good Manufacturing Practice for pharmaceuticals.
The normal precautions for handling radioactive materials should also be observed. For details of the storage, elution, handling and disposal of the 99mTc sterile generator used as the source of Sodium Pertechnetate [99mTc] Injection required for reconstitution of Myoview the user is referred to the instructions for use supplied with the generator by the manufacturer. The disposal of all radioactive wastes should be carried out in accordance with the NHMRC "Code of Practice for the Disposal of Radioactive Wastes by the User, (1985)".
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. 99mTc-tetrofosmin should not be mixed or diluted with any other substance other than those recommended for reconstitution.
This product is a component for use in the preparation of a radioactive injection 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.
Technetium-99m has a short half-life (6 hours) and, therefore, no special precautions are needed by the patient for the disposal of urine or faeces, other than normal hygiene procedures.
For each patient, exposure to ionizing 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 ionizing 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 events will occur with negligible frequency because of the low radiation dose incurred.
For most diagnostic investigations using a nuclear medicine procedure, the radiation dose (E) delivered is less than 20 mSv. Higher doses may be justified in some clinical circumstances.
Use in the elderly.
No data available.
Paediatric use.
99mTc-tetrofosmin is not recommended for use in children less than 12 years of age or adolescents as data are not available for this age group.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
The interaction of Myoview with other drugs has not been systematically investigated, however, no interactions were reported in clinical studies in which Myoview was administered to patients receiving comedication. Drugs which influence myocardial function and/or blood flow, for example, beta blockers, calcium antagonists or nitrates, can lead to false negative results in diagnosis of coronary artery disease. The results of imaging studies should always, therefore, be considered in the light of current medication.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
It is not known whether 99mTc-tetrofosmin causes impairment of fertility in animals or humans.
Myoview is contraindicated in pregnancy. Animal reproductive toxicity studies have not been performed with 99mTc-tetrofosmin. There have been no studies of 99mTc-tetrofosmin in pregnant women. Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus. Administration of 99mTc-tetrofosmin at doses of 250 MBq at exercise, followed by 750 MBq at rest results in absorbed dose to the uterus of 8.1 mGy. A radiation dose above 0.5 mGy (equivalent to the 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 the minimum consistent with achieving the desired clinical information. Alternative techniques which do not involve ionizing radiation should be considered.
It is not known whether 99mTc-tetrofosmin is secreted in human milk. 99mTc-pertechnetate is excreted in human milk during lactation.
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, therefore if administration is considered necessary, formula feeding should be substituted for breastfeeding for at least 24 hours.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
Adverse reactions reported following administration of 99mTc-tetrofosmin injection are listed below. The frequency of these is rare (approximately 0.03%).
A few patients have experienced a feeling of bodily warmth, flushing, vomiting (12-24 hours postinjection), headache, dizziness, a transient metallic taste, disturbance of smell and a mild burning sensation in the mouth after injection. Hypersensitivity reactions have occurred including flushing, urticarial or erythematous rash, facial oedema, hypotension and dyspnoea. Some reactions were delayed by several hours following administration of 99mTc-tetrofosmin.
In addition to the above, during clinical trials a small number of patients (less than 4%) experienced a transient, and clinically insignificant, increase in white blood cells following administration of 99mTc-tetrofosmin but a causal relationship was not established.
Isolated cases of serious reactions have been reported, including anaphylactic reaction (0.001%) and severe allergic reaction (single report).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
In cases of overdosage of radioactivity frequent micturition and defaecation should be encouraged in order to minimise radiation dosage to the patient.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: diagnostic radiopharmaceutical for cardiovascular system imaging. ATC code: V09GA02.
99mTc-tetrofosmin complex has been shown to accumulate in myocardial tissue. Studies in animals have shown that myocardial uptake of 99mTc-tetrofosmin complex is linearly related to regional myocardial perfusion. After it is taken up by the myocardium, 99mTc-tetrofosmin does not undergo appreciable redistribution over the subsequent 4 hours. Separate stress and resting studies are required to differentiate between transiently and persistently reduced myocardial uptake.
5.2 Pharmacokinetic Properties
Absorption.
99mTc-tetrofosmin is rapidly cleared from the blood after intravenous injection; less than 5% of the administered activity remains in whole blood at 10 minutes postinjection. Uptake in the myocardium is rapid, reaching a maximum of about 1.2% of injected dose with sufficient retention to allow imaging of the myocardium by planar or SPECT techniques from 5 minutes up to 4 hours postadministration.
The uptake of free 99mTc-pertechnetate as a small fraction of the total radioactivity is a normal property of 99mTc-tetrofosmin. It should be noted, however, that a small fraction of the 99mTc-tetrofosmin is taken up by the thyroid gland and that observed thyroid uptake is, therefore, not necessarily an indicator of free 99mTc-pertechnetate in the pharmaceutical.
Excretion.
Approximately 66% of the injected activity is excreted within 48 hours post-injection, with approximately 40% excreted in the urine and 26% in the faeces.
Background tissue clearance is rapid from lung and liver and activity is reduced in these organs following exercise, with enhanced sequestration in skeletal muscle.
5.3 Preclinical Safety Data
Acute toxicity studies employing Myoview at dosage levels of approximately 1050 times the maximum human single dose failed to reveal mortality or any significant signs of toxicity in rats or rabbits. In repeated dose studies, some evidence of toxicity was observed in rabbits, but only at cumulative doses exceeding 10,000 times the maximum human single dose. In rats receiving these doses, there was no significant evidence of toxicity.
Genotoxicity.
No mutagenicity data are available for 99mTc-tetrofosmin. However, Tetrofosmin sulphosalicylate was not mutagenic in gene mutation assays in bacteria and mouse lymphoma L5178, and was negative in studies for chromosomal aberrations in the mouse bone marrow micronucleus test and in human lymphocytes in vitro.
Carcinogenicity.
There are no data on the carcinogenicity of 99mTc-tetrofosmin in experimental animals and humans.6 Pharmaceutical Particulars
6.1 List of Excipients
See Section 2 Qualitative and Quantitative Composition.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging and the product should not be used after this date. The reconstituted product should be used within 12 hours of preparation.
6.4 Special Precautions for Storage
The product should be stored at 2-8°C and protected from light. The reconstituted product should be stored below 25°C. Do not freeze. The reconstituted product should be used within 12 hours of preparation.
6.5 Nature and Contents of Container
Radiopharmaceutical kit - powder for solution for injection following reconstitution with 4-8 mL of sterile Sodium Pertechnetate [99mTc] Injection Ph Eur. at a radioactive concentration not exceeding 1.5 GBq/mL to yield 99mTc-tetrofosomin injection, a diagnostic radiopharmaceutical imaging agent.
The product is supplied in a 10 mL clear glass vial, sealed with a chlorobutyl rubber closure and flip off overseal. Pack sizes 2 or 5 vials. Not all pack sizes may be marketed.
6.6 Special Precautions for Disposal
The disposal of all radioactive wastes should be carried out in accordance with the NHMRC "Code of Practice for the Disposal of Radioactive Wastes by the User, (1985)".
6.7 Physicochemical Properties
Chemical structure.
The structural formula of tetrofosmin is:
When sodium pertechnetate [99mTc] is added to tetrofosmin in the presence of stannous tin, a lipophilic, cationic complex of 99mTc-labelled tetrofosmin is formed. The structure of the labelled complex is as follows:
CAS number.
127502-06-1.7 Medicine Schedule (Poisons Standard)
Not scheduled.
Summary Table of Changes
