TECHNESCAN PYP - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

TechneScan PYP 20 mg kit for radiopharmaceutical preparation

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 20 mg sodium pyrophosphate decahydrate and 4 mg stannous chloride dihydrate (corresponding to 2.1 mg stannous).

The radionuclide is not part of the kit.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation.

Powder for solution for injection.

Off-white to slightly yellow lyophilizate.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

This medicinal product is for diagnostic use only.

a) Red blood cell labelling for blood pool scintigraphy.

Major indications are:

Angiocardioscin­tigraphy for:

– evaluation of ventricular ejection fraction,

– evaluation of global and regional cardiac wall motion ,

– Myocardial phase imaging.

Organ perfusion and vascular abnormalities imaging for the detection of hemangioma.

Diagnosis and localization of occult gastro-intestinal bleeding.

b) Determination of blood volume.

c) Spleen scintigraphy.

4.2. Posology and Method of Administration

Adults

a) Blood pool scintigraphy:

The average activity administered by intravenous injection for in vivo or after in vitro labelling is 890 MBq (740–925 MBq).

b) Determination of blood volume:

The average activity administered by intravenous injection after in vitro labelling is 3 MBq (1–5 MBq).

c) Spleen scintigraphy:

The average activity administered by intravenous injection after invitro labelling of denaturated erythrocytes is 50 MBq (20–70 MBq).

The optimal amount of non-radioactive stannous tin for preparation of red blood cells (RBCs) in vivo or in vitro is 10 to 20 ^g/kg body weight in adults. Especially in cases of in vitro labelling this dose should not be exceeded. Sodium pertechnetate (99mTc) should be injected (in vivo) or added to the incubation mixture (in vitro) after 30 minutes.

Renal impairment

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

Paediatric population

The use in children and adolescents has to be considered carefully, based upon clinical needs and assessing the risk/benefit ratio in this patient group.

The activities to be administered to children and to adolescents may be calculated according to the EANM dosage card version 2016 for the indication:

Blood pool scintigraphy:           A[M­Bq]Administered = 56.0 x Multiple from table 1

Spleen scintigraphy:               ­A[MBq]Adminis­tered = 2.8 x Multiple from table 1

Table 1

For blood scintigraphy, in very young infants (up to 1 year) a minimum dose of 80 MBq is necessary in order to obtain images of sufficient quality. For spleen scintigraphy a minimum dose of 20 MBq is necessary.

Method of administration

Multidose vial.

For intravenous injection.

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

For instructions regarding reconstitution see section 12.

For patient preparation, see section 4.4.

The freeze-dried stannous pyrophosphate lyophilisate (non-radioactive substance) is first reconstituted with isotonic sodium chloride solution for injection.

Injection of the reconstituted solution of the stannous pyrophosphate complex followed by injection of sodium pertechnetate (99mTc) 30 minutes later.

Sampling of 6 ml of the patient’s blood

In vitro incubation of the reconstituted solution of the taken total blood sample or separated RBCs, followed by adding sodium pertechnetate (99m Tc) 30 minutes later.

Second in vitro incubation of the RBCs and reinjection of the labelled RBCs 30 minutes later.

Modified in vivo RBCs labelling method (in vivo/in vitro):

Injection of the reconstituted solution of the stannous pyrophosphate for in vivo “stannous-loading” of RBCs.

In vitro RBCs labeling with sodium pertechnetate (99m Tc) after taking a blood sample.

Reinjection of the labelled RBCs.

Denatured RBCs labelling method:

In vitro labelling of RBCs (see above) followed by denaturation e.g. heating of the labelled erythrocytes at 49–50°C for 25 minutes.

Reinjection of the labelled denatured RBCs.

Image acquisition

Angiocardioscin­tigraphy:

The acquisition of images starts immediately after the injection of the tracer.

Occult digestive haemorrhages:

Since digestive bleeding occurs usually intermittently, it is recommended to perform several acquisitions over a period of 24 hours in addition to the images acquired initially after the injection.

Spleen scintigraphy:

Images are performed from 30 to 120 minutes after the injection. In case of accessory spleen research, the entire abdomen should be studied. If the patient has diaphragm rupture due to previous trauma, the chest should also be studied.

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

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.

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

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

Paediatric population

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

Careful consideration of the indication is required since the effective dose per MBq is higher than in adults, see section 11.

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 to reduce radiation.

After the procedure

Close contact with infants and pregnant women should be restricted during 2 hours after administration of the labelled RBCs or sodium pertechnetate (99mTc).

Specific warnings

Scintigraphy repeatability

Because of the long-lasting fixation of stannous salts on red blood cells, it is recommended not to repeat the procedure before 3 months.

Interaction with iodinated contrast media

It is recommended to perform the scintigraphy with (99mTc)-labelled red blood cells in advance of any administration of the iodinated contrast media, otherwise the efficiency of the red blood cell labelling will be adversely affected (see section 4.5).

Sodium content

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

Reduction in red blood cell labelling yield has been reported with heparin, tin overload, aluminium, prazosin, methyldopa, hydralazin, digitalic related compounds, quinidine, P-adrenergic blockers (e.g. propranolol), calcium channel blockers (e.g. verapamil, nifedipine), nitrates (e.g. nitroglycerin), anthracycline antibiotic, iodinated contrast agents and teflon catheter (the Sn++ can react with the catheter).

4.6 Fertility, pregnancy and lactation

Women of 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 a period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient.

Pregnancy

Radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus. Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by mother and foetus. Administration of 925 MBq results in an absorbed dose to the uterus of 3.6 mGy.

Breast-feeding

Before administering radiopharmace­uticals to a mother who is breast-feeding a consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breastfeeding, and to what is the most appropriate choice of radiopharmace­uticals, bearing in mind the secretion of activity in breast milk.

Sodium pertechnetate (99mTc) is excreted in human milk. If the administration is considered necessary and depending on the RBCs labelling method, breastfeeding should at least be interrupted for about 12 hours after the sodium pertechnetate (99mTc) injection (in vivo labelling method) or for about 4 hours after the reinjection of the labelled RBCs (other labelling methods), and the expressed feeds discarded. Close contact with infants should be restricted during 2 hours (see section 4.4).

Fertility

There are no data on possible harmful effects of TechneScan PYP on fertility.

4.7 Effects on ability to drive and use machines

TechneScan PYP has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 6.5 mSv when the maximal recommended activity of 925 MBq is administered these adverse effects are expected to occur with a low probability.

Information on adverse reactions is available from spontaneous reporting. The reports describe anaphylactoid, vasovagal and injection site reactions.

Adverse Reactions sorted by System Organ Class:

* Frequency cannot be estimated from the available data.

Anaphylactoid reactions

Reported anaphylactoid reactions were mild to moderate, however the occurrence of severe reactions cannot be excluded. If anaphylactoid reactions occur, the medicinal product must no longer be administered. Appropriate instruments (including endotracheal tube and ventilator) and medications should be to hand to be able to react immediately in an emergency.

Vasovagal reactions

Vasovagal reactions are most probably caused by the procedure itself, especially in anxious patients, but a contribution of the product cannot be excluded.

Injection site reactions

Local reactions at the injection site may include rashes, pruritus, cellulitis, swelling, inflammation and pain. In most cases such reactions are probably caused by extravasation. Extended extravasation may necessitate surgical treatment.

Paediatric population

It must be taken into account that the effective dose per MBq is higher than in adults (see section 11 „Dosimetry“).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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:

The Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

In the event of an administered radiation overdose on TechneScan PYP, very little can be done since the elimination of it completely depends of the regular haemolytic process.

Forced diuresis and frequent bladder voiding are recommended in the case of overdosage with sodium pertechnetate (99mTc).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmace­uticals for cardiovascular system, Technetium (99mTc) compounds.

ATC code: V09GA06.

At doses used for diagnostic procedures, neither stannous pyrophosphate, sodium pertechnetate (99mTc) nor stannous pyrophosphate (99mTc), nor labelled Red BIood Cells appear to have any pharmacodynamic effect.

5.2 Pharmacokinetic properties

Distribution

Intravenous injection of stannous salts induces a “stannous loading” of erythrocytes. Subsequent sodium pertechnetate (99mTc) injection results in an accumulation and a retention of sodium pertechnetate (99mTc) in the choroid plexus and red blood cells. Intravenous administration of 10–20 ^g stannous ion/kg body weight (in form of stannous pyrophosphate) followed 30 minutes later by 370–740 MBq pertechnetate injection results in efficient labelling of blood pool.

Organ uptake

Under normal circumstances intravenously injected pertechnetate freely diffuses into and out from the erythrocytes. However, when the erythrocytes have been preloaded with stannous ion, the sodium pertechnetate (99mTc) is reduced within the cells and becomes bound to the chains of globin. The mechanisms by which sodium pertechnetate (99mTc) becomes attached to tin primed red blood cells are not clearly understood. However, 20% of injected pertechnetate enters the red cell and binds to a beta chain of globin, while the remaining 70–80% of pertechnetate is believed to be located in the cytoplasm or on the red cell membrane. On the other hand, reducing the surface charge of the erythrocytes decreases the efficiency of labelling down to 20%.

Elimination

The most beneficial time for the injection of (99mTc) pertechnetate for the in vivo labelling is 20–30 min after the administration of pyrophosphate. At 10 and 100 minutes post injection, 77 ± 15% and 71 ± 14% respectively, of the injected activity is found in the blood. This value remains constant for about 2 hours after injection with only about 6% decrease in total blood radioactivity during this period.

Half-life

Up to eight days after the examination, labelling of erythrocytes with (99mTc) pertechnetate may still be observed. There is no appreciable effect with doses of up to 0.02 mg of tin/kg. The heat-denatured erythrocytes are sequestrated by splenic tissue.

Technetium-99m (99mTc) has a physical half-life of 6 hours.

5.3 Preclinical safety data

There are no preclinical safety data specific to technetium labelled erythrocytes. The toxicity of pertechnetate ion and stannous salts has been studied and reported in the literature. Systemic toxic effects are only observed at relatively high parenteral doses, giving a safety ratio of at least 150. Repeated dose toxicity studies in rats with 50–100 times human dose do not cause macroscopic nor microscopic alterations. Stannous salts are reported to have a weak potential for mutagenicity.

There are no studies describing possible effects on reproduction or tumour incidence.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Stannous chloride dihydrate

Hydrochloric acid

Sodium hydroxide (for pH-adjustment)

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.

After reconstitution: 4 hours. After reconstitution, store in a refrigerator (2–8°C).

From microbiological point of view the product should be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2–8°C).

For storage conditions after reconstitution of the medical product, see section 6.3. Storage should be in accordance with national regulations for radioactive material.

6.5 Nature and contents of container

10 ml glass vial (Type 1) closed with a bromobutyl stopper, sealed with an aluminium cap.

Pack size: five vials in a carton.

6.6 Special precautions for disposal and other handling

General warning

Radiopharmace­uticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licenses 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 radiopharmace­uticals and are not to be administered directly to the patient without first undergoing the reconstitution 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.

The content of the kit is not radioactive. However, after sodium pertechnetate (99mTc) is added to the RBCs during in vitro RBC labelling, 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.

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

7. MARKETING AUTHORISATION HOLDER

Curium Netherlands B.V.

Westerduinweg 3

1755 LE Petten

Netherlands

8. MARKETING AUTHORISATION NUMBERS

PL 12288/0015

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

21 March 2001

10. DATE OF REVISION OF THE TEXT

11. DOSIMETRY

Technetium (99mTc) is produced by means of a (99Mo/99m 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 (99Tc) which, in view of its long half-life of 2.13 × 105 years can be regarded as quasi stable.

The radiation doses absorbed by a patient with a body weight of 70 kg, after intravenous injection of 99mTc-labelled erythrocytes according to ICRP 128 (2015) and 99mTc-labelled denatured erythrocytes according to ICRP 53 (1988), are as following.

For blood pool scintigraphy the effective dose resulting from the administration of a (maximum recommended) activity of 925 MBq is 6.5 mSv (for an adult weighing 70 kg) and the typical radiation dose to the critical organ (heart) is 21.3 mGy.

For blood volume determination the effective dose resulting from the administration of a (maximal recommended) activity of 5 MBq is 0.035 mSv (for an adult weighing 70 kg) and the typical radiation dose to the critical organ (heart) is 0.12 mGy.

* Calculation according to ICRP 60

For spleen scintigraphy the effective dose resulting from the administration of a (maximum recommended) activity of 70 MBq is 1.3 mSv (for an adult weighing 70 kg) and the typical radiation dose to the critical organ (spleen) is 39.2 mGy.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Withdrawals should be performed under aseptic conditions. The vials must never 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.

The freeze-dried stannous pyrophosphate lyophilisate (non-radioactive substance) is first reconstituted with isotonic sodium chloride solution. TechneScan PYP is a colourless solution after reconstitution. Reconstituted solution is then used for in vivo, in vitro or in vivo/in vitro labelling of red blood cells by different methods.

In vivo RBCs labelling

Blood pool scintigraphy:

In the case of ca. 70 kg body weight: slowly inject (10–20 seconds) 1/3 of the whole contents of one vial TechneScan PYP dissolved in 6 ml of an isotonic sodium chloride solution (2 ml for 70 kg). The volume should be adapted for other body weights.

Inject approximately 30 minutes later 740–925 MBq pertechnetate (99mTc) intravenously

30 minutes later, collect 6 ml blood from the patient in ACD tubes. Add sodium pertechnetate (99mTc) and incubate 30 minutes at room temperature.