THALLIUM (201T1) CHLORIDE INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Thallium [201Tl] chloride injection, CIS bio international

Reference : TL-201-S-1

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Thallium [201TI] chloride injection is a sterile isotonic solution with a pH ranging between 4.0 and 7.0. The specific radioactivity is greater than or equal to 3.7 MBq/qg (0.1 mC’i/qg) of thallium. The radioactive concentration is 37 MBq/mL (1 mCi/mL) at the reference date stated on the label (calibration date). The radiochemical purity is at least equal to 95 %.

Composition of the medicinal product :

Active ingredient :

Thallium [201TI] chloride:

Other ingredients :

Sodium chloride:

Water for injections:

37 MBq/mL (at calibration date)

up to isotonicity

up to 1 ml

Thallium [201Tl] (atomic number : 81, atomic weight: 201) decays to mercury [201Hg] by electron capture with an half-life of 3.0408 ± 0.0420 days. Not less than 97.0 % of the total radioactivity is due to thallium [201Tl]. At the calibration date, not more than 0.25 % of the total radioactivity is due to thallium [200Tl], not more than 0.50 % is due to thallium [202Tl] and not more than 0.10 % is due to lead [203Pb].

Radiation characteristics of thallium [201Tl] :

Thallium [201Tl] decay chart :

Solution for injections.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

– Myocardial scintigraphy in the evaluation of coronary perfusion and cellular viability : ischeamic heart disease, cardiomyopathies, myocarditis, myocardial contusions and secondary cardiac lesions.

– Scintigraphy of the muscles : muscle perfusion in peripheral vascular disorders.

– Parathyroid scintigraphy.

– Thallium-avid tumour visualisation in different organs, especially for the brain tumours and thyroid tumours and metastases.

4.2. Posology and method of administration

Injection of 0.74 to 1.11 MBq/kg (0.02 to 0.03 mCi/kg) in adults and the elderly of thallium [201Tl] chloride solution via the intravenous route. This activity can be increased by fifty percent if SPECT-imaging is considered until a maximum activity of 110 MBq (3 mCi).

a) Myocardial scintigraphy :

Fasting during 4 hours before the examination is recommended.

Thallium [201TI] chloride injection can be done either at rest or during intervention tests : conventional stress test or a similar test like electrostimulation or pharmacological tes­t.

The first set of images can be acquired few minutes after injection.

Thallium redistribution can be studied with a new set of images acquisition obtained between 3 to 24 hours after injection. In some cases, instead of the redistribution study (or after it), reinjection of 37 MBq (1 mCi) of thallium can be done to evaluate myocardium viability.

b) Non-myocardial indications :

Image acquisitions can be started during/or few minutes after injection (“Flow images”) and/or later (“cell uptake images”).

4.3. Contra-indications

– Hypersensitivity to Thallium [201TI] chloride injection.

– Thallium [201TI] chloride injection must not be administered to pregnant women

and breast feeding mothers as well as to children and adolescents. –

– The specific contra-indications of associated interventional tests should be considered.

4.4. Special warnings and precautions for use

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.

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 study in order to reduce radiation. The insertion of a flexible in-dwelling catheter is recommended during the entire examination.

Strict cardiological monitoring and the material required for emergency treatment are essential when performing interventional tests (exercise, pharmacological, electrical.

It is usually not possible to differentiate recent from old myocardial infarction, or to differentiate exactly between recent myocardial infarction and ischemia.

If anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and, if necessary, intravenous treatment initiated.

Respective medicinal products and equipment (e.g. endotracheal tube and ventilator) have to be readily available.

Paravenous injection must be avoided due to the risk of local tissue necrosis. Injection should be strictly intravenous to avoid thallium [201TI] chloride local deposit and irradiation. In the event of paravenous injection, the injection should be immediately stopped and the site of injection should be cooled and rested in elevated position. When radiation necrosis occurs, surgical intervention may be necessary.

General warnings

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 licences of the competent official organisation. 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.

4.5 Interaction with other medicinal products and other forms of interaction Some drugs are responsible for interferences modifying the thallium [201Tl] myocardial uptake.

Three processes could be implied :

– Direct or indirect variations of the coronary blood flow (dipyridamole, adenosine, isoprenaline, dobutamine, nitrates…) ;

– Interferences with the interventional tests (beta blockers and stress tests, methylxanthines (i.e. theophyllin) and dipyridamole…) ;

– Thallium cell uptake modifications, although no definitive data are available (digitalis analogues, insulin have been mentioned as examples).

4.6. Fertility, pregnancy and lactation

No data are available on the use of thallium [201TI] chloride in pregnancy. According to the high uterus radiation doses, thallium [201TI] chloride injection is contraindicated during pregnancy.

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

Breastfeeding

Thallous [201Tl] chloride injection is contraindicated in breast-feeding mothers. Before administering radiopharmaceutical to a mother who is breast-feeding consideration should be given as to the possibility of delaying the administration of radionuclide until the mother has ceased breast-feeding and to what is the most appropriate choice of radiopharmace­utical, bearing in mind the lack of data concerning the secretion of thallium [201TI] in the milk. If the administration is considered necessary, breast feeding should be discontinued.

4.7 Effects on ability to drive and use machines

Effects on ability to drive vehicles or to operate machines have not been described.

4.8 Undesirable effects

Information on adverse reactions is available from spontaneous reporting. The reports describe anaphylactoid, vasovagal and injection site reactions which were mild to moderate and usually resolved with either no or symptomatic treatment.

Local radiation necrosis has been reported after paravenous injection.

The following list subsumes the observed reaction types and symptoms sorted by System Organ Class. The frequency listed below is defined using the following convention:

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); not known (cannot be estimated from the available data).

Immune system disorders

Frequency unknown*: Anaphylactic reactions (e.g. laryngospasm, pharyngitis, laryngea oedema, dyspnoea, rash pustular, rash erythematous, hypersensitivity, pain of skin, facial pain, tongue oedema, face oedema, oedema, conjunctivitis, lacrimal disorder, erythema, pruritus, rash, urticaria, flushing, hyperhydrosis, cou­gh)

Nervous system disorders

Frequency unknown*: Vasovagal reactions (e.g. syncope, dizziness, bradycardia, hypotension, tremor, headache, pallor)

General disorders and administration site conditions

Frequency unknown*: Injection site reaction

Injury, poisoning and procedural complications

Frequency unknown*: Local radiation necrosis after paravenous injection.

* Adverse reactions derived from spontaneous reporting

Thallium (201TI) chloride is often used in combination with a cardiac stress-test. The cardiac stress is hereby induced by ergometric exercise or by the use of appropriate medication. A patient may experience adverse reactions as a result of cardiac stress. Depending on the method used for inducing stress, such reactions include cardiovascular symptoms like palpitations, ECG abnormalities, arrhythmia, chest pain, shortness of breath, and ultimately myocardial infarction. Other symptoms related to the induced stress are hypertension or hypotension, chills, dysgeusia, nausea, vomiting and general fatigue or malaise.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 15.4 mSv when the maximal recommended activity of 110 MBq is administered these adverse reactions are expected to occur with a low probability.

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

The risk of overdose lies in an unintentional high exposure to ionising radiation. In the event of the administration of a radiation overdose with thallium [201TI] chloride the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by forced diuresis with frequent voiding and stimulation of the gastro-intestinal passage. Gastro-intestinal absorption of thallous [201Tl] chloride may be prevented by administration of the antidote ferric hexacyanoferra­te(II).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

At the chemical concentrations and activities used for diagnostic procedures, thallium [201TI] chloride does not appear to exert any pharmacodynamic effects.

5.2 Pharmacokinetic properties

After intravenous injection of thallium [201TI] chloride, the thallium rapidly leaves the blood as approximately 90 % is cleared after the first pass. The relative uptake depends on regional perfusion and on the cell extraction efficacy of different organs. The myocardial extraction fraction of thallium [201TI] is about 85 % during the first pass and the peak myocardial activity is 4–5 % of the injected dose, relatively constant for about 20–25 minutes. The precise cellular uptake process is still questioned but the sodium-potassium ATPase pump is probably involved, at least in part. The muscular uptake is dependent on workload and compared with the resting condition, the uptake in skeletal muscle and myocardium is increased 2–3 fold during exercise with consequently reduction in other organs.

Thallium is mainly excreted in the faeces (80 %) and in the urine (20 %). The effective half-life is about 60 hours and its biological half-life about 10 days.

5.3 Preclinical safety data

Thallium is one of the most toxic chemical elements with a lethal dose in man of about 500 mg. Toxicological studies in animals with thallous salts using intravenous administration show lethal doses ranging from 8 to 45 mg/kg of body weight. The doses used in man for scintigraphy are ten thousand times smaller than these toxic doses. Studies in the mouse and the rat demonstrated considerable transplacental passage of thallium.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

– Sodium chloride

– Water for injections

6.2 Incompatibilities

None known.

6.3 Shelf life

The expiry date for this product is 14 days from the manufacturing date. The expiry date is indicated on the outer packaging of each vial.

6.4 Special precautions for storage

This product should be stored at a temperature ranging between +15 °C and

+25 °C in its original packaging.

Storage should take place in accordance with national regulations for radioactive materials.

6.5 Nature and contents of container

15 mL, colourless, European Pharmacopoeia type I, drawn glass vial, closed with rubber stopper and aluminium capsule.

6.6 Special precautions for disposal

Usual precautions regarding sterility and radiation safety should be respected.

The vial must be kept inside its lead shielding.

Before use, packaging, pH, radioactivity and gamma spectrum will be checked.

The vial should never be opened. After desinfection of the stopper, the solution should be withdrawn aseptically through the stopper using single use sterile needle and syringe.

After first withdrawing, the remaining thallium [201Tl] chloride injection should be kept at a temperature ranging between +2 °C and +8 °C and should be used within 24 hours.

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

The disposal of radioactive waste should be in accordance with relevant national and international regulations.

7 MARKETING AUTHORISATION HOLDER

CIS bio international

B.P. 32

91192 Gif-sur-Yvette Cedex

FRANCE

Tel.    : +33-(0)1.69.85.70.70

Fax    : +33-(0)1.69.85.70.71

8 MARKETING AUTHORISATION NUMBER(S)

PL 11876/0012

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03 October 1996

10 DATE OF REVISION OF THE TEXT

25/08/2016

11. DOSIMETRY

According to Publication 106 of the ICRP (International Commission on Radiological Protection), doses of radiation absorbed by patients are as follows:

For thallium [201TI] chloride, the effective dose resulting from an administered activity of 110 MBq is typically 15.4 mSv (per 70 kg individual). For this administered activity of 110 MBq (2.1 mCi), the typical radiation dose to the target organ (myocardium) is 20.9 mGy and the typical radiation doses to the critical organs (kidneys andLower Large Intestine) are 52.8 mGy and 37.4 mGy respectively.

According to Publication 53 of the ICRP (International Commission on Radiological Protection):