SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

TechneScan® MAG3

(Mallinckrodt Medical catalogue number: DRN 4334

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains:

Betiatide 1 mg

To be used with sodium pertechnetate (^99mTc) for the preparation of the diagnostic agent: Technetium (^99mTc) tiatide.

3    PHARMACEUTICAL FORM

Powder for solution for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

After reconstitution and labelling with sodium pertechnetate (^99mTc) solution the diagnostic agent technetium (^99mTc) tiatide may be used for the evaluation of nephrological and urological disorders in particular for the study of morphology, perfusion, function of the kidney and characterisation of urinary outflow.

4.2 Posology and method of administration

Adults and the elderly:

37-185 MBq (1-5 mCi), depending on the pathology to be studied and the method to be used. Studies of renal blood flow or transport through the ureters generally require a larger dose than studies of intra-renal transport, whereas renography requires smaller activities than sequential scintigraphy.

Children:

Although TechneScan MAG3 may be used in paediatric patients, formal studies have not been performed. Clinical experience indicates that for paediatric use the activity should be reduced. Because of the variable relationship between the size and body weight of patients it is sometimes more satisfactory to adjust activities to body surface area. A practical approach is to adopt the recommendations of the Paediatric Task Group of the European Association of Nuclear Medicine (EANM). See table below.

Activities in children. Fraction of adult activity (Paediatric Task Group EANM, 1990).

3 kg = 0.1	22 kg = 0.50	42 kg = 0.78
4 kg = 0.14	24 kg = 0.53	44 kg = 0.80
6 kg = 0.19	26 kg = 0.56	46 kg = 0.82
8 kg = 0.23	28 kg = 0.58	48 kg = 0.85
10 kg = 0.27	30 kg = 0.62	50 kg = 0.88
12 kg = 0.32	32 kg = 0.65	52-54 kg = 0.90
14 kg = 0.36	34 kg = 0.68	56-58 kg = 0.92
16 kg = 0.40	36 kg = 0.71	60-62 kg = 0.96
18 kg = 0.44	38 kg = 0.73	64-66 kg = 0.98
20 kg = 0.46	40 kg = 0.76	68 kg = 0.99

Reduction of the amount of radioactivity to less than 10% of the dose for adults will generally result in technically unsatisfactory procedures. In general, the risks are likely to relate to the level of radiation, as the chemical doses are quite small (about 0.2 mg for 185 MBq). The administration of a diuretic or an ACE inhibitor during the diagnostic procedure is sometimes used for differential diagnosis of nephrological and urological disorders. The scintigraphic investigation is usually performed immediately after administration.

4.3 Contraindications

None.

4.4 Special warnings and precautions for use

4.4.1 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.

4.4.2 Radiopharmaceutical agents should only be used by qualified personnel with the appropriate government authorization for the use and manipulation of radionuclides.

4.4.3 This radiopharmaceutical may 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 local competent official organisations.

4.4.4 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.

4.4.5 The agent is not suited for exact monitoring of effective renal plasma flow respectively blood flow in patients with seriously impaired renal function.

4.4.6 Small amounts of ^99mTc-labeIled impurities may be present and/or are formed during the labelling process. As some of these impurities are distributed to the liver and excreted via the gall bladder they may influence the late phase (after 30 minutes) of a dynamic renal study due to the overlap of kidney and liver in the region of interest.

4.5 Interaction with other medicinal products and other forms of interaction

Technetium (^99mTc) tiatide has not been described to interfere with agents commonly prescribed to given to patients requiring the above mentioned investigations (e.g. antihypertensives and medicinal agents used to treat or prevent organ transplant rejection). However, the single administration of a diuretic or ACE inhibitor is sometimes used in the differential diagnosis of nephrological and urological disorders. Administered contrast media may impair tubular renal excretion and thereby influence the technetium (^99mTc) tiatide clearance.

4.6 Fertility, Pregnancy and lactation

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 ionising radiation should be considered. Radionuclide procedures carried out on pregnant women also involve radiation doses to the fetus. Only imperative investigations should be carried out during pregnancy, when likely benefit exceeds the risks incurred by mother and fetus.

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 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 8 hours and the expressed feeds discarded. In the event of uncertainty it is usually advised that breast-feeding can be restarted when the level in the milk will not result in a radiation dose to a child greater than 1 mSv.

4.7 Effects on ability to drive and use machines

Have not been described.

4.8 Undesirable effects

Occurences of anaphylactoid reactions have been reported, such as urticaria, swelling of eyelids, itching, nausea and headache. Although the probability of occurrence of such a reaction is small, the appropriate treatment of allergic reactions (adrenaline, corticosteroids and antihistamines) should always be kept available for immediate use. In addition mild vasovagal reactions have been reported.

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. 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 low frequency because of the low radiation doses incurred. For most diagnostic investigations using nuclear medicine procedures the radiation dose delivered (Effective Dose Equivalent) is less than 20 mSv. Higher doses might be justified in some clinical circumstances.

4.9 Overdose

The risk of an excessive technetium (^99mTc) tiatide dose is largely theoretical and most likely to be due to excessive radiation exposure. In such circumstances the radiation to the body (kidney, bladder and gall bladder) can be reduced by forced diuresis and frequent bladder voiding.

5.1 Pharmacodynamic properties

At the chemical doses envisaged technetium (^99mTc) tiatide Injection has no known pharmacodynamic action. Measuring the activity over the kidneys allows renal blood flow, intrarenal tubular transit times and excretion via the outflow tracts to be recorded separately for both kidneys.

5.2 Pharmacokinetic properties

After intravenous injection technetium (^99mTc) tiatide is rapidly cleared from the blood by the kidneys. Technetium (^99mTc) tiatide has a relatively high binding to plasma proteins. In normal renal function 70% of the administered dose has been excreted after 30 mm. and more than 95% after 3 hours. These latter percentages are dependent on the pathology of the kidneys and the urogenital system. The mechanism of excretion is predominantly based on tubular secretion. Glomerular filtration accounts for 11 % of total clearance.

5.3 Preclinical safety data

Acute, subacute (8 days) and chronic (13 weeks) toxicity studies as well as mutagenicity studies were performed. At the studied dose levels, up to 1000 times the maximal human dose, no toxicological effects were observed. Similarly, mutagenic effects have not been observed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

One vial contains 16.9 mg disodium tartrate and 0.04 mg tin(lI)chloride. After reconstitution of the vial contents and after labelling with the eluate of a ^99mTc-generator (usually 0.9% sodium chloride) the aqueous injection solution will in addition to sodium chloride also contain disodium tartrate and tin(II) chloride. The vial does not contain a preservative agent. Properties of the medicinal product after labelling:

Clear to slightly opalescent, colourless, aqueous solution. pH    : 5.0-6.0

Osmolality    : slightly hypertonic.

6.2 Incompatibilities

Major incompatibilities: not known. However, in order not to compromise the stability of ^99mTc-tiatide preparations should not be administered together with other drugs.

6.3 Shelf life

TechneScan® MAG3 expires 12 months after the date of manufacture. The expiry date is stated on the label of the immediate packaging vial and on the carton.

After labelling Technetium (^99mTc) tiatide Injection expires:

•    4 hours after labelling when the labelling was done in an end volume of 10 ml.

•    1 hour after labelling when the labelling was done in an end volume of 4 ml.

6.4 Special precautions for storage

TechneScan® MAG3 is to be stored at 2-8 °C. If the labelled preparation is to be used for multiple administrations, it must be stored at 2-8 °C during the shelf life of the labelled injection solution. Storage should be in accordance with national regulations for radioactive materials.

6.5 Nature and contents of container

10 ml Type 1 Ph.Eur glass vial closed with a butyl rubber stopper Ph.Eur and sealed with an aluminium crimpcap. TechneScan® MAG3 is supplied as five vials in a carton.

6.6 Special precautions for disposal

The contents of the vial is to be labelled with Sodium Pertechnetate (^99mTc) Injection Ph.Eur. After reconstitution with a sodium pertechnetate (^99m Tc) solution the diagnostic agent technetium (^99mTc) tiatide is obtained upon boiling. The formation of labelled impurities is minimal, when using an eluate with the smallest possible volume. Therefore, labelling should be done using an eluate with the highest possible radioactive concentration. Only eluates obtained from a ^99mTc generator, which has been eluted once in the preceding 24 hours should be used. Moreover, only eluates obtained from a ^99mTc generator, which has not been in use for more than one week, have to be used. Dilution of the preparation should be done with saline. After reconstitution and labelling the solution may be used for one or more administrations.

6.6.1    Instructions for labelling

For labelling it is recommended to use an eluate with the highest possible radioactive concentration, as the formation of labelled impurities is the least when using an eluate with the smallest possible volume.

Dilute a ^99mTc generator in a 5 ml volume, according to the fractionated elution technique and follow the directions for use for the generator.

Use 3 ml eluate.

The desired amount of ^99mTc, with a maximum of 1110 MBq (30 mCi) must be diluted to a volume of 10 ml with saline solution (0.9%). Add this volume to a vial of TechneScan® MAG3. For this a thin needle must be used (G20 or higher) so that the puncture hole closes again. This prevents the water from entering the vial during the heating and cooling steps that follow.

Heat immediately during 10 minutes in boiling water. During heating the vial should be standing upright in order to prevent traces of metal coming off the rubber stopper, so influencing the labelling procedure unfavourably.

Cool down the vial to room temperature in cold water. The preparation is ready for administration. This ^99mTc labelled preparation having a concentration of 1110 MBq per 10 ml can be used until four hours after completion of the heating step.

To obtain a more concentrated preparation, use no more than 1 ml eluate, with a maximum activity of 925 MBq (25 mCi) and dilute to 4 ml with saline solution (0.9%). Follow the procedure as described above to complete the preparation. This preparation is stable for one hour only.

Preferably use eluates obtained by fractionated elution. Follow the pertinent directions for use of the generator.

6.6.2    Precaution during the labelling procedure

To indicate that during the heating and the cooling step no contamination of the contents of the vial has occurred, the user is advised to add a suitable dyestuff to the heating bath and to the cooling bath (e.g. methylene blue to make a concentration of 1 % or sodium fluorescein to make a concentration of

0. 1 %). The radiolabelled product vial should be examined for contamination (taking appropriate radiological protective measures) prior to use.

6.6.3 Instructions for quality control

The following methods may be used:

1.    HPLC method:

The radiochemical purity of the labelled substance is examined by high performance liquid chromatography (HPLC) using a suitable detector of radioactivity, on a 25 cm RP18 column, flow rate 1.0 ml/mm. Mobile phase A is a 19 :1 mixture of phosphate solution (1000 parts 0.01 M NaH₂PO₄ and 114 parts 0.01 M Na₂HPO₄, adjusted to pH 6) and ethanol. Mobile phase B is a 1 : 9 mixture of water and methanol. Use a gradient elution program with the following parameters:

Time	Flow	%	%
(mm):	(mi/mm):	A	B
10	1	10	0
		0
7	1	0 100
4	2	10	0
		0

The tiatide peak appears at the end of the passage of mobile phase A. The injection volume is 5 pl and the total count rate per channel must not exceed 30.000.

Requirement:

2. Simplified rapid procedure.

This method may be used as an alternative for the above mentioned methods. The purpose of this method is to check the labelling procedure, as performed by the user in the hospital. The method is based on cartridges, which are widely used as sample pretreatment of aqueous solutions for chromatography. The cartridge (e.g. Sep-Pak C18, Waters) is washed with 10 ml absolute ethanol, followed by 10 ml 0.001 hydrochloric acid. Remaining residues of the solutions are removed by 5 ml of air. The Tochnetium (^99mTc) tiatide solution (e.g. 0.1 ml) is applied on the cartridge. Elute with 5 ml 0.001 M HCI and collect the eluate. Elute with 5 ml of a phosphate buffer (0.01 M, pH=6.0) containing 0.5% ethanol. Add the eluate to the first eluate (together: sum of

hydrophilic impurities). Flute the cartridge with 10 ml phosphate buffer (pH=6.0) containing 7% ethanol. This second eluate contains Technetium ( ^9mTc) tiatide. Finally, elute the cartridge with 10 ml absolute ethanol. This third eluate contains lipophilic impurities. Measure the radioactivity and calculate the respective percentages. Use the combined eluted radioactivity as 100%.

Requirement:

Technetium (^99mTc) tiatide: not less than 90 %. Hydrophilic impurities: not more than 5%. Lipophilic impurities: not more than 5%. Other information/precautions: The administration of radiopharmaceuticals created 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. Waste must be disposed of according to national regulations for radioactive material.

7    MARKETING AUTHORISATION HOLDER

Mallinckrodt Medical B.V.

Westerduinweg 3 1755 LE Petten Netherlands

8 MARKETING AUTHORISATION NUMBER(S)

PL 12288/0014

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21 March 2001

10    DATE OF REVISION OF THE TEXT

27/02/2015

11    DOSIMETRY (IF APPLICABLE)

Estimated absorbed dose (according to the MIRD method)

Effective Dose Equivalent(EDE)

The effective dose equivalent after a dose of 185 MBq for a 70 kg individual would be 2.0 mSv when the bladder is voided 2 hours after administration. Although no comparative dosimetric studies have been performed in patients, it is anticipated that the EDE will be lower in patients with renal insufficiency/failure than those with normal renal function. This relates to the contribution of urinary bladder to overall tissue exposure.

12 INSTRUCTIONS FOR PREPARATION OF

RADIOPHARMACEUTICALS (IF APPLICABLE)