Renoscan Mag3 1 mg kit for Radiopharmaceutical Preparation – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Renoscan MAG3 1 mg kit for radiopharmaceutical preparation

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains Betiatide, 1 mg

It has to be reconstituted with sodium (^99mTc) pertechnetate solution (not included in this kit) for the preparation of the diagnostic radiopharmaceutical: Technetium (^99mTc) tiatide solution.

Excipient with known effect:

Each vial contains 4 mg sodium ions.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation

The vial contains a sterile, white lyophilized powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

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

Posology and method of administration

Posology

Adults and the elderly

37-185 MBq, 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.

Pediatric population

Although Renoscan MAG3 may be used in paediatric patients, formal studies have not been performed. Clinical experience indicates that for pediatric 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.

The activity to be administered in children and adolescents is determined according to the EANM dosage card (2016) using the following formula: The activity to be administered A[MBq] = Baseline activity (of 11.9 MBq ) x Multiple

The activities to be applied are listed in the following table:

In very young children, a minimum dose of 15 MBq is necessary in order to obtain images of sufficient quality.

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

Method of administration

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

For intravenous use.

For multidose use.

The scintigraphic investigation is usually performed immediately after administration.

For instructions on reconstitution and labelling of the medicinal product before administration, see section 12.

For patient preparation, see section 4.4.

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 reaction

If hypersensitivity or anaphylactic reactions occurs, 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, 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 information.

Pediatric population

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

For information on the use in the pediatric 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 in order to reduce radiation.

Specific warnings

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

Small amounts of ^99mTc-labelled 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.

Inadvertent or accidental subcutaneous administration of technetium (^99mTc) tiatide should be avoided as perivascular inflammation has been described.

Excipients

This medicinal product contains less than 1 mmol sodium (23mg) per vial, that is to say essentially ‘sodium free’.

Depending on the time when you administer the injection, the content of the 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.

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 or given to patients requiring investigations with Technetium (^99mTc) tiatide (e.g. antihypertensives and medicinal products 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

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.

Pregnancy

Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus.

Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by the mother and the foetus.

Breast-feeding

Before administering radiopharmaceuticals to a mother who is breastfeeding, 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 radiopharmaceutical, bearing in mind the secretion of activity in breast milk.

If the administration is considered necessary, breastfeeding should be interrupted for 4 hours and the expressed feeds discarded.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

The frequencies of undesirable effects are defined as follows:

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) and not known (cannot be estimated from the available data)

¹ Seen in a 15 days old child. Causal relationship not established.

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, EDE) is less than 20 mSv. Higher doses might be justified in some clinical circumstances

Reporting 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, renal system, technetium (^99mTc) compounds.

ATC Code: V 09 CA 03

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

Distribution

After intravenous injection technetium (^99mTc) tiatide is rapidly cleared from the blood by the kidneys.

Organ uptake

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 minutes and more than 95 % after 3 hours. These latter percentages are dependent on the pathology of the kidneys and the urogenital system.

Elimination

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

• Disodium tartrate dihydrate
• Stannous (II) chloride dihydrate
• Hydrochloric acid for pH adjustment

6.2 Incompatibilities

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

This medicinal product must not be mixed with other medicinal products except those mentioned in section 12.

6.3 Shelf life

18 months.

The expiry date is stated on the label of the immediate packaging vial and on the carton.

After radiolabelling: 8 hours. Store below 25 °C.

6.4 Special precautions for storage

Store in a refrigerator (2-8 °C).

Store in the outer carton in order to protect from light.

For storage conditions after radiolabelling of the medicinal product, see section 6.3. 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 chlorobutyl rubber stopper Ph.Eur and sealed with an aluminium flip-cap.

Renoscan MAG3 is supplied as six or two vials in a carton.

Pack sizes

1 pack contains 6 vials.

Sample package: 2 vials.

6.6 Special precautions for disposal

General warning

This radiopharmaceutical should 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.

The contents of the vial are to be labelled with Sodium Pertechnetate (^99mTc) Injection. After reconstitution with the sodium (^99mTc) pertechnetate solution, the diagnostic agent technetium (^99mTc) tiatide is obtained upon boiling.

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

Only eluates obtained from a ^99mTc-generator, which has been eluted within the preceding 24 hours, should 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.

The vial does not contain a preservative agent.

Properties of the medicinal product after labelling:

• Clear to slightly opalescent, colourless, aqueous solution.
• pH 5.0-7.5
• Osmolality: slightly hypertonic.

7 MARKETING AUTHORISATION HOLDER

Medi-Radiopharma Ltd.

2030 Érd, Szamos st. 10-12

Hungary

8 MARKETING AUTHORISATION NUMBER(S)

PL 27151/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

30/04/2024

10 DATE OF REVISION OF THE TEXT

30/04/2024

11 DOSIMETRY

The following radiation dosimetry is calculated according to the MIRD system. The data are given in ICRP publication 80 in 1998.

The following assumptions have been made in this model:

• In the normal case following intravenous administration of MAG3, the substance is rapidly distributed in the extracellular fluid and excreted entirely by the renal system according to the kidney-bladder model. Total body retention is described by a three-exponential function. The renal transit time is assumed to be 4 minutes as for Hippuran.
• When renal function is bilaterally impaired, it is assumed that the clearance rate of the substance is one tenth of that of the normal case, that the renal transit time is increased to 20 minutes, and that a fraction of 0.04 is taken up in the liver.
• As an example of acute unilateral renal blockage, it is assumed that a fraction of 0.5 of the administered radiopharmaceutical is taken up by one kidney and slowly released to the blood with a half-time of 5 days and subsequently excreted by the other kidney, which is assumed to function normally.

Normal renal function:

Absorbed doses ^99mTc MAG3, ^99mTc 6.02 h

Absorbed dose per unit activity administered

(mGy/MBq)

Organ Adult 15 years 10 years 5 years 1 year

Adrenals 0.00039 0.00051 0.00082 0.0012 0.0025

Bladder 0.11 0.14 0.17 0.18 0.32

Bone surfaces 0.0013 0.0016 0.0021 0.0024 0.0043

Brain 0.0001 0.00013 0.00022 0.00035 0.00061

Breast 0.00010 0.00014 0.00024 0.00039 0.00082

Gall bladder 0.00057 0.00087 0.0020 0.0017 0.0028

GI-tract

Stomach 0.00039 0.00049 0.00097 0.0013 0.0025

SI 0.0023 0.0030 0.0042 0.0046 0.0078

Colon 0.0034 0.0043 0.0059 0.0060 0.0098

ULI 0.0017 0.0023 0.0034 0.0040 0.0067)

LLI 0.0057 0.0070 0.0092 0.0087 0.014)

Heart 0.00018 0.00024 0.00037 0.00057 0.0012

Kidneys 0.0034 0.0042 0.0059 0.0084 0.015

Liver 0.00031 0.00043 0.00075 0.0011 0.0021

Lungs 0.00015 0.00021 0.00033 0.00050 0.0010

Muscles 0.0014 0.0017 0.0022 0.0024 0.0041

Oesophagus 0.00013 0.00018 0.00028 0.00044 0.00082

Ovaries 0.0054 0.0069 0.0087 0.0087 0.014

Pancreas 0.0004 0.0005 0.00093 0.0013 0.0025

Red marrow 0.00093 0.0012 0.0016 0.0015 0.0021

Skin 0.00046 0.00057 0.00083 0.00097 0.0018

Spleen 0.00036 0.00049 0.00079 0.0012 0.0023

Testes 0.0037 0.0053 0.0081 0.0087 0.016

Thymus 0.00013 0.00018 0.00028 0.00044 0.00082

Thyroid 0.00013 0.00016 0.00027 0.00044 0.00082

Uterus 0.012 0.014 0.019 0.019 0.031

Remaining Organs 0.0013 0.0016 0.0021 0.0022 0.0036

Effective dose (mSv/MBq)

0.007

0.0090

0.012

0.012

0.022

The bladder wall contributes up to 80 % of the effective dose.

Effective dose if bladder is emptied 1 or 0,5 hours after administration:

1 hour

30 min.

0.0025 0.0017

0.0031 0.0021

0.0045 0.0029

0.0064 0.0039

0.0064 0.0068

For an administered activity of 185 MBq (Maximal dose) the effective dose is 1.3 mSv. The absorbed dose in the target organ (kidney) is 0.63 mGy and the typical radiation dose to the critical organ (bladder wall) is 20 mGy.

Abnormal renal function:

Absorbed doses ^99mTc MAG3, ^99mTc 6.02 h

Absorbed dose per unit activity administered

(mGy/MBq)

Organ Adult 15 years 10 years 5 years 1 year

Adrenals 0.0016 0.0021 0.0032 0.0048 0.0086

Bladder 0.083 0.11 0.13 0.13 0.23

Bone surfaces 0.0022 0.0027 0.0038 0.0050 0.0091

Brain 0.00061 0.00077 0.0013 0.0020 0.0036

Breast 0.00054 0.00070 0.0011 0.0017 0.0032

Gall bladder 0.0016 0.0022 0.0038 0.0046 0.0064

GI-tract

Stomach 0.0012 0.0015 0.0026 0.0035 0.0061

SI 0.0027 0.0035 0.0050 0.0060 0.010

Colon 0.0035 0.0044 0.0061 0.0069 0.011

ULI 0.0022 0.0030 0.0043 0.0056 0.0093) LLI 0.0051 0.0063 0.0085 0.0086 0.014)

Heart 0.00091 0.0012 0.0018 0.0027 0.0048

Kidneys 0.014 0.017 0.024 0.034 0.059

Liver 0.0014 0.0018 0.0027 0.0038 0.0066

Lungs 0.00079 0.0011 0.0016 0.0024 0.0045

Muscles 0.0017 0.0021 0.0029 0.0036 0.0064

Oesophagus 0.00074 0.00097 0.0015 0.0023 0.0041

Ovaries 0.0049 0.0063 0.0081 0.0087 0.014

Pancreas 0.0015 0.0019 0.0029 0.0043 0.0074

Red marrow 0.0015 0.0019 0.0026 0.0031 0.0050

Skin 0.00078 0.00096 0.0015 0.0020 0.0038

Spleen 0.0015 0.0019 0.0029 0.0043 0.0074

Testes 0.0034 0.0047 0.0071 0.0078 0.014

Thymus 0.00074 0.00097 0.0015 0.0023 0.0041

Thyroid 0.00073 0.00095 0.0015 0.0024 0.0044

Uterus 0.010 0.012 0.016 0.016 0.027

Remaining

Organs

0.0017 0.0021 0.0028 0.0034 0.0060

Effective dose

(mSv/MBq)

0.0061 0.0078 0.010 0.011 0.019

For an administered activity of 185 MBq (Maximal dose) the effective dose is 1.1 mSv. The absorbed dose in the target organ (kidney) is 2.6 mGy and the typical radiation dose to the critica organ (bladder wall) is 15 mGy.

Acute unilateral renal function:

Absorbed doses ^99mTc MAG3, ^99mTc 6.02 h

Absorbed dose per unit activity administered

(mGy/MBq)

Organ Adult 15 years 10 years 5 years 1 year

Adrenals 0.011 0.014 0.022 0.032 0.055

Bladder 0.056 0.071 0.091 0.093 0.17

Bone surfaces 0.0031 0.0040 0.0058 0.0084 0.017

Brain 0.00011 0.00014 0.00023 0.00039 0.00075

Breast 0.00038 0.00051 0.0010 0.0016 0.0030

Gall bladder 0.0062 0.0073 0.010 0.016 0.023 GI-tract

Stomach 0.0039 0.0044 0.0070 0.0093 0.012

SI 0.0043 0.0055 0.0085 0.012 0.019

Colon 0.0039 0.0050 0.0072 0.0092 0.0015

ULI 0.0040 0.0051 0.0076 0.010 0.016)

LLI 0.0038 0.0048 0.0067 0.0082 0.013)

Heart 0.0013 0.0016 0.0027 0.0040 0.0061

Kidneys 0.20 0.24 0.33 0.47 0.81

Liver 0.0044 0.0054 0.0081 0.011 0.017

Lungs 0.0011 0.0016 0.0025 0.0039 0.0072

Muscles 0.0022 0.0027 0.0037 0.0051 0.0089

Oesophagus 0.00038 0.00054 0.00085 0.0015 0.0023

Ovaries 0.0038 0.0051 0.0071 0.0092 0.015

Pancreas 0.0074 0.0090 0.013 0.018 0.029

Red marrow 0.0030 0.0036 0.0050 0.0060 0.0083

Skin 0.00082 0.0010 0.0015 0.0022 0.0042

Spleen 0.0098 0.012 0.018 0.026 0.040

Testes 0.0020 0.0029 0.0045 0.0050 0.0098

Thymus 0.00038 0.00054 0.00085 0.0015 0.0023

Thyroid 0.00017 0.00023 0.00045 0.00092 0.00160

Uterus 0.0072 0.0087 0.012 0.013 0.022

Remaining

Organs 0.0021 0.0026 0.0036 0.0047 0.0080

Effective dose

(mSv/MBq) 0.010 0.012 0.017 0.022 0.038

For an administered activity of 185 MBq (Maximal dose) the effective dose is 1.85 mSv.

The absorbed dose in the target organ (kidney) is 37 mGy and the typical radiation dose to the critical organ (bladder wall) is 10 mGy.

12 INSTRUCTIONS FOR PREPARATION OF

RADIOPHARMACEUTICALS

Method of preparation

Elute a ^99mTc generator in a 5 ml volume, according to the fractionated elution technique and follow the directions for use for the generator. The desired amount of ^99mTc, with a maximum of 2960 MBq (80 mCi) must be diluted to a volume of 10 ml with a sterile saline solution (0.9 %). Add this volume to a vial of Renoscan 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 a heating block previously heated to 120°C or boiling water bath. 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. If needed, a dilution with 0.9 % saline solution is possible.

This ^99mTc labelled preparation having a concentration of 2960 MBq per 10 ml can be used until 8 hours after completion of the heating step.

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

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 fluor-escein to make a concentration of 0.1 %). The radiolabelled product vial should be examined for contamination (taking appropriate radiological protective measures) prior to use.

Quality control

The following methods may be used:

1. 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/min.

Mobile phase A is a 93:7 mixture of phosphate solution (1.36 g KH₂PO₄, adjusted with 0.1 M NaOH to pH 6) and ethanol. Mobile phase B is a 1:9 mixture of water and methanol.

Use an elution program with the following parameters:

The technetium (^99mTc) tiatide peak appears at the end of the passage of mobile phase A.

The injection volume is 20 µl and the total count rate per channel must not exceed 30.000.

Requirement:

1. 2. TLC method

Method: thin layer chromatography

Hydrophilic impurities

Requirement:

location of radioactive impurities: in the front Rf=0.8-1.0

quantity: max.: 5 %

Method:

Sample solution: drop 2 μl labelled product on the layer

Reference solution: drop 2 μl eluate on the layer (pertechnetate ion)

Test parameters:

• Layer: ITLC-SG
• application: 2 cm from the bottom edge of the plate
• start of developing: right after application of the sample
• Front distance: 6 cm
• Developing solution: ethyl acetate: methyl ethyl ketone = 60:40
• Jar: saturated
• Saturation time: 30 minutes
• Drying: allowed to dry at room temperature after development
• Time of application: 20 minutes after labeling

Detection: radioactivity measuring detector.

Evaluation:

The radioactive impurities migrate in the front Rf=0.8-1.0, reading of the corresponding quantity (in percentage of the total radioactivity in %) from the chromatogram.

3 Paperchromatographic method

Radioactive impurities (method: paperchromatography)

Impurity A: (^99mTc) Technetium in colloidal form

Requirement:

location of radioactive impurities: on the start point Rf=0.0-0.1 quantity: max.: 2 %

Method:

Sample solution: drop 2 µl labelled product on the paper

Reference solution: drop 2 µl eluate on the layer (pertechnetate ion)

Test parameters:

• Layer: chromatography paper
• application: 2 cm from the bottom edge of the plate
• start of developing: right after application of the sample
• Front distance: 15 cm
• Developing solution: water: acetonitril=40:60
• Jar: saturated
• Saturation time: 30 minutes
• Paper drying: allowed to dry at room temperature after development
• Time of application: 20 minutes after labeling

Detection: radioactivity measuring detector.

Evaluation:

The radioactive impurities remain in the start point Rf=0.0-0.1, reading of the corresponding quantity (in percentage of the total radioactivity in %) from the chromatogram.

Calculate the percentage of radioactivity due to ^99mTc technetium mertiatide using the following expression:

100-(A+B)

Where

A = percentage of radioactivity due to impurity A, (^99mTc) Technetium in colloidal form resulting from paper chromatographic method

B= percentage of radioactivity due to hydrophilic impurities, including impurity B resulting from TLC method

A radiochemical purity of at least 94 % may be expected provided the test samples have been taken and analysed within 8 hours of reconstitution.