IELMAG3 0.2 MG KIT FOR RADIOPHARMACEUTICAL PREPARATION - Summary of medicine characteristics

IELMAG3 0.2 mg kit for radiopharmaceutical preparation

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The kit contains two different vials: (1) and (2).

Vial (1) contains 0.2 mg of the mertiatide ( mercaptoacetyl­triglycine).

Vial (2) contains 2.5 mL phosphate buffer solution.

For a full list of excipients, see section 6.1.

The radionuclide is not part of the kit. The kit contains all non radioactive components required for the reconstitution of technetium-(99mTc) mertiatide solution for injection.

Kit for radiopharmaceutical preparation.

Vial 1: white to off-white powder

Vial 2: clear, colourless solution

4.1 Therapeutic indications

This medicinal product is for diagnostic use only. This is indicated for adults. For paediatric population see section 4.2.

After radiolabelling with sodium pertechnetate(99mTc) solution, the solution of technetium-(99mTc) mertiatide, is used for the evaluation of nephrological and urological disorders in particular for the study of function, morphology and perfusion of the kidneys and characterisation of urinary outflow.

4.2 Posology and method of administration

Posology

Adults and elderly population

40 – 200 MBq, depending on the pathology to be studied and the method to be used.

Population aged less than 18 years

Although IELMAG3 0.2 mg kit for radiopharmaceutical preparation 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.

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 recommendations of the European Association of Nuclear Medicine (EANM) paediatric dosage card; the activity administered to children and to adolescents may be calculated by multiplying a baseline activity (for calculation purposes) by the weight-dependent multiples given in the table below.

A[MBq]Administered = Baseline Activity x Multiple The baseline activity is 11,9 MBq.

The minimum activity is 15 MBq.

Method of administration

For intravenous use.

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

The scintigraphic investigation is usually started immediately after administration.

For patient preparation, see section 4.4

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

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients listed in section

6.1or or to any of the components of the labelled radiopharmace­utical.

4.4 Special warnings and precautions for use

Pregnancy, see section 4.6.

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.

Paediatric population

Paediatric population, see sections 4.2.

Careful consideration of the indication is required since the effective dose per MBq is higher than in adults (see section 11 “Dosimetry”).

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.

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 pharmaceuticals quality requirements. Appropriate aseptic precautions should be taken.

Specific warnings

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

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.

Precautions with respect to environmental hazard see section 6.6.

4.5 Interaction with other medicinal products and other forms of interaction Technetium-(99mTc) mertiatide is not known to interfere with agents commonly prescribed to patients requiring the above mentioned investigations (e.g. antihypertensives or medicinal agents used to treat or prevent organ transplant rejection).

Under the influence of tubulary secreted hydrochlorothiazide a reduced tubular secretion of the product has to be expected. This can in principle occur with other drugs that are secreted in the proximal tubule (e.g. nonsteroidal anti-inflammatory drugs).

The previous administration of substances such as benzylpenicillin or iodinated contrast media may also cause lower efficiency of the transport mechanism of the tubular cells.

It is reported that co-administration of metoclopramide reduces renal plasma flow. Therapeutic doses may result in reduced clearance values. Dehydration and acidosis can also cause a prolonged elimination of the product.

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 a pregnant woman also involve radiation doses to the foetus.

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

Breastfeeding

Before administering a radioactive medicinal product 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 radiopharmace­uticals, bearing in mind the secretion of activity into breast milk. If the administration is considered necessary, breastfeeding should be interrupted for 24 hours and the expressed feeds discarded.

Moreover, for radioprotection reasons, the mother is recommended to avoid close contact with the baby during the initial 24 hours following injection.

Fertility

Effects on fertility are not known.

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 following table presents how the frequencies are reflected in this section:

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)

Very rare mild anaphylactoid reactions have been reported (< 0.01 %), characterised by uriticarial rash, swelling of eyelids and coughing.

Occasionally vasovagal reactions of a mild nature have been reported. A cerebral convulsion in a sedated fifteen days old child has been reported, but causative relation with the administration of the radiopharmaceutical was not proven.

Exposure to ionisation radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic nuclear medicine investigations current evidence suggests that these adverse effects might only occur with low frequency because of the low radiation doses incurred.

For most diagnostic nuclear medical procedures, the radiation dose delivered (E) is less than 20 mSv. A worst case calculation for the procedure in question gives values of 2 mSv for an adult and 0.76 mSv for a 1 year old child after injection of 200 and 20 MBq respectively.

Undesirable effects

The attending physician should request the patient to communicate each side effect.

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 the national reporting system listed in Appendix V.

4.9 Overdose

In the event of administration of a radiation overdose with technetium-(99mTc) mertiatide the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by frequent micturition or and frequent bladder voiding. It might be helpful to estimate the effective dose that was applied.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: radiopharmace­uticals, ATC Code: V09CA03

No pharmaco-dynamic effect is known for technetium-(99mTc) mertiatide at the chemical doses envisaged.

Measuring the counts rate in the kidneys, over time, allows the evaluation of the renal perfusion, function and urinary outflow.

5.2 Pharmacokinetic properties

Distribution

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

Organ uptake

Technetium-(99mTc) mertiatide binds in a 78–90 % proportion to plasma proteins. In normal renal function 70 % of the administered activity is excreted within 30 min. and more than 95 % within 3 hours. These values 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

It has been reported that no acute, subacute, subchronic or mutagenic effects have been observed in preclinical studies. However, no detailed information is available for these studies.

6.1 List of excipients

vial (1):

Stannous chloride dihydrate,

Disodium (R,R)-tartrate dihydrate

Sodium hydroxide

Hydrochloric acid

vial (2):

Sodium monohydrogenphos­phate dihydrate

Sodium dihydrogenphosphate dihydrate

Hydrochloric acid

Water for injections

6.2 Incompatibilities

Not known. However, in order not to compromise the stability of technetium-(99mTc) mertiatide, preparations should not be administered together with other drugs.

6.3

Vial (1): 15 months

Vial (2): 24 months

After radiolabelling: 8 hours.

Store the radiolabelled preparation below 25°C.

6.4 Special precautions for storage

Store in a refrigerator (2 – 8 °C).

Store in the original package in order to protect from light.

For storage conditions of the radiolabelled medicinal product, see section 6.3

Storage of radiopharmace­uticals should be in accordance with national regulations on radioactive material.

6.5 Nature and contents of container

Glass vial (10 mL) closed with a butyl rubber stopper and sealed with an aluminium crimpcap. IELMAG3 0.2 mg kit for radiopharmaceutical preparation is supplied in packages containing five vials with powder (active substance: mertiatide) and five vials with 2.5 mL sterile phosphate buffer solution.

6.6 Special precautions for disposal

The content of the kit before reconstitution is not radioactive. However, after [e.g. sodium pertechnetate (99mTc) Injection, Ph. Eur.] is added, 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.

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 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 technetium (99mTc) mertiatide and are not to be administered directly to the patient without first undergoing the preparative procedure.

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.

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

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

7 MARKETING AUTHORISATION HOLDER

ROTOP Pharmaka GmbH

Bautzner Landstraße 400

013228 Dresden

Germany

Phone: +49 351 26 310 210

Fax: +49 351 26 310 313

E-Mail: service@rotop-pharmaka.de

8 MARKETING AUTHORISATION NUMBER(S)

PL 45925/0005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 12 July 2013

Date of last renewal: 22 January 2018

10 DATE OF REVISION OF THE TEXT

18/06/2019

11 DOSIMETRY (IF APPLICABLE)

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

The data listed below are from ICRP publication 80 in 1998 and are calculated according to the MIRD system:

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.

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Radiolabelling should be done using an eluate with a radioactive concentration between 40 and 500 MBq/mL. Only eluates obtained from a generator, which has been eluted once in the preceding 24 hours, should be used.

The content of vial (1) is labelled with sodium pertechnetate (99mTc) solution at room temperature. The radiolabelling reaction is stopped after 15 minutes by adding the buffer solution.

Withdrawals should be performed under aseptic conditions. The vials must not 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 authorized automated application system.

As with any pharmaceutical product, if at any time in the preparation of this product the integrity of this vial is compromised it should not be used.

Method of preparation

The radiopharmaceutical is prepared according to the following labelling instructions immediately before use:

The radiolabelling procedure has to be carried out under aseptic conditions.

Place vial (1) into an adequate lead shielding. Swab the rubber septum with an appropriate disinfectant and let it dry.

Inject 8 mL of sodium pertechnetate (99mTc) solution into vial (1) using a syringe. Then withdraw the same volume of nitrogen from the vial with the same syringe for pressure compensation.

Shake the vial carefully in order to moisten. The complete content of the vial is for complete dissolution of any powder.

After 15 minutes reaction time transfer a volume of 2 mL buffer solution from vial (2) into vial (1) using a new syringe. Then withdraw the same volume of nitrogen from the vial with the same syringe for pressure compensation.

Shake carefully for good mixing. Determine the total radioactivity and calculate the volume to be injected.

Properties of the product after radiolabelling:

Appearance: Clear to slightly opalescent, colourless, aqueous solution.

pH:          7.1–7.5

Quality control

The following methods may be used:

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 a gradient elution program with the following parameters:

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

The injection volume is 10 pl and the total count rate per channel must not exceed 30.000.

Specification:

This method is based on cartridges, which are widely used as sample pre-treatment of aqueous solutions for chromatography. The cartridge (e.g. Sep-Pak Plus C 18, Waters) is washed with 10 mL absolute ethanol, followed by 10 mL 0.001 M hydrochloric acid. Remaining residues of the solutions are removed by 5 mL of air.

0.05 mL technetium-(99mTc) mertiatide solution is applied on the cartridge. Elute with 10 mL of 0.001 M hydrochloric acid and collect this first eluate (hydrophilic impurities). Elute the cartridge with ethanol/ 9 g/L sodium chloride solution in a ratio of 1:1. This second eluate contains technetium-(99mTc) mertiatide. The cartridge contains the lipophilic impurities.

Measure the radioactivity of each portion. Sum up the radioactivity of the eluates and the cartridge as 100 % and calculate the respective percentages.

Be aware to elute slowly (drop wise).

Sum of impurities: < 6.5 %

This method is used for

Chromatographic system:

Stripes:

Eluent:

Running distance:

Volume of the probe:

Detector:

ITLC-SA

methyl ethyl ketone

6–8cm

1–2gl

a suitable detector

Technetium ( 99mTc) pertechnetate migrates with the solvent front ( Rf = 0.8 to 1.0 ). If you do not have a scanner, you cut the strip 5 cm from the bottom. Measure separately the radioactivity of both parts. Put the activity of the upper part in relation to the total activity.

j                       . r -, Activity v&psr part [M&4]

portsc/wwtats [S'il =--------;---------:----=— X

■      ■                 L J      To tai activity

Specification for r=→ < =■■ 7:                j y r: r=→ :-;s–7.; 7– (impurity A): < 5,0%

Chromatographic system:

Stripes:

Eluant:

Running distance:

Volume:

Detector:

ITLC-SA

water for injection 6–8cm

1–2gl

a suitable detector

12 INSTRUCTIONS FOR PREPARATION OFRADIOPHARMACEUTICALS

Radiolabelling should be done using an eluate with a radioactive concentration between 40 and 500 MBq/mL. Only eluates obtained from a generator, which has been eluted once in the preceding 24 hours, should be used.

The content of vial (1) is labelled with sodium pertechnetate (99mTc) solution at room temperature. The radiolabelling reaction is stopped after 15 minutes by adding the buffer solution.

Withdrawals should be performed under aseptic conditions. The vials must not 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 authorized automated application system.

As with any pharmaceutical product, if at any time in the preparation of this product the integrity of this vial is compromised it should not be used.

Method of preparation

The radiopharmaceutical is prepared according to the following labelling instructions immediately before use:

The radiolabelling procedure has to be carried out under aseptic conditions.

Place vial (1) into an adequate lead shielding. Swab the rubber septum with an appropriate disinfectant and let it dry.

Inject 8 mL of sodium pertechnetate (99mTc) solution into vial (1) using a syringe. Then withdraw the same volume of nitrogen from the vial with the same syringe for pressure compensation.

Shake the vial carefully in order to moisten. The complete content of the vial is for complete dissolution of any powder.

After 15 minutes reaction time transfer a volume of 2 mL buffer solution from vial (2) into vial (1) using a new syringe. Then withdraw the same volume of nitrogen from the vial with the same syringe for pressure compensation.

Shake carefully for good mixing. Determine the total radioactivity and calculate the volume to be injected.

Properties of the product after radiolabelling:

Appearance: Clear to slightly opalescent, colourless, aqueous solution.

pH:          7.1–7.5

Quality control

The following methods may be used:

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 a gradient elution program with the following parameters:

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

The injection volume is 10 pl and the total count rate per channel must not exceed 30.000.

Specification:

This method is based on cartridges, which are widely used as sample pre-treatment of aqueous solutions for chromatography. The cartridge (e.g. Sep-Pak Plus C 18, Waters) is washed with 10 mL absolute ethanol, followed by 10 mL 0.001 M hydrochloric acid. Remaining residues of the solutions are removed by 5 mL of air.

0.05 mL technetium-(99mTc) mertiatide solution is applied on the cartridge. Elute with 10 mL of 0.001 M hydrochloric acid and collect this first eluate (hydrophilic impurities). Elute the cartridge with ethanol/ 9 g/L sodium chloride solution in a ratio of 1:1. This second eluate contains technetium-(99mTc) mertiatide. The cartridge contains the lipophilic impurities.

Measure the radioactivity of each portion. Sum up the radioactivity of the eluates and the cartridge as 100 % and calculate the respective percentages.

Be aware to elute slowly (drop wise).

Sum of impurities: < 6.5 %

This method is used for

Chromatographic system:

Stripes:

Eluent:

Running distance:

Volume of the probe:

Detector:

ITLC-SA

methyl ethyl ketone

6–8cm

1–2gl

a suitable detector

Technetium ( 99mTc) pertechnetate migrates with the solvent front ( Rf = 0.8 to 1.0 ). If you do not have a scanner, you cut the strip 5 cm from the bottom. Measure separately the radioactivity of both parts. Put the activity of the upper part in relation to the total activity.

j                       . r -, Activity v&psr part [M&4]

portsc/wwtats [S'il =--------;---------:----=— X

■      ■                 L J      To tai activity

Specification for r=→ < =■■ 7:                j y r: r=→ :-;s–7.; 7– (impurity A): < 5,0%