SOMAKIT TOC 40mcg kit for radio pharmaceuticals medication leaflet

SomaKit TOC 40 micrograms kit for radiopharmaceutical preparation

Each vial of powder contains 40 micrograms of edotreotide.

The radionuclide is not part of the kit.

For the full list of excipients, see section 6.1.

Kit for radiopharmaceutical preparation containing:

- Powder for solution for injection: the vial contains a white lyophilised powder.

- Reaction buffer: the vial contains a clear, colourless solution.

For radiolabelling with gallium (68Ga) chloride solution.

This medicinal product is for diagnostic use only.

After radiolabelling with gallium (68Ga) chloride solution, the solution of gallium (68Ga) edotreotideobtained is indicated for positron emission tomography (PET) imaging of somatostatin receptoroverexpression in adult patients with confirmed or suspected well-differentiated gastro-enteropancreatic neuroendocrine tumours (GEP-NET) for localising primary tumours and theirmetastases.

The medicinal product should only be administered by trained healthcare professionals with technicalexpertise in using and handling nuclear medicine diagnostic agents and only in a designated nuclearmedicine facility.

The recommended activity for an adult weighing 70 kg is 100 to 200 MBq, administered by directslow intravenous injection.

The activity will be adapted to patient characteristics, the type of PET camera used and acquisitionmode.

No special dose regimen for elderly patients is required.

Renal/Hepatic impairment

The safety and efficacy of gallium (68Ga) edotreotide have not been studied in patients with renal orhepatic impairment.

The safety and efficacy of gallium (68Ga) edotreotide have not been established in paediatricpopulations, where the effective dose might be different than in adults. There is no recommendationfor use of SomaKit TOC in paediatric patients.

SomaKit TOC is for intravenous use and for single use only.

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

The activity of gallium (68Ga) edotreotide must be measured with an activimeter immediately prior toinjection.

The injection of gallium (68Ga) edotreotide must be administered intravenously in order to avoid localextravasation resulting in inadvertent radiation to the patient and imaging artefacts.

For instructions on extemporaneous preparation of the medicinal product before administration, seesections 6.6 and 12.

For patient preparation, see section 4.4.

Image acquisition

Radiolabelled SomaKit TOC is suitable for PET medical imaging. The acquisition must include awhole body acquisition from skull to mid-thigh. The recommended time for imaging is 40 to90 minutes post injection. Imaging acquisition start time and duration should be adapted according tothe equipment used, the patient and the tumour characteristics in order to obtain the best image qualitypossible.

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to any of thecomponents of the labelled radiopharmaceutical.

Potential for hypersensitivity or anaphylactic reactions

If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must bediscontinued immediately and intravenous treatment initiated, if necessary. To enable immediateaction in emergencies, the necessary medicinal products and equipment such as endotracheal tubemust be immediately available.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activityadministered should in every case be as low as reasonably achievable to obtain the required diagnosticinformation.

Renal/Hepatic impairment

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

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

Patient preparation

The patient should be well hydrated before the start of the examination and urged to void as often aspossible during the first hours after examination in order to reduce radiation.

Errors of interpretation of gallium (68Ga) edotreotide images

PET images with gallium (68Ga) edotreotide reflect the presence of somatostatin receptors in thetissues.

The organs with high physiological uptake of gallium (68Ga) edotreotide include spleen, kidneys, liver,pituitary gland, thyroid gland and adrenals. High physiological uptake of gallium (68Ga) edotreotide bythe pancreas uncinate process can also be observed.

An increased uptake of gallium (68Ga) edotreotide is not specific for GEP-NET. Healthcareprofessionals should be aware that further imaging or histological and/or other relevant investigationsmay be required to establish the diagnosis.

Due to physiological uptake of gallium (68Ga) edotreotide, splenosis and accessory intrapancreaticspleen may be incidentally detected with somatostatin receptor targeted diagnostics. Cases in whichsuch uptake has been misdiagnosed as neuroendocrine tumours, leading to unnecessary intervention,have been reported. Spleen disorders (e.g. splenectomy, splenosis and accessory intrapancreaticspleen) should therefore be considered as a relevant factor when reporting the outcome of somatostatinreceptor targeted diagnostics.

Positive results also require evaluating the possibility that another disease, characterised by high localsomatostatin receptor concentrations, may be present. As an example, an increase in somatostatinreceptor density can also occur in the following pathological conditions: subacute inflammations(areas of lymphocyte concentrations, including reactive lymph nodes, for example followingvaccination), thyroid diseases (e.g. thyroid autonomy and Hashimoto’s disease), tumours of thepituitary gland, neoplasms of the lungs (small-cell carcinoma), meningiomas, mammary carcinomas,lymphoproliferative disease (e.g. Hodgkin's disease and non-Hodgkin lymphomas) and tumoursarising from tissue embryologically derived from the neural crest (e.g. paragangliomas, medullarythyroid carcinomas, neuroblastomas, pheochromocytomas).

In case of Cushing syndrome, a long-term exposure to endogenous hypercortisolism may downregulate somatostatin receptor expression and negatively influence the results of somatostatin receptorimaging with gallium (68Ga) edotreotide. Thus, in patients with GEP-NET and Cushing syndrome,normalisation of hypercortisolism should be suggested before performing PET with gallium (68Ga)edotreotide.

Limitations of gallium (68Ga) edotreotide imaging

In GEP-NET, a more intense gallium (68Ga) edotreotide uptake than normal background is a consistentfinding. However, lesions of GEP-NET not expressing sufficient density of somatostatin receptorscannot be visualised with gallium (68Ga) edotreotide. PET images with gallium (68Ga) edotreotideshould be interpreted visually, and semiquantitative measurement of gallium (68Ga) edotreotide uptakeshould not be used for clinical interpretation of images.

Data supporting efficacy of gallium (68Ga) edotreotide for predicting and monitoring of therapeuticresponse to peptide receptor radionuclide therapy (PRRT) in histologically confirmed metastatic NETare limited (see section 5.1).

Concomitant use of somatostatin analogues

It is preferable to perform imaging with gallium (68Ga) edotreotide the day(s) before the nextadministration of a somatostatin analogue. See section 4.5.

After the procedure

Close contact with infants and pregnant women should be restricted during the first 12 hours afteradministration.

Specific warnings

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

Due to the acidic pH of the radiolabelled gallium (68Ga) edotreotide solution, accidental extravasationmay cause local irritation. In case of extravasation, the injection must be stopped, the site of injectionmust be changed and the affected area should be irrigated with sodium chloride solution.

Precautions with respect to environmental hazard are in section 6.6.

Somatostatin and its analogues are probably competing to bind to the same somatostatin receptors.

Therefore, when treating patients with somatostatin analogues, it is preferable to perform imaging withgallium (68Ga) edotreotide the day(s) preceding the next administration of a somatostatin analogue.

A long-term exposure to endogenous hypercortisolism may down-regulate somatostatin receptorexpression and negatively influence the results of somatostatin receptor imaging with gallium (68Ga)edotreotide. In patients with Cushing syndrome, the normalisation of hypercortisolism should beconsidered before performing PET with SomaKit TOC.

Some evidence exists that corticosteroids can induce down-regulation of somatostatin subtype 2receptors (SSTR2). Repeated administration of high-doses of glucocorticosteroids prior to gallium(68Ga) edotreotide administration may cause insufficient SSTR2 expression for adequate visualisationof somatostatin receptor-positive NETs.

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it isimportant to determine whether or not she is pregnant. Any woman who has missed a period should beassumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if thewoman has missed a period, if her periods are very irregular, etc.), alternative techniques not usingionising radiation (if there are any) should be offered to the patient.

No data are available regarding the use of this medicinal product during pregnancy. Radionuclideprocedures carried out on pregnant women also involve radiation doses to the fœtus. Only essentialinvestigations should therefore be carried out during pregnancy, when the likely benefit far exceedsthe risk incurred by the mother and fœtus.

Before administering radiopharmaceuticals to a mother who is breast-feeding, consideration should begiven to the possibility of delaying the administration of radionuclide until the mother has ceasedbreast-feeding, and to what is the most appropriate choice of radiopharmaceuticals, bearing in mindthe secretion of activity in breast milk. If the administration is considered necessary, breast-feedingshould be interrupted for 12 hours and the expressed feeds discarded.

Close contact with infants should be restricted during the initial 12 hours following injection.

No studies were conducted to assess the impact on fertility.

Gallium (68Ga) edotreotide has no or negligible influence on the ability to drive and use machines.

Exposure to ionising radiation is linked with cancer induction and a potential for development ofhereditary defects. As the effective dose is about 4.5 mSv when the maximal recommended activity of200 MBq is administered, these adverse reactions are expected to occur with a low probability.

Adverse reactions are divided into groups according to the MedDRA convention frequencies: Verycommon (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Not known: injection site pain

Cases in which physiological uptake of gallium (68Ga) edotreotide by splenic tissue has beenmisdiagnosed as neuroendocrine tumour, leading to unnecessary intervention, have been reported (seesection 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of administration of a radiation overdose, the absorbed dose to the patient should bereduced where possible by increasing the elimination of the radionuclide from the body by reinforcedhydration and by frequent micturition. It might be helpful to estimate the effective dose that wasapplied.

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals; other diagnostic radiopharmaceuticalsfor tumour detection. ATC code: V09IX09.

Gallium (68Ga) edotreotide binds to somatostatin receptors. In vitro, this radiopharmaceutical bindswith high affinity mainly to SSTR2 but also, to a lesser extent, to SSTR5.

In vivo, semiquantitative correlation was not assessed between gallium (68Ga) edotreotide uptake intumours and the density of SSTR in histopathological samples either in GEP-NET patients or innormal organs. Moreover, the in vivo binding of gallium (68Ga) edotreotide to structures or receptorsother than SSTR remains unknown.

At the chemical concentrations used for diagnostic examinations, gallium (68Ga) edotreotide does notappear to have any clinically relevant pharmacodynamic effect.

Edotreotide is a somatostatin analogue. Somatostatin is a neurotransmitter in the central nervoussystem, but also a hormone which binds to cells of neuroendocrine origin and inhibits the release ofgrowth hormone, insulin, glucagon and gastrin. There are no data on whether the intravenousadministration of edotreotide produces variation of serum gastrin and serum glucagon levels.

For the detection of the primary GEP-NET site in case of rising levels of a relevant biochemicaltumour marker or in case of proven NET metastasis, patient-based sensitivity and specificity ofgallium (68Ga) edotreotide PET were 100% (4/4) and 89% (8/9), respectively, in the prospective studyof Gabriel et al. 2007. Lesion-detection rate was 75% (3/4) in the subgroup of patients with unknownprimary tumour site in the prospective study of Frilling et al. 2010. In the retrospective paper of

Schreiter et al. 2014, the intra-individual comparison in a subgroup of 20 patients showed that gallium(68Ga) edotreotide permitted to localise the primary tumour in 9/20 (45%) patients while indium (111In)pentetreotide did in 2/20 (10%).

A prospective intra-individual comparison showed that gallium (68Ga) edotreotide is able to detectlesions better than indium (111In) pentetreotide. A lesion detection rate of 100% (40/40) versus 85%(34/40) was observed in the study of Hofmann et al. 2001 recruiting patients with histologicallyproven bronchial (n=2) or midgut (n=6) NETs. In the study of Buchmann et al. 2007, conducted in27 patients mostly with GEP-NET (59%) or NETs of unknown primary (30%), gallium (68Ga)edotreotide identified 279 lesions versus 157 lesions seen with indium (111In) pentetreotide. In thestudy of Van Binnebeek et al. 2015 in 53 patients with metastatic GEP-NET [mostly GEP-NET (n=39)or NET of unknown origin (n=6)], the lesion-based detection rate of gallium (68Ga) edotreotide was99.9% (1098/1099) versus 60% (660/1099) for indium (111In) pentetreotide based on the follow-upscans. In the study of Lee et al. 2015 in 13 GEP-NET patients, a total of 35 positive lesions weredetected in 10 patients on either gallium (68Ga) edotreotide PET/CT or indium (111In) pentetreotide

SPECT/CT while 3 patients did not exhibit any positive lesions on either imaging method. Gallium(68Ga) edotreotide detected 35/35 (100%) lesions vs 19/35=54% for indium (111In) pentetreotide

SPECT/CT. In the study of Kowalski et al. 2003 in 4 patients with GEP-NET, gallium (68Ga)edotreotide showed a better patient-based detection rate (100%) than indium (111In) pentetreotide(50%).

Data available on clinical efficacy of gallium (68Ga) edotreotide for the indication of predicting andmonitoring of therapeutic response to peptide receptor radionuclide therapy (PRRT) in histologicallyconfirmed metastatic NET are limited. Five studies have been submitted, one of them prospective(Gabriel et al. 2009) and four retrospective (Kroiss et al. 2013, Ezziddin et al. 2012, Kratochwil et al.

2015 and Luboldt et al.2010a). In the study by Gabriel et al. 2009 pre-PRRT gallium (68Ga)edotreotide was compared with CT or MRI using the Response Evaluation Criteria in Solid Tumors(RECIST). Gallium (68Ga) edotreotide PET and CT showed a concordant result in 32 patients (70%)and discrepancies in 14 patients (30%) presenting 9 with progressive disease and 5 with remission.

The retrospective study of Kroiss et al. 2013 in 249 NET patients showed that PRRT does notsignificantly influence semiquantitative uptake of gallium (68Ga) edotreotide PET, except in livermetastases of patients with NET, but the study lacked histological confirmation. The three remainingretrospective studies recruited small samples (ranging from 20 to 28 GEP-NET patients or those withcancer of unknown origin) and found that semiquantitative uptake in the pre-PRRT gallium (68Ga)edotreotide PET scan correlated with the tumour-absorbed doses per injected activity of thesubsequent first treatment cycle, differed between those lesions classified as responding and non-responding after three PRRT cycles, and helped to separate hepatic metastases from normal livertissue.

After intravenous injection, gallium (68Ga) edotreotide is rapidly cleared from the blood following bi-exponential elimination of activity with half-lives of 2.0 ± 0.3 min and 48 ± 7 min, respectively.

Organ uptake

The organ with the highest physiological uptake of gallium (68Ga) edotreotide is the spleen, followedby the kidneys. The uptake in the liver and in the pituitary, thyroid and adrenal glands is lower. Highphysiological uptake of gallium (68Ga) edotreotide by the pancreas uncinate process can also beobserved. About 50 minutes after intravenous administration, gallium (68Ga) edotreotide accumulationshows plateauing in all organs.

The organ uptake has been shown to be age-independent in normal adult human tissues and alsopredominantly gender-independent (except for the thyroid and head of pancreas).

No radioactive metabolites were detected in serum within 4 hours after intravenous injection ofgallium (68Ga) edotreotide.

Approximately 16% of gallium (68Ga) edotreotide activity is removed from the body in the urinewithin 2 to 4 hours. The peptide is excreted via the kidneys as intact compound.

Half-life

Given that the elimination rate is substantially slower than the physical half-life of gallium (68Ga)(68 min), the biological half-life will have little impact on the effective half-life of the medicinalproduct, which then would be expected to be somewhat less than 68 minutes.

Renal/Hepatic impairment

The pharmacokinetics in patients with renal or hepatic impairment have not been characterised.

Non-clinical data did not reveal any special hazard for gallium (68Ga) edotreotide in humans.

Local tolerance assessment resulted in mild to moderate inflammation signs in the perivascular regionof some animals which can be attributed to the acidic pH of the solution.

No studies on fertility, embryology, mutagenicity or long-term carcinogenicity have been conducted.

Regarding the novel excipient (1,10-phenanthroline), during the toxicity study conducted with the kitformulation of SomaKit TOC including 1,10-phenanthroline at a dose 400 fold higher than the humandose, no toxicity signs were observed.

Genotoxicity studies on 1,10-phenanthroline available in the literature show negative results inbacterial mutation assay (Ames test), while in a mouse lymphoma assay an indication of possiblegenotoxicity was obtained at concentrations 750 times higher than the maximum 1,10-phenanthrolineblood concentration achievable in patients. However, even taking as worst case reference the limits forgenotoxic and carcinogenic impurities, the risk related to the trace amounts of 1,10-phenanthroline in

SomaKit TOC formulation is considered negligible at the dose to be administered in patients: theexposure to 1,10-phenanthroline (5 µg/dose) is 24 fold lower than the acceptable daily intake for agenotoxic impurity (120 µg/day for exposures <1 month).

Powder1,10-phenanthroline

Gentisic acid

Mannitol (E421)

Buffer

Formic acid

Sodium hydroxide (E524)

Water for injections

After radiolabelling, the solution obtained also contains, as excipient, hydrochloric acid from thegenerator eluate.

Radiolabelling of carrier molecules with gallium (68Ga) chloride is very sensitive to the presence oftrace metal impurities. Only syringe and syringe needles able to minimise trace metal impurity levels(for example, non-metallic or coated with silicone needles) should be used.

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

Kit as packaged for sale2 years.

After radiolabelling4 hours.

Do not store above 25°C after radiolabelling.

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2°C to 8°C).

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

For storage conditions after radiolabelling of the medicinal product, see section 6.3.

Storage of radiopharmaceuticals should be in accordance with national regulation on radioactivematerials.

Each pack contains:

* One vial of powder for solution for injection: 10 ml Type I glass vial closed with a bromobutylrubber stopper and sealed with a flip-off cap. Each vial contains 40 micrograms of edotreotide.

* One vial of reaction buffer: 10 ml cyclic olefin polymer vial closed with a teflon stopper andsealed with a flip-off cap. Each vial contains 1 ml of reaction buffer.

General warnings

Radiopharmaceuticals should be received, used and administered only by authorised persons indesignated clinical settings. Their receipt, storage, use, transfer and disposal are subject to theregulations and/or appropriate licenses of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety andpharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Contents of the vials are intended only for use in the preparation of gallium (68Ga) edotreotide solutionfor injection and are not to be administered directly to the patient without first undergoing thepreparative procedure.

Each 40 microgram vial contains an excess of medicinal product. However, it is recommended that thevial be prepared as instructed and used for a single patient dose, based on the activity to be injected;any remaining material should be discarded after radiolabelling and use.

Precautions to be taken before handling or administration of the medicinal product

For instructions on radiolabelling of the medicinal product before administration, see section 12.

If at any time in the preparation of this medicinal product the integrity of the vials is compromised itshould not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of themedicinal product and irradiation of the operators. Adequate shielding is mandatory.

The content of the kit before radiolabelling is not radioactive. However, after gallium (68Ga) chloridesolution is added, adequate shielding of the final preparation must be maintained.

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

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

Advanced Accelerator Applications8-10 Rue Henri Sainte-Claire Deville92500 Rueil-Malmaison

France

EU/1/16/1141/001

Date of first authorisation: 08/12/2016

Date of latest renewal: 12/11/2021

Gallium-68 decays with a half-life of 68 min to stable zinc-68, 89% through positron emission with amean energy of 836 keV followed by photonic annihilation radiations of 511 keV (178%), 10%through orbital electron capture (X-ray or Auger emissions), and 3% through 13 gamma transitionsfrom 5 excited levels.

The dosimetry of gallium (68Ga) edotreotide was calculated by Sandstrom et al. (2013), using

OLINDA/EXM 1.1 software (Table 1).

Table 1: Dosimetry of gallium (68Ga) edotreotide

Absorbed dose in selected organs mGy/MBq

Organs Mean

Adrenals 0.077

Brain 0.010

Breasts 0.010

Gallbladder wall 0.015

Lower large intestine wall 0.015

Small intestine 0.023

Stomach wall 0.013

Upper large intestine wall 0.020

Heart wall 0.020

Kidneys 0.082

Liver 0.041

Lungs 0.007

Muscle 0.012

Ovaries 0.015

Pancreas 0.015

Red marrow 0.016

Osteogenic cells 0.021

Skin 0.010

Spleen 0.108

Testes 0.011

Thymus 0.011

Thyroid 0.011

Urinary bladder wall 0.119

Uterus 0.015

Total body 0.014

Effective dose0.021mSv/MBq

The effective dose resulting from the administration of an activity of 200 MBq to an adult weighing70 kg is about 4.2 mSv.

For an administered activity of 200 MBq the typical radiation dose to the critical organs, which are theurinary bladder wall, the spleen, the kidneys and the adrenals, are about 24, 22, 16 and 15 mGy,respectively.

Radiation safety - Medicinal product handling

Use waterproof gloves, effective radiation shielding, and appropriate safety measures when handlingthe radiolabelled SomaKit TOC to avoid unnecessary radiation exposure to the patient, occupationalworkers, clinical personnel, and other persons.

Radiopharmaceuticals should be used by or under the control of healthcare professionals who arequalified by specific training and experienced in the safe use and handling of radionuclides, and whoseexperience and training have been approved by the appropriate governmental agency authorised tolicense the use of radionuclides.

The gallium (68Ga) edotreotide solution must be prepared in accordance with radioprotection andpharmaceutical quality standards, especially concerning aseptic technique. If at any time in thepreparation of this medicinal product the integrity of the vials is compromised, the medicinal productshould not be used.

A low dead space 1 ml plastic syringe must be used in order to precisely measure the adequate volumeof reaction buffer to be added during the preparation. Glass syringes must not be used.

For administration, the solution should be withdrawn via the stopper using a single-dose syringe fittedwith suitable protective shielding and a disposable sterile needle or using an authorised automatedapplication system.

Method of preparation

SomaKit TOC is supplied as a kit containing two vials. It is intended to be radiolabelled with agallium (68Ga) chloride solution compliant with the Ph. Eur. monograph 2464 Gallium (68Ga) chloridesolution for radiolabelling and that, in addition, is sterile and has been tested for compatibility with

SomaKit TOC. Only generators that have been authorised as medicinal products in the EU should beused. Refer to the Summary of Product Characteristics of the particular generator for moreinformation.

The following authorised generators have shown to be compatible with SomaKit TOC:

* GalliaPharm, 0.74 - 1.85 GBq, radionuclide generator (Eckert & Ziegler Radiopharma GmbH),

* Galli Ad, 0.74 - 1.85 GBq, radionuclide generator (IRE-Elit).

The gallium (68Ga) edotreotide solution for intravenous injection must be prepared according toaseptic procedure, local regulation and the following instructions.

Reconstitution with GalliaPharm generator:

a. If possible, for more convenience in the preparation of radiolabelled SomaKit TOC, the heatingplatform should be placed right beside the generator.

b. Set the temperature of the shielded dry bath with holes of 25 mm diameter at 95°C. Using athermometer, ensure the temperature reaches the set point and stabilises before starting thereconstitution procedure.

c. Flip off the cap from the vial of powder (vial 1) and swab the top of the vial closure with anappropriate antiseptic to disinfect the surface, then allow the stopper to dry.

d. Pierce vial 1 (powder for solution for injection) septum with a 0.2 µm sterile vent filter in orderto maintain atmospheric pressure within the vial during the radiolabelling process. The 0.2 µmsterile vent filter needle should not come into contact with the eluate at any time to avoid metalcontamination.

e. Flip off the cap from vial 2 (reaction buffer) and swab the top of the vial closure with anappropriate antiseptic to disinfect the surface, then allow the stopper to dry. With a low deadspace 1 ml sterile syringe carefully withdraw 0.5 ml reaction buffer, and keep the reactionbuffer in the syringe for step “i”.

f. Connect the male luer of the outlet line of the 68Ge/68Ga generator with a sterile needle (coatedwith silicone or other appropriate material able to reduce metal impurity trace).

g. Connect vial 1 to the outlet line of the generator by pushing the elution needle through therubber septum. Keep the elution needle below the 0.2 µm sterile vent filter needle. Ensure thatthe needles do not come into contact with each other and do not submerge in the eluate at anytime.

h. Elute the generator directly into vial 1 (through the needle) according to the generatormanufacturer instructions for use, in order to reconstitute the powder with the eluate. Theelution can be performed either manually or by means of a pump.

i. At the end of the elution, disconnect the generator from vial 1, withdrawing the needle from therubber septum, and immediately add the reaction buffer previously dosed in the 1 ml sterilesyringe. Withdraw the syringe and the 0.2 µm sterile vent filter and move the vial to the hole ofthe dry bath at 95°C, using pliers. Leave the vial at 95°C for at least 7 minutes (do not exceed10 minutes heating) without agitation or stirring.

j. After 7 minutes, remove the vial from the dry bath, place it in an appropriately labelled leadshield and let it cool down at room temperature for approximately 10 minutes.

k. Assay the vial radioactivity using a suitable radioactivity calibration system and record theresult. Report the activity value, the calibration time, the batch number and the expiry time onthe shield label included in the pack to be applied on the lead shielding container afterradiolabelling.

l. Perform the quality control according to the recommended methods in order to checkcompliance with the specifications (see section “Quality control”).

m. The solution should be visually inspected prior to use. Only clear solutions, free from visibleparticles should be used. The visual inspection should be performed under a shielded screen forradioprotection purposes.

n. Store the vial containing the gallium (68Ga) edotreotide solution below 25°C until use. At thetime of administration, the medicinal product must be aseptically withdrawn and theradioprotection standards must be followed. The patient dose should be measured using asuitable radioactivity calibration system immediately prior to patient administration. Medicinalproduct administration data should also be recorded.

A schematic representation of the radiolabelling procedure is shown in Figure 1.

Figure 1: Radiolabelling procedure when using GalliaPharm generator

Reconstitution with Galli Ad generator:

a. If possible, for more convenience in the preparation of radiolabelled SomaKit TOC, the heatingplatform should be placed right beside the generator.

b. Set the temperature of the shielded dry bath with holes of 25 mm diameter at 95°C. Using athermometer, ensure the temperature reaches the set point and stabilises before starting thereconstitution procedure.

c. Flip off the cap from the vial of powder (vial 1) and swab the top of the vial closure with anappropriate antiseptic to disinfect the surface, then allow the stopper to dry.

d. Pierce vial 1(powder for solution for injection) septum with a 0.2 µm sterile vent filter in orderto maintain atmospheric pressure within the vial during the radiolabelling process. The 0.2 µmsterile vent filter needle should not come into contact with the eluate at any time to avoid metalcontamination.

e. Flip off the cap from vial 2 (reaction buffer) and swab the top of the vial closure with anappropriate antiseptic to disinfect the surface, then allow the stopper to dry. With a low deadspace 1 ml sterile syringe carefully withdraw 100 µl and keep the reaction buffer in the syringefor step “g”.

f. With a 5 ml sterile syringe and a sterile needle (coated with silicone or other appropriatematerial able to reduce metal impurity trace), carefully withdraw 4 ml of water for injectionsand reconstitute the powder in vial 1.

g. Add the reaction buffer previously dosed in the 1 ml sterile syringe.

h. Connect the male luer of the outlet line of the 68Ge/68Ga generator with a sterile needle (coatedwith silicone or other appropriate material able to reduce metal impurity trace).

i. Connect vial 1 to the outlet line of the generator by pushing the elution needle through therubber septum. Keep the elution needle below the 0.2 µm sterile vent filter needle. Ensure thatthe needles do not come into contact with each other and do not submerge in the eluate at anytime. Turn the button by 90° to the loading position, then wait 10 seconds before turning thebutton back to the initial position, according to the generator’s instructions for use.

j. Connect vial 1 through the 0.2 µm sterile vent filter to a vacuum vial or to a pump to start theelution. Elute the generator directly into vial 1 (through the needle).

k. At the end of the elution, first withdraw the needle from the vacuum vial in order to establishatmospheric pressure into vial 1, then disconnect vial 1 from the generator by removing theneedle from the rubber septum. Finally, remove the 0.2 µm sterile vent filter and move the vialto the hole of the dry bath at 95°C, using pliers. Leave the vial at 95°C for at least 7 minutes (donot exceed 10 minutes heating) without agitation or stirring.

l. After 7 minutes, remove the vial from the dry bath, place it in an appropriately labelled leadshield and let it cool down at room temperature for approximately 10 minutes.

m. Assay the vial radioactivity using a suitable radioactivity calibration system and record theresult. Report the activity value, the calibration time, the batch number and the expiry time onthe shield label included in the pack to be applied on the lead shielding container afterradiolabelling.

n. Perform the quality control according to the recommended methods in order to checkcompliance with the specifications (see section “Quality control”).

o. The solution should be visually inspected prior to use. Only clear solutions, free from visibleparticles should be used. The visual inspection should be performed under a shielded screen forradioprotection purposes.

p. Store the vial containing the gallium (68Ga) edotreotide solution below 25°C until use. At thetime of administration, the medicinal product must be aseptically withdrawn and theradioprotection standards must be followed. The patient dose should be measured using asuitable radioactivity calibration system immediately prior to patient administration. Medicinalproduct administration data should also be recorded.

A schematic representation of the radiolabelling procedure is shown in Figure 2.

Figure 2: Radiolabelling procedure when using Galli Ad generator

Gallium (68Ga) edotreotide solution is stable up to 4 hours after preparation. Therefore, theradiolabelled solution can be used within 4 hours after preparation according to the radioactivityrequired for the administration.

Radioactive waste must be disposed of in accordance with relevant national regulations.

After radiolabelling with the correct volume of reaction buffer and generator eluate, any furtherdilution with any diluent is prohibited.

Quality control

Table 2: Specifications of the gallium (68Ga) edotreotide

Test Acceptance Criteria Method

Clear solutions free

Appearance Visual inspectionof visible particlespH 3.2 - 3.8 pH-indicator strips

Labelling efficiency Thin layer chromatography≤3%colloidal gallium-68 species (ITLC1, see details below)

Labelling efficiency Thin layer chromatography≤2%% Free gallium-68 (ITLC2, see details below)

The quality controls should be performed under a shielded screen for radioprotection purposes.

Recommended method for determining labelling efficiency of gallium (68Ga) edotreotide:

ITLC1:

Material

* Glass-fibre ITLC paper (e.g. Agilent ITLC SGI001) pre-cut to 1 cm x 12 cm strips

* Mobile phase: 77 g/L solution of ammonium acetate in water/methanol 50:50 V/V

* Developing tank

* Radiometric ITLC scanner

Sample analysis

a. The TLC developing tank is prepared by pouring the mobile phase to a depth of 3 to 4 mm.

Cover the tank and allow to equilibrate.

b. Apply a drop of the gallium (68Ga) edotreotide on a pencil line 1 cm from the bottom of the

ITLC strip.

c. Place the ITLC strip in the developing tank and allow it to develop for a distance of 9 cm fromthe point of application.

d. Scan the ITLC with a radiometric ITLC scanner

e. The retention factor (Rf) specifications are as follows:

Not complexed gallium (68Ga) = 0 to 0.1

Gallium (68Ga) edotreotide = 0.8 to 1

The labelling efficiency is calculated by integration of peak with Rf = 0 to 0.1 that must be ≤3%.

ITLC2:

Material

* Glass-fibre ITLC paper (e.g. Agilent ITLC SGI001) pre-cut to 1 cm x 12 cm strips

* Mobile phase: sodium citrate 0.1 M (pH 5) in water

* Developing tank

* Radiometric ITLC scanner

Sample analysis

a. The TLC developing tank is prepared by pouring the mobile phase to a depth of 3 to 4 mm.

Cover the tank and allow to equilibrate.

b. Apply a drop of the gallium (68Ga) edotreotide solution on a pencil line 1 cm from the bottom ofthe ITLC strip.

c. Place the ITLC strip in the developing tank and allow it to develop for a distance of 9 cm fromthe point of application.

d. Scan the ITLC with a radiometric ITLC scanner

The retention factor (Rf) specifications are as follows:

Gallium (68Ga) edotreotide = 0.1 to 0.2

Free gallium-68 = 0.9 to 1

The labelling efficiency is calculated by integration of peak with Rf = 0.9 to 1.0 that must be ≤2%.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.