LOCAMETZ 25mcg kit for radio pharmaceuticals medication leaflet

Locametz 25 micrograms kit for radiopharmaceutical preparation

The vial contains 25 micrograms of gozetotide.

The radionuclide is not part of the kit.

The vial contains 28.97 mg of sodium.

For the full list of excipients, see section 6.1.

Kit for radiopharmaceutical preparation

One vial of white lyophilised powder (powder for solution for injection).

This medicinal product is for diagnostic use only.

Locametz, after radiolabelling with gallium-68, is indicated for the detection of prostate-specificmembrane antigen (PSMA)-positive lesions with positron emission tomography (PET) in adults withprostate cancer (PCa) in the following clinical settings:

* Primary staging of patients with high-risk PCa prior to primary curative therapy,

* Suspected PCa recurrence in patients with increasing levels of serum prostate-specific antigen(PSA) after primary curative therapy,

* Identification of patients with PSMA-positive progressive metastatic castration-resistantprostate cancer (mCRPC) for whom PSMA-targeted therapy is indicated (see section 4.4).

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

The recommended dose of gallium (68Ga) gozetotide is 1.8-2.2 MBq/kg of body weight, with aminimum dose of 111 MBq up to a maximum dose of 259 MBq.

No dose adjustment is required in patients aged 65 years and above.

There are no data with gallium (68Ga) gozetotide in patients with moderate to severe/end-stage renalimpairment. No dose adjustment is considered necessary in patients with renal impairment (seesection 5.2).

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

There is no relevant use of Locametz in the paediatric population for the identification of

PSMA-positive lesions in prostate cancer.

This medicinal product is for intravenous and multidose use. It should be reconstituted andradiolabelled before administration to the patient.

After reconstitution and radiolabelling, gallium (68Ga) gozetotide solution should be administered byslow intravenous injection. Local extravasation resulting in inadvertent radiation exposure to thepatient and imaging artefacts should be avoided. The injection should be followed by an intravenousflush of sterile sodium chloride 9 mg/ml (0.9%) solution for injection to ensure full delivery of thedose.

The total radioactivity in the syringe should be verified with a dose calibrator immediately before andafter administration to the patient. The dose calibrator must be calibrated and comply withinternational standards. Instructions regarding the dilution of the gallium (68Ga) gozetotide solutionshould be followed (see section 12).

For patient preparation, see section 4.4.

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

Image acquisition

Gallium (68Ga) gozetotide PET image acquisition should be performed by scanning the whole bodystarting at mid-thigh and proceeding to skull base. PET images should be acquired 50 to 100 minutesafter the intravenous administration of gallium (68Ga) gozetotide solution.

Image acquisition start time and duration should be adapted to the equipment used, the patient and thetumour characteristics, in order to obtain the best image quality possible.

Use of computer tomography (CT) or magnetic resonance imaging (MRI) for attenuation correction isrecommended.

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

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.

To date no outcome data exist to inform subsequent management of patients with high-risk diseasewhen PSMA PET/CT is utilised for primary staging.

Experience of use of gallium (68Ga) gozetotide PET for selection of patients for PSMA-based therapyis limited to patients with progressive metastatic castration-resistant prostate cancer (mCRPC) whohave been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy,and to selection of patients for treatment with lutetium (177Lu) vipivotide tetraxetan. Benefit-risk ratiomay not be generalisable to other types of PSMA-based therapy and patients with mCRPC withdifferent prior treatments.

Radiation risk

Gallium (68Ga) gozetotide contributes to the patient’s overall long-term cumulative radiation exposure,which is associated with an increased risk of cancer. Safe handling, reconstitution and radiolabellingprocedures should be ensured to protect patients and healthcare professionals from unintentionalradiation exposure (see sections 6.6 and 12).

Interpretation of gallium (68Ga) gozetotide images

PET images with gallium (68Ga) gozetotide should be interpreted by visual assessment. Suspicion ofmalignant lesions is based on gallium (68Ga) gozetotide uptake in comparison with tissue background.

Gallium (68Ga) gozetotide uptake is not specific to prostate cancer and may occur in normal tissues(see section 5.2), other types of cancers and non-malignant processes, potentially leading to falsepositive findings. Moderate to high physiological PSMA uptake is noted in the kidneys, lacrimalglands, liver, salivary glands and urinary bladder wall. False positive findings include, but are notlimited to, renal cell carcinoma, hepatocellular carcinoma, breast cancer, lung cancer, benign bonediseases (e.g. Paget’s disease), pulmonary sarcoidosis/granulomatosis, gliomas, meningiomas,paragangliomas and neurofibromas. Ganglia can mimic lymph nodes.

The diagnostic performance of gallium (68Ga) gozetotide may be affected by serum PSA levels,androgen-receptor-targeting treatments, disease stage and size of malignant lymph nodes (seesection 5.1).

Gallium (68Ga) gozetotide PET images should be interpreted only by readers trained in theinterpretation of PET images with gallium (68Ga) gozetotide PET. Findings on gallium (68Ga)gozetotide PET images should always be interpreted in conjunction with and be confirmed by otherdiagnostic methods (including histopathology) before subsequent change in patient management isinitiated.

Patient preparation

Patients should be well hydrated prior to gallium (68Ga) gozetotide administration and should beadvised to void immediately prior to and frequently during the first hours after image acquisition inorder to reduce radiation exposure.

Specific warnings

This medicinal product contains 28.97 mg sodium per injection, equivalent to 1.5% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Acidic pH and extravasation

Low pH of gallium (68Ga) gozetotide may lead to injection site reactions after administration.

Accidental extravasation may cause local irritation, due to the acidic pH of the solution. Cases ofextravasation should be managed as per institutional guidelines.

Based on in vitro interaction studies, gallium (68Ga) gozetotide is not expected to have any clinicallysignificant interaction with other medicinal products (see section 5.2). No interaction studies havebeen performed.

Locametz is not indicated for use in females. There are no data on the use of gallium (68Ga) gozetotidein females. Reproductive toxicity studies in animals have not been conducted with gallium (68Ga)gozetotide. However, all radiopharmaceuticals, including gallium (68Ga) gozetotide, have the potentialto cause foetal harm.

Locametz is not indicated for use in females. There are no data on the effects of gallium (68Ga)gozetotide on the breast-fed newborn/infant or on milk production. Lactation studies have not beenconducted in animals with gallium (68Ga) gozetotide.

There are no data on the effect of gallium (68Ga) gozetotide on human fertility.

Gallium (68Ga) gozetotide 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 0.0166 mSv/MBq, with a maximal recommended dose of259 MBq (4.3 mSv), these adverse reactions are expected to occur with a low probability.

Mild to moderate adverse reactions occurred in patients receiving gallium (68Ga) gozetotide, with theexception of a grade 3 fatigue event (0.1%).

The most common adverse reactions are fatigue (1.2%), nausea (0.8%), constipation (0.5%) andvomiting (0.5%).

The safety profile of gallium (68Ga) gozetotide at median dose per body weight of 1.9 MBq/kg (range:

0.9-3.7 MBq/kg) was evaluated in 1 003 patients with metastatic castration-resistant prostate cancerreceiving physician’s discretion for best standard of care (VISION study).

Adverse reactions (Table 1) are listed by MedDRA system organ class. Within each system organclass, the adverse reactions are ranked by frequency, with the most frequent reactions first. Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness. Inaddition, the corresponding frequency category for each adverse reaction is based on the followingconvention (CIOMS III): 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).

Table 1 Adverse reactions observed with gallium (68Ga) gozetotide

System organ class Frequency category Adverse reaction

Uncommon Nausea

Uncommon Constipation

Gastrointestinal disorders Uncommon Vomiting

Uncommon Diarrhoea

Uncommon Dry mouth

Common Fatigue

General disorders and administration site

Uncommon Injection site reactions1conditions

Uncommon Chills1 Injection site reactions includes: injection site haematoma, injection site warmth, injection site pruritus

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 with gallium (68Ga) gozetotide, the radiationabsorbed dose to the patient should be reduced where possible by increasing the elimination of theradionuclide from the body by hydration and frequent bladder voiding. It might be helpful to estimatethe effective radiation dose that was applied.

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, other diagnostic radiopharmaceuticalsfor tumour detection, ATC code: V09IX14

Gallium (68Ga) gozetotide binds to cells that express PSMA, including malignant prostate cancer cells,which overexpress PSMA. Gallium-68 is a radionuclide with an emission yield that allows PETimaging. Based on the intensity of the signals, PET images obtained with gallium (68Ga) gozetotideindicate the presence of PSMA protein in tissues.

At the chemical concentrations used for diagnostic examinations, gallium (68Ga) gozetotide does nothave any pharmacodynamic activity.

The sensitivity and specificity of gallium (68Ga) gozetotide were evaluated in the two followingprospective studies:

In van Kalmthout et al, 2020, 103 adult male patients with biopsy-proven prostate cancer andintermediate- and high-risk features indicated for extended pelvic lymph node dissection (ePLND)underwent gallium (68Ga) gozetotide PET/CT imaging. PET/CT scans were read by two independentblinded readers and ePLND was the histopathology reference standard for 96 out of 103 (93%)patients. Patient-based sensitivity, specificity, positive and negative predictive value (PPV and NPV,respectively) of gallium (68Ga) gozetotide PET/CT imaging to detect lymph node metastasis (LNM)are summarised in Table 2.

Table 2 Efficacy results in primary staging in patients with biopsy-proven prostate cancer

Patient-based

N=961

Sensitivity (95% CI) 42% (27, 58)

Specificity (95% CI) 91% (79, 97)

PPV 77% (54, 91)

NPV 68% (56, 78)1 Evaluable population

Inter-reader agreement was κ = 0.67 for the 2 independent blinded readers. Of the 67 LNM analysed,26 were detected by gallium (68Ga) gozetotide PET/CT, resulting in 38.8% node-based sensitivity.

Median diameter of the metastatic deposit in these detected LNM was 7 mm (range: 0.3-35). The PETreading missed 41 LNM with a median metastatic deposit of 3.0 mm (range: 0.5 to 35.0).

In Fendler et al, 2019, 635 adult male patients with histopathology-proven and biochemical recurrence(BCR) prostate cancer after prostatectomy (N=262), radiation therapy (N=169) or both (N=204)underwent gallium (68Ga) gozetotide PET/CT or PET/MRI imaging. BCR was defined by serum PSAof ≥0.2 ng/mL more than 6 weeks after prostatectomy or by an increase in serum PSA of at least2 ng/mL above nadir after definitive radiotherapy. Patients had median PSA level of 2.1 ng/mL abovenadir after radiation therapy (range: 0.1-1 154 ng/mL). A composite reference standard, includinghistopathology, serial serum PSA levels and imaging (CT, MRI, and/or bone scan) findings wasavailable for 223 of 635 (35.1%) patients, while histopathology reference standard alone was availablefor 93 (14.6%) patients. PET/CT scans were read by 3 independent readers blinded to clinicalinformation other than the type of primary therapy and most recent serum PSA level.

Detection of PSMA-positive lesions occurred in 475 of 635 (75%) patients receiving gallium (68Ga)gozetotide and the detection rate was significantly increased with PSA levels. The detection rate ofgallium (68Ga) gozetotide PET positive lesion increased with increasing serum PSA levels (seesection 4.4). Sensitivity and positive predictive value (PPV) of gallium (68Ga) gozetotide PET/CTimaging are summarised in Table 3. Inter-reader Fleiss κ for gallium (68Ga) gozetotide PET/CTimaging ranged from 0.65 (95% CI: 0.61, 0.70) to 0.78 (95% CI: 0.73, 0.82) across the assessedregions (prostate bed, pelvic nodes, extrapelvic soft tissues and bones).

Table 3 Efficacy results in patients with histopathology-proven and BCR prostate cancer

Composite Histopathologyreference standard reference standard

N=2231 N=931

Sensitivity per-patient (95% CI) NA 92% (84, 96)

Sensitivity per-region (95% CI) NA 90% (82, 95)

PPV per-patient (95% CI) 92% (88, 95) 84% (75, 90)

PPV per-region (95% CI) 92% (88, 95) 84% (76, 91)1 Evaluable population

Gallium (68Ga) gozetotide PET/CT imaging was used to identify adult patients with progressive,

PSMA-positive mCRPC cancer for the randomised, multicentre, open-label, phase III study VISION,which tested efficacy of Pluvicto plus best standard of care or best standard of care alone. A total of1 003 male patients, who had been treated with at least one androgen receptor (AR) pathway inhibitorand 1 or 2 prior taxane-based chemotherapy regimens, were selected based on the PSMA expressionof their prostate cancer lesions. Patients underwent a gallium (68Ga) gozetotide PET/CT scan toevaluate PSMA expression in lesions defined by central read criteria. Improved overall survival andradiographic progression-free survival were reported in the PSMA-targeted therapy arm.

The European Medicines Agency has waived the obligation to submit the results of studies with

Locametz in all subsets of the paediatric population for visualisation of PSMA in prostate cancer (seesection 4.2 for information on paediatric use).

Gallium (68Ga) gozetotide exhibits bi-exponential behaviour in blood, with a biological half-life of6.5 minutes for the fast component and a terminal half-life of 4.4 hours for the slower component.

Based on in vitro data, gozetotide mainly distributes to plasma, with a mean blood-to-plasma ratio of0.71. Gozetotide is 33% bound to human plasma proteins.

Organ uptake

The highest radiation absorbed dose of gallium (68Ga) gozetotide occurred in the kidneys, lacrimalglands, salivary glands, urinary bladder wall and liver.

The estimated radiation absorbed doses to these organs for an administered activity of 259 MBq are62.1 mGy (kidneys), 28.5 mGy (lacrimal glands), 23.1 mGy (salivary glands), 14.8 mGy (urinarybladder wall) and 13.7 mGy (liver).

Based on in vitro data, gallium (68Ga) gozetotide undergoes negligible hepatic and renal metabolism.

Gallium (68Ga) gozetotide is mainly eliminated via the renal route. Approximately 14% of the gallium(68Ga) gozetotide dose administered is excreted in the urine after 2 hours post-injection.

Half-life

Based on the gallium (68Ga) gozetotide biological and terminal half-life of 4.4 hours and on thegallium-68 physical half-life of 68 minutes, the resulting gallium (68Ga) gozetotide effective half-life is54 minutes.

In vitro evaluation of drug interaction potential

CYP450 enzymes

Gozetotide is not a substrate, inhibitor or inducer of cytochrome P450 (CYP450) enzymes. Gallium(68Ga) gozetotide is not expected to have any drug interactions with CYP450 substrates, inhibitors orinducers.

Gozetotide is not a substrate of BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3 or OCT2. Gozetotideis not an inhibitor of BCRP, BSEP, P-gp, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3,

OCT1 or OCT2. Gallium (68Ga) gozetotide is not expected to have any drug interactions with thesubstrates of these transporters.

In the VISION clinical study, 752 of 1 003 (75%) patients were aged 65 years or older. No overalldifferences in safety and efficacy were observed between these patients and younger patients.

Renal impairment/hepatic impairment

Gallium (68Ga) gozetotide pharmacokinetics and biodistribution are not expected to be affected byrenal/hepatic impairment to any clinically relevant extent.

Gozetotide was evaluated in safety pharmacology and single-dose toxicity studies. Non-clinical datareveal no special hazard for humans based on conventional studies of safety pharmacology andsingle-dose toxicity.

Mutagenicity studies and carcinogenicity studies have not been carried out with gallium (68Ga)gozetotide.

Gentisic acid

Sodium acetate trihydrate

Sodium chloride

This medicinal product must not be mixed with other medicinal products except those mentioned insections 6.6 and 12.

Unopened vial: 1 year.

After reconstitution and radiolabelling, chemical and physical in-use stability have been demonstratedfor 6 hours at 30°C (see section 6.4). Store upright.

From a microbiological point of view, unless the method of opening, reconstitution, radiolabelling, ordilution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

Before reconstitution, store below 25°C.

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

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

Locametz is supplied as a multidose kit for the radiopharmaceutical preparation of gallium (68Ga)gozetotide solution for injection (see sections 2 and 3). Locametz contains one 10 mL type I Plus glassvial closed with a rubber stopper and sealed with a flip-off cap.

General warning

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 licences 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.

The content of the vial is intended only for use in the preparation of gallium (68Ga) gozetotide solutionfor injection and is not to be administered directly to the patient without first undergoing thepreparative procedure (see sections 4.2 and 12).

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

Before reconstitution, the content of Locametz is not radioactive. After reconstitution andradiolabelling, effective radiation shielding of the gallium (68Ga) gozetotide solution for injection mustbe maintained (see section 3).

After reconstitution and radiolabelling, Locametz contains a sterile solution for injection of gallium(68Ga) gozetotide at an activity of up to 1 369 MBq. The gallium (68Ga) gozetotide solution forinjection also contains hydrochloric acid derived from the gallium-68 chloride solution.

Gallium (68Ga) gozetotide solution for injection is a sterile, clear, colourless solution for intravenousadministration, without undissolved matter and with pH between 3.2 to 6.5.

Appropriate aseptic precautions should be taken when withdrawing and administering gallium (68Ga)gozetotide solution for injection.

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

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

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

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/22/1692/001

09 December 2022

Gallium-68 is produced by means of a germanium-68/gallium-68 (68Ge/68Ga) generator and decayswith a half-life of 68 min to stable zinc-68. Gallium-68 decays as follows:

* 89% through positron emission with a mean energy of 836 keV, followed by photonicannihilation radiations of 511 keV (178%).

* 10% through orbital electron capture (X-ray or Auger emissions), and

* 3% through 13 gamma transitions from 5 excited levels.

The effective radiation dose of gallium (68Ga) gozetotide is 0.022 mSv/MBq, resulting in anapproximate effective radiation dose of 5.70 mSv for an administered maximum activity of 259 MBq.

Median radiation absorbed doses for organs and tissues of adult patients (N=6) following intravenousinjection of gallium (68Ga) gozetotide including observed ranges were calculated by Sandgren et al,2019, using ICRP/ICRU voxel phantom with the software IDAC-Dose 2.1. Median radiation absorbeddoses of gallium (68Ga) gozetotide are shown in Table 4.

Table 4 Estimated median radiation absorbed doses of gallium (68Ga) gozetotide

Radiation absorbed dose (mGy/MBq)1

N=6

Organ Median (mGy/MBq) Range (mGy/MBq)

Adrenals 0.048 0.0405 - 0.0548

Brain 0.008 0.0065 - 0.0079

Breast 0.008 0.0077 - 0.0087

Endosteum (bone surface)* 0.011 0.0095 - 0.0110

Eye lenses* 0.0051 0.0047 - 0.0054

Gallbladder wall 0.027 0.0212 - 0.0343

Heart wall 0.026 0.0236 - 0.0317

Kidneys* 0.240 0.2000 - 0.2800

Lacrimal glands* 0.110 0.0430 - 0.2000

Left colon wall** 0.014 0.0120 - 0.0140

Liver* 0.053 0.0380 - 0.0710

Lungs* 0.016 0.0130 - 0.0170

Muscle 0.0083 0.0073 - 0.0086

Oesophagus* 0.014 0.0110 - 0.0150

Pancreas 0.019 0.0173 - 0.0209

Recto-sigmoid colon wall 0.013 0.0108 - 0.0149

Red (active) bone marrow* 0.015 0.0140 - 0.0150

Right colon wall** 0.014 0.0120 - 0.0140

Salivary glands* 0.089 0.0740 - 0.1500

Skin* 0.007 0.0059 - 0.0069

Small intestine wall 0.014 0.0129 - 0.0149

Spleen* 0.046 0.0300 - 0.1000

Stomach wall* 0.015 0.0150 - 0.0170

Testes* 0.009 0.0074 - 0.0089

Thymus 0.0081 0.0072 - 0.0085

Thyroid* 0.010 0.0090 - 0.0100

Urinary bladder wall* 0.057 0.0280 - 0.0840

Effective dose (mSv/MBq)*2 0.022 0.0204 - 0.0242

* as reported by Sandgren et al, 2019; all other organ estimates were estimated based on the time-integratedactivity coefficients of the source organs published in the paper

** reported in Sandgren as a single value labelled “Colon”1 doses were calculated using the software IDAC-Dose 2.1.2 derived according to ICRP Publication 103

Method of preparation

Step 1: Reconstitution and radiolabelling

Locametz allows the direct preparation of gallium (68Ga) gozetotide solution for injection with theeluate from one of the following generators (see below for specific instructions for use with eachgenerator):

* Eckert & Ziegler GalliaPharm germanium-68/gallium-68 (68Ge/68Ga) generator

* IRE ELiT Galli Ad germanium-68/gallium-68 (68Ge/68Ga) generator

The instructions for use provided by the germanium-68/gallium-68 generator manufacturer should alsobe followed.

Gallium (68Ga) gozetotide solution for injection should be prepared according to the following asepticprocedure:

a. Flip the cap off the Locametz vial and swab the septum with an appropriate antiseptic, thenallow the septum to dry.

b. Pierce the Locametz vial septum with a sterile needle connected to a 0.2 micron sterile airventing filter to maintain atmospheric pressure within the vial during the reconstitution process.

Place the Locametz vial in a lead shield container.

Follow the generator-specific reconstitution and radiolabelling procedures as shown in Table 5 and in

Figures 1 and 2. Then continue with Step 2.

Table 5 Reconstitution and radiolabelling with Eckert & Ziegler GalliaPharm and IRE

ELiT Galli Ad generators

If Eckert & Ziegler GalliaPharm generator is If IRE ELiT Galli Ad generator is usedused

* Connect the male luer of the outlet line of the generator to a sterile elution needle(size 21G-23G).

* Connect the Locametz vial directly to the outlet line of the generator by pushing the elutionneedle through the rubber septum.

* Elute directly from the generator into the Locametz vial.

Perform the elution manually or by means of a Connect the Locametz vial through the ventpump according to the generator instructions for needle with 0.2 micron sterile air venting filteruse. to a vacuum vial (25 mL minimum volume) bymeans of a sterile needle (size 21G-23G) or to apump to start the elution.

Reconstitute the lyophilised powder with 5 mL Reconstitute the lyophilised powder with 1.1 mLof eluate. of eluate.

At the end of the elution, disconnect the At the end of the elution, first withdraw the

Locametz vial from the generator by removing sterile needle from the vacuum vial orthe elution needle and the vent needle with the disconnect the vacuum pump in order to0.2 micron sterile air venting filter from the establish atmospheric pressure into therubber septum. Then, invert the Locametz vial Locametz vial, then disconnect the vial from theonce and place it upright. generator by removing both the elution needleand the vent needle with the 0.2 micron sterileair venting filter needle from the rubber septum.

Figure 1 Reconstitution and radiolabelling procedure for Eckert & Ziegler GalliaPharmgenerator5 mL HCl0.1 M68Ga in HCl68Ge/68Gagenerator20-30°C

upright for5 mins

Lyophilised gallium (68Ga)powder gozetotide

Figure 2 Reconstitution and radiolabelling procedure for IRE ELiT Galli Ad generator1.1 mL HCl0.1 M68Ga in HCl68Ge/68Gagenerator

Vacuum20-30°C

upright for5 mins

Lyophilised gallium (68Ga)powder gozetotide

Step 2: Incubation

a. Incubate the Locametz vial upright at room temperature (20-30°C) for at least 5 minutes withoutagitation or stirring.

b. After 5 minutes, assay the vial containing the gallium (68Ga) gozetotide solution for injection fortotal radioactivity concentration using a dose calibrator and record the result.

c. Perform quality controls according to the recommended methods in order to check compliancewith the specifications (see Step 3).

d. Store the Locametz vial containing the gallium (68Ga) gozetotide solution for injection uprightin a lead shield container below 30°C until use.

e. After addition of gallium-68 chloride to the Locametz vial, use gallium (68Ga) gozetotidesolution for injection within 6 hours.

Step 3: Specifications and quality control

Perform the quality controls in Table 6 behind a lead glass shield for radioprotection purposes.

Table 6 Specifications of the gallium (68Ga) gozetotide solution for injection

Test Acceptance criteria Method

Appearance Clear, colourless and without Visual inspectionundissolved matterpH 3.2 - 6.5 pH-indicator strips

Labelling efficiency Non-complexed gallium-68 species ≤3% Instant thin layer chromatography(ITLC, see details below)

Determine labelling efficiency of gallium (68Ga) gozetotide solution for injection by performinginstant thin layer chromatography (ITLC).

Perform ITLC using ITLC SG strips and using ammonium acetate 1M: Methanol (1:1 V/V) as mobilephase.

ITLC method

a. Develop the ITLC SG strip for a distance of 6 cm from the point of application (i.e. to 7 cmfrom the bottom of the ITLC strip).

b. Scan the ITLC SG strip with a radiometric ITLC scanner.

c. Calculate labelling efficiency by integration of the peaks on the chromatogram. Do not use thereconstituted and radiolabelled product if the percentage (%) of non-complexed gallium-68species is higher than 3%.

The retention factor (Rf) specifications are as follows:

* Non-complexed gallium-68 species, Rf = 0 to 0.2;

* Gallium (68Ga) gozetotide, Rf = 0.8 to 1

Step 4: Administration

a. Aseptic technique and radiation shielding should be used when withdrawing and administeringgallium (68Ga) gozetotide solution for injection (see sections 4.2 and 6.6).

b. Prior to use, visually inspect the prepared gallium (68Ga) gozetotide solution for injection behinda lead glass shield for radioprotection purposes. Only solutions that are clear, colourless andwithout undissolved matter should be used (see sections 4.2 and 6.6).

c. After reconstitution and radiolabelling, gallium (68Ga) gozetotide solution for injection can bediluted with water for injections or sodium chloride 9 mg/mL (0.9%) solution for infusion up toa final volume of 10 mL. For the IRE ELiT Galli Ad generator, dilution to a minimum volumeof 4 mL is required in order to reduce osmolality.

d. Using a single-dose syringe fitted with a sterile needle (size 21G-23G) and protective shielding,aseptically withdraw the prepared gallium (68Ga) gozetotide solution for injection prior toadministration (see sections 4.2 and 6.6).

e. The total radioactivity in the syringe should be verified with a dose calibrator immediatelybefore and after gallium (68Ga) gozetotide administration to the patient. The dose calibratormust be calibrated and comply with international standards (see section 4.2).

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

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