Locametz 25 micrograms kit for radiopharmaceutical preparation

Kit for radiopharmaceutical preparation containing one vial of white lyophilised powder (powder for solution for injection). For radiolabelling with gallium-68 chloride solution.

4.1 Therapeutic indications This medicinal product is for diagnostic use only. Locametz, after radiolabelling with gallium-68, is a radioactive diagnostic agent indicated for the identification of prostate-specific membrane antigen (PSMA)-positive lesions by positron emission tomography (PET) in adult patients with prostate cancer.4.2 Posology and method of administration This medicinal product should only be administered by trained healthcare professionals with technical expertise in using and handling nuclear medicine imaging agents and only in a designated nuclear medicine facility. **Posology** The recommended dose of gallium (68Ga) gozetotide is 1.8-2.2 MBq/kg of body weight, with a minimum dose of 111 MBq up to a maximum dose of 259 MBq. ***Special populations*** *Elderly* No dose adjustment is required in patients aged 65 years and above (see section 5.2). *Renal impairment / Hepatic impairment* No dose adjustment is required in patients with renal or hepatic impairment (see section 5.2). *Paediatric population* There is no relevant use of Locametz in the paediatric population for the identification of PSMA-positive lesions in prostate cancer. **Method of administration** This medicinal product is for intravenous and multidose use. It should be reconstituted before administration to the patient. After reconstitution, gallium (68Ga) gozetotide solution should be administered by slow intravenous injection, in order to avoid local extravasation resulting in inadvertent radiation exposure to the patient and imaging artefacts. Accidental extravasation may cause local irritation, due to the acidic pH of the solution. Cases of extravasation should be managed as per institutional guidelines. The total radioactivity in the syringe should be verified with a dose calibrator immediately before and after administration to the patient. The dose calibrator must be calibrated and comply with international standards (see section 12). For patient preparation, see section 4.4. For instructions on reconstitution of the medicinal product before administration, see section 12. **Image acquisition** Gallium (68Ga) gozetotide PET image acquisition should be performed by scanning the whole body starting at mid-thigh and proceeding to skull base. PET images should be acquired 50 to 100 minutes after the intravenous administration of gallium (68Ga) gozetotide solution. Image acquisition start time and duration should be adapted to the equipment used, the patient and the tumour characteristics, in order to obtain the best image quality possible.4.3 Contraindications Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to any of the components of the labelled radiopharmaceutical.4.4 Special warnings and precautions for use **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. **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 and reconstitution procedures should be ensured to protect patients and healthcare professionals from unintentional radiation exposure (see sections 6.6 and 12). **Interpretation of gallium (68Ga) gozetotide images** Gallium (68Ga) gozetotide binds to PSMA on the surface of PSMA-expressing cells. Based on the intensity of the signals, PET images obtained with gallium (68Ga) gozetotide indicate the presence of PSMA protein in tissues. While the uptake of gallium (68Ga) gozetotide reflects the levels of PSMA expression in prostate cancer, gallium (68Ga) gozetotide uptake is not specific to prostate cancer and may occur in other types of cancers, non-malignant processes and normal tissues. Interpretation of gallium (68Ga) gozetotide PET imaging findings in the context of histopathology and/or other diagnostic procedures is recommended. The diagnostic performance of gallium (68Ga) gozetotide may be affected by serum PSA levels (see section 5.1). **Patient preparation** Patients should be well hydrated prior to gallium (68Ga) gozetotide administration and should be advised to void immediately prior to and frequently during the first hours after image acquisition in order to reduce radiation exposure. **Specific warnings** ***Sodium content*** This medicinal product contains 28.97 mg sodium per injection, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.4.5 Interaction with other medicinal products and other forms of interaction Based on *in vitro* interaction studies, gallium (68Ga) gozetotide is not expected to have any clinically significant interaction with other medicinal products (see section 5.2). No clinical drug interaction studies were required.4.6 Fertility, pregnancy and lactation **Pregnancy** Locametz is not indicated for use in females. There are no data on the use of gallium (68Ga) gozetotide in females. Reproductive toxicity studies in animals have not been conducted with gallium (68Ga) gozetotide. However, all radiopharmaceuticals, including gallium (68Ga) gozetotide, have the potential to cause foetal harm. **Breast-feeding** 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 been conducted in animals with gallium (68Ga) gozetotide. **Fertility** There are no data on the effect of gallium (68Ga) gozetotide on human fertility.4.7 Effects on ability to drive and use machines Gallium (68Ga) gozetotide has no or negligible influence on the ability to drive and use machines.4.8 Undesirable effects **Summary of safety profile** Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 0.0166 mSv/MBq, with a maximal recommended dose of 259 MBq (4.3 mSv), these adverse reactions are expected to occur with a low probability. The safety profile of gallium (68Ga) gozetotide was evaluated in 1 003 patients receiving gallium (68Ga) gozetotide at median dose per body weight of 1.9 MBq/kg (range: 0.9-3.7 MBq/kg). Patients underwent PET/CT imaging to establish their eligibility for the VISION clinical study, based on the PSMA expression of their prostate cancer lesions. Gallium (68Ga) gozetotide was concomitantly administered with physician's discretion for best standard of care. Mild to moderate adverse reactions occurred in patients receiving gallium (68Ga) gozetotide, with the exception of a grade 3 fatigue event (0.1%). No serious adverse reactions occurred in patients receiving gallium (68Ga) gozetotide. The most common adverse reactions of any grade (incidence ≥0.5%) are fatigue (1.2%), nausea (0.8%), constipation (0.5%) and vomiting (0.5%). The adverse reactions of any grade in patients receiving gallium (68Ga) gozetotide are shown in Table 1. **Tabulated list of adverse reactions** Adverse reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following convention (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 in the VISION clinical study** | | | | | --- | --- | --- | | **System organ class** | **Frequency category** | **Adverse reaction** | | Gastrointestinal disorders | Uncommon | Nausea | | Uncommon | Constipation | | Uncommon | Vomiting | | Uncommon | Diarrhoea | | Uncommon | Dry mouth | | General disorders and administration site conditions | Common | Fatigue | | Uncommon | Injection site reactions1 | | Uncommon | Chills | | 1 Injection site reactions includes: injection site haematoma, injection site warmth | | | **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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose In the event of administration of a radiation overdose with gallium (68Ga) gozetotide, the radiation absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by hydration and frequent bladder voiding. It might be helpful to estimate the effective radiation dose that was applied.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other diagnostic radiopharmaceuticals for tumour detection, ATC code: V09IX14 **Mechanism of action** 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 PET imaging. Based on the intensity of the signals, PET images obtained with gallium (68Ga) gozetotide indicate the presence of PSMA protein in tissues. **Pharmacodynamic effects** At the chemical concentrations used for diagnostic examinations, gallium (68Ga) gozetotide does not have any pharmacodynamic activity. **Clinical efficacy and safety** The safety and efficacy of gallium (68Ga) gozetotide as a patient-identification method for PSMA-targeted therapy were established in the multicentre, randomised, open-label, phase III study VISION and in the VISION reviewer variability sub-study. Gallium (68Ga) gozetotide PET/CT imaging was used to identify adult patients with metastatic prostate cancer and establish their eligibility for the VISION clinical study, based on the PSMA expression of their prostate cancer lesions. A total of 1,003 adult male patients received gallium (68Ga) gozetotide at median dose per body weight of 1.9 MBq/kg (range: 0.9-3.7 MBq/kg) and underwent PET/CT image acquisition at approximately 60 minutes (range: 50-100 minutes) after injection. Gallium (68Ga) gozetotide PET/CT scans were assessed in conjunction with contrast-enhanced CT and/or MRI images and were read by independent central readers blinded to clinical information. Eight hundred and thirty-one of 1,003 patients were identified as eligible for the VISION clinical study. Patients were then randomised in a 2:1 ratio to receive either PSMA-targeted therapy (Pluvicto) 7,400 MBq every 6 weeks for up to a total of 6 doses plus best standard of care (BSoC, N=551) or BSoC alone (N=280). BSoC was administered at the physician's discretion. Patients were males of median age 71 years (range: 40 to 94 years), White (86.8%), Black or African American (6.6%) and Asian (2.4%) and had median baseline PSA levels of 76 ng/mL (range: 0-8,995 ng/mL). The alternate primary efficacy endpoints of the VISION clinical study were overall survival (OS) and radiographic progression-free survival (rPFS) by blinded independent central review per PCWG3 criteria. Patients identified by gallium (68Ga) gozetotide PET/CT imaging had median OS of 15.3 months (95% CI: 14.2, 16.9) when receiving PSMA-targeted therapy (Pluvicto) plus BSoC and 11.3 months (95% CI: 9.8, 13.5) when receiving BSoC alone, with a hazard ratio of 0.62 (95% CI: 0.52, 0.74). The median rPFS was 8.7 months (99.2% CI: 7.9, 10.8) in patients receiving PSMA-targeted therapy (Pluvicto) plus BSoC, and 3.4 months (99.2% CI: 2.4, 4.0) in patients receiving BSoC alone, with a hazard ratio of 0.40 (99.2% CI: 0.29, 0.57). OS and rPFS outcomes support gallium (68Ga) gozetotide PET/CT imaging as a patient identification method for PSMA-targeted therapy in metastatic prostate cancer. A total of 125 gallium (68Ga) gozetotide PET/CT baseline scans were evaluated in conjunction with contrast-enhanced CT and/or MRI images by three independent readers blinded to clinical information to assess inter-reader variability. Of the 125 PET/CT scans, 20 were used to assess intra-reader reproducibility. Inter-reader Fleiss κ was 0.60 (95% CI: 0.50, 0.70) across the three independent readers, while intra-reader Cohen κ was 0.78 (95% CI: 0.49, 0.99), 0.76 (95% CI: 0.46, 0.99) and 0.89 (95% CI: 0.67, 0.99) for each reader. The efficacy of Locametz was further established in the two following prospective studies: In Study 1, 300 adult male patients with untreated, biopsy-proven prostate cancer and high-risk features were randomised 1:1 and underwent gallium (68Ga) gozetotide PET/CT (N=148) or CT and bone scanning imaging (N=152). A composite reference standard, including histopathology, imaging, clinical and biochemical findings, was available for 295 of 300 (98%) patients and the PET/CT scans were read by two independent readers. Gallium (68Ga) gozetotide PET/CT had improved sensitivity and specificity compared to CT and bone scanning imaging, as summarised in Table 2. Radiation exposure from gallium (68Ga) gozetotide was lower (8.4 mSv, 95% CI: 8.1, 8.7) than CT and bone scanning imaging radiation exposure (19.2 mSv, 95% CI: 18.2, 20.3). A change in patient management intent occurred in 28% (95% CI: 21, 36) of patients undergoing gallium (68Ga) gozetotide PET/CT and in 15% (95% CI: 10, 22) of patients undergoing CT and bone scanning imaging. The change in patient management upon gallium (68Ga) gozetotide PET/CT imaging included either a transition from curative to palliative treatment intent or a change in treatment approach (14% of patients each). **Table 2 Efficacy results in patients with untreated, biopsy-proven prostate cancer** | | | | | --- | --- | --- | | | **Gallium (68Ga) gozetotide** **PET/CT** **N=1451** | **CT and bone scanning** **N=1501** | | Sensitivity (95% CI) | 85% (74, 96) | 38% (24, 52) | | Specificity (95% CI) | 98% (95, 100) | 91% (85, 97) | | 1 Evaluable population | | | In Study 2, 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 PSA of ≥0.2 ng/mL more than 6 weeks after prostatectomy or by an increase in serum PSA of at least 2 ng/mL above nadir after definitive radiotherapy. Patients had median PSA level of 2.1 ng/mL above nadir after radiation therapy (range: 0.1-1 154 ng/mL). A composite reference standard, including histopathology, serial serum PSA levels and imaging (CT, MRI, and/or bone scan) findings was available for 223 of 635 (35.1%) patients, while histopathology reference standard alone was available for 93 (14.6%) patients. PET/CT scans were read by 3 independent readers blinded to clinical information 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 of gallium (68Ga) gozetotide PET positive lesion increased with increasing serum PSA levels (see section 4.4). Sensitivity and positive predictive value (PPV) of gallium (68Ga) gozetotide PET/CT imaging are summarised in Table 3. Inter-reader Fleiss κ for gallium (68Ga) gozetotide PET/CT imaging ranged from 0.65 (95% CI: 0.61, 0.70) to 0.78 (95% CI: 0.73, 0.82) across the assessed regions (prostate bed, pelvic nodes, extrapelvic soft tissues and bones). **Table 3 Efficacy results in patients with histopathology-proven and BCR prostate cancer** | | | | | --- | --- | --- | | | **Composite reference standard** **N=2231** | **Histopathology reference standard** **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 | | | **Paediatric population** The licensing authority 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 (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties **Distribution** Gallium (68Ga) gozetotide exhibits bi-exponential behaviour in blood, with a biological half-life of 6.5 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 of 0.71. Gozetotide is 33% bound to human plasma proteins. **Organ uptake** The highest radiation absorbed dose of gallium (68Ga) gozetotide occurred in the kidneys, salivary glands, bladder wall, lacrimal glands, spleen and liver. The estimated radiation absorbed doses to these organs for an administered activity of 259 MBq are 64 mGy (kidneys), 25 mGy (salivary glands), 22 mGy (bladder wall), 10 mGy (lacrimal glands), 10 mGy (spleen) and 8 mGy (liver). **Biotransformation** Based on *in vitro* data, gallium (68Ga) gozetotide undergoes negligible hepatic and renal metabolism. **Elimination** 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 the gallium-68 physical half-life of 68 minutes, the resulting gallium (68Ga) gozetotide effective half-life is 54 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 or inducers. ***Transporters*** Gozetotide is not a substrate of BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3 or OCT2. Gozetotide is 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 the substrates of these transporters. **Other special populations** ***Elderly*** In the VISION clinical study, 752 of 1,003 (75%) patients were aged 65 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients. ***Renal impairment / hepatic impairment*** Gallium (68Ga) gozetotide pharmacokinetics and biodistribution are not affected by renal/hepatic impairment to any clinically relevant extent.5.3 Preclinical safety data Gozetotide was evaluated in safety pharmacology and single-dose toxicity studies. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and single-dose toxicity. **Safety pharmacology** Based on safety pharmacology studies, gozetotide did not have any effect on the central nervous and respiratory systems in rats at doses up to 0.75 mg/kg, which is equivalent to an estimated safety margin of approximately 300-fold based on body surface area scaling at the gallium (68Ga) gozetotide maximum mass dose of 25 micrograms. Gozetotide did not have any effect on the cardiovascular system in minipigs at doses up to 0.29 mg/kg, which is equivalent to an estimated safety margin of approximately 690-fold based on body surface area scaling at the gallium (68Ga) gozetotide maximum mass dose of 25 micrograms. In an *in vitro* study, gozetotide did not inhibit the human Ether-à-go-go-Related Gene (hERG) channels up to 100 micromolar, which is equivalent to 10,000-fold the highest theoretical Cmax in patients receiving gallium (68Ga) gozetotide at the maximum mass dose of 25 micrograms. **Single-dose toxicity** Based on an extended single-dose acute toxicity study in rats, a single intravenous administration of gozetotide at doses up to 1.33 mg/kg No-Observed-Adverse-Effect Level (NOAEL) was equivalent to an estimated safety margin of 530-fold based on body surface area scaling in patients receiving gallium (68Ga) gozetotide at the maximum mass dose of 25 micrograms. **Carcinogenicity and mutagenicity** Mutagenicity studies and carcinogenicity studies have not been carried out with gallium (68Ga) gozetotide.

6.1 List of excipients Gentisic acid Sodium acetate trihydrate Sodium chloride6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in sections 6.6 and 12.6.3 Shelf life Unopened vial: 1 year. **After reconstitution** Use within 6 hours.6.4 Special precautions for storage Before reconstitution, store below 25°C. After reconstitution, store upright below 30°C. For storage conditions after reconstitution of the medicinal product, see section 6.3. Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials.6.5 Nature and contents of container 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 glass vial closed with a rubber stopper and sealed with a flip-off cap.6.6 Special precautions for disposal and other handling **General warning** 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. The content of the vial is intended only for use in the preparation of gallium (68Ga) gozetotide solution for injection and is not to be administered directly to the patient without first undergoing the preparative 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, effective radiation shielding of the gallium (68Ga) gozetotide solution for injection must be maintained (see section 3). After reconstitution, 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 for injection also contains hydrochloric acid derived from the gallium-68 chloride solution. Gallium (68Ga) gozetotide solution for injection is a sterile, clear, colourless solution for intravenous administration, 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 the medicinal 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 it should not be used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For instructions on reconstitution of the medicinal product before administration, see section 12.