Kit For The Preparation Of Gallium Ga 68 Gozetotide

1 INDICATIONS AND USAGE LOCAMETZ, after radiolabeling with gallium-68, is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer: with suspected metastasis who are candidates for initial definitive therapy. with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. for selection of patients who are indicated for PSMA-directed therapy as described in the prescribing information of the therapeutic products. LOCAMETZ, after radiolabeling with gallium-68, is a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer: with suspected metastasis who are candidates for initial definitive therapy with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level for selection of patients who are indicated for PSMA-directed therapy as described in the prescribing information of the therapeutic products. ( 1 )

2 DOSAGE AND ADMINISTRATION Use appropriate radiation safety measures and aseptic precautions while handling and administering gallium Ga 68 gozetotide injection. ( 2.1 ) The recommended amount of radioactivity is 111 MBq to 259 MBq (3 mCi to 7 mCi). Administered as slow intravenous injection. ( 2.2 ) Advise patients to be well hydrated prior to the administration and to void immediately prior to and frequently after image acquisition. ( 2.3 ) A diuretic expected to act within the uptake time period may be administered at the time of radiotracer injection. ( 2.6 ) Acquire PET whole body images 50 minutes to 100 minutes after administration. ( 2.7 ) See the full prescribing information for detailed instructions on preparation, administration, imaging, and radiation dosimetry. ( 2 ) 2.1 Radiation Safety – Drug Handling After reconstitution and radiolabeling of LOCAMETZ, the vial contains gallium Ga 68 gozetotide injection. Handle the gallium Ga 68 gozetotide injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.2)] . Use waterproof gloves, effective radiation shielding, and other appropriate safety measures when preparing and handling gallium Ga 68 gozetotide injection. Radiopharmaceuticals should be used by or under the control of health care providers who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the governmental agency authorized to license the use of radionuclides. 2.2 Recommended Dosage In adults, the recommended amount of radioactivity to be administered for PET is 111 MBq to 259 MBq (3 mCi to 7 mCi) by slow intravenous injection. 2.3 Patient Preparation Advise patients to be well hydrated prior to gallium Ga 68 gozetotide injection administration and to void immediately prior to and frequently during the first hours after image acquisition to reduce radiation exposure [see Warnings and Precautions (5.2)] . 2.4 Drug Preparation LOCAMETZ allows the direct preparation of gallium Ga 68 gozetotide injection with the eluate from one of the following generators (see below for specific instruction for use with each generator): Eckert & Ziegler GalliaPharm germanium-68/gallium-68 ( 68 Ge/ 68 Ga) generator IRE ELiT Galli Eo germanium-68/gallium-68 ( 68 Ge/ 68 Ga) generator The instructions for use provided by the germanium-68/gallium-68 generator manufacturer should also be followed. Prepare gallium Ga 68 gozetotide injection according to the following aseptic procedure: a. Use suitable shielding to reduce radiation exposure. b. Wear waterproof gloves. c. Flip the cap off the LOCAMETZ vial and swab the septum with an appropriate antiseptic, then allow the septum to dry. d. Pierce the LOCAMETZ vial septum with a sterile needle connected to a 0.2-micron sterile air venting filter to maintain atmospheric pressure within the vial during the reconstitution process. e. Place the LOCAMETZ vial in a lead shield container. f. Follow the generator specific procedures below. Schematic diagrams are provided in Figures 1 and 2. Preparation with Eckert & Ziegler GalliaPharm Generator 1) Connect the male luer of the outlet line of the generator to a sterile elution needle (size 21G to 23G). 2) Connect the LOCAMETZ vial directly to the outlet line of the generator by pushing the elution needle through the rubber septum. 3) Elute directly from the generator into the LOCAMETZ vial. 4) Perform the elution manually or by means of a pump according to the generator instructions for use. 5) Reconstitute the lyophilized powder with 5 mL of eluate. 6) At the end of the elution, disconnect the LOCAMETZ vial from the generator by removing the elution needle and the vent needle with the 0.2-micron sterile air venting filter from the rubber septum. Then, invert LOCAMETZ vial once and place it upright. 7) Incubate the LOCAMETZ vial upright between 20°C to 30°C (68°F to 86°F) for at least 5 minutes without agitation or stirring. 8) After 5 minutes, assay the vial containing the gallium Ga 68 gozetotide injection for total radioactivity using a dose calibrator, calculate the radioactivity concentration and record the result. 9) After radiolabeling, gallium Ga 68 gozetotide injection may be diluted with Sterile Water for Injection, USP or 0.9% Sodium Chloride Injection, USP up to a final volume of 10 mL. 10) Perform quality controls according to the recommended methods in order to check compliance with the specifications [see Dosage and Administration (2.5)] . 11) Store the LOCAMETZ vial containing the gallium Ga 68 gozetotide injection upright in a lead shield container below 30°C (86°F) until use. 12) After addition of gallium-68 chloride to the LOCAMETZ vial, use gallium Ga 68 gozetotide injection within 6 hours. Preparation with IRE ELiT Galli Eo Generator 1) Connect the male luer of the outlet line of the generator to a sterile elution needle (size 21G to 23G). 2) Connect the LOCAMETZ vial directly to the outlet line of the generator by pushing the elution needle through the rubber septum. 3) Connect the LOCAMETZ vial through the vent needle with 0.2-micron sterile air venting filter to a vacuum vial (25 mL minimum volume) by means of a sterile needle (size 21G to 23G) or to a vacuum pump to start the elution. 4) Elute directly from the generator into the LOCAMETZ vial. 5) Reconstitute the lyophilized powder with 1.1 mL of eluate. 6) At the end of the elution, first withdraw the sterile needle from the vacuum vial or disconnect the vacuum pump in order to establish atmospheric pressure into the LOCAMETZ vial, then disconnect the vial from the generator by removing both the elution needle and the vent needle with the 0.2-micron sterile air venting filter needle from the rubber septum. Inversion of the LOCAMETZ vial is not needed. 7) Incubate the LOCAMETZ vial upright between 20°C to 30°C (68°F to 86°F) for at least 5 minutes without agitation or stirring. 8) After 5 minutes, assay the vial containing the gallium Ga 68 gozetotide injection for total radioactivity using a dose calibrator, calculate the radioactivity concentration and record the result. 9) After radiolabeling, gallium Ga 68 gozetotide injection may be diluted with Sterile Water for Injection, USP or 0.9% Sodium Chloride Injection, USP up to a final volume of 10 mL. 10) Perform quality controls according to the recommended methods in order to check compliance with the specifications [see Dosage and Administration (2.5)] . 11) Store the LOCAMETZ vial containing the gallium Ga 68 gozetotide injection upright in a lead shield container below 30°C (86°F) until use. 12) After addition of gallium-68 chloride to the LOCAMETZ vial, use gallium Ga 68 gozetotide injection within 6 hours. Figure 1. Preparation with Eckert & Ziegler GalliaPharm Generator Figure 2. Preparation with IRE ELiT Galli Eo Generator 2.5 Specifications and Quality Control Perform the quality controls in Table 1 behind a lead glass shield for radioprotection purposes. Table 1. Specifications of Gallium Ga 68 Gozetotide Injection Test Acceptance criteria Method Appearance Clear, colorless and free from particulate matter Visual inspection pH 3.2 to 6.5 pH-indicator strips Radiochemical purity gallium Ga 68 gozetotide ≥ 95% Non-complexed gallium-68 species ≤ 5% Instant thin layer chromatography (ITLC, see details below) Determine radiochemical purity of gallium Ga 68 gozetotide injection by performing instant thin layer chromatography (ITLC). Perform ITLC using ITLC SG strips and using ammonium acetate 1M: Methanol (1:1 V/V) as mobile phase. ITLC Method a. Develop the ITLC SG strip for a distance of 6 cm from the point of application (i.e., to 7 cm from the bottom of the ITLC strip). b. Scan the ITLC SG strip with a radiometric ITLC scanner. c. Calculate radiochemical purity by integration of the peaks on the chromatogram. Do not use the reconstituted product if the percentage (%) of non-complexed gallium-68 species is higher than 5%. The retention factor (Rf) specifications are as follows: Non-complexed gallium-68 species, Rf = 0 to 0.2; Gallium Ga 68 gozetotide, Rf = 0.8 to 1. 2.6 Administration a. Use aseptic technique and radiation shielding when withdrawing and administering gallium Ga 68 gozetotide injection. b. Calculate the necessary volume to administer based on calibration time and required dose. c. Inspect the prepared gallium Ga 68 gozetotide injection for particulate matter and discoloration behind a lead glass shield for radioprotection purposes. Use only solutions that are clear, colorless and free from particulate matter. d. Using a single-dose syringe fitted with a sterile needle (size 21G to 23G) and protective shielding, aseptically withdraw the prepared gallium Ga 68 gozetotide injection. e. Verify the total radioactivity in the syringe with a dose calibrator immediately before and after gallium Ga 68 gozetotide injection administration to the patient. The dose calibrator must be calibrated with NIST traceable standards. f. After injection of gallium Ga 68 gozetotide, administer an intravenous flush of sterile 0.9% Sodium Chloride Injection, USP to ensure full delivery of the dose. g. Dispose of any unused gallium Ga 68 gozetotide injection in a safe manner in compliance with applicable regulations. h. If clinically necessary, a diuretic expected to act within the uptake time period may be administered at the time of radiotracer injection to potentially decrease artifact from radiotracer accumulation in the urinary bladder and ureters. 2.7 Image Acquisition Begin PET scanning 50 minutes to 100 minutes after the intravenous administration of gallium Ga 68 gozetotide injection. Patients should void immediately prior to image acquisition and image acquisition should begin at the mid-thighs and proceed cranially to the skull base or skull vertex. Adapt imaging technique according to the equipment used and patient characteristics in order to obtain the best image quality possible. 2.8 Image Interpretation Gallium Ga 68 gozetotide binds to PSMA. Based on the intensity of the signals, PET images obtained using gallium Ga 68 gozetotide injection indicate the presence of PSMA in tissues. Imaging Prior to Initial Definitive or Suspected Recurrence Therapy Lesions should be considered suspicious if uptake is greater than physiologic uptake in that tissue or greater than adjacent background if no physiologic uptake is expected. Tumors that do not bear PSMA will not be visualized. Increased uptake in tumors is not specific for prostate cancer [see Warnings and Precautions (5.1)]. Imaging to Select Patients for PSMA-Directed Therapy For instructions on patient selection, refer to the prescribing information of the PSMA-directed therapeutic product. 2.9 Radiation Dosimetry Estimated radiation absorbed doses per injected activity for organs and tissues of 13 adult male patients with an early stage of disease following an intravenous bolus of gallium Ga 68 gozetotide injection are shown in Table 2. The effective radiation dose resulting from the administration of 259 MBq (7 mCi) is 4.4 mSv. The radiation doses for this administered dose to the critical organs, which are the kidneys, urinary bladder, and spleen, are 96.2 mGy, 25.4 mGy, and 16.8 mGy, respectively. These radiation doses are for gallium Ga 68 gozetotide injection alone. If CT or a transmission source are used for attenuation correction, the radiation dose will increase by an amount that varies by technique. Table 2. Estimated Mean Radiation Absorbed Doses per Activity of Intravenously Administered Gallium Ga 68 Gozetotide Injection in Selected Organs and Tissues Absorbed dose (mGy/MBq) Organ Mean SD Adrenals 0.0156 0.0014 Brain 0.0104 0.0011 Breasts 0.0103 0.0011 Gallbladder 0.0157 0.0012 Lower colon 0.0134 0.0009 Small intestine 0.014 0.002 Stomach 0.0129 0.0008 Heart 0.012 0.0009 Kidneys 0.3714 0.0922 Liver 0.0409 0.0076 Lungs 0.0111 0.0007 Muscle 0.0103 0.0003 Pancreas 0.0147 0.0009 Red marrow 0.0114 0.0016 Skin 0.0091 0.0003 Spleen 0.065 0.018 Testes 0.0111 0.0006 Thymus 0.0105 0.0006 Thyroid 0.0104 0.0006 Urinary bladder 0.0982 0.0286 Total body 0.0143 0.0013 Effective dose (mSv/MBq) 0.0169 0.0015 Figure 1. Reconstitution Procedure for Eckert & Ziegler GalliaPharm Generator Figure 2. Reconstitution Procedure for IRE ELiT Galli Eo Generator

6 ADVERSE REACTIONS The adverse reactions (incidence ≥ 0.5%) are fatigue, nausea, constipation, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of LOCAMETZ has been established based on three prospective studies of gallium Ga 68 gozetotide in patients with prostate cancer (i.e., Studies 1, 2, and 3). Adverse reactions from these studies are reported below. In Studies 1 and 2 using another formulation of gallium Ga 68 gozetotide injection, 960 patients received one dose of gallium Ga 68 gozetotide intravenously with the amount (mean ± SD) of radioactivity 188.7 ± 40.7 MBq (5.1 ± 1.1 mCi) [see Clinical Studies (14.1, 14.2)] . The most commonly reported adverse reactions were nausea, diarrhea and dizziness, occurring at a rate of < 1%. In a randomized, multicenter, open-label clinical study (NCT03511664, referred to as Study 3) in which gallium Ga 68 gozetotide was used to identify PSMA-positive patients on PET imaging to determine eligibility for PSMA-directed therapy, 1,003 patients with progressive metastatic castration-resistant prostate cancer (mCRPC) received one dose of gallium Ga 68 gozetotide intravenously with the amount of radioactivity 167.1 ± 23.1 MBq (4.52 ± 0.62 mCi). Patients were males with median age of 70 years (range, 40 to 94 years), were White (87%), Black or African American (7%), or Asian (2.4%), and had median baseline PSA levels of 74 ng/mL (range, 0 to 8995 ng/mL). Adverse reactions occurring at ≥ 0.5% in patients with metastatic prostate cancer who received gallium Ga 68 gozetotide injection in Study 3 are presented in Table 3. Table 3. Adverse Reactions (≥ 0.5%) in Patients with Metastatic Prostate Cancer Who Received Gallium Ga 68 Gozetotide Injection in Study 3 Adverse reactions Gallium Ga 68 Gozetotide Injection N = 1003 n (%) General disorders Fatigue 12 (1.2) Gastrointestinal disorders Nausea 8 (0.8) Constipation 5 (0.5) Vomiting 5 (0.5) Adverse reactions occurring at a rate of < 0.5% in the study were diarrhea, dry mouth, injection site reactions including injection site hematoma and injection site warmth, and chills.

12.3 Pharmacokinetics Distribution Intravenously injected gallium Ga 68 gozetotide is cleared from the blood and is accumulated preferentially in the liver (15%), kidneys (7%), spleen (2%), and salivary glands (0.5%). Gallium Ga 68 gozetotide uptake is also seen in the adrenals and prostate. There is no uptake in the cerebral cortex or in the heart, and usually lung uptake is low. Gozetotide exhibits a mean blood-to-plasma ratio (% CV) of 0.71 (26%) and is approximately 33% bound to human plasma proteins at 1 mcg/mL to 5 mcg/mL in vitro . Elimination A total of 14% of the injected dose is excreted in urine in the first 2 hours post-injection. In Vitro Drug Interaction Studies CYP450 enzymes Gozetotide is not a substrate of cytochrome P450 (CYP450) enzymes, not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A4, and not an inducer of CYP1A2, CYP2B6 and CYP3A4 in vitro . Transporters Gozetotide is not a substrate of BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3 or OCT2. Gozetotide is not an inhibitor of BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2 in vitro .