Vipivotide tetraxetan

PLUVICTO (lutetium Lu 177 vipivotide tetraxetan) is a radioligand therapeutic agent. Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator radiolabeled with lutetium-177. The chemical name is 2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxy propyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate; lutetium-177(3+). The molecular mass is 1216.06 g/mol and the molecular formula is C 49 H 68 177 LuN 9 O 16 . The chemical structure for lutetium Lu 177 vipivotide tetraxetan is shown below: PLUVICTO Injection containing 1,000 MBq/mL (27 mCi/mL) of lutetium Lu 177 vipivotide tetraxetan at calibration time is supplied as a sterile, clear, colorless to slightly yellow solution for intravenous use containing 7.4 GBq (200 mCi) ± 10% of lutetium Lu 177 vipivotide tetraxetan at administration time. Each single-dose vial contains acetic acid (0.30 mg/mL), sodium acetate (0.41 mg/mL), gentisic acid (0.39 mg/mL), sodium ascorbate (50.0 mg/mL), pentetic acid (0.10 mg/mL), and water for injection (q.s. to 1 mL). The pH range of the solution is 4.5 to 7.0. Chemical Structure of lutetium 11.1 Physical Characteristics Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 498 keV (79%) and photonic radiation (γ) of 208 keV (11%) and 113 keV (6.4%). The main radiations of lutetium-177 are detailed in Table 9. Table 9: Lutetium-177 Main Radiations Radiation Energy (keV) Iβ - % Iγ% β - 176.5 12.2 β - 248.1 0.05 β - 384.9 9.1 β - 497.8 78.6 γ 71.6 0.15 γ 112.9 6.40 γ 136.7 0.05 γ 208.4 11.0 γ 249.7 0.21 γ 321.3 0.22 11.2 External Radiation Table 10 summarizes the radioactive decay properties of lutetium-177. Table 10: Physical Decay Chart: Lutetium-177 Physical Half-life = 6.647 days Hours Fraction remaining 0 1.000 1 0.996 2 0.991 5 0.979 10 0.958 24 (1 day) 0.901 48 (2 days) 0.812 72 (3 days) 0.731 120 (5 days) 0.594 168 (7 days) 0.482 336 (14 days) 0.232 720 (30 days) 0.044 1080 (45 days) 0.009

PLUVICTO is a radioligand therapeutic agent indicated: Metastatic Androgen Pathway Modulation-Naïve or -Sensitive (mAPMN/S) Prostate Cancer in combination with androgen receptor pathway inhibitor (ARPI) therapy for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer. ( 1.1 ) Metastatic Androgen Pathway Modulation-Resistant (mAPMR) Prostate Cancer for the treatment of adult patients with PSMA-positive metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer who have been treated with ARPI therapy, and are considered appropriate to delay taxane-based chemotherapy, or have received prior taxane-based chemotherapy. ( 1.2 ) 1.1 Metastatic Androgen Pathway Modulation-Naïve or -Sensitive Prostate Cancer PLUVICTO is indicated in combination with androgen receptor pathway inhibitor (ARPI) therapy for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer. 1.2 Metastatic Androgen Pathway Modulation-Resistant Prostate Cancer PLUVICTO is indicated for the treatment of adult patients with PSMA-positive metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer who have been treated with ARPI therapy, and are considered appropriate to delay taxane-based chemotherapy, or have received prior taxane-based chemotherapy.

PLUVICTO Injection containing 1,000 MBq/mL (27 mCi/mL) of lutetium Lu 177 vipivotide tetraxetan at calibration time is a sterile, preservative-free and clear, colorless to slightly yellow solution for intravenous use supplied in a clear, colorless Type I glass 30 mL single-dose vial containing 7.4 GBq (200 mCi) ± 10% of lutetium Lu 177 vipivotide tetraxetan at administration time (NDC# 0078-1217-61). The solution volume in the vial can range from 7.5 mL to 12.5 mL in order to provide a total of 7.4 GBq (200 mCi) of radioactivity at administration time. The product vial is enclosed within a lead shielded container (NDC# 0078-1217-61) for protective shielding and placed in a plastic sealed container. The product is shipped in a type A package. The shelf life is 120 hours (5 days) from the date and time of calibration. Store below 30°C (86°F). Do not freeze. Store in the original package to protect from ionizing radiation (lead shielding). Store PLUVICTO in accordance with local and federal laws on radioactive materials. Do not use PLUVICTO after the expiration date and time which are stated on the label. Dispose of any unused medicinal product or waste material in accordance with local and federal laws. Lutetium-177 for PLUVICTO may be prepared using two different sources of stable nuclides (either lutetium-176 or ytterbium-176) that require different waste management. Lutetium-177 for PLUVICTO is prepared using ytterbium-176 (“non-carrier added”) unless otherwise communicated on the product batch release certificate.

Select patients for treatment using LOCAMETZ ® or another approved PSMA positron emission tomography (PET) product based on PSMA expression in tumors. ( 2.2 ) mAPMN/S Prostate Cancer : The recommended dosage of PLUVICTO in combination with ARPI is 7.4 GBq (200 mCi) every 6 weeks for 6 doses, or until disease progression or unacceptable toxicity. ( 2.3 ) mAPMR Prostate Cancer : The recommended dosage of PLUVICTO is 7.4 GBq (200 mCi) every 6 weeks for 6 doses, or until disease progression or unacceptable toxicity. ( 2.3 ) Dose interruption, reduction, or permanent discontinuation may be required due to adverse reactions. ( 2.4 ) 2.1 Important Safety Instructions PLUVICTO is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)] . Use waterproof gloves and effective radiation shielding when handling PLUVICTO. Radiopharmaceuticals, including PLUVICTO, should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals. 2.2 Patient Selection Select patients with metastatic prostate cancer for treatment with PLUVICTO using LOCAMETZ or another approved PSMA positron emission tomography (PET) product based on PSMA expression in tumors. Additional selection criteria were used in clinical studies [see Clinical Studies (14)] . 2.3 Recommended Dosage Metastatic Androgen Pathway Modulation-Naïve or -Sensitive Prostate Cancer The recommended dosage of PLUVICTO in combination with ARPI is 7.4 GBq (200 mCi) every 6 weeks for 6 doses, or until disease progression or unacceptable toxicity. Refer to the Prescribing Information for ARPI for recommended dosing information. Metastatic Androgen Pathway Modulation-Resistant Prostate Cancer The recommended dosage of PLUVICTO is 7.4 GBq (200 mCi) every 6 weeks for 6 doses, or until disease progression or unacceptable toxicity. Patients receiving PLUVICTO for metastatic prostate cancer should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. 2.4 Dosage Modifications for Adverse Reactions Recommended dosage modifications of PLUVICTO for adverse reactions are provided in Table 1. Management of adverse reactions may require temporary dose interruption, dose reduction, or permanent discontinuation of treatment with PLUVICTO. If a treatment delay due to an adverse reaction persists for > 4 weeks, consider permanent discontinuation of PLUVICTO. The dose of PLUVICTO may be reduced by 20% to 5.9 GBq (160 mCi) once; do not re-escalate dose. If a patient has further adverse reactions that would require an additional dose reduction, treatment with PLUVICTO must be discontinued. Table 1: Recommended Dosage Modifications of PLUVICTO for Adverse Reactions Abbreviations: CLcr, creatinine clearance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal. Grading according to most current Common Terminology Criteria for Adverse Events (CTCAE). Adverse reaction Severity Dosage modification Myelosuppression (Anemia, thrombocytopenia, leukopenia, or neutropenia) [see Warnings and Precautions (5.2)] Grade 2 Withhold PLUVICTO until improvement to Grade 1 or baseline. Grade ≥ 3 Withhold PLUVICTO until improvement to Grade 1 or baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). Recurrent Grade ≥ 3 myelosuppression after one dose reduction Permanently discontinue PLUVICTO. Renal toxicity [see Warnings and Precautions (5.3)] Defined as: Confirmed serum creatinine increase (Grade ≥ 2) Confirmed CLcr < 30 mL/min; calculate using Cockcroft-Gault with actual body weight Withhold PLUVICTO until improvement. Defined as: Confirmed ≥ 40% increase from baseline serum creatinine and Confirmed > 40% decrease from baseline CLcr; calculate using Cockcroft-Gault with actual body weight Withhold PLUVICTO until improvement or return to baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). Grade ≥ 3 renal toxicity Permanently discontinue PLUVICTO. Recurrent renal toxicity after one dose reduction Permanently discontinue PLUVICTO. Dry mouth [see Adverse Reactions (6.1)] Grade 2 Withhold PLUVICTO until improvement or return to baseline. Consider reducing PLUVICTO dose by 20% to 5.9 GBq (160 mCi). Grade 3 Withhold PLUVICTO until improvement or return to baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). Recurrent Grade 3 dry mouth after one dose reduction Permanently discontinue PLUVICTO. Gastrointestinal toxicity [see Adverse Reactions (6.1)] Grade ≥ 3 (not amenable to medical intervention) Withhold PLUVICTO until improvement to Grade 2 or baseline. Reduce PLUVICTO dose by 20% to 5.9 GBq (160 mCi). Recurrent Grade ≥ 3 gastrointestinal toxicity after one dose reduction Permanently discontinue PLUVICTO. Fatigue [see Adverse Reactions (6.1)] Grade ≥ 3 Withhold PLUVICTO until improvement to Grade 2 or baseline. Electrolyte or metabolic abnormalities [see Adverse Reactions (6.1)] Grade ≥ 2 Withhold PLUVICTO until improvement to Grade 1 or baseline. Other non-hematologic toxicity [see Adverse Reactions (6.1)] Any unacceptable toxicity Permanently discontinue PLUVICTO. Any adverse reaction that requires treatment delay of > 4 weeks Permanently discontinue PLUVICTO. Any recurrent Grade 3 or 4 or persistent and intolerable Grade 2 adverse reaction after one dose reduction Permanently discontinue PLUVICTO. 2.5 Preparation and Administration Preparation Instructions Use aseptic technique and radiation shielding when handling or administering PLUVICTO, using tongs as needed to minimize radiation exposure. Inspect the product visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates and/or discoloration are present. Do not inject the PLUVICTO solution directly into any other intravenous solution. Confirm the amount of radioactivity of PLUVICTO delivered to the patient with an appropriately calibrated dose calibrator prior to and after each PLUVICTO administration. Dispose of any unused medicinal product or waste material in accordance with local and federal laws. Administration Instructions Prior to administration, flush the intravenous catheter used exclusively for PLUVICTO administration with ≥ 10 mL of 0.9% Sodium Chloride Injection, USP to ensure patency and to minimize the risk of extravasation. Manage cases of extravasation as per institutional guidelines. The recommended dosage of PLUVICTO may be administered intravenously as an injection using the syringe method, as an infusion using the gravity method, or as an infusion using the peristaltic pump method. When using the gravity or peristaltic pump method, infuse PLUVICTO directly from its original container. Use the syringe method or the peristaltic pump method when administering a reduced dose of PLUVICTO following a dosage modification for an adverse reaction. When using the gravity method for a reduced dose, adjust the PLUVICTO dose before the administration to avoid the delivery of an incorrect volume of PLUVICTO. Intravenous Methods of Administration Instructions for the Syringe Method Withdraw an appropriate volume of PLUVICTO solution to deliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and a disposable sterile needle that is 9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, a filtered 2.5 cm, 20 gauge needle (short venting needle) can be used to reduce the resistance from the pressurized vial. Ensure that the short needle does not touch the PLUVICTO solution in the vial. Administer PLUVICTO to the patient by slow intravenous push within approximately 1 to 10 minutes (either with a syringe pump or manually without a syringe pump) via an intravenous catheter that is primed with 0.9% Sodium Chloride Injection, USP and that is used exclusively for PLUVICTO administration to the patient. If using a syringe pump, fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringe and an intravenous catheter primed with 0.9% Sodium Chloride Injection, USP and used for PLUVICTO administration to the patient. When the desired PLUVICTO radioactivity has been delivered, stop the syringe pump and then change the position of the 3-way stopcock valve to flush the syringe with 25 mL of 0.9% Sodium Chloride Injection, USP. Restart the syringe pump. After the flush of the syringe has been completed, perform an intravenous flush of ≥ 10 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. Instructions for the Gravity Method Insert a 2.5 cm, 20 gauge needle (short needle) into the PLUVICTO vial and connect via a catheter to 500 mL 0.9% Sodium Chloride Injection, USP (used to transport the PLUVICTO solution during the infusion). Ensure that the short needle does not touch the PLUVICTO solution in the vial and do not connect the short needle directly to the patient. Do not allow the 0.9% Sodium Chloride Injection, USP to flow into the PLUVICTO vial prior to the initiation of the PLUVICTO infusion and do not inject the PLUVICTO solution directly into the 0.9% Sodium Chloride Injection, USP. Insert a second needle that is 9 cm, 18 gauge (long needle) into the PLUVICTO vial, ensuring that the long needle touches and is secured to the bottom of the PLUVICTO vial during the entire infusion. Connect the long needle to the patient by an intravenous catheter that is primed with 0.9% Sodium Chloride Injection, USP and that is used exclusively for the PLUVICTO infusion into the patient. Use a clamp or an infusion pump to regulate the flow of the 0.9% Sodium Chloride Injection, USP via the short needle into the PLUVICTO vial (the 0.9% Sodium Chloride Injection, USP entering the vial through the short needle will carry the PLUVICTO solution from the vial to the patient via the intravenous catheter connected to the long needle within approximately 30 minutes). During the infusion, ensure that the level of solution in the PLUVICTO vial remains constant. Disconnect the vial from the long needle line and clamp the 0.9% Sodium Chloride Injection, USP line once the level of radioactivity is stable for at least five minutes. Follow the infusion with an intravenous flush of ≥ 10 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. Instructions for the Peristaltic Pump Method Insert a filtered 2.5 cm, 20 gauge needle (short venting needle) into the PLUVICTO vial. Ensure that the short needle does not touch the PLUVICTO solution in the vial and do not connect the short needle directly to the patient or to the peristaltic pump. Insert a second needle that is 9 cm, 18 gauge (long needle) into the PLUVICTO vial, ensuring that the long needle touches and is secured to the bottom of the PLUVICTO vial during the entire infusion. Connect the long needle and a 0.9% Sodium Chloride Injection, USP to a 3-way stopcock valve via appropriate tubing. Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic pump according to manufacturer’s instructions. Prime the line by opening the 3-way stopcock valve and pumping the PLUVICTO solution through the tubing until it reaches the exit of the valve. Prime the intravenous catheter which will be connected to the patient by opening the 3-way stopcock valve to the 0.9% Sodium Chloride Injection, USP and pumping the 0.9% Sodium Chloride Injection, USP until it exits the end of the catheter tubing. Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve such that the PLUVICTO solution is in line with the peristaltic pump. Infuse an appropriate volume of PLUVICTO solution at approximately 25 mL/h to deliver the desired radioactivity. When the desired PLUVICTO radioactivity has been delivered, stop the peristaltic pump and then change the position of the 3-way stopcock valve so that the peristaltic pump is in line with the 0.9% Sodium Chloride Injection, USP. Restart the peristaltic pump and infuse an intravenous flush of ≥ 10 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. 2.6 Radiation Dosimetry Dosimetry of lutetium Lu 177 vipivotide tetraxetan was collected in 29 patients in the VISION sub-study, in order to calculate whole body and organ radiation dosimetry. The mean and standard deviation (SD) of the estimated radiation absorbed doses to different organs for adults receiving PLUVICTO are shown in Table 2. The organs with the highest radiation absorbed doses are lacrimal glands, salivary glands, large intestine (left and right colon), kidneys, and urinary bladder wall. The maximum penetration of lutetium-177 in tissue is approximately 2 mm and the mean penetration is 0.67 mm. Table 2: Estimated Radiation Absorbed Dose a for PLUVICTO in VISION a Radiation absorbed dose estimates were derived using OLINDA v2.4 radiation dosimetry software, using measured time-activity data from patient imaging as input. Specific methods and software used for bone marrow and osteogenic cells dosimetry estimates are included below: * Estimated radiation absorbed dose based on activity measured in blood samples collected from patients, and dosimetry calculations using OLINDA v2.4. ** Estimated radiation absorbed dose based on activity measured in patient imaging (voxelized analysis of measured activity in bone marrow regions approximately 1 cm adjacent to bone metastasis activity within the vertebrae T8-L5) from 81 individual volume of interest (VOI) collected from 28 patients, and dosimetry calculations using Hermia Voxel Dosimetry v3.1.0. Absorbed dose per unit activity (Gy/GBq) N = 29 Calculated absorbed dose for 7.4 GBq administration (Gy) Calculated absorbed dose for 6 x 7.4 GBq (44.4 GBq cumulative activity) (Gy) Organ Mean SD Mean SD Mean SD Adrenals 0.033 0.026 0.25 0.19 1.5 1.1 Brain 0.0069 0.0051 0.051 0.038 0.30 0.23 Esophagus 0.025 0.026 0.18 0.19 1.1 1.2 Eyes 0.022 0.025 0.16 0.18 0.98 1.1 Gallbladder wall 0.028 0.026 0.21 0.19 1.3 1.2 Heart wall 0.17 0.12 1.3 0.88 7.8 5.3 Kidneys 0.42 0.19 3.1 1.4 19 8.4 Lacrimal glands 2.1 0.48 15 3.6 92 21 Left colon 0.58 0.14 4.3 1.0 26 6.1 Liver 0.093 0.050 0.69 0.37 4.1 2.2 Lungs 0.11 0.11 0.78 0.83 4.7 5.0 Osteogenic cells: -blood-based* 0.036 0.029 0.26 0.21 1.6 1.3 -image-based** 0.048 0.038 0.36 0.28 2.1 1.7 Pancreas 0.027 0.026 0.20 0.19 1.2 1.2 Prostate 0.027 0.026 0.20 0.19 1.2 1.2 Rectum 0.56 0.14 4.1 1.1 25 6.3 Red marrow: -blood-based* 0.035 0.020 0.26 0.15 1.5 0.91 -image-based** 0.055 0.046 0.41 0.34 2.5 2.1 Right colon 0.32 0.079 2.4 0.58 14 3.5 Salivary glands 0.63 0.37 4.6 2.7 28 16 Small intestine 0.071 0.031 0.52 0.23 3.1 1.4 Spleen 0.061 0.028 0.45 0.21 2.7 1.2 Stomach wall 0.025 0.026 0.19 0.19 1.1 1.2 Testes 0.023 0.025 0.17 0.19 1.0 1.1 Thymus 0.024 0.026 0.18 0.19 1.1 1.2 Thyroid 0.26 0.37 1.9 2.8 11 17 Total body 0.037 0.027 0.28 0.20 1.7 1.2 Urinary bladder wall 0.32 0.025 2.4 0.19 14 1.1

None. None. ( 4 )

Risk From Radiation Exposure : Minimize radiation exposure during and after treatment with PLUVICTO consistent with institutional good radiation safety practices and patient treatment procedures. Ensure patients increase oral fluid intake and advise patients to void as often as possible to reduce bladder radiation. ( 5.1 ) Myelosuppression : Perform complete blood counts. Withhold, reduce dose, or permanently discontinue PLUVICTO based on severity. ( 2.4 , 5.2 ) Renal Toxicity : Advise patients to remain well hydrated and to urinate frequently. Perform kidney function laboratory tests. Withhold, reduce dose, or permanently discontinue PLUVICTO based on severity. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.4 , 8.1 , 8.3 ) Infertility : PLUVICTO may cause temporary or permanent infertility. ( 5.5 , 8.3 ) 5.1 Risk From Radiation Exposure PLUVICTO contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Minimize radiation exposure to patients, medical personnel, and others during and after treatment with PLUVICTO consistent with institutional good radiation safety practices, patient treatment procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home. Ensure patients increase oral fluid intake and advise patients to void as often as possible to reduce bladder radiation. Before the patient is released, inform patients about the necessary radioprotection precautions to follow to minimize radiation exposure to others [see Patient Counseling Information (17)] . After each administration of PLUVICTO, advise patients to: Limit close contact (less than 3 feet) with others for 2 days or with children and pregnant women for 7 days. Refrain from sexual activity for 7 days. Sleep in a separate room from others for 3 days, from children for 7 days, or from pregnant women for 15 days. 5.2 Myelosuppression PLUVICTO can cause severe and life-threatening myelosuppression, including anemia, thrombocytopenia, leukopenia, and neutropenia. In the PSMAddition study, Grade 3 or 4 decreased leukocytes (7%), decreased neutrophils (4.4%), decreased hemoglobin (4.3%), and decreased platelets (1.1%) occurred in patients treated with PLUVICTO. In the PSMAfore study, Grade 3 or 4 decreased hemoglobin (7%), decreased leukocytes (4.4%), decreased neutrophils (3.5%), and decreased platelets (2.7%) occurred in patients treated with PLUVICTO. One death occurred due to bone marrow failure during long-term follow-up in a patient who received PLUVICTO. In the VISION study, Grade 3 or 4 decreased hemoglobin (15%), decreased platelets (9%), decreased leukocytes (7%), and decreased neutrophils (4.5%) occurred in patients treated with PLUVICTO. Grade ≥ 3 pancytopenia occurred in 1.1% (which includes two fatal events) of patients treated with PLUVICTO. Two deaths (0.4%) occurred due to intracranial hemorrhage and subdural hematoma in association with thrombocytopenia, one death (0.2%) occurred due to sepsis and concurrent neutropenia, and one death (0.2%) occurred due to bone marrow failure in patients treated with PLUVICTO. Perform complete blood counts before and during treatment with PLUVICTO. Withhold, reduce dose, or permanently discontinue PLUVICTO based on the severity of myelosuppression [see Dosage and Administration (2.4)] . 5.3 Renal Toxicity PLUVICTO can cause severe renal toxicity. In the PSMAddition study, Grade 3 or 4 acute kidney injury (1.6%) occurred in patients treated with PLUVICTO. In the PSMAfore study, Grade 3 or 4 acute kidney injury (1.3%) occurred in patients treated with PLUVICTO. In the VISION study, Grade 3 or 4 acute kidney injury (3.4%) occurred in patients treated with PLUVICTO. Advise patients to remain well hydrated and to urinate frequently before and after administration of PLUVICTO. Perform kidney function laboratory tests, including serum creatinine and calculated creatinine clearance (CLcr), before and during treatment with PLUVICTO. Withhold, reduce dose, or permanently discontinue PLUVICTO based on the severity of renal toxicity [see Dosage and Administration (2.4)] . 5.4 Embryo-Fetal Toxicity The safety and efficacy of PLUVICTO have not been established in females. Based on its mechanism of action, PLUVICTO can cause fetal harm [see Clinical Pharmacology (12.1)] . No animal studies using lutetium Lu 177 vipivotide tetraxetan have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from PLUVICTO, can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception during treatment with PLUVICTO and for 14 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)] . 5.5 Infertility PLUVICTO may cause infertility in males. The recommended cumulative dose of 44.4 GBq of PLUVICTO results in a radiation absorbed dose to the testes within the range where PLUVICTO may cause temporary or permanent infertility [see Use in Specific Populations (8.3)] .

Risk From Radiation Exposure Ensure patients increase oral fluid intake and advise patients to void as often as possible to reduce bladder radiation. Before the patient is released, inform patients about the necessary radioprotection precautions to follow to minimize radiation exposure to others. After each administration of PLUVICTO, advise patients to: Limit close contact (less than 3 feet) with others for 2 days or with children and pregnant women for 7 days. Refrain from sexual activity for 7 days. Sleep in a separate room from others for 3 days, from children for 7 days, or from pregnant women for 15 days [see Warnings and Precautions (5.1)] . Myelosuppression Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression, such as tiredness, weakness, pale skin, shortness of breath, bleeding or bruising more easily than normal or difficulty to stop bleeding, or frequent infections with signs, such as fever, chills, sore throat or mouth ulcers [see Warnings and Precautions (5.2)] . Renal Toxicity Advise patients to remain well hydrated and to urinate frequently before and after administration of PLUVICTO. Advise patients to contact their healthcare provider for any signs or symptoms of renal toxicity, such as passing urine less often than usual or passing much smaller amounts of urine than usual [see Warnings and Precautions (5.3)] . Embryo-Fetal Toxicity Advise males that PLUVICTO can cause fetal harm [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)] . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PLUVICTO and for 14 weeks after the last dose [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)] . Infertility Advise males of reproductive potential that PLUVICTO may cause temporary or permanent infertility [see Warnings and Precautions (5.5), Use in Specific Populations (8.3)] . Distributed by: Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2026 Novartis PLUVICTO ® is a registered trademark of Novartis AG and/or its affiliates. U.S. Patents 10398791; 10406240; 11318121; 11951190; 12208102 T2026-26

Carcinogenicity and mutagenicity studies have not been conducted with lutetium Lu 177 vipivotide tetraxetan; however, radiation is a carcinogen and mutagen. No animal studies were conducted to determine the effects of lutetium Lu 177 vipivotide tetraxetan on fertility.

Risk Summary The safety and efficacy of PLUVICTO have not been established in females. Based on its mechanism of action, PLUVICTO can cause fetal harm [see Clinical Pharmacology (12.1)] . There are no available data on PLUVICTO use in pregnant females. No animal studies using lutetium Lu 177 vipivotide tetraxetan have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radioactive emissions, including those from PLUVICTO, can cause fetal harm.

The safety and effectiveness of PLUVICTO in pediatric patients have not been established.

Of the 564 patients who received at least one dose of PLUVICTO in combination with ARPI in the PSMAddition study, 379 patients (67%) were 65 years of age or older and 115 patients (20%) were 75 years of age or older. No overall differences in effectiveness were observed between patients ≥ 75 years of age and younger patients. Serious adverse reactions occurred in 43% of patients ≥ 75 years of age and in 29% of younger patients. Grade ≥ 3 adverse reactions occurred in 59% of patients ≥ 75 years of age and in 49% of younger patients. Of the 227 patients who received at least one dose of PLUVICTO in the PSMAfore study, 177 patients (78%) were 65 years of age or older and 83 patients (37%) were 75 years of age or older. No overall differences in effectiveness were observed between patients ≥ 75 years of age and younger patients. Serious adverse reactions occurred in 20% of patients ≥ 75 years of age and in 20% of younger patients. Grade ≥ 3 adverse reactions occurred in 39% of patients ≥ 75 years of age and in 34% of younger patients. Of the 529 patients who received at least one dose of PLUVICTO plus BSoC in the VISION study, 387 patients (73%) were 65 years of age or older and 143 patients (27%) were 75 years of age or older. No overall differences in effectiveness were observed between patients ≥ 75 years of age and younger patients. Serious adverse reactions occurred in 41% of patients ≥ 75 years of age and in 35% of younger patients. Grade ≥ 3 adverse reactions occurred in 56% of patients ≥ 75 years of age and in 53% of younger patients.

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.2)] Renal Toxicity [see Warnings and Precautions (5.3)] Most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased lymphocytes, decreased hemoglobin, fatigue, dry mouth, decreased neutrophils, nausea, decreased platelets, decreased estimated glomerular filtration rate, increased aspartate aminotransferase, decreased sodium, increased magnesium, increased potassium, decreased calcium, and increased alkaline phosphatase. ( 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. In the pooled safety population for the PSMAddition, PSMAfore and VISION studies (N = 1320), the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased lymphocytes (86%), decreased hemoglobin (68%), fatigue (51%), dry mouth (46%), decreased neutrophils (35%), nausea (35%), decreased platelets (33%), decreased estimated glomerular filtration rate (28%), increased aspartate aminotransferase (25%), decreased sodium (22%), increased magnesium (22%), increased potassium (21%), decreased calcium (21%), and increased alkaline phosphatase (20%). Metastatic Androgen Pathway Modulation-Naïve or -Sensitive Prostate Cancer PSMAddition The safety of PLUVICTO in combination with ARPI was evaluated in the PSMAddition study in patients with PSMA-positive mAPMN/S prostate cancer [see Clinical Studies (14.1)] . Patients could have been treated with ARPI in the metastatic setting for up to 45 days prior to consent. Patients received at least one dose of either PLUVICTO 7.4 GBq (200 mCi) administered every 6 weeks in combination with ARPI (N = 564) or ARPI alone (N = 565). Among patients who received PLUVICTO in combination with ARPI, the median duration of exposure to PLUVICTO was 8.3 months (range, 1.3 to 11.2) and the median number of doses of PLUVICTO received was 6 (range, 1 to 6). The median cumulative administered activity of PLUVICTO was 43.4 GBq (range, 7.1 to 47.3). Serious adverse reactions occurred in 32% of patients who received PLUVICTO in combination with ARPI. Serious adverse reactions in > 1% of patients included acute kidney injury (1.6%), pneumonia and sepsis (1.4% each), anemia, basal cell carcinoma, general physical health deterioration, and syncope (1.1% each). Fatal adverse reactions occurred in 2.7% of patients who received PLUVICTO in combination with ARPI, including general physical health deterioration (0.5%), respiratory failure and sudden death (0.4% each), arrhythmia, cardiac arrest, congestive heart failure, cholangiocarcinoma, COVID-19, malignant neoplasm of unknown primary site, multiple organ dysfunction syndrome, and subdural hemorrhage (0.2% each). PLUVICTO was permanently discontinued due to adverse reactions in 8% of patients who received PLUVICTO in combination with ARPI. The most frequent (≥ 1%) adverse reaction leading to permanent discontinuation of PLUVICTO was anemia (1.1%). Adverse reactions leading to a dose interruption of PLUVICTO occurred in 12% of patients who received PLUVICTO in combination with ARPI. The most frequent (≥ 1%) adverse reactions leading to a dose interruption of PLUVICTO were neutropenia (2%), leukopenia, and COVID-19 (1.2% each). Adverse reactions leading to a dose reduction of PLUVICTO occurred in 3.9% of patients who received PLUVICTO in combination with ARPI. The most frequent (≥ 1%) adverse reaction leading to a dose reduction of PLUVICTO was dry mouth (1.1%). Table 3 and Table 4 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in PSMAddition. Table 3: Adverse Reactions (≥ 10%) in Patients With PSMA-Positive mAPMN/S Prostate Cancer Who Received PLUVICTO in Combination With ARPI or ARPI in PSMAddition Abbreviation: ARPI, androgen receptor pathway inhibitors. a Includes multiple similar terms. Adverse reactions PLUVICTO in combination with ARPI (N = 564) ARPI (N = 565) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) General disorders Fatigue a 51 1.4 41 1.8 Decreased appetite 14 0.9 7 0.2 Gastrointestinal disorders Dry mouth a 46 0 3.7 0 Nausea 34 0.2 9 0 Constipation 18 0 16 0 Vomiting a 14 0.7 3.7 0 Diarrhea 12 0.2 10 0 Nervous system disorders Dysgeusia a 13 0 4.1 0 Headache 12 0 9 0.4 Clinically relevant adverse reactions in < 10% of patients who received PLUVICTO in combination with ARPI included abdominal pain, dizziness, acute kidney injury, dry eye, dry skin, stomatitis, gastroesophageal reflux disease, vertigo, eye irritation, oral fungal infection, dysphagia, and esophagitis. Table 4: Select Laboratory Abnormalities (≥ 10%) That Worsened From Baseline in Patients With PSMA-Positive mAPMN/S Prostate Cancer Who Received PLUVICTO in Combination With ARPI or ARPI (Between Arm Difference of ≥ 5% All Grades) in PSMAddition Abbreviation: ARPI, androgen receptor pathway inhibitors. a The denominator used to calculate the rate for each laboratory parameter varied from 563 to 564 based on the number of patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate for each laboratory parameter varied from 557 to 558 based on the number of patients with a baseline value and at least one post-treatment value. c No Grade 4 laboratory abnormalities worsening from baseline were reported. d “All grades” column represents patients having any worsened eGFR category of < 90 mL/min/1.73 m 2 and “Grade 3 or 4” column represents patients having any worsened eGFR category of < 30 mL/min/1.73 m 2 calculated using the CKD-EPI formula. Laboratory abnormalities PLUVICTO in combination with ARPI a ARPI b All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Hematology Decreased lymphocytes 91 24 61 10 Decreased hemoglobin 72 4.3 c 46 2.5 c Decreased neutrophils 41 4.4 30 3 Decreased platelets 23 1.1 9 1.1 Chemistry Decreased estimated glomerular filtration rate (eGFR) d 43 1.8 44 1.1 Metastatic Androgen Pathway Modulation-Resistant Prostate Cancer PSMAfore The safety of PLUVICTO was evaluated in the PSMAfore study in patients with progressive, PSMA-positive mAPMR prostate cancer previously treated with ARPI therapy, for whom it was considered appropriate to delay taxane-based chemotherapy by the investigator [see Clinical Studies (14.2)] . Patients received at least one dose of either PLUVICTO 7.4 GBq (200 mCi) administered every 6 weeks (N = 227) or a change in ARPI (N = 232). The median duration of exposure to PLUVICTO was 8.4 months (range, 0.4 to 11.6) and the median number of doses of PLUVICTO received was 6 (range, 1 to 6). The median cumulative administered activity of PLUVICTO was 42.4 GBq (range, 7.0 to 45.4). Serious adverse reactions occurred in 20% of patients who received PLUVICTO. Serious adverse reactions in > 1% of patients included anemia (1.8%), urinary tract infection (1.8%), hemorrhage (1.3%), and sepsis (1.3%). Fatal adverse reactions occurred in 1.8% of patients who received PLUVICTO, including COVID-19 pneumonia, cardiac arrest, intestinal ischemia, and sepsis (0.4% each). PLUVICTO was permanently discontinued due to adverse reactions in 6% of patients who received PLUVICTO. The most frequent (≥ 1%) adverse reactions leading to permanent discontinuation of PLUVICTO were thrombocytopenia (1.8%) and dry mouth (1.3%). Adverse reactions leading to a dose interruption of PLUVICTO occurred in 12% of patients who received PLUVICTO. The most frequent (≥ 1%) adverse reactions leading to a dose interruption of PLUVICTO were COVID-19 (3.1%) and anemia (1.8%). Adverse reactions leading to a dose reduction of PLUVICTO occurred in 3.5% of patients who received PLUVICTO. The most frequent (≥ 0.5%) adverse reaction leading to a dose reduction of PLUVICTO was dry mouth (0.9%). Table 5 and Table 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in PSMAfore. Table 5: Adverse Reactions (≥ 10%) in Patients With PSMA-Positive mAPMR Prostate Cancer Who Received PLUVICTO or Change in ARPI in PSMAfore Abbreviation: ARPI, androgen receptor pathway inhibitor. a Includes multiple similar terms. Adverse reactions PLUVICTO (N = 227) ARPI (N = 232) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal disorders Dry mouth a 61 0.9 2.6 0 Nausea 32 0 12 0.4 Constipation 22 0.4 14 0 Diarrhea 17 0 9 0.4 Vomiting 11 0 4.7 0 General disorders Fatigue a 53 1.3 53 5 Metabolism and nutrition disorders Decreased appetite 22 0 19 0.4 Musculoskeletal and connective tissue disorders Arthralgia 20 0 23 0.4 Back pain 14 1.3 20 2.6 Clinically relevant adverse reactions in < 10% of patients who received PLUVICTO included abdominal pain, dysgeusia, peripheral edema, headache, acute kidney injury, weight decreased, dry eye, urinary tract infection, dizziness, dry skin, oral fungal infection, gastroesophageal reflux disease, pyrexia, vertigo, stomatitis, dysphagia, esophagitis, pancytopenia, and bone marrow failure. Table 6: Select Laboratory Abnormalities (≥ 10%) That Worsened From Baseline in Patients With PSMA-Positive mAPMR Prostate Cancer Who Received PLUVICTO or Change in ARPI (Between Arm Difference of ≥ 5% All Grades) in PSMAfore Abbreviation: ARPI, androgen receptor pathway inhibitor. a The denominator used to calculate the rate for each laboratory parameter was based on 226 patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate for each laboratory parameter varied from 231 to 232 based on the number of patients with a baseline value and at least one post-treatment value. c No Grade 4 laboratory abnormalities worsening from baseline were reported. d “All grades” column represents patients having any worsened eGFR category of < 90 mL/min/1.73 m 2 and “Grade 3 or 4” column represents patients having any worsened eGFR category of < 30 mL/min/1.73 m 2 calculated using the CKD-EPI formula. Laboratory abnormalities PLUVICTO a ARPI b All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Hematology Decreased lymphocytes 78 27 57 12 Decreased hemoglobin 67 7 c 50 7 c Decreased neutrophils 38 3.5 18 1.3 Decreased platelets 30 2.7 11 1.7 Chemistry Decreased estimated glomerular filtration rate (eGFR) d 41 0.9 c 42 3 Increased alkaline phosphatase 31 8 50 10 c Increased magnesium 19 0.9 c 28 0 c Decreased calcium 18 0.9 11 0.9 Decreased sodium 11 0 c 18 0 c Decreased potassium 6 0.9 c 18 2.6 VISION The safety of PLUVICTO was evaluated in the VISION study in patients with progressive, PSMA-positive mAPMR prostate cancer previously treated with ARPI therapy and taxane-based chemotherapy [see Clinical Studies (14.2)] . Patients received at least one dose of either PLUVICTO 7.4 GBq (200 mCi) administered every 6 weeks plus BSoC (N = 529) or BSoC alone (N = 205). The median duration of exposure to PLUVICTO plus BSoC was 7.8 months (range, 0.3 to 36.5). Among patients who received PLUVICTO plus BSoC, the median number of doses of PLUVICTO received was 5 (range, 1 to 6). The median cumulative administered activity of PLUVICTO was 37.5 GBq (range, 7.0 to 48.3). Serious adverse reactions occurred in 37% of patients who received PLUVICTO plus BSoC. Serious adverse reactions in > 1% of patients included musculoskeletal pain (4%), hemorrhage (4%), sepsis (3.2%), urinary tract infection (3%), anemia (2.8%), acute kidney injury (1.9%), pneumonia (1.7%), pyrexia (1.5%), pancytopenia (1.3%), spinal cord compression (1.1%), and pulmonary embolism (1.1%). Fatal adverse reactions occurred in 3% of patients who received PLUVICTO plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). PLUVICTO was permanently discontinued due to adverse reactions in 12% of patients who received PLUVICTO plus BSoC. The most frequent (≥ 1%) adverse reactions leading to permanent discontinuation of PLUVICTO were anemia (2.8%), thrombocytopenia (2.8%), and leukopenia (including neutropenia) (1.7%). Adverse reactions leading to a dose interruption of PLUVICTO occurred in 16% of patients who received PLUVICTO plus BSoC. The most frequent (≥ 3%) adverse reactions leading to a dose interruption of PLUVICTO were anemia (5%) and thrombocytopenia (3.6%). Adverse reactions leading to a dose reduction of PLUVICTO occurred in 6% of patients who received PLUVICTO plus BSoC. The most frequent (≥ 1%) adverse reactions leading to a dose reduction of PLUVICTO were thrombocytopenia (1.9%) and anemia (1.3%). Table 7 and Table 8 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in VISION. Table 7: Adverse Reactions (≥ 10%) in Patients With PSMA-Positive mAPMR Prostate Cancer Who Received PLUVICTO Plus BSoC or BSoC in VISION Abbreviation: BSoC, best standard of care. a Includes multiple similar terms. Adverse reactions PLUVICTO plus BSoC (N = 529) BSoC (N = 205) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) General disorders Fatigue a 48 7 29 2.4 Decreased appetite 21 1.9 15 0.5 Weight decreased 11 0.4 10 0.5 Peripheral edema a 10 0.4 7 1 Gastrointestinal disorders Dry mouth a 39 0 1 0 Nausea 36 1.3 17 0.5 Constipation 20 1.1 11 0.5 Vomiting a 19 0.9 6 0.5 Diarrhea 19 0.8 2.9 0.5 Abdominal pain a 12 1.3 6 0.5 Musculoskeletal and connective tissue disorders Back pain 24 3.6 15 3.9 Arthralgia 22 1.1 13 0.5 Bone pain 11 2.5 8 2.4 Renal and urinary disorders Urinary tract infection a 12 3.8 1 0.5 Clinically relevant adverse reactions in < 10% of patients who received PLUVICTO plus BSoC included acute kidney injury, dizziness, dysgeusia, headache, pyrexia, dry eye, oral fungal infection, vertigo, gastroesophageal reflux disease, stomatitis, pancytopenia, dry skin, dysphagia, esophagitis, and bone marrow failure. Table 8: Select Laboratory Abnormalities (≥ 10%) That Worsened From Baseline in Patients With PSMA-Positive mAPMR Prostate Cancer Who Received PLUVICTO Plus BSoC or BSoC (Between Arm Difference of ≥ 5% All Grades) in VISION Abbreviation: BSoC, best standard of care. a The denominator used to calculate the rate for each laboratory parameter varied from 506 to 529 based on the number of patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate for each laboratory parameter varied from 194 to 198 based on the number of patients with a baseline value and at least one post-treatment value. c No Grade 4 laboratory abnormalities worsening from baseline were reported. d “All grades” column represents patients having any worsened eGFR category of < 90 mL/min/1.73 m 2 and “Grade 3 or 4” column represents patients having any worsened eGFR category of < 30 mL/min/1.73 m 2 calculated using the CKD-EPI formula. Laboratory abnormalities PLUVICTO plus BSoC a BSoC b All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Hematology Decreased lymphocytes 85 47 51 18 Decreased hemoglobin 64 15 c 34 7 c Decreased platelets 45 9 20 2.5 Decreased neutrophils 28 4.7 9 0.5 Chemistry Decreased estimated glomerular filtration rate (eGFR) d 42 3.4 31 2.5 Decreased sodium 34 0.6 c 23 1 Decreased calcium 34 1.9 18 1.5 Increased aspartate aminotransferase (AST) 29 1.1 18 1 c Increased potassium 24 0.6 18 0.5 c Increased sodium 11 0 c 5 0 c

In the event of administration of a radiation overdosage with PLUVICTO, reduce the radiation absorbed dose to the patient by increasing the elimination of the radionuclide from the body by frequent micturition or by forced diuresis and frequent bladder voiding. Estimate the effective radiation dose that was applied and treat with additional supportive care measures as clinically indicated.