PLUVICTO

2 DOSAGE AND ADMINISTRATION Select patients for treatment using LOCAMETZ ® or another approved PSMA positron emission tomography (PET) product based on PSMA expression in tumors. ( 2.2 ) Recommended Dosage: Administer 7.4 GBq (200 mCi) every 6 weeks for 6 doses. ( 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 previously treated mCRPC 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 The recommended PLUVICTO dosage is 7.4 GBq (200 mCi) intravenously every 6 weeks for 6 doses, or until disease progression, or unacceptable toxicity. 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 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 v2.2 radiation dosimetry software, using measured time-activity data from patient imaging as input. * Estimated radiation absorbed dose for bone marrow is not included given the wide expected variability based on location and burden of bone metastases between patients [see Warnings and Precautions (5.2)] . 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 0.025 0.24 0.19 1.5 1.1 Brain 0.007 0.005 0.049 0.035 0.30 0.22 Esophagus 0.025 0.026 0.18 0.19 1.1 1.1 Eyes 0.022 0.024 0.16 0.18 0.99 1.1 Gallbladder wall 0.028 0.026 0.20 0.19 1.2 1.1 Heart wall 0.17 0.12 1.2 0.83 7.8 5.2 Kidneys 0.43 0.16 3.1 1.2 19 7.3 Lacrimal glands 2.1 0.47 15 3.4 92 21 Left colon 0.58 0.14 4.1 1.0 26 6.0 Liver 0.090 0.044 0.64 0.32 4.0 2.0 Lungs 0.11 0.11 0.76 0.81 4.7 4.9 Pancreas 0.027 0.026 0.19 0.19 1.2 1.1 Prostate 0.027 0.026 0.19 0.19 1.2 1.1 Rectum 0.56 0.14 4.0 1.1 25 6.2 Right colon 0.32 0.078 2.3 0.58 14 3.4 Salivary glands 0.63 0.36 4.5 2.6 28 16 Small intestine 0.071 0.031 0.50 0.23 3.1 1.4 Spleen 0.067 0.027 0.48 0.20 3.0 1.2 Stomach wall 0.025 0.026 0.18 0.19 1.1 1.1 Testes 0.023 0.025 0.16 0.18 1.0 1.1 Thymus 0.025 0.026 0.18 0.19 1.1 1.1 Thyroid 0.26 0.37 1.8 2.7 11 16 Total body 0.037 0.027 0.27 0.20 1.6 1.2 Urinary bladder wall 0.32 0.025 2.3 0.19 14 1.1

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1 INDICATIONS AND USAGE PLUVICTO is indicated for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibitor (ARPI) therapy, and are considered appropriate to delay taxane-based chemotherapy, or have received prior taxane-based chemotherapy.