Vipivotide Tetraxetan for Prostate Cancer

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. PLUVICTO is a radioligand therapeutic agent 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. ( 1 )

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 < 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. Instr

WARNINGS AND PRECAUTIONS 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 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. 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 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)] .

ADVERSE REACTIONS 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 platelets, decreased estimated glomerular filtration rate, nausea, decreased neutrophils, decreased calcium, decreased sodium, increased aspartate aminotransferase, increased alkaline phosphatase, arthralgia, decreased appetite, increased potassium, constipation, and back pain. ( 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 PSMAfore and VISION studies (N = 756), the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased lymphocytes (83%), decreased hemoglobin (65%), fatigue (49%), dry mouth (46%), decreased platelets (40%), decreased estimated glomerular filtration rate (37%), nausea (35%), decreased neutrophils (31%), decreased calcium (29%), decreased sodium (27%), increased aspartate aminotransferase (26%), increased alkaline phosphatase (24%), arthralgia (22%), decreased appetite (21%), increased potassium (21%), constipation (21%), and back pain (21%). PSMAfore The safety of PLUVICTO was evaluated in the PSMAfore study in patients with progressive, PSMA-positive mCRPC previously treated with ARPI therapy, for whom it was considered appropriate to delay taxane-based chemotherapy by the investigator [see Clinical Studies (14.1)] . 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 who received PLUVICTO 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. Adverse reactions leading to permanent discontinuation of PLUVICTO in ≥ 1% of patients who received PLUVICTO were thrombocytopenia (1.8%) and dry mouth (1.3%). Adverse reactions leading to a dose interruption of PLUVICTO occurred in 12% of patients. The most frequent (≥ 1%) adverse reactions leading to a dose interruption of PLUVICTO in patients who received 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. The most frequent (≥ 0.5%) adverse reaction leading to a dose reduction of PLUVICTO in patients who received PLUVICTO was dry mouth (0.9%). Table 3 and Table 4 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in PSMAfore. Table 3: Adverse Reactions (≥ 10%) in Patients With PSMA-Positive mCRPC Who Received PLUVICTO 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 dysgeusia, abdominal pain, peripheral edema, headache, acute kidney injury, weight decreased, urinary tract infection, dry eye, dizziness, dry skin, oral fungal infection, gastroesophageal reflux disease, pyrexia, vertigo, stomatitis, dysphagia, esophagitis, pancytopenia, and bone marrow failure. Table 4: Select Laboratory Abnormalities (≥ 10%) That Worsened From Baseline in Patients With PSMA-Positive mCRPC 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. 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 Increased alkaline phosphatase 31 8 50 10 c Decreased estimated glomerular filtration rate (eGFR) 23 0.9 c 22 3.5 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 mCRPC 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 who received PLUVICTO plus BSoC 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. Adverse reactions leading to permanent discontinuation of PLUVICTO in ≥ 1% of patients who received PLUVICTO plus BSoC 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. The most frequent (≥ 3%) adverse reactions leading to a dose interruption of PLUVICTO in patients who received PLUVICTO plus BSoC were anemia (5%) and thrombocytopenia (3.6%). Adverse reactions leading to a dose reduction of PLUVICTO occurred in 6% of patients. The most frequent (≥ 1%) adverse reactions leading to a dose reduction of PLUVICTO