Lutetium Lu 177 Vipivotide Tetraxetan

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.

Injection: 1,000 MBq/mL (27 mCi/mL) of lutetium Lu 177 vipivotide tetraxetan at calibration time as a clear and colorless to slightly yellow solution in a single-dose vial containing 7.4 GBq (200 mCi) ± 10% at administration time. Injection: 1,000 MBq/mL (27 mCi/mL) at calibration time in a single-dose vial containing 7.4 GBq (200 mCi) ± 10% at administration time. ( 3 )

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)] .

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. […]

8.1 Pregnancy 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.

8.2 Lactation Risk Summary The safety and efficacy of PLUVICTO have not been established in females. There are no data on the presence of lutetium Lu 177 vipivotide tetraxetan in human milk or its effects on the breastfed child or on milk production.

8.3 Females and Males of Reproductive Potential Contraception Males 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 Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)] . Infertility 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.

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

8.5 Geriatric Use 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.

8.6 Renal Impairment Exposure of lutetium Lu 177 vipivotide tetraxetan is expected to increase with the degree of renal impairment [see Clinical Pharmacology (12.3)] . No dose adjustment is recommended for patients with mild (baseline CLcr 60 to 89 mL/min by Cockcroft-Gault) to moderate (CLcr 30 to 59 mL/min) renal impairment; however, patients with mild to moderate renal impairment may be at greater risk of toxicity. Frequently monitor renal function and adverse reactions in patients with mild to moderate renal impairment [see Dosage and Administration (2.4)] . The pharmacokinetics and safety of PLUVICTO have not been studied in patients with severe (CLcr 15 to 29 mL/min) renal impairment or end-stage renal disease.

Lutetium Lu 177 vipivotide tetraxetan is a radioligand therapeutic agent. The active moiety of lutetium Lu 177 vipivotide tetraxetan is the radionuclide lutetium-177 which is linked to a moiety that binds to PSMA, a transmembrane protein that is expressed in prostate cancer. Upon binding of lutetium Lu 177 vipivotide tetraxetan to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing cells, as well as to surrounding cells, and induces DNA damage which can lead to cell death.