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-11 imaging agent based on PSMA expression in tumors. Additional selection criteria were used in the VISION study [see Clinical Studies (14)].

Refer to the prescribing information for the PSMA imaging agent.

2.3 Recommended Dosage

The recommended PLUVICTO dosage is 7.4 GBq (200 mCi) intravenously every 6 weeks for up to 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 (extending the dosing interval from every 6 weeks up to every 10 weeks), dose reduction or permanent discontinuation of treatment with PLUVICTO. If a treatment delay due to an adverse reaction persists for > 4 weeks, treatment with PLUVICTO must be discontinued. 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.

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 vial visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates or discoloration are present.
• Do not inject the PLUVICTO solution directly into any other intravenous solution.
• Confirm the amount of radioactivity delivered to the patient with an appropriately calibrated dose calibrator prior to and after PLUVICTO administration.
• Dispose of any unused medicinal product or waste material in accordance with local and federal laws.

Administration Instructions

The recommended dosage of PLUVICTO may be administered intravenously as an injection using a disposable syringe fitted with a syringe shield (with or without a syringe pump), as an infusion using the gravity method (with or without an infusion pump), or as an infusion using the vial (with a peristaltic infusion pump).

A reduced dose of PLUVICTO should be administered using the syringe method (with or without a syringe pump) or the vial method (with a peristaltic infusion pump). Using the gravity method to administer a reduced dose of PLUVICTO is not recommended since it may result in delivery of the incorrect volume of PLUVICTO, if the dose is not adjusted prior to administration.

Prior to administration, flush the intravenous catheter used exclusively for PLUVICTO administration with ≥ 10 mL of 0.9% sterile sodium chloride solution to ensure patency and to minimize the risk of extravasation. Manage cases of extravasation as per institutional guidelines.

Instructions for the Syringe Method (With or Without a Syringe Pump)

• After disinfecting the vial stopper, 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.
• 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 pre-filled with 0.9% sterile sodium chloride solution and that is used exclusively for PLUVICTO administration to the patient.
• Once the desired PLUVICTO radioactivity has been administered, perform an intravenous flush of ≥ 10 mL of 0.9% sterile sodium chloride solution through the intravenous catheter to the patient.

Instructions for the Gravity Method (With or Without an Infusion Pump)

• Insert a 2.5 cm, 20 gauge needle (short needle) into the PLUVICTO vial and connect via a catheter to 500 mL 0.9% sterile sodium chloride solution (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 sodium chloride solution to flow into the PLUVICTO vial prior to the initiation of the PLUVICTO infusion and do not inject the PLUVICTO solution directly into the sodium chloride solution.
• 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 pre-filled with 0.9% sterile sodium chloride solution 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 sodium chloride solution via the short needle into the PLUVICTO vial (the sodium chloride solution 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 saline 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% sterile sodium chloride solution through the intravenous catheter to the patient.

Instructions for the Vial Method (With a Peristaltic Infusion Pump)

• Insert a 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 infusion 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% sterile sodium chloride solution 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 infusion pump following the pump manufacturer’s instructions.
• Pre-fill 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.
• Pre-fill the intravenous catheter which will be connected to the patient by opening the 3-way stopcock valve to the 0.9% sterile sodium chloride solution and pumping the 0.9% sterile sodium chloride solution until it exits the end of the catheter tubing.
• Connect the pre-filled intravenous catheter to the patient and set the 3-way stopcock valve such that the PLUVICTO solution is in line with the peristaltic infusion 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 infusion pump and then change the position of the 3-way stopcock valve so that the peristaltic infusion pump is in line with the 0.9% sterile sodium chloride solution. Restart the peristaltic infusion pump and infuse an intravenous flush of ≥ 10 mL of 0.9% sterile sodium chloride solution 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 adult patients 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.

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 household contacts 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, the healthcare provider should explain the necessary radioprotection precautions that the patient should follow to minimize radiation exposure to others [see Patient Counseling Information (17)]. Following administration of PLUVICTO, advise patients to limit close contact (less than 3 feet) with household contacts for 2 days or with children and pregnant women for 7 days. Following administration of PLUVICTO, advise patients to refrain from sexual activity for 7 days. Following administration of PLUVICTO, advise patients to sleep in a separate bedroom from household contacts 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 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) in patients treated with PLUVICTO. Two deaths (0.4%) due to intracranial hemorrhage and subdural hematoma in association with thrombocytopenia were observed in patients who received PLUVICTO. One death due to sepsis and concurrent neutropenia was observed in patients who received PLUVICTO.

Perform complete blood counts before and during treatment with PLUVICTO. Withhold, reduce dose, or permanently discontinue PLUVICTO and clinically treat patients based on the severity of myelosuppression [see Dosage and Administration (2.4)].

5.3 Renal Toxicity

PLUVICTO can cause severe renal toxicity. In the VISION study, Grade 3 or 4 acute kidney injury (3%) and increased creatinine (0.9%) 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 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, all radiopharmaceuticals, including PLUVICTO, have the potential to cause fetal harm. 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 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)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of PLUVICTO was evaluated in the VISION study in patients with progressive, PSMA-positive mCRPC [see Clinical Studies (14)]. Of the 831 patients randomized, 734 patients received at least one dose of randomized treatment. Patients received at least one dose of either PLUVICTO 7.4 GBq (200 mCi) administered every 6 to 10 weeks plus BSoC (N = 529) or BSoC alone (N = 205). The median duration of exposure to randomized treatment was 7.8 months (range, 0.3 to 24.9) for patients who received PLUVICTO plus BSoC. Among patients who received PLUVICTO plus BSoC, the median number of doses of PLUVICTO received was 5 (range, 1 to 6). The median cumulative dose of PLUVICTO was 37.5 GBq (range, 7.0 to 48.3). The median duration of follow-up was 14.8 months for patients receiving PLUVICTO plus BSoC.

Serious adverse reactions occurred in 36% of patients who received PLUVICTO plus BSoC. Serious adverse reactions in > 1% of patients who received PLUVICTO plus BSoC included hemorrhage (4%), musculoskeletal pain (3.8%), sepsis (3.2%), anemia (2.8%), urinary tract infection (2.6%), acute kidney injury (1.7%), pneumonia (1.7%), pancytopenia (1.3%), pyrexia (1.3%), spinal cord compression (1.1%), and pulmonary embolism (1.1%).

Fatal adverse reactions occurred in 2.8% 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 in patients who received PLUVICTO plus BSoC were thrombocytopenia (1.9%) and anemia (1.3%).

The most common adverse reactions (≥ 20%) occurring at a higher incidence in patients who received PLUVICTO plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.

The most common laboratory abnormalities that worsened from baseline in ≥ 30% of patients who received PLUVICTO plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

Table 3 and Table 4 summarize the incidence of adverse reactions and laboratory abnormalities, respectively.

Clinically relevant adverse reactions in < 5% of patients who received PLUVICTO plus BSoC included dry eye, vertigo, and pancytopenia (including bicytopenia).

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 radiopharmaceuticals, including PLUVICTO, have the potential to 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

Based on its mechanism of action, 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 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 529 patients who received at least one dose of PLUVICTO plus BSoC in the VISION study, 387 patients (73%) were 65 years or older and 143 patients (27%) were 75 years or older. No overall differences in effectiveness were observed between patients ≥ 75 years of age and younger patients. Serious adverse reactions occurred in 11% of patients ≥ 75 years of age and in 11% of younger patients. Grade ≥ 3 adverse reactions occurred in 40% of patients ≥ 75 years of age and in 31% 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 or 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.

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 0.498 MeV (79%) and photonic radiation (γ) of 0.208 MeV (11%) and 0.113 MeV (6.4%).

The main radiations of lutetium-177 are detailed in Table 5.

11.2 External Radiation

Table 6 summarizes the radioactive decay properties of lutetium-177.

12.1 Mechanism of Action

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, including mCRPC. 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.

12.2 Pharmacodynamics

Lutetium Lu 177 vipivotide tetraxetan exposure-efficacy relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

At the recommended dosage, PLUVICTO does not cause large mean increases (> 20 ms) in the QTc interval.

12.3 Pharmacokinetics

Pharmacokinetics of lutetium Lu 177 vipivotide tetraxetan are expressed as geometric mean (geometric mean coefficient of variation) unless otherwise specified.

The blood lutetium Lu 177 vipivotide tetraxetan area under the curve (AUC) is 52.3 ng.h/mL (31.4%) and the maximum blood concentration is 6.58 ng/mL (43.5%) at the recommended dosage.

Distribution

Lutetium Lu 177 vipivotide tetraxetan volume of distribution is 123 L (78.1%).

Within 2.5 hours of administration, lutetium Lu 177 vipivotide tetraxetan distributes to gastrointestinal tract, liver, lungs, kidneys, heart wall, bone marrow, and salivary glands.

Vipivotide tetraxetan and non-radioactive lutetium vipivotide tetraxetan are 60% to 70% bound to human plasma proteins.

Elimination

The lutetium Lu 177 vipivotide tetraxetan terminal elimination half-life is 41.6 hours (68.8%) and the clearance (CL) is 2.04 L/h (31.5%).

Excretion

Lutetium Lu 177 vipivotide tetraxetan is primarily eliminated renally.

Specific Populations

Exposure (AUC) of lutetium Lu 177 vipivotide tetraxetan increased with decreasing creatinine clearance (CLcr). The effect of baseline CLcr < 54 mL/min on lutetium Lu 177 vipivotide tetraxetan pharmacokinetics has not been studied.

Drug Interaction Studies

In Vitro Studies

CYP450 enzymes: Vipivotide tetraxetan is not a substrate of cytochrome P450 (CYP450) enzymes. Vipivotide tetraxetan did not induce CYP1A2, 2B6 or 3A4; and did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A in vitro.

Transporters: Vipivotide tetraxetan is not a substrate of BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3 or OCT2. Vipivotide tetraxetan did not inhibit BCRP, P-gp, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2 in vitro.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenicity and carcinogenicity 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.