Pluvicto Drug Information

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.

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.

Important Safety Instructions PLUVICTO is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure. 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.

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.

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. Patients receiving PLUVICTO for metastatic prostate cancer should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

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.

Adverse reaction Severity Dosage modification Myelosuppression (Anemia, thrombocytopenia, leukopenia, or neutropenia) 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).

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. 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.

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

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. 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. Patients could have been treated with ARPI in the metastatic setting for up to 45 days prior to consent.

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. 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 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 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.

The median cumulative administered activity of PLUVICTO was 42.4 GBq (range, 7.0 to 45.4). 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). The most frequent (≥ 1%) adverse reactions leading to permanent discontinuation of PLUVICTO were thrombocytopenia (1.8%) and dry mouth (1.3%).

The most frequent (≥ 1%) adverse reactions leading to a dose interruption of PLUVICTO were COVID-19 (3.1%) and anemia (1.8%). 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 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.

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. Fatal adverse reactions occurred in 3% of patients who received PLUVICTO plus BSoC, including sepsis ( %). PLUVICTO was permanently discontinued due to adverse reactions in 12% of patients who received PLUVICTO plus BSoC.

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 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

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. 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.

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

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.