Posology : מינונים

4          DOSAGE AND ADMINISTRATION
4.1        Important Safety Instructions
PLUVICTO is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (7.1)]. 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.
4.2        Patient Selection
Patients should be identified for treatment by PSMA imaging.
4.3        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.
4.4        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.
Table 1: Recommended Dosage Modifications of PLUVICTO for Adverse Reactions Adverse reaction                          Severity                           Dosage modification Myelosuppression                       Grade 2                            Withhold PLUVICTO until improvement to (Anemia, thrombocytopenia,                                                Grade 1 or baseline.
leukopenia, or neutropenia)            Grade ≥ 3                          Withhold PLUVICTO until improvement to [see Warnings and Precautions (7.2)]                                      Grade 1 or baseline.
Reduce PLUVICTO dose by 20% to 5.9 GBq
(160 mCi).



PLU API APR23 V1.0                                                            USPI October 2022 Adverse reaction                               Severity                             Dosage modification Recurrent Grade ≥ 3 myelosuppression      Permanently discontinue PLUVICTO.
after one dose reduction



Renal toxicity                           Defined as:                               Withhold PLUVICTO until improvement.
[see Warnings and Precautions (7.3)]     •     Confirmed serum creatinine increase (Grade ≥ 2)
•     Confirmed CLcr < 30 mL/min;
calculate using Cockcroft-Gault with actual body weight
Defined as:                               Withhold PLUVICTO until improvement or •     Confirmed ≥ 40% increase from       return to baseline.
baseline serum creatinine           Reduce PLUVICTO dose by 20% to 5.9 GBq and                                       (160 mCi).
•   Confirmed > 40% decrease from baseline CLcr; calculate using
Cockcroft-Gault with actual body weight
Grade ≥ 3 renal toxicity                  Permanently discontinue PLUVICTO.
Recurrent renal toxicity after one dose   Permanently discontinue PLUVICTO.
reduction
Dry mouth                                Grade 2                                   Withhold PLUVICTO until improvement or [see Adverse Reactions (8.1)]                                                      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     Permanently discontinue PLUVICTO.
dose reduction
Gastrointestinal toxicity                Grade ≥ 3 (not amenable to medical        Withhold PLUVICTO until improvement to [see Adverse Reactions (8.1)]            intervention)                             Grade 2 or baseline.
Reduce PLUVICTO dose by 20% to 5.9 GBq
(160 mCi).
Recurrent Grade ≥ 3 gastrointestinal      Permanently discontinue PLUVICTO.
toxicity after one dose reduction

Fatigue                                  Grade ≥ 3                                 Withhold PLUVICTO until improvement to [see Adverse Reactions (8.1)]                                                      Grade 2 or baseline.
Electrolyte or metabolic abnormalities   Grade ≥ 2                                 Withhold PLUVICTO until improvement to [see Adverse Reactions (8.1)]                                                      Grade 1 or baseline.
AST or ALT elevation                     AST or ALT > 5 times ULN in the           Permanently discontinue PLUVICTO.
[see Adverse Reactions (8.1)]            absence of liver metastases

Any unacceptable toxicity                 Permanently discontinue PLUVICTO.

PLU API APR23 V1.0                                                                  USPI October 2022 Adverse reaction                                Severity                                 Dosage modification Other non-hematologic toxicity            Any serious adverse reaction that             Permanently discontinue PLUVICTO.
[see Adverse Reactions (8.1)]             requires treatment delay of > 4 weeks Any recurrent Grade 3 or 4 or persistent      Permanently discontinue PLUVICTO.
and intolerable Grade 2 adverse reaction after one dose reduction
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).

4.5        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 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.


PLU API APR23 V1.0                                                                           USPI October 2022 •     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.
4.6       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.



PLU API APR23 V1.0                                                                 USPI October 2022 Table 2: Estimated Radiation Absorbed Dose for PLUVICTO in VISION
Absorbed dose per unit       Calculated absorbed dose for         Calculated absorbed dose for 6 x 7.4 GBq activity                7.4 GBq administration                 (44.4 GBq cumulative activity) (Gy/GBq)                           (Gy)                                     (Gy) N = 29
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 *Estimated radiation absorbed dose for bone marrow is not included [see Warnings and Precautions (7.2)].

5          DOSAGE FORMS AND STRENGTHS
Injection: 1,000 MBq/mL (27 mCi/mL) of lutetium Lu 177 vipivotide tetraxetan as a clear and colorless to slightly yellow solution in a single-dose vial.