▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the full leaflet for how to report adverse reactions. NAME OF THE MEDICINAL PRODUCT: Pluvicto 1 000 MBq/mL solution for injection/infusion. QUALITATIVE AND QUANTITATIVE COMPOSITION: One mL of solution contains 1 000 MBq of lutetium (177Lu) vipivotide tetraxetan at the date and time of calibration. The total amount of radioactivity per single-dose vial is 7 400 MBq ± 10% at the date and time of administration. Given the fixed volumetric activity of 1 000 MBq/mL at the date and time of calibration, the volume of the solution in the vial can range from 7.5 mL to 12.5 mL in order to provide the required amount of radioactivity at the date and time of administration. 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 photon radiation (γ) of 0.208 MeV (11%) and 0.113 MeV (6.4%). Excipient with known effect: Each mL of solution contains up to 0.312 mmol (7.1 mg) of sodium. Each vial contains up to 88.75 mg of sodium. For the full list of excipients, see section 6.1 of the full leaflet. PHARMACEUTICAL FORM: Solution for injection/infusion. Clear, colourless to slightly yellow solution, pH: 4.5 to 7.0. THERAPEUTIC INDICATIONS: Pluvicto in combination with androgen deprivation therapy (ADT) with or without androgen receptor (AR) pathway inhibition is indicated for the treatment of adult patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with AR pathway inhibition and taxane-based chemotherapy (see section 5.1 of the full leaflet). POSOLOGY AND METHOD OF ADMINISTRATION: Important safety instructions: Pluvicto should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings (see section 6.6 of the full SmPC) and after evaluation of the patient by a qualified physician. Radiopharmaceuticals, including Pluvicto, should be used by or under the control of healthcare professionals 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 authorised to license the use of radiopharmaceuticals. Patient identification: Patients should be identified for treatment by PSMA imaging. Posology: The recommended treatment regimen of Pluvicto is 7 400 MBq intravenously every 6 weeks (±1 week) for up to a total of 6 doses, unless there is disease progression or unacceptable toxicity. Medical castration with a gonadotropin-releasing hormone (GnRH) analogue should be continued during treatment in patients not surgically castrated. Treatment monitoring: Laboratory tests should be performed before and during treatment with Pluvicto. Dosing may need to be modified based on the test results (see Table 1 of the full leaflet). (1) Haematology (haemoglobin, white blood cell count, absolute neutrophil count, platelet count) (2) Kidney function (serum creatinine, calculated creatinine clearance [CLcr]) (3) Liver function (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood serum albumin, total blood bilirubin). Dose modifications for adverse reactions: Recommended dose modifications of Pluvicto for adverse reactions are provided in Table 1 (see full leaflet). Management of severe or intolerable adverse reactions may require temporary dose interruption (extending the dosing interval by 4 weeks from 6 weeks up to 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% once; the dose should not be re-escalated. If a patient has further adverse reactions that would require an additional dose reduction, treatment with Pluvicto must be discontinued. Special populations: Elderly: No dose adjustment is recommended in patients aged 65 years or older. Renal impairment: No dose adjustment is recommended for patients with mild to moderate renal impairment with baseline CLcr ≥50 mL/min by Cockcroft-Gault. Treatment with Pluvicto is not recommended in patients with moderate to severe renal impairment with baseline CLcr <50 mL/min or end-stage renal disease as the pharmacokinetic profile and safety of Pluvicto have not been studied in these patients (see sections 4.4 and 5.2 of the full leaflet). Hepatic impairment: No dose adjustment is recommended for patients with hepatic impairment. Pluvicto has not been studied in patients with moderate or severe hepatic impairment (see section 5.2 of the full leaflet). Paediatric population: There is no relevant use of Pluvicto in the paediatric population in the indication of treatment of PSMA-expressing prostate cancer. Method of administration: Pluvicto is a ready-to-use solution for injection/infusion for single use only. Administration instructions: The recommended dose 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 2 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 sterile sodium chloride 9 mg/mL (0.9%) solution for injection to ensure patency and to minimise the risk of extravasation. Cases of extravasation should be managed as per institutional guidelines. Patients should be advised to remain well hydrated and to urinate frequently before and after administration of Pluvicto (see section 4.4 of the full leaflet). For instructions on the method of preparation and intravenous methods of administration, see section 12 of the full leaflet. For patient preparation, see section 4.4 of the full leaflet. CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the full leaflet. UNDESIRABLE EFFECTS: Summary of the safety profile: Unless otherwise stated, the frequency of listed adverse reactions is based on data from the VISION study in which 529 patients received at least one dose of 7 400 MBq (median number of doses was five). The most common adverse reactions include: fatigue (43.1%), dry mouth (39.3%), nausea (35.3%), anaemia (31.8%), decreased appetite (21.2%) and constipation (20.2%). The most common grade 3 to 4 adverse reactions include: anaemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%) and fatigue (5.9%). Tabulated list of adverse reactions: see full leaflet. Description of selected adverse reactions: Myelosuppression: In the VISION study, myelosuppression occurred more frequently in patients who received Pluvicto plus BSoC compared to patients who received BSoC alone (all grades/grade ≥3): anaemia (31.8%/12.9%) versus (13.2%/4.9%); thrombocytopenia (17.2%/7.9%) versus (4.4%/1.0%); leukopenia (12.5%/2.5%) versus (2.0%/0.5%); lymphopenia (14.2%/7.8%) versus (3.9%/0.5%); neutropenia (8.5%/3.4%) versus (1.5%/0.5%); pancytopenia (1.5%/1.1%) versus (0%/0%) including two fatal events of pancytopenia in patients who received Pluvicto plus BSoC; and bicytopenia (0.2%/0.2%) versus (0%/0%). Myelosuppression adverse reactions that led to permanent discontinuation in ≥0.5% of patients who received Pluvicto plus BSoC included: anaemia (2.8%), thrombocytopenia (2.8%), leukopenia (1.3%), neutropenia (0.8%) and pancytopenia (0.6%). Myelosuppression adverse reactions that led to dose interruptions/dose reductions in ≥0.5% of patients who received Pluvicto plus BSoC included: anaemia (5.1%/1.3%), thrombocytopenia (3.6%/1.9%), leukopenia (1.5%/0.6%) and neutropenia (0.8%/0.6%). Renal toxicity: In the VISION study, renal toxicity occurred more frequently in patients who received Pluvicto plus BSoC compared to patients who received BSoC alone (all grades/grades 3 to 4): blood creatinine increased (5.3%/0.2%) versus (2.4%/0.5%); acute kidney injury (3.6%/3.0%) versus (3.9%/2.4%); renal failure (0.2%/0%) versus (0%/0%); and blood urea increased (0.2%/0%) versus (0%/0%). Renal adverse reactions that led to permanent discontinuation in ≥0.2% of patients who received Pluvicto plus BSoC included: blood creatinine increased (0.2%). Renal adverse reactions that led to dose interruptions/dose reductions in ≥0.2% of patients who received Pluvicto plus BSoC included: blood creatinine increased (0.2%/0.4%) and acute kidney injury (0.2%/0%). Second primary malignancies: Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiation are less than from the disease itself. As Pluvicto contributes to a patient’s overall long-term radiation exposure, which is associated with an increased risk for cancer (see section 4.4 of the full leaflet), a potential risk of second primary malignancies cannot be ruled out for radiopharmaceuticals such as Pluvicto. At the time of the VISION primary analysis (cut-off date 27-Jan-2021), cases of squamous cell carcinoma (4 patients; 0.8%) and basal cell carcinoma, malignant melanoma and squamous cell carcinoma of the skin (1 patient each; 0.2% each) were reported in patients who received Pluvicto plus BSoC. Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. MARKETING AUTHORISATION HOLDER: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. MARKETING AUTHORISATION NUMBER(S): EU/1/22/1703/001 MODE OF DELIVERY. Medicinal product subject to medical prescription. DATE OF REVISION OF THE TEXT. 18.10.2023. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu