PLUVICTO

6) 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.

4). Waterproof gloves and effective radiation shielding should be used when handling Pluvicto. Patient identification Patients should be identified for treatment by PSMA imaging. Posology The recommended Pluvicto dose is 7,400 MBq intravenously every 6 weeks (±1 week) for a total of 6 doses.

Treatment monitoring Laboratory tests should be performed before and during treatment with Pluvicto. • Haematology (haemoglobin, white blood cell count, absolute neutrophil count, platelet count) • Kidney function (serum creatinine, calculated creatinine clearance [CLcr]) • Liver function (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood serum albumin, total blood bilirubin) Dose modifications for adverse drug reactions (ADRs) Recommended dose modifications of Pluvicto for ADRs are provided in Table 1.

Management of severe or intolerable ADRs may require temporary dose interruption, dose reduction or permanent discontinuation of treatment with Pluvicto. If a treatment delay due to an adverse drug reaction persists for > 4 weeks, treatment with Pluvicto must be discontinued.

The dose of Pluvicto may be reduced by 20% to 5 900 MBq once; the dose should not be re-escalated. If a patient has further adverse drug reactions that would require an additional dose reduction, treatment with Pluvicto must be discontinued.

Table 1 Recommended dose modifications of Pluvicto for ADRs ADR Severitya Dose modification Dry mouth Grade ≥3 Reduce Pluvicto dose by 20% to 5 900 MBq. Gastrointestinal toxicity Grade ≥3 (not amenable to medical intervention) Withhold Pluvicto until improvement to grade 2 or baseline.

Reduce Pluvicto dose by 20% to 5 900 MBq. Grade 2 Withhold Pluvicto until improvement to grade 1 or baseline. Manage as deemed appropriate. The use of growth factors is permitted but should be discontinued once improved to grade 1 or baseline.

Checking haematinic levels (iron, B12 and folate) and providing supplementation is advocated. Transfusions may be given as clinically indicated. Myelosuppresion (anaemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia) Grade ≥3 Withhold Pluvicto until improvement to Grade 1 or baseline.

Reduce Pluvicto dose by 20% to 5 900 MBq. Renal toxicity Defined as: • Confirmed serum creatinine increase (grade ≥2) • Confirmed CLcr < 30 mL/min; calculate using Cockcroft-Gault with actual body weight Withhold Pluvicto until improvement.

Defined as: • Confirmed ≥40% increase from baseline serum creatinine and • Confirmed >40% decrease from baseline CLcr; calculate using Cockcroft-Gault with actual body weight Withhold Pluvicto until improvement or return to baseline.

Reduce Pluvicto dose by 20% to 5 900 MBq. Recurrent renal toxicity (grade ≥3) Permanently discontinue Pluvicto. Spinal cord compression Any Withhold Pluvicto until the compression has been adequately treated and any neurological sequela have stabilised and ECOG performance status has stabilised.

Fracture in weight-bearing bones Any Withhold Pluvicto until the fracture has been adequately stabilised/treated and ECOG performance status has stabilised. AST or ALT elevation AST or ALT >20 times ULN in the absence of liver metastases Permanently discontinue Pluvicto.

Abbreviations:

CLcr, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal. Grading according to most current Common Terminology Criteria for Adverse Events (CTCAE).

a The same thresholds are also applicable to baseline values at the time of treatment initiation with Pluvicto. 2). Renal impairment 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.

2). Hepatic impairment No dose adjustment is recommended for patients with hepatic impairment. 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 for intravenous use. It is a ready to use radiopharmaceutical medicinal product for single use only. Preparation instructions • Aseptic technique and radiation shielding should be used when handling or administering Pluvicto, using tongs as needed to minimise radiation exposure.

• The product should be visually inspected under a shielded screen for particulate matter and discoloration prior to administration. The vial should be discarded if particulates or discoloration are present. • The Pluvicto solution should not be injected directly into any other intravenous solution.

• The amount of radioactivity delivered to the patient should be confirmed with an appropriately calibrated dose calibrator prior to and after each Pluvicto administration. Administration instructions The recommended dose of Pluvicto may be administered intravenously as an injection using the syringe method, as […]

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.

PSMAfore Study:

Summary of the safety profile The safety of Pluvicto was evaluated in the Phase III PSMAfore study in patients with progressive, PSMA-positive mCRPC previously treated with ARPI therapy. Of the 468 patients randomised, 459 patients received at least one dose of randomised treatment.

Patients received either Pluvicto 7,400 MBq administered every 6 weeks (N = 227) or a change in ARPI (N = 232). 4% of patients who received all 6 doses of Pluvicto. The median cumulative dose of Pluvicto was 42,400 MBq (range: 7,000 to 45,400).

2) for patients who received a change in ARPI. The data analyses presented below do not include patients who crossed over to receive Pluvicto after receiving treatment in the change in ARPI arm. Table 2 summarises the incidence of adverse drug reactions.

6%). 2%). Tabulated list of ADRs ADRs (Table 2) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

4) Abbreviation: ARPI, androgen receptor pathway inhibitor. *Patients in the Pluvicto arm do not include patients who crossed over to receive Pluvicto after receiving treatment in the change in ARPI arm. 0. bOnly includes Grades 3 to 4 adverse drug reactions, no grade 5 adverse drug reactions recorded during treatment phase.

cUrinary tract infection includes urinary tract infection, cystitis, and urinary tract infection enterococcal. dOral fungal infection includes candida infection, oral candidiasis, oral fungal infection, and oropharyngeal candidiasis.

eLeukopenia includes neutropenia and leukopenia. fDysgeusia includes dysgeusia and taste disorder. gDry eye includes dry eye and xerophthalmia. hDry mouth includes dry mouth, mucosal dryness, salivary hyposecretion, dry throat, and lip dry.

iAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, and epigastric discomfort. jOesophageal disorder includes gastrooesophageal reflux disease, dysphagia, oesophagitis, and burn oesophageal.

kDry skin includes xerosis and dry skin. lAcute kidney injury includes blood creatinine increased, acute kidney injury, renal failure, and blood urea increased. mFatigue includes asthenia and fatigue. 4%/0%). One fatal case of bone marrow failure occurred during the long term follow-up period in a patient treated with Pluvicto.

3%). 4%). Renal toxicity In the PSMAfore study, renal toxicity […]

Individual benefit/risk justification For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required therapeutic effect.

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. Radiation exposure to patients, medical personnel, and others should be minimised during and after treatment with Pluvicto consistent with institutional good radiation safety practices, patient management procedures, and instructions to the patient for follow-up radiation protection at home.

g. for radionuclide therapy. After the procedure Before the patient is released, the nuclear medicine physician or healthcare provider should explain the necessary radioprotection precautions that the patient should follow to minimise radiation exposure to others.

Following administration of Pluvicto, patients should be advised to: • limit close contact (less than 1 meter) 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.

8). Haematology laboratory tests, including haemoglobin, white blood cell count, absolute neutrophil count and platelet count, should be performed before and during treatment with Pluvicto. 2). 8). Patients should be advised to remain well hydrated and to urinate frequently before and after administration of Pluvicto.

Kidney function laboratory tests, including serum creatinine and calculated CLcr, should be performed before and during treatment with Pluvicto. 2). Renal/Hepatic impairment Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible.

2). Patients with mild or moderate renal impairment may be at greater risk of toxicity. 2). The pharmacokinetic profile and safety of lutetium (177Lu) vipivotide tetraxetan have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease.

4% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 6.

1.