Pluvicto is indicated for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy or who are not medically suitable for taxanes.

Important safety instructions

Pluvicto should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings (see section 6.6) 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.

Pluvicto is a radiopharmaceutical and should be handled with appropriate safety measures to minimise radiation exposure (see section 4.4). 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 (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 drug 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 drug reactions that would require an additional dose reduction, treatment with Pluvicto must be discontinued.

Table 1 Recommended dose modifications of Pluvicto for ADRs

Special populations

Elderly

No dose adjustment is recommended in patients aged 65 years or older (see section 5.2).

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. The pharmacokinetic profile 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 (see sections 4.4 and 5.2).

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 vial 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 Pluvicto administration.

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 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 minimise the risk of extravasation. Cases of extravasation should be managed as per institutional guidelines.

Intravenous methods of administration

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.

For patient preparation, see section 4.4.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 household contacts 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.

Patient preparation

Patients should be encouraged to increase oral fluids and urged to void as often as possible to reduce bladder radiation, especially after high activities, e.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 in their household for 2 days or with children and pregnant women for 7 days.

• refrain from sexual activity for 7 days.

• sleep in a separate bedroom from others in their household for 3 days, from children for 7 days, or from pregnant women for 15 days.

Myelosuppression

In the VISION study, myelosuppression occurred more frequently in patients who received Pluvicto plus best standard of care (BSoC) compared to patients who received BSoC alone (see section 4.8).

Haematology laboratory tests, including haemoglobin, white blood cell count, absolute neutrophil count and platelet count, should be performed before and during treatment with Pluvicto. Pluvicto should be withheld, dose reduced, or permanently discontinued and patients should be clinically managed as deemed appropriate based on the severity of myelosuppression (see section 4.2).

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 (see section 4.8).

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. Pluvicto should be withheld, dose reduced, or permanently discontinued based on the severity of renal toxicity (see section 4.2).

Renal/Hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible.

Exposure (AUC) of lutetium (¹⁷⁷Lu) vipivotide tetraxetan is expected to increase with the degree of renal impairement (see section 5.2). Patients with mild or moderate renal impairment may be at greater risk of toxicity. Renal function and adverse drug reactions should be frequently monitored in patients with mild to moderate renal impairment (see section 4.2). 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.

Specific warnings

Sodium content

This medicinal product contains up to 3.9 mmol (88.75 mg) sodium per dose, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Precautions with respect to environmental hazard see section 6.6.

No clinical drug interaction studies were required.

Contraception in males

Based on its mechanism of action, male patients should be advised not to father a child and to use condoms for intercourse during treatment with Pluvicto and for 14 weeks after the last dose.

Pregnancy

The safety and efficacy of Pluvicto have not been established in females as Pluvicto is not indicated for use in females. No animal studies using lutetium (¹⁷⁷Lu) vipivotide tetraxetan have been conducted to evaluate its effect on female reproduction and embryo-foetal development; however, all radiopharmaceuticals, including Pluvicto, have the potential to cause foetal harm. Based on its mechanism of action, Pluvicto can cause foetal harm when administered to a pregnant woman (see section 5.1).

Breast-feeding

The safety and efficacy of Pluvicto have not been established in females as Pluvicto is not indicated for use in females. There are no data on the presence of lutetium (¹⁷⁷Lu) vipivotide tetraxetan in human milk or its effects on the breast-fed newborn/infant or on milk production.

Fertility

No studies were conducted to determine the effects of lutetium (¹⁷⁷Lu) vipivotide tetraxetan on fertility. The recommended cumulative dose of 44,400 MBq of Pluvicto results in a radiation absorbed dose to the testes within the range where Pluvicto may cause infertility.

Pluvicto has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

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.

The safety of Pluvicto was evaluated in the phase III VISION study in patients with progressive, PSMA-positive mCRPC. Of the 831 patients randomised, 734 patients received at least one dose of randomised treatment. Patients received at least one dose of either Pluvicto 7,400 MBq administered every 6 to 10 weeks plus BSoC (n=529) or BSoC alone (n=205).

Among patients who received Pluvicto plus BSoC, the median number of doses of Pluvicto received was 5 (range: 1 to 6), with 67.7% of patients who received at least 4 doses of Pluvicto and 46.5% of patients who received a total of 6 doses of Pluvicto. The median cumulative dose of Pluvicto was 37,500 MBq (range: 7,000 to 48,300). The median duration of exposure to randomised treatment was 7.8 months (range: 0.3 to 24.9) for patients who received Pluvicto plus BSoC and 2.1 months (range: 0.0 to 26.0) for patients who received BSoC alone.

Table 2 summarises the incidence of ADRs. The most common ADRs (≥ 20%) occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone 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 ADRs (≥ 5%) occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone include: anaemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%) and fatigue (5.9%).

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).

Table 2 ADRs occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone in VISION^a

Description of selected ADRs

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 ADRs 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 ADRs 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 ADRs that led to permanent discontinuation in ≥ 0.2% of patients who received Pluvicto plus BSoC included: blood creatinine increased (0.2%). Renal ADRs 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%).

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the event of administration of a radiation overdose with Pluvicto, the radiation absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by frequent micturition or by forced diuresis and frequent bladder voiding. It might be helpful to estimate the effective radiation dose that was applied.

Pharmacotherapeutic group: Other therapeutic radiopharmaceuticals, ATC code: V10XX05

Mechanism of action

The active moiety of Pluvicto is the radionuclide lutetium-177 which is linked to a targeting moiety that binds with high affinity to PSMA, a transmembrane protein that is highly expressed in prostate cancer, including mCRPC. Upon the binding of Pluvicto to PSMA-expressing cancer cells, the beta-minus emission from lutetium-177 delivers therapeutic radiation to the targeted cell, as well as to surrounding cells, and induces DNA damage which can lead to cell death.

Pharmacodynamic effects

There are no data regarding lutetium (¹⁷⁷Lu) vipivotide tetraxetan exposure-efficacy relationships and the time course of pharmacodynamic response.

There are limited data regarding lutetium (¹⁷⁷Lu) vipivotide tetraxetan exposure-safety relationships and the time course of pharmacodynamic response.

Unlabelled vipivotide tetraxetan does not have any pharmacodynamic activity.

Clinical efficacy and safety

The efficacy of Pluvicto in patients with progressive, PSMA-positive mCRPC was established in VISION, a randomised, multicentre, open-label phase III study. Eight hundred and thirty-one (N=831) adult patients were randomised (2:1) to receive either Pluvicto 7,400 MBq every 6 weeks for up to a total of 6 doses plus best standard of care (BSoC) (N=551) or BSoC alone (N=280).

Eligible patients were required to have PSMA-positive mCRPC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, at least one metastatic lesion present on computed tomography (CT), magnetic resonance imaging (MRI) or bone scan imaging, and adequate renal, hepatic and haematological function. Eligible patients were also required to have received at least one AR pathway inhibitor, such as abiraterone acetate or enzalutamide, and 1 or 2 prior taxane-based chemotherapy regimens (with a regimen defined as a minimum exposure of 2 cycles of a taxane). Patients with unstable symptomatic central nervous system metastases or symptomatic or clinically/radiologically impending spinal cord compression were not eligible for the study. Patients underwent a gallium (⁶⁸Ga) gozetotide positron emission tomography (PET) scan to evaluate PSMA expression in lesions defined by central read criteria. Eligible patients were required to have at least one PSMA-positive lesion identified by this scan, and no CT/MRI measurable lesions that showed poor or no gallium (⁶⁸Ga) gozetotide uptake on the PET scan.

BSoC administered at the physician's discretion included: supportive measures including pain medications, hydration, blood transfusions, etc.; ketoconazole; radiation therapy (including seeded form or any external beam radiotherapy [including stereotactic body radiotherapy and palliative external beam]) to localised prostate cancer targets; bone-targeted agents including zoledronic acid, denosumab and any bisphosphonates; androgen-reducing agents including any corticosteroid and 5-alpha reductases; AR pathway inhibitors. BSoC excluded investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radioisotopes, and hemi-body radiotherapy treatment.

Patients continued randomised treatment until evidence of tumour progression (based on investigator assessment per Prostate Cancer Working Group 3 [PCWG3] criteria), unacceptable toxicity, use of prohibited treatment, non-compliance or withdrawal, or lack of clinical benefit.

The alternate primary efficacy endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) by blinded independent central review (BICR) per PCWG3 criteria. Additional secondary efficacy endpoints were overall response rate (ORR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and time to first symptomatic skeletal event (SSE) defined as first new symptomatic pathological bone fracture, spinal cord compression, tumour-related orthopaedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death from any cause, whichever occurred first.

Demographic and baseline disease characteristics were balanced between the treatment arms. The median age was 71 years (range: 40 to 94 years); 86.8% White; 6.6% Black or African American; 2.4% Asian; 92.4% had ECOG PS0-1; 7.6% had ECOG PS2. Randomisation was stratified by baseline lactase dehydrogenase (LDH), presence of liver metastases, ECOG PS score and inclusion of an AR pathway inhibitor as part of BSoC at the time of randomisation. At randomisation, all patients (100.0%) had received at least one prior taxane-based chemotherapy regimen and 41.2% of patients had received two. At randomisation, 51.3% of patients had received one prior AR pathway inhibitor, 41.0% of patients had received 2, and 7.7% of patients had received 3 or more. During the randomised treatment period, 52.6% of patients in the Pluvicto plus BSoC arm and 67.8% of patients in the BSoC alone arm received at least one AR pathway inhibitor.

Efficacy results for VISION are presented in Table 3 and Figures 1 and 2. The final analyses of OS and rPFS were event-driven and conducted after the occurrence of 530 deaths and 347 events, respectively. Treatment with Pluvicto plus BSoC demonstrated a statistically significant improvement in OS and rPFS by BICR compared to treatment with BSoC alone. The primary efficacy results are supported by a statistically significant difference between the treatment arms in the time to first SSE (p <0.001) and ORR (p <0.001). There was an estimated 38% risk reduction of death, an estimated 60% risk reduction of radiographic disease progression or death, and an estimated 50% risk reduction of SSE or death based on hazard ratios in favour of Pluvicto plus BSoC treatment.

Table 3 Efficacy results in VISION

Figure 1 Kaplan-Meier plot of overall survival in VISION

Stratified log-rank test and stratified Cox model using strata per Interactive Response Technology (IRT) defined by LDH level, presence of liver metastases, ECOG score and inclusion of an AR pathway inhibitor in BSoC at time of randomisation.

n/N: Number of events/number of patients in treatment arm.

Figure 2 Kaplan-Meier plot of BICR-assessed radiographic progression-free survival (rPFS) in VISION

Stratified log-rank test and stratified Cox model using strata per IRT defined by LDH level, presence of liver metastases, ECOG score and inclusion of an AR pathway inhibitor in BSoC at time of randomisation.

n/N: Number of events/number of patients in treatment arm.

Mean and median baseline prostate-specific antigen (PSA) levels were similar in both treatment arms. Serum PSA levels decreased by ≥ 50% from baseline in 177 of 385 (46.0%) patients who received Pluvicto plus BSoC and in 14 of 196 (7.1%) patients who received BSoC alone.

FACT-P total score showed an estimated 46% risk reduction of worsening from baseline, clinical progression or death based on hazard ratios in favour of Pluvicto plus BSoC, indicating patient stabilisation and delay in time to deterioration while on Pluvicto plus BSoC treatment. Specifically, time to worsening of the FACT-P total score was delayed by 3.5 months for Pluvicto plus BSoC with a median time to deterioration of 5.7 months (95% CI: 4.8, 6.6) compared to 2.2 months (95% CI: 1.8, 2.8) for BSoC alone. BPI-SF pain intensity scale showed an estimated 48% risk reduction of worsening from baseline, clinical progression or death based on hazard ratios in favour of Pluvicto plus BSoC, indicating patient stabilisation and less pain while on Pluvicto plus BSoC treatment. Specifically, time to worsening of the BPI-SF pain intensity scale was delayed by 3.7 months for Pluvicto plus BSoC with a median time to deterioration of 5.9 months (95% CI: 4.8, 6.9) compared to 2.2 months (95% CI: 1.8, 2.8) for BSoC alone.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pluvicto in all subsets of the paediatric population in the treatment of PSMA-expressing prostate cancer (see section 4.2 for information on paediatric use).

The pharmacokinetics of lutetium (¹⁷⁷Lu) vipivotide tetraxetan have been characterised in 30 patients in the phase III VISION sub-study.

Absorption

Pluvicto is administered intravenously and is immediately and completely bioavailable.

The geometric mean blood exposure (area under the curve [AUC_inf]) for lutetium (¹⁷⁷Lu) vipivotide tetraxetan at the recommended dose is 52.3 ng.h/mL (geometric mean coefficient of variation [CV] 31.4%). The geometric mean maximum blood concentration (C_max) for lutetium (¹⁷⁷Lu) vipivotide tetraxetan is 6.58 ng/mL (CV 43.5%).

Distribution

The geometric mean volume of distribution (V_z) for lutetium (¹⁷⁷Lu) vipivotide tetraxetan is 123 L (CV 78.1%).

Unlabelled vipivotide tetraxetan and non-radioactive lutetium (¹⁷⁵Lu) vipivotide tetraxetan are each 60% to 70% bound to human plasma proteins.

Organ uptake

The biodistribution of lutetium (¹⁷⁷Lu) vipivotide tetraxetan shows primary uptake in lacrimal glands, salivary glands, kidneys, urinary bladder wall, liver, small intestine and large intestine (left and right colon).

Elimination

The geometric mean clearance (CL) for lutetium (¹⁷⁷Lu) vipivotide tetraxetan is 2.04 L/h (CV 31.5%).

Lutetium (¹⁷⁷Lu) vipivotide tetraxetan is primarily eliminated renally.

Half-life

Pluvicto shows a bi-exponential elimination with a geometric mean terminal elimination half-life (T_½ ) of 41.6 hours (CV 68.8%).

Biotransformation

Lutetium (¹⁷⁷Lu) vipivotide tetraxetan does not undergo hepatic or renal metabolism.

In vitro drug interaction potential

CYP450 enzymes

Vipivotide tetraxetan is not a substrate of cytochrome P450 (CYP450) enzymes. It does not induce cytochrome P450 (CYP) 1A2, 2B6 or 3A4, and it does not inhibit cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5 in vitro.

Transporters

Vipivotide tetraxetan is not a substrate of BCRP, Pgp, MATE1, MATE2K, OAT1, OAT3 or OCT2, and it is not an inhibitor of BCRP, Pgp, BSEP, MATE1, MATE2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2 in vitro.

Elderly

Of the 529 patients who received at least one dose of Pluvicto plus BSoC in the VISION study, 387 patients (73%) were aged 65 years or older and 143 patients (27%) were aged 75 years or older.

Effects of age, body weight and renal impairment

No clinically significant effects on the pharmacokinetic parameters of lutetium (¹⁷⁷Lu) vipivotide tetraxetan were identified for the following covariates assessed in 30 patients in the phase III VISION sub-study: age (median: 67 years; range: 52 to 80 years) and body weight (median: 88.8 kg; range: 63.8 to 143.0 kg). Exposure (AUC) of lutetium (¹⁷⁷Lu) vipivotide tetraxetan increased with decreasing creatinine clearance (CLcr), however CLcr ≥ 54 mL/min (CockcroftGault) did not have a clinically meaningful effect on the pharmacokinetics of lutetium (¹⁷⁷Lu) vipivotide tetraxetan.

Cardiac electrophysiology

The ability of Pluvicto to prolong the QTc interval at the recommended dose was assessed in 30 patients in the phase III VISION sub-study. Pluvicto did not prolong the QT/QTc interval.

No toxicological effects were observed in safety pharmacology or single-dose toxicity studies in rats and minipigs administered a non-radioactive formulation containing unlabelled vipivotide tetraxetan and lutetium (¹⁷⁵Lu) vipivotide tetraxetan, or in repeat-dose toxicity studies in rats administered unlabelled vipivotide tetraxetan.

Mutagenicity and long-term carcinogenicity studies have not been carried out with lutetium (¹⁷⁷Lu) vipivotide tetraxetan; however, radiation is a carcinogen and mutagen.

Acetic acid

Sodium acetate

Gentisic acid

Sodium ascorbate

Pentetic acid

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 4.2.

120 hours (5 days) from the date and time of calibration.

Do not freeze.

Store in the original package in order to protect from ionising radiation (lead shielding).

Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials.

Clear, colourless type I glass vial, closed with a bromobutyl rubber stopper and aluminum seal.

Each vial contains a volume of solution that can range from 7.5 mL to 12.5 mL corresponding to a radioactivity of 7,400 MBq at the date and time of administration.

The vial is enclosed within a lead container for protective shielding.

General warning

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

For instructions on preparation of the medicinal product before administration, see section 12.

If at any time in the preparation of this medicinal product the integrity of this vial is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

The surface dose rates and the accumulated dose depend on many factors. Measurements on the location and during work are critical and should be practiced for more precise and instructive determination of overall radiation dose to the staff. Healthcare personnel are advised to limit the time of close contact with patients administered lutetium (¹⁷⁷Lu) vipivotide tetraxetan. The use of television monitor systems to monitor the patients is recommended. Given the half-life of lutetium-177, it is specially recommended to avoid internal contamination. It is necessary to use protective high quality (latex/nitrile) gloves to avoid direct contact with the radiopharmaceutical (vial/syringe). For minimising radiation exposure, always use the principles of time, distance and shielding (reducing the manipulation of the vial and using the material already supplied par the manufacturer).

This preparation is likely to result in a relatively high radiation dose to most patients. The administration of Pluvicto may result in significant environmental hazard. This may be of concern to the immediate family of those individuals undergoing treatment or the general public depending on the level of radioactivity administered hence radioprotection rules should be followed (section 4.4). Suitable precautions in accordance with national regulations should be taken concerning the radioactivity eliminated by the patients in order to avoid any contaminations.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Lutetium-177 for Pluvicto is prepared using the stable isotope ytterbium-176 (“ non-carrier added” ).