4.1     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).

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.

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).

·                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 reactions

Recommended dose modifications of Pluvicto for adverse reactions are provided in Table 1. 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.

Table 1 Recommended dose modifications of Pluvicto for adverse reactions

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).

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).

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 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).

For instructions on the method of preparation and intravenous methods of administration, see section 12.

For patient preparation, see section 4.4.

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 professional should explain the necessary radioprotection precautions that the patient should follow to minimise radiation exposure to others.

After each administration of Pluvicto, the following general recommendations for patients can be considered along with national, local and institutional procedures and regulations.

·                Limit close contact (less than 1 metre) 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, including fatal cases, 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).

Before and after administration of Pluvicto, patients should be encouraged to increase oral fluids and urged to void as often as possible, especially after high activities, e.g. for radionuclide therapy. 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 impairment (see section 5.2). Patients with mild or moderate renal impairment may be at greater risk of toxicity. Renal function and adverse reactions should be frequently monitored in patients with mild to moderate renal impairment (see section 4.2). 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.

Fertility

Radiations of lutetium (¹⁷⁷Lu) vipivotide tetraxetan may potentially have toxic effects on male gonads and spermatogenesis. 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. Genetic consultation is recommended if the patient wishes to have children after treatment. Cryopreservation of sperm can be discussed as an option for male patients before treatment (see section 4.6).

Contraception in males

Male patients are advised not to father a child and to use a condom for intercourse during treatment with Pluvicto and for 14 weeks after the last dose (see section 4.6).

Specific warnings

Sodium content

This medicinal product contains up to 3.9 mmol (88.75 mg) sodium per vial, 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 performed.

Contraception in males

Because of potential effects on spermatogenesis associated with radiations of lutetium (¹⁷⁷Lu) vipivotide tetraxetan, male patients are advised not to father a child and to use a condom for intercourse during treatment with Pluvicto and for 14 weeks after the last dose (see section 4.4).

Pregnancy

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 when administered to a pregnant woman.

Breast‑feeding

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. Radiations of lutetium (¹⁷⁷Lu) vipivotide tetraxetan may potentially have toxic effects on male gonads and spermatogenesis. 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. Genetic consultation is recommended if the patient wishes to have children after treatment. Cryopreservation of sperm can be discussed as an option for male patients before treatment (see section 4.4).

Pluvicto may have a minor influence on the ability to drive and use machines.

Summary of 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

Adverse reactions (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse reaction 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       Adverse reactions occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone in VISION^a

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), 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.

To report any side effect(s):

·         Saudi Arabia

-          The National Pharmacovigilance Centre (NPC):

o Fax: +966-11-205-7662

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

In the event of administration of a radiation overdose with Pluvicto, the 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 dose that was applied.

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Therapeutic radiopharmaceuticals, Other therapeutic radiopharmaceuticals, ATC code: V10XX05

Mechanism of action

The active moiety of Pluvicto is the radionuclide lutetium‑177 which is linked to a small‑molecule ligand that targets and 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

Unlabelled vipivotide tetraxetan does not have any pharmacodynamic activity.

Clinical efficacy and safety

VISION

The efficacy of Pluvicto in patients with progressive, PSMA‑positive mCRPC was evaluated 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). Patients who received 4 doses of Pluvicto were reassessed for evidence of response, signs of residual disease, and tolerability and could receive up to 2 additional doses per physician’s discretion.

To maintain castration status, all patients continued to receive a GnRH analogue or had prior bilateral orchiectomy. Eligible patients were required to have progressive, 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 treated with only 1 prior taxane‑based chemotherapy regimen were eligible if the patient was unwilling or the physician deemed the patient unsuitable to receive a second regimen. 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 PSMA‑positive mCRPC defined as having at least one tumour lesion with gallium (⁶⁸Ga) gozetotide uptake greater than in normal liver. Patients were excluded if any lesions exceeding size criteria in short axis (organs ≥1 cm, lymph nodes ≥2.5 cm, bones [soft‑tissue component] ≥1 cm) had uptake less than or equal to uptake in normal liver.

BSoC administered at the physician’s discretion included: supportive measures including pain management, 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 GnRH analogues, 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 primary efficacy endpoints were overall survival (OS) and radiographic progression‑free survival (rPFS) as determined by blinded independent central review (BICR) per PCWG3 criteria. Among the secondary efficacy endpoints were overall response rate (ORR) as determined 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. Radiographic imaging for tumour assessment (CT with contrast/MRI imaging and bone scan) was done every 8 weeks (±4 days) after the first dose for the first 24 weeks (independent of dose delays), then every 12 weeks (±4 days).

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 lactate dehydrogenase (LDH ≤260 IU/L vs. >260 IU/L), presence of liver metastases (yes vs. no), ECOG PS score (0 or 1 vs. 2), and inclusion of an AR pathway inhibitor as part of BSoC at the time of randomisation (yes vs. no). At randomisation, all patients (100.0%) had received at least one prior taxane‑based chemotherapy regimen and 41.2% of patients had received two; 97.1% of patients had received docetaxel and 38.0% of patients had received cabazitaxel. 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.

Table 3 Efficacy results in VISION

Figure 1      Kaplan‑Meier plot of OS 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 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.

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 evaluation of 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, P‑gp, MATE1, MATE2‑K, OAT1, OAT3 or OCT2, and it is not an inhibitor of BCRP, P‑gp, BSEP, MATE1, MATE2‑K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2 in vitro.

Special populations

Effects of age and body weight

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).

Renal impairment

Exposure (AUC) of lutetium (¹⁷⁷Lu) vipivotide tetraxetan increased by 20% in patients with mild renal impairment compared to normal renal function. Kidney dosimetry half‑life also increased in patients with mild renal impairment compared to normal renal function, 51 hours vs. 37 hours, respectively. Patients with mild or moderate renal impairment may be at greater risk of toxicity (see section 4.4). No pharmacokinetic data are available for patients with moderate to severe renal impairment with baseline CLcr <50 mL/min or end‑stage renal disease.

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.

Carcinogenicity and mutagenicity

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

6.1     List of excipients

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 sections 4.2 and 12.

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 aluminium 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 ±10% at the date and time of administration.

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

Not all pack sizes may be marketed.

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 the lead container or the 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.

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 activity administered. Suitable precautions in accordance with national regulations should be taken concerning the activity eliminated by the patients in order to avoid any contaminations.

Lutetium‑177 for Pluvicto may be prepared using two different sources of stable isotopes (either lutetium‑176 or ytterbium‑176). Lutetium‑177 for Pluvicto prepared using the stable isotope lutetium‑176 (“carrier added”) requires special attention with regard to waste management due to the presence of the long‑lived metastable lutetium‑177 (^177mLu) impurity with a half‑life of 160.4 days. Lutetium‑177 for Pluvicto is prepared using ytterbium‑176 (“non‑carrier added”) unless otherwise communicated on the product batch release certificate. The user must consult the product batch release certificate provided before using Pluvicto to ensure appropriate waste management.

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