PLUVICTO 1 000 MBQ/ml injection / infusion solution medication leaflet

Pluvicto 1 000 MBq/mL solution for injection/infusion

One mL of solution contains 1 000 MBq of lutetium (177Lu) vipivotide tetraxetan at the date and timeof calibration.

The total amount of radioactivity per single-dose vial is 7 400 MBq ± 10% at the date and time ofadministration. Given the fixed volumetric activity of 1 000 MBq/mL at the date and time ofcalibration, the volume of the solution in the vial can range from 7.5 mL to 12.5 mL in order toprovide 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 emittingbeta-minus radiation with a maximum energy of 0.498 MeV (79%) and photon radiation (γ) of0.208 MeV (11%) and 0.113 MeV (6.4%).

Each mL of solution contains up to 0.312 mmol (7.1 mg) of sodium. Each vial contains up to88.75 mg of sodium.

For the full list of excipients, see section 6.1.

Solution for injection/infusion.

Clear, colourless to slightly yellow solution, pH: 4.5 to 7.0.

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 progressiveprostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer(mCRPC) who have been treated with AR pathway inhibition and taxane-based chemotherapy (seesection 5.1).

Important safety instructions

Pluvicto should be administered only by persons authorised to handle radiopharmaceuticals indesignated clinical settings (see section 6.6) and after evaluation of the patient by a qualifiedphysician.

Radiopharmaceuticals, including Pluvicto, should be used by or under the control of healthcareprofessionals who are qualified by specific training and experience in the safe use and handling ofradiopharmaceuticals, and whose experience and training have been approved by the appropriategovernmental agency authorised to license the use of radiopharmaceuticals.

Patient identification

Patients should be identified for treatment by PSMA imaging.

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 continuedduring treatment in patients not surgically castrated.

Laboratory tests should be performed before and during treatment with Pluvicto. Dosing may need tobe 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 permanentdiscontinuation 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 requirean additional dose reduction, treatment with Pluvicto must be discontinued.

Table 1 Recommended dose modifications of Pluvicto for adverse reactions

Adverse reaction Severitya Dose modification

Dry mouth Grade 3 Reduce Pluvicto dose by 20%.

Withhold Pluvicto until improvement to

Gastrointestinal Grade ≥3 (not amenable tograde 2 or baseline.toxicity medical intervention)

Reduce Pluvicto dose by 20%.

Withhold Pluvicto until improvement tograde 1 or baseline.

Manage as deemed appropriate. The use ofgrowth factors is permitted but should be

Anaemia, Grade 2 discontinued once improved to grade 1 orthrombocytopenia, baseline. Checking haematinic levels (iron,leukopenia, B12 and folate) and providingneutropenia, supplementation is advocated. Transfusionspancytopenia may be given as clinically indicated.

Withhold Pluvicto until improvement to

Grade ≥3 grade 1 or baseline.

Reduce Pluvicto dose by 20%.

Defined as:

* Confirmed serumcreatinine increase(grade ≥2)

Withhold Pluvicto until improvement.

* Confirmed CLcr<50 mL/min; calculateusing Cockcroft-Gaultwith actual body weight

Defined as:

* Confirmed ≥40%

Renal toxicityincrease from baselineserum creatinine

Withhold Pluvicto until improvement orandreturn to baseline.

* Confirmed >40%

Reduce Pluvicto dose by 20%.

decrease from baseline

CLcr; calculate using

Cockcroft-Gault withactual body weight

Recurrent renal toxicity

Permanently discontinue Pluvicto.

(grade ≥3)

Withhold Pluvicto until the compression has

Spinal cord been adequately treated and any neurological

Anycompression sequela have stabilised and ECOGperformance status has stabilised.

Withhold Pluvicto until the fracture has been

Fracture in

Any adequately stabilised/treated and ECOGweight-bearing bonesperformance status has stabilised.

Withhold Pluvicto until improvement to

Fatigue Grade ≥3

Grade 2 or baseline.

Electrolyte or

Withhold Pluvicto until improvement tometabolic Grade ≥2

Grade 1 or baseline.

abnormalities

Non-haematologicaltoxicity (clinically Withhold Pluvicto until improvement to

Grade ≥2significant, not Grade 1 or baseline.

otherwise stated)

AST or ALT >5 times ULN

AST or ALTin the absence of liver Permanently discontinue Pluvicto.elevationmetastases

Abbreviations: CLcr, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; AST, aspartateaminotransferase; 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.

No dose adjustment is recommended in patients aged 65 years or older.

No dose adjustment is recommended for patients with mild to moderate renal impairment withbaseline CLcr ≥50 mL/min by Cockcroft-Gault. Treatment with Pluvicto is not recommended inpatients with moderate to severe renal impairment with baseline CLcr <50 mL/min or end-stage renaldisease as the pharmacokinetic profile and safety of Pluvicto have not been studied in these patients(see sections 4.4 and 5.2).

No dose adjustment is recommended for patients with hepatic impairment. Pluvicto has not beenstudied in patients with moderate or severe hepatic impairment (see section 5.2).

There is no relevant use of Pluvicto in the paediatric population in the indication of treatment of

PSMA-expressing prostate cancer.

Pluvicto is a ready-to-use solution for injection/infusion for single use only.

The recommended dose of Pluvicto may be administered intravenously as an injection using adisposable syringe fitted with a syringe shield (with or without a syringe pump), as an infusion usingthe gravity method (with or without an infusion pump), or as an infusion using the vial (with aperistaltic infusion pump).

A reduced dose of Pluvicto should be administered using the syringe method (with or without asyringe pump) or the vial method (with a peristaltic infusion pump). Using the gravity method toadminister a reduced dose of Pluvicto is not recommended since it may result in delivery of theincorrect volume of Pluvicto if the dose is not adjusted prior to administration.

Prior to administration, flush the intravenous catheter used exclusively for Pluvicto administrationwith ≥10 mL of sterile sodium chloride 9 mg/mL (0.9%) solution for injection to ensure patency andto minimise the risk of extravasation. Cases of extravasation should be managed as per institutionalguidelines. Patients should be advised to remain well hydrated and to urinate frequently before andafter administration of Pluvicto (see section 4.4).

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

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 activityadministered should in every case be as low as reasonably achievable to obtain the requiredtherapeutic effect.

Risk from radiation exposure

Pluvicto contributes to a patient’s overall long-term cumulative radiation exposure. Long-termcumulative radiation exposure is associated with an increased risk for cancer.

Radiation exposure to patients, medical personnel, and household contacts should be minimised duringand after treatment with Pluvicto consistent with institutional good radiation safety practices, patientmanagement 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 reducebladder 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 explainthe necessary radioprotection precautions that the patient should follow to minimise radiation exposureto others.

After each administration of Pluvicto, the following general recommendations for patients can beconsidered 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 childrenand 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.

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

Haematology laboratory tests, including haemoglobin, white blood cell count, absolute neutrophilcount and platelet count, should be performed before and during treatment with Pluvicto. Pluvictoshould be withheld, dose reduced or permanently discontinued and patients should be clinicallymanaged 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 andurged to void as often as possible, especially after high activities, e.g. for radionuclide therapy. Kidneyfunction laboratory tests, including serum creatinine and calculated CLcr, should be performed beforeand during treatment with Pluvicto. Pluvicto should be withheld, dose reduced or permanentlydiscontinued 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 radiationexposure is possible.

Exposure (AUC) of lutetium (177Lu) vipivotide tetraxetan is expected to increase with the degree ofrenal impairment (see section 5.2). Patients with mild or moderate renal impairment may be at greaterrisk of toxicity. Renal function and adverse reactions should be frequently monitored in patients withmild to moderate renal impairment (see section 4.2). Treatment with Pluvicto is not recommended inpatients with moderate to severe renal impairment with baseline CLcr <50 mL/min or end-stage renaldisease.

Radiations of lutetium (177Lu) vipivotide tetraxetan may potentially have toxic effects on male gonadsand spermatogenesis. The recommended cumulative dose of 44 400 MBq of Pluvicto results in aradiation absorbed dose to the testes within the range where Pluvicto may cause infertility. Geneticconsultation is recommended if the patient wishes to have children after treatment. Cryopreservationof 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 treatmentwith Pluvicto and for 14 weeks after the last dose (see section 4.6).

Specific warnings

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 forintercourse during treatment with Pluvicto and for 14 weeks after the last dose (see section 4.4).

Pluvicto is not indicated for use in females. No animal studies using lutetium (177Lu) vipivotidetetraxetan have been conducted to evaluate its effect on female reproduction and embryo-foetaldevelopment. However, all radiopharmaceuticals, including Pluvicto, have the potential to cause foetalharm when administered to a pregnant woman.

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 milkproduction.

No studies were conducted to determine the effects of lutetium (177Lu) vipivotide tetraxetan onfertility. Radiations of lutetium (177Lu) vipivotide tetraxetan may potentially have toxic effects on malegonads and spermatogenesis. The recommended cumulative dose of 44 400 MBq of Pluvicto results ina radiation absorbed dose to the testes within the range where Pluvicto may cause infertility. Geneticconsultation is recommended if the patient wishes to have children after treatment. Cryopreservationof 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.

Unless otherwise stated, the frequency of listed adverse reactions is based on data from the VISIONstudy in which 529 patients received at least one dose of 7 400 MBq (median number of doses wasfive).

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 to4 adverse reactions include: anaemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%) andfatigue (5.9%).

Adverse reactions (Table 2) are listed by MedDRA system organ class. Within each system organclass, 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 Pluvictoplus BSoC compared to BSoC alone in VISIONa

System organ class Frequency category All grades Grades

Adverse reaction n (%) 3 to 4bn (%)

Anaemia Very common 168 (31.8) 68 (12.9)

Thrombocytopenia Very common 91 (17.2) 42 (7.9)

Leukopeniac Very common 83 (15.7) 22 (4.2)

Lymphopenia Very common 75 (14.2) 41 (7.8)

Pancytopeniad Common 9 (1.7) 7 (1.3)b

Dizziness Common 44 (8.3) 5 (0.9)

Headache Common 37 (7.0) 4 (0.8)

Dysgeusiae Common 37 (7.0) 0 (0.0)

Dry eye Common 16 (3.0) 0 (0.0)

Ear and labyrinth disorders

Vertigo Common 11 (2.1) 0 (0.0)

Dry mouthf Very common 208 (39.3) 0 (0.0)

Nausea Very common 187 (35.3) 7 (1.3)

Constipation Very common 107 (20.2) 6 (1.1)

Vomitingg Very common 101 (19.1) 5 (0.9)

Diarrhoea Very common 100 (18.9) 4 (0.8)

Abdominal painh Very common 59 (11.2) 6 (1.1)

Urinary tract infectioni Very common 61 (11.5) 20 (3.8)

Acute kidney injuryj Common 45 (8.5) 17 (3.2)

Fatigue Very common 228 (43.1) 31 (5.9)

Decreased appetite Very common 112 (21.2) 10 (1.9)

Weight decreased Very common 57 (10.8) 2 (0.4)

Oedema peripheralk Common 52 (9.8) 2 (0.4)

Pyrexia Common 36 (6.8) 2 (0.4)

Abbreviation: BSoC, best standard of care.a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)

Version 5.0.b Only includes grades 3 to 4 adverse reactions, with the exception of pancytopenia. Grade 5 (fatal)pancytopenia was reported in 2 patients who received Pluvicto plus BSoC.c Leukopenia includes leukopenia and neutropenia.d Pancytopenia includes pancytopenia and bicytopenia.e Dysgeusia includes dysgeusia and taste disorder.f Dry mouth includes dry mouth, aptyalism and dry throat.g Vomiting includes vomiting and retching.h Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort,abdominal pain lower, abdominal tenderness and gastrointestinal pain.i Urinary tract infection includes urinary tract infection, cystitis and cystitis bacterial.j Acute kidney injury includes blood creatinine increased, acute kidney injury, renal failure andblood urea increased.k Oedema peripheral includes oedema peripheral, fluid retention and fluid overload.

In the VISION study, myelosuppression occurred more frequently in patients who received Pluvictoplus 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%) includingtwo 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 whoreceived 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 doseinterruptions/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 creatinineincreased (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 todose 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 ofhereditary defects. The radiation dose resulting from therapeutic exposure may result in higherincidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiationare less than from the disease itself. As Pluvicto contributes to a patient’s overall long-term radiationexposure, which is associated with an increased risk for cancer (see section 4.4), a potential risk ofsecond primary malignancies cannot be ruled out for radiopharmaceuticals such as Pluvicto. At thetime 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 theskin (1 patient each; 0.2% each) were reported in patients who received Pluvicto plus BSoC.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

Unlabelled vipivotide tetraxetan does not have any pharmacodynamic activity.

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 atotal of 6 doses plus best standard of care (BSoC) (N=551) or BSoC alone (N=280). Patients whoreceived 4 doses of Pluvicto were reassessed for evidence of response, signs of residual disease, andtolerability 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 bilateralorchiectomy. 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 lesionpresent on computed tomography (CT), magnetic resonance imaging (MRI) or bone scan imaging, andadequate renal, hepatic and haematological function.

Eligible patients were also required to have received at least one AR pathway inhibitor, such asabiraterone acetate or enzalutamide, and 1 or 2 prior taxane-based chemotherapy regimens (with aregimen defined as a minimum exposure of 2 cycles of a taxane). Patients treated with only 1 priortaxane-based chemotherapy regimen were eligible if the patient was unwilling or the physiciandeemed the patient unsuitable to receive a second regimen. Patients with unstable symptomatic centralnervous system metastases or symptomatic or clinically/radiologically impending spinal cordcompression were not eligible for the study. Patients underwent a gallium (68Ga) gozetotide positronemission tomography (PET) scan to evaluate PSMA expression in lesions defined by central readcriteria. Eligible patients were required to have PSMA-positive mCRPC defined as having at least onetumour lesion with gallium (68Ga) gozetotide uptake greater than in normal liver. Patients wereexcluded 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 painmanagement, hydration, blood transfusions, etc.; ketoconazole; radiation therapy (including seededform or any external beam radiotherapy [including stereotactic body radiotherapy and palliativeexternal beam]) to localised prostate cancer targets; bone-targeted agents including zoledronic acid,denosumab and any bisphosphonates; androgen-reducing agents including GnRH analogues, anycorticosteroid, and 5-alpha reductases; AR pathway inhibitors. BSoC excluded investigational agents,cytotoxic chemotherapy, immunotherapy, other systemic radioisotopes and hemi-body radiotherapytreatment.

Patients continued randomised treatment until evidence of tumour progression (based on investigatorassessment per Prostate Cancer Working Group 3 [PCWG3] criteria), unacceptable toxicity, use ofprohibited 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 thesecondary 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-relatedorthopaedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death fromany cause, whichever occurred first. Radiographic imaging for tumour assessment (CT withcontrast/MRI imaging and bone scan) was done every 8 weeks (±4 days) after the first dose for thefirst 24 weeks (independent of dose delays), then every 12 weeks (±4 days).

Demographic and baseline disease characteristics were balanced between the treatment arms. Themedian 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 baselinelactate 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 ofrandomisation (yes vs. no). At randomisation, all patients (100.0%) had received at least one priortaxane-based chemotherapy regimen and 41.2% of patients had received two; 97.1% of patients hadreceived docetaxel and 38.0% of patients had received cabazitaxel. At randomisation, 51.3% ofpatients had received one prior AR pathway inhibitor, 41.0% of patients had received 2, and 7.7% ofpatients 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 ARpathway inhibitor.

Efficacy results for VISION are presented in Table 3 and Figures 1 and 2. The final analyses of OSand rPFS were event-driven and conducted after the occurrence of 530 deaths and 347 events,respectively.

Table 3 Efficacy results in VISION

Efficacy parameters Pluvicto plus BsoC BSoC

Alternate primary efficacy endpoints

Overall survival (OS)a N=551 N=280

Deaths, n (%) 343 (62.3%) 187 (66.8%)

Median, months (95% CI)b 15.3 (14.2; 16.9) 11.3 (9.8; 13.5)

Hazard ratio (95% CI)c 0.62 (0.52; 0.74)

P-valued <0.001

Radiographic progression-free survival (rPFS)e,f N=385 N=196

Events (progression or death), n (%) 254 (66.0%) 93 (47.4%)

Radiographic progressions, n (%) 171 (44.4%) 59 (30.1%)

Deaths, n (%) 83 (21.6%) 34 (17.3%)

Median, months (99.2% CI)b 8.7 (7.9; 10.8) 3.4 (2.4; 4.0)

Hazard ratio (99.2% CI)c 0.40 (0.29; 0.57)

P-valued <0.001

Secondary efficacy endpoints

Time to first symptomatic skeletal event (SSE)f N=385 N=196

Events (SSE or death), n (%) 256 (66.5%) 137 (69.9%)

SSEs, n (%) 60 (15.6%) 34 (17.3%)

Deaths, n (%) 196 (50.9%) 103 (52.6%)

Median, months (95% CI)b 11.5 (10.3; 13.2) 6.8 (5.2; 8.5)

Hazard ratio (95% CI)c 0.50 (0.40; 0.62)

P-valueg <0.001

Best overall response (BOR)

Patients with evaluable disease at baseline N=319 N=120

Complete response (CR), n (%) 18 (5.6%) 0 (0%)

Partial response (PR), n (%) 77 (24.1%) 2 (1.7%)

Overall response rate (ORR)h,i 95 (29.8%) 2 (1.7%)

P-valuej <0.001

Duration of response (DOR)h

Median, months (95% CI)b 9.8 (9.1; 11.7) 10.6 (NE; NE)k

BSoC: Best standard of care; CI: Confidence interval; NE: Not evaluable; BICR: Blinded independent centralreview; PCWG3: Prostate Cancer Working Group 3; RECIST: Response Evaluation Criteria in Solid Tumors.a Analysed on an intent-to-treat (ITT) basis in all randomised patients.b Based on Kaplan-Meier estimate.c Hazard ratio based on the stratified Cox PH model. Hazard ratio <1 favours Pluvicto plus BSoC.d Stratified log-rank test one-sided p-value.e By BICR per PCWG3 criteria. The primary analysis of rPFS included censoring of patients who had ≥2consecutive missed tumour assessments immediately prior to progression or death. Results for rPFS withand without censoring for missed assessments were consistent.f Analysed on an ITT basis in all patients randomised on or after 05-Mar-2019, when actions wereimplemented to mitigate early drop-out from BSoC arm.g Stratified log-rank test two-sided p-value.h By BICR per RECIST v1.1.i ORR: CR+PR. Confirmed response for CR and PR.j Stratified Wald’s Chi-square test two-sided p-value.k Median DOR in the BSoC only arm was not reliable since only 1 of the 2 patients who responded had

RECIST v1.1 radiographic progression or death.

Figure 1 Kaplan-Meier plot of OS in VISION

Censoring times(a) Lu-PSMA-617+BSoC(b) BSoC only

No. patients still at risk

Time from randomisation (months)

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

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

Event-free probability (%)

Figure 2 Kaplan-Meier plot of BICR-assessed rPFS in VISION

Censoring times(a) Lu-PSMA-617+BSoC(b) BSoC only

No. patients still at risk

Time from randomisation (months)

Stratified log-rank test and stratified Cox model using strata per IRT defined by LDH level, presence of livermetastases, 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.

Event-free probability (%)

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 prostatecancer (see section 4.2 for information on paediatric use).

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

Pluvicto is administered intravenously and is immediately and completely bioavailable.

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

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

Unlabelled vipivotide tetraxetan and non-radioactive lutetium (175Lu) vipivotide tetraxetan are each60% 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 rightcolon).

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 (t½)of 41.6 hours (CV 68.8%).

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 inducecytochrome 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.

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.

Effects of age and body weight

No clinically significant effects on the pharmacokinetic parameters of lutetium (177Lu) vipivotidetetraxetan were identified for the following covariates assessed in 30 patients in the phase III VISIONsub-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 by 20% in patients with mild renalimpairment compared to normal renal function. Kidney dosimetry half-life also increased in patientswith 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 withbaseline CLcr <50 mL/min or end-stage renal disease.

No toxicological effects were observed in safety pharmacology or single-dose toxicity studies in ratsand minipigs administered a non-radioactive formulation containing unlabelled vipivotide tetraxetanand lutetium (175Lu) vipivotide tetraxetan, or in repeat-dose toxicity studies in rats administeredunlabelled 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 insections 4.2 and 12.

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 radioactivematerials.

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 aradioactivity of 7 400 MBq ±10% 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 indesignated clinical settings. Their receipt, storage, use, transfer and disposal are subject to theregulations and/or appropriate licences of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety andpharmaceutical 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 vialis compromised it should not be used.

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

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

This preparation is likely to result in a relatively high radiation dose to most patients. Theadministration of Pluvicto may result in significant environmental hazard. This may be of concern tothe immediate family of those individuals undergoing treatment or the general public depending on thelevel of activity administered. Suitable precautions in accordance with national regulations should betaken 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 (eitherlutetium-176 or ytterbium-176). Lutetium-177 for Pluvicto prepared using the stable isotopelutetium-176 (“carrier added”) requires special attention with regard to waste management due to thepresence 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 otherwisecommunicated on the product batch release certificate. The user must consult the product batch releasecertificate provided before using Pluvicto to ensure appropriate waste management.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/22/1703/001

09 December 2022

Radiation dose to specific organs, which may not be the target organ of therapy, can be influencedsignificantly by pathophysiological changes induced by the disease process. This should be taken intoconsideration when using the following information.

Dosimetry of lutetium (177Lu) vipivotide tetraxetan was collected in 29 patients in the phase III

VISION sub-study, in order to calculate whole body and organ radiation dosimetry. The mean andstandard deviation (SD) of the estimated absorbed doses to different organs for adult patients receiving

Pluvicto are shown in Table 4. The organs with the highest absorbed doses are lacrimal glands andsalivary glands.

The maximum penetration of lutetium-177 in tissue is approximately 2 mm and the mean penetrationis 0.67 mm.

Table 4 Estimated absorbed dose for Pluvicto in the VISION sub-study

Absorbed dose per unit Calculated Calculatedactivity (mGy/MBq)a absorbed dose absorbed dose(N=29) for 7 400 MBq foradministration 6 x 7 400 MBq(Gy)a (44 400 MBqcumulativeactivity)(Gy)a

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

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

Oesophagus 0.025 0.026 0.18 0.19 1.1 1.1

Osteogenic cells 0.036 0.028 0.26 0.21 1.6 1.3

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

Red marrow 0.035 0.020 0.25 0.15 1.5 0.90

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

Effective doseb 0.120 0.043 0.886 0.315 5.319 1.892mSv/MBq mSv/MBq Sv Sv Sv Sva Absorbed dose estimates were derived using OLINDA v2.2. Values have been calculated based ondosimetry estimates at full precision and rounded to relevant digits.b Derived according to ICRP Publication 103.

The user must consult the product batch release certificate provided before using Pluvicto to ensureappropriate waste management (see section 6.6).

Withdrawals should be performed under aseptic conditions. The vials must not be opened beforedisinfecting the stopper, the solution should be withdrawn via the stopper using a single-dose syringefitted with suitable protective shielding and a disposable sterile needle or using an authorisedautomated application system.

* Use aseptic technique and radiation shielding when handling or administering Pluvicto, usingtongs as needed to minimise radiation exposure.

* Visually inspect the vial under a shielded screen for particulate matter and discolouration priorto administration. Discard the vial if particulates and/or discolouration 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 calibrateddose calibrator prior to and after Pluvicto administration.

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 todeliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and adisposable sterile needle.

* Administer Pluvicto to the patient by slow intravenous push within approximately 1 to10 minutes (either with a syringe pump or manually without a syringe pump) via an intravenouscatheter that is pre-filled with sterile sodium chloride 9 mg/mL (0.9%) solution for injection andthat 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 sterile sodium chloride 9 mg/mL (0.9%) solution for injection through theintravenous 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 catheterto 500 mL sterile sodium chloride 9 mg/mL (0.9%) solution for injection (used to transport the

Pluvicto solution during the infusion). Ensure that the short needle does not touch the Pluvictosolution in the vial and do not connect the short needle directly to the patient. Do not allow thesterile sodium chloride 9 mg/mL (0.9%) solution for injection to flow into the Pluvicto vialprior to the initiation of the Pluvicto infusion and do not inject the Pluvicto solution directly intothe sterile sodium chloride 9 mg/mL (0.9%) solution for injection.

* Insert a second needle that is 9 cm, 18 gauge (long needle) into the Pluvicto vial, ensuring thatthe long needle touches and is secured to the bottom of the Pluvicto vial during the entireinfusion. Connect the long needle to the patient by an intravenous catheter that is pre-filled withsterile sodium chloride 9 mg/mL (0.9%) solution for injection and that is used exclusively forthe Pluvicto infusion into the patient.

* Use a clamp or an infusion pump to regulate the flow of the sterile sodium chloride 9 mg/mL(0.9%) solution for injection via the short needle into the Pluvicto vial (the sterile sodiumchloride 9 mg/mL (0.9%) solution for injection entering the vial through the short needle willcarry the Pluvicto solution from the vial to the patient via the intravenous catheter connected tothe 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 sodium chloride line once the levelof radioactivity is stable for at least five minutes.

* Follow the infusion with an intravenous flush of ≥10 mL of sterile sodium chloride 9 mg/mL(0.9%) solution for injection 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 theshort needle does not touch the Pluvicto solution in the vial and do not connect the short needledirectly 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 thatthe long needle touches and is secured to the bottom of the Pluvicto vial during the entireinfusion. Connect the long needle and a sterile sodium chloride 9 mg/mL (0.9%) solution forinjection 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 theperistaltic infusion pump following the pump manufacturer’s instructions.

* Pre-fill the line by opening the 3-way stopcock valve and pumping the Pluvicto solution throughthe 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-waystopcock valve to the sterile sodium chloride 9 mg/mL (0.9%) solution for injection andpumping the sterile sodium chloride 9 mg/mL (0.9%) solution for injection until it exits the endof the catheter tubing.

* Connect the pre-filled intravenous catheter to the patient and set the 3-way stopcock valve suchthat 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 thedesired radioactivity.

* When the desired Pluvicto radioactivity has been delivered, stop the peristaltic infusion pumpand then change the position of the 3-way stopcock valve so that the peristaltic infusion pump isin line with the sterile sodium chloride 9 mg/mL (0.9%) solution for injection. Restart theperistaltic infusion pump and infuse an intravenous flush of ≥10 mL of sterile sodium chloride9 mg/mL (0.9%) solution for injection through the intravenous catheter to the patient.

Quality control

The solution should be visually inspected for damage and contamination before use, and only clearsolutions free of visible particles should be used. The visual inspection of the solution should beperformed under a shielded screen for radioprotection purposes. The vial must not be opened.

If at any time in the preparation of this medicinal product the integrity of the lead container or the vialis compromised, it should not be used.

The amount of radioactivity in the vial must be measured prior to administration using a suitableradioactivity calibration system in order to confirm that the actual amount of radioactivity to beadministered is equal to the planned amount at the administration time.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.