Pluvicto should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings 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 appropriate 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. Waterproof gloves and effective radiation shielding should be used when handling Pluvicto.

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 PSMAfore study in patients with progressive, PSMA-positive mCRPC previously treated with ARPI therapy. Of the 468 patients randomised, 459 patients received at least one dose of randomised treatment. Patients received either Pluvicto 7,400 MBq administered every 6 weeks (N=227) or a change in ARPI (N=232). 

The most common adverse drug reactions (ADRs) (≥20%) in patients who received Pluvicto include: dry mouth (60.8%), fatigue (52.9%), nausea (31.7%), anaemia (27.3%), constipation (22.0%) and decreased appetite (21.6%). The most common grade 3 to 4 ADRs (≥5%) in patients who received Pluvicto include: anaemia (6.2%).

ADRs 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).

ADRs in patients who received Pluvicto compared to a change in ARPI in PSMAfore*

Adapted from Pluvicto Summary of Product Characteristics.¹

Patients in the Pluvicto arm do not include patients who crossed over to receive Pluvicto after receiving treatment in the change in ARPI arm.

*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.^1
†Only includes grades 3 to 4 ADRs, no grade 5 ADRs recorded during treatment phase.^1

‡Urinary tract infection includes urinary tract infection, cystitis, and urinary tract infection enterococcal.^1

§Oral fungal infection includes candida infection, oral candidiasis, oral fungal infection and oropharyngeal candidiasis.^1

¶Leukopenia includes neutropenia and leukopenia.^1

‖Dysgeusia includes dysgeusia and taste disorder.¹

**Dry eye includes dry eye and xerophthalmia.^1

††Dry mouth includes dry mouth, mucosal dryness, salivary hyposecretion, dry throat and lip dry.^1

‡‡Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and epigastric discomfort.^1

§§Oesophageal disorder includes gastro-oesophageal reflux disease, dysphagia, oesophagitis and burn oesophageal.^1

¶¶Acute kidney injury includes blood creatinine increased, acute kidney injury, renal failure and blood urea increased.1^‖‖Fatigue includes asthenia and fatigue.¹

The safety of Pluvicto was evaluated in the Phase III VISION study in patients with progressive, PSMA-positive mCRPC. At the time of VISION final analysis, after a median follow-up duration of 14.2 months (range: 0.6–60.9 months), the overall safety profile remained consistent with that previously reported).¹

The most common ADRs (≥20%) occurring at a higher incidence in patients who received Pluvicto + best standard of care (BSoC) compared to BSoC alone include: fatigue (48.0%), dry mouth (39.3%), nausea (35.7%), anaemia (31.9%), decreased appetite (21.4%) and constipation (20.2%). The most common grade 3 to 4 ADRs (≥5%) occurring at a higher incidence in patients who received Pluvicto + BSoC compared to BSoC alone include: anaemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%) and fatigue (6.6%).¹

ADRs are listed below 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 (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000).

ADRs occurred at a higher incidence in patients who received Pluvicto + BSoC compared to BSoC alone in VISION***

Adapted from Pluvicto Summary of Product Characteristics.¹

***NCI CTCAE Version 5.0.^{1

†††}Only includes grades 3 to 4 ADRs, with the exception of pancytopenia and bone marrow failure. Grade 5 (fatal) pancytopenia was reported in two patients who received Pluvicto + BSoC. Grade 5 (fatal) bone marrow failure was reported in one patient who received Pluvicto + BSoC.^{1

‡‡‡}Oral fungal infection includes oral candidiasis, candida infection, oral fungal infection, oropharyngitis fungal and tongue fungal infection.1
§§§Leukopenia includes leukopenia and neutropenia.^1

¶¶¶Pancytopenia includes pancytopenia and bicytopenia.^{1

‖‖‖}Dysgeusia includes dysgeusia and taste disorder.¹
****Dry mouth includes dry mouth, lip dry, salivary hyposecretion and dry throat.^{1

††††}Vomiting includes vomiting and retching.^{1

‡‡‡‡}Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness and gastrointestinal pain.^{1

§§§§}Oesophageal disorder includes gastro-oesophageal reflux disease, dysphagia and oesophagitis.^{1

¶¶¶¶}Dry skin includes dry skin and xeroderma.^{1

‖‖‖‖}Urinary tract infection includes urinary tract infection, cystitis and cystitis bacterial.¹
*****Acute kidney injury includes blood creatinine increased, acute kidney injury, renal failure and blood urea increased.1
†††††Fatigue includes fatigue and asthenia.^{1

‡‡‡‡‡}Oedema peripheral includes oedema peripheral, fluid retention and hypervolaemia.¹

Recommended dose modifications of Pluvicto for ADRs are provided below. 

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

The dose of Pluvicto may be reduced by 20% to 5900 MBq once; the dose should not be re-escalated.

If a patient has further ADRs that would require an additional dose reduction, treatment with Pluvicto must be discontinued.

Adapted from Pluvicto Summary of Product Characteristics.¹

Grading according to most current NCI-CTCAE.

^§§§§§The same thresholds are also applicable to baseline values at the time of treatment initiation with Pluvicto.

Special populations¹

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

Renal impairment
No dose adjustment is recommended for patients with mild (baseline creatinine clearance [CrCl] 60–89 mL/min by Cockcroft-Gault) to moderate (CrCl 30–59 mL/min) renal impairment. The pharmacokinetic profile and safety of Pluvicto have not been studied in patients with severe (CrCl 15–29 mL/min) renal impairment or end-stage renal disease.

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.

Hypersensitivity to the active substance or to any of the excipients listed below:¹

• Acetic acid

• Sodium acetate

• Gentisic acid

• Sodium ascorbate

• Pentetic acid

• Water for injections

Individual benefit/risk justification

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

Risk from radiation exposure

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

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

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 metre) with others for 2 days or with children and pregnant women for 7 days

• refrain from sexual activity for 7 days

• sleep in a separate room from others for 3 days, from children for 7 days or from pregnant women for 15 days

Myelosuppression

In the PSMAfore study, myelosuppression occurred more frequently in patients who received Pluvicto compared to patients who switched to another ARPI therapy.

In the VISION study, myelosuppression occurred more frequently in patients who received Pluvicto + BSoC compared to patients who received BSoC alone.

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.

Renal toxicity

In the PSMAfore study, renal toxicity was comparable in patients who received Pluvicto compared to patients who switched to another ARPI therapy.

In the VISION study, renal toxicity occurred more frequently in patients who received Pluvicto + BSoC compared to patients who received BSoC alone.

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 CrCl, 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.

Renal/hepatic impairment

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

Exposure area under the curve of Pluvicto is expected to increase with the degree of renal impairment. Patients with mild or moderate renal impairment may be at greater risk of toxicity. Renal function and ADRs should be frequently monitored in patients with mild to moderate renal impairment. The pharmacokinetic profile and safety of Pluvicto have not been studied in patients with severe renal impairment (CrCl 15–29 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 World Health Organization recommended maximum daily intake of 2 g sodium for an adult.

Please refer to section 6.6 of the SmPC for precautions with respect to environmental hazard.

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 Pluvicto have been conducted to evaluate its effect on female reproduction and embryo-foetal development; however, all radioactive emissions, including those from Pluvicto, can cause foetal harm. Based on its mechanism of action, Pluvicto can cause foetal harm when administered to a pregnant woman.

Breastfeeding

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 Pluvicto 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 Pluvicto 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.

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.

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.

Please refer to the SmPC for instructions on preparation of the medicinal product before administration.

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 Pluvicto. 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 per the manufacturer).

This preparation is likely to result in a relatively high radiation dose to most patients. The administration of Pluvicto may result in a 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. 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 nuclide ytterbium-176 (‘non-carrier added’).