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.¹

The safety of Pluvicto was evaluated in the Phase III VISION study in patients with progressive, PSMA-positive mCRPC.¹

The most common adverse drug reactions (ADRs) (≥20%) occurring at a higher incidence in patients who received Pluvicto plus best standard of care (BSoC) compared to BSoC alone include: fatigue (43.1%), dry mouth (39.3%), nausea (35.3%), anaemia (31.8%), decreased appetite (21.2%) and constipation (20.2%). The most common grade 3 to 4 ADRs (≥5%) occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone include: anaemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%) and fatigue (5.9%).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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

ADRs occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone in VISION*¹

*National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) Version 5.0.

^†Only includes grades 3 to 4 ADRs, with the exception of pancytopenia. Grade 5 (fatal) pancytopenia was reported in 2 patients who received Pluvicto plus BSoC.

^‡Leukopenia includes leukopenia and neutropenia.

^§Pancytopenia includes pancytopenia and bicytopenia.

^¶Dysgeusia includes dysgeusia and taste disorder.

^‖Dry mouth includes dry mouth, aptyalism and dry throat.

**Vomiting includes vomiting and retching.

^††Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness and gastrointestinal pain.

^‡‡Urinary tract infection includes urinary tract infection, cystitis and cystitis bacterial.

^§§Acute kidney injury includes blood creatinine increased, acute kidney injury, renal failure and blood urea increased.

^¶¶Oedema peripheral includes oedema peripheral, fluid retention and fluid overload.

Recommended dose modifications of Pluvicto for ADRs are provided below. 

Management of severe or intolerable ADRs may require temporary dose interruption (extending the dosing interval by 4 weeks from 6 weeks up to 10 weeks), dose reduction or permanent discontinuation of treatment with Pluvicto. If a treatment delay due to an adverse drug reaction persists for >4 weeks, treatment with Pluvicto must be discontinued.¹

The dose of Pluvicto may be reduced by 20% once; the dose should not be re-escalated.¹

If a patient has further adverse drug reactions that would require an additional dose reduction, treatment with Pluvicto must be discontinued.¹

Grading according to most current Common Terminology Criteria for Adverse Events(CTCAE).

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

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

Risk from radiation exposure
Pluvicto contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer.
Radiation exposure to patients, medical personnel, and household contacts should be minimised during and after treatment with Pluvicto consistent with institutional good radiation safety practices, patient management procedures, and instructions to the patient for follow-up radiation protection at home.

Patient preparation
Patients should be encouraged to increase oral fluids and urged to void as often as possible to reduce bladder radiation, especially after high activities, e.g. for radionuclide therapy.

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

Following administration of Pluvicto, patients should be advised to:

• limit close contact (less than 1 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 occurred more frequently in patients who received Pluvicto plus best standard of care (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 VISION study, renal toxicity occurred more frequently in patients who received Pluvicto plus 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 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.

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

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

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

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

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 lutetium (¹⁷⁷Lu) vipivotide tetraxetan in human milk or its effects on the breast-fed newborn/infant or on milk production.

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

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.

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

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

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

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

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