PLUVICTO Solution for injection/infusion Ref.[50608] Active ingredients: Lutetium ¹⁷⁷Lu vipivotide tetraxetan

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:

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 and blood urea increased.
^k Oedema peripheral includes oedema peripheral, fluid retention and fluid overload.

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 via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in sections 4.2 and 12.