Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
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).
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.
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 continued during treatment in patients not surgically castrated.
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).
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:
| Adverse reaction | Severitya | Dose modification |
|---|---|---|
| Dry mouth | Grade 3 | Reduce Pluvicto dose by 20%. |
| Gastrointestinal toxicity | Grade ≥3 (not amenable to medical intervention) | Withhold Pluvicto until improvement to grade 2 or baseline. Reduce Pluvicto dose by 20%. |
| Anaemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia | Grade 2 | Withhold Pluvicto until improvement to grade 1 or baseline. Manage as deemed appropriate. The use of growth factors is permitted but should be discontinued once improved to grade 1 or baseline. Checking haematinic levels (iron, B12 and folate) and providing supplementation is advocated. Transfusions may be given as clinically indicated. |
| Grade ≥3 | Withhold Pluvicto until improvement to grade 1 or baseline. Reduce Pluvicto dose by 20%. | |
| Renal toxicity | Defined as: • Confirmed serum creatinine increase (grade ≥2) • Confirmed CLcr <50 mL/min; calculate using Cockcroft-Gault with actual body weight | Withhold Pluvicto until improvement. |
| Defined as: • Confirmed ≥40% increase from baseline serum creatinine and • Confirmed >40% decrease from baseline CLcr; calculate using Cockcroft-Gault with actual body weight | Withhold Pluvicto until improvement or return to baseline. Reduce Pluvicto dose by 20%. | |
| Recurrent renal toxicity (grade ≥3) | Permanently discontinue Pluvicto. | |
| Spinal cord compression | Any | Withhold Pluvicto until the compression has been adequately treated and any neurological sequela have stabilised and ECOG performance status has stabilised. |
| Fracture in weight-bearing bones | Any | Withhold Pluvicto until the fracture has been adequately stabilised/treated and ECOG performance status has stabilised. |
| Fatigue | Grade ≥3 | Withhold Pluvicto until improvement to Grade 2 or baseline. |
| Electrolyte or metabolic abnormalities | Grade ≥2 | Withhold Pluvicto until improvement to Grade 1 or baseline. |
| Non-haematological toxicity (clinically significant, not otherwise stated) | Grade ≥2 | Withhold Pluvicto until improvement to Grade 1 or baseline. |
| AST or ALT elevation | AST or ALT >5 times ULN in the absence of liver metastases | Permanently discontinue Pluvicto. |
Abbreviations: CLcr, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; AST, aspartate aminotransferase; 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 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).
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).
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 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.
Radiation dose to specific organs, which may not be the target organ of therapy, can be influenced significantly by pathophysiological changes induced by the disease process. This should be taken into consideration 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 and standard 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 and salivary glands.
The maximum penetration of lutetium-177 in tissue is approximately 2 mm and the mean penetration is 0.67 mm.
Table 4. Estimated absorbed dose for Pluvicto in the VISION sub-study:
| Absorbed dose per unit activity (mGy/MBq)a (N=29) | Calculated absorbed dose for 7 400 MBq administration (Gy)a | Calculated absorbed dose for 6 × 7 400 MBq (44 400 MBq cumulative activity) (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 | 0.03 | 5 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 mSv/MBq | 0.043 mSv/MBq | 0.886 Sv | 0.315 Sv | 5.319 Sv | 1.892 Sv |
a Absorbed dose estimates were derived using OLINDA v2.2. Values have been calculated based on dosimetry estimates at full precision and rounded to relevant digits.
b Derived according to ICRP Publication 103.
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.
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 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.
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.
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