Posology : מינונים

4.2      Posology and method of administration

LuNET-SRY should be administered only by persons authorized to handle radiopharmaceuticals in designated clinical settings (see section 6.6) and after evaluation of the patient by a qualified physician.

Before starting treatment with LuNET-SRY, overexpression of somatostatin receptor in the tumor tissuemust be confirmed by medical imaging, such as positron-emission tomography (PET), wherein tumor uptake is higher than that of the normal liver parenchyma.



Posology
Adults
The recommended treatment regimen of LuNET-SRY in adults consists of 4 infusions of 7,400 MBq each. The recommended interval between each administration is 8 weeks, which could be extended up to 16 weeks in case of dose modifying toxicity (DMT).


Information on dose modifications to manage severe or intolerable adverse drug reactions is provided further under this section.

For renal protection purpose, an amino acid solution must be administered by i.v. infusion during 4 hours. The infusion of the amino acid solution should start 30 min prior to the start of LuNET-SRY infusion. To alleviate the nauseous effect of the amino acid infusion, premedication with antiemetics should be started at least 30 min prior to the start of amino acid infusion, according to the respective product information.

Amino acid solution
The amino acid solution can be prepared as a compounded product, in compliance with the hospital’s sterile medicinal product preparation good practices and according to the composition specified in Table 1.

Table 1.     Composition of the compounded amino acid solution
Compound                                                                                 Amount 
L-lysine HCl                                                                             25 g* L-arginine HCl                                                                           25 g** Sodium chloride 9 mg/mL (0.9%) solution (saline) for injection or water for injection    1L *Equivalent to 20.0 g lysine; ** Equivalent to 20.7 g arginine

Some commercially available amino acid solutions containing a minimum 25 g lysine and 25 g arginine can also be used.

Treatment monitoring
Prior to each administration and between the treatments, adequate tests should be performed to assess the patient’s condition and treatment toxicity and adapt the therapeutic protocol if necessary (administered dose, infusion interval and/or the total number of infusions).
The minimum laboratory tests needed before each infusion include:
• Hematology (hemoglobin (Hb), white blood cell count and platelet count).
• Kidney function (serum creatinine and creatinine clearance).
• Liver function (alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin andbilirubin).
These tests should be performed at least once within 2 to 4 weeks prior to administration, and shortly before the administration. It is also recommended to perform these tests every 4 weeks for at least 3 months after the last infusion of LuNET-SRY and every 6 months thereafter, to be able to detect possible delayed adverse reactions (see section 4.8). Dosing should be adjusted based on the test results.


Dose modification
Management of severe or intolerable adverse drug reactions may require temporary dose interruption, extending dosing interval from 8 weeks up to 16 weeks, dose reduction, or discontinuation of treatment with LuNET-SRY (see below). In case of major surgery, treatment should be withheld for 12 weeks after the date of surgery.


Proposed dose adjustments of LuNET-SRY in cases of adverse drug reactions (ADRs) Thrombocytopenia
In case of grade 2 or higher thrombocytopenia (platelet count <75,000/mL), withhold dose until complete or partial resolution (grade 0 - 1). Subsequently, resume [177Lu]DOTA-TATE at 3,700 MBq (100 mCi). If no grade  2 - 4 thrombocytopenia occurs after the reduced dose, administer LuNET-SRY at 7,400 MBq (200 mCi) in the subsequent dose.
Treatment with LuNET-SRY should be permanently discontinued:
• In grade 2 thrombocytopenia or higher requiring a treatment delay of 16 weeks or longer.
• In recurrent grade 2-4 thrombocytopenia.
Anemia and neutropenia
In case of grade 2 or higher anemia (hemoglobin (Hb) <10 g/dL) or neutropenia (absolute neutrophil count (ANC) per mL <1500), withhold dose until complete or partial resolution (grade 0 - 1). Subsequently, resume [177Lu]DOTA-TATE at 3,700 MBq (100 mCi). If no grade 3 - 4 anemia or neutropeina occurs after the reduced dose, administer LuNET-SRY at 7,400 MBq (200 mCi) in the subsequent dose.
LuNET-SRY should be permanently discontinued:
• In grade 3 - 4 anemia or neutropenia requiring a treatment delay of 16 weeks or longer.
• In recurrent grade 3 - 4 anemia or neutropenia.
Nephrotoxicity
In case of mild renal impairment (creatinine clearance (CrCL) <40 mL/min) or 40% increase in serum creatinine or 40% decrease in CrCL compared to baseline, withhold LuNET-SRY dose until complete resolution or return to baseline values. Subsequently, resume [177Lu]DOTA-TATE at 3,700 MBq (100 mCi). If no renal toxicity occurs after the reduced dose, administer LuNET-SRY at 7,400 MBq (200 mCi) in the subsequent dose.
LuNET-SRY should be permanently discontinued:
• In case of nephrotoxicity requiring a treatment delay of 16 weeks or longer.
• In recurrent nephrotoxicity.
Hepatotoxicity
In case of grade 3 - 4 hyperbilirubinemia (total serum bilirubin >3.0× the upper limit of normal (ULN)), or hypoalbuminemia (serum albumin <30 g/L with a prothrombin ratio < 70%), withhold LuNET-SRY dose until complete resolution or return to baseline values. Subsequently, resume [177Lu]DOTA-TATE at 3,700 MBq (100 mCi). If no hepatotoxicity occurs after the reduced dose, administer LuNET-SRY at 7,400 MBq (200 mCi) in the subsequent dose.
LuNET-SRY should be permanently discontinued:
• In case of hepatotoxicity requiring a treatment delay of 16 weeks or longer.
• In recurrent hepatotoxicity.
Any other ADR possibly related to LuNET-SRY
In case of grade 3 - 4 ADR, withhold dose until complete or partial resolution (grade 0 - 2). Subsequently, resume [177Lu]DOTA-TATE at 3,700 MBq (100 mCi). If no grade 3 -4 toxicity occurs after the reduced dose, administer LuNET-SRY at 7,400 MBq (200 mCi) in the subsequent dose.
LuNET-SRY should be permanently discontinued:
• In case of grade 3 or higher ADR requiring a treatment delay of 16 weeks or longer.
• In recurrent grade 3 - 4 ADR.


Special populations
Elderly
No dosage adjustment is required in patients of 65 years-old or above. However, since increased risk of hematotoxicity has been associated with [177Lu]DOTA-TATE treatment, close monitoring of this population is warranted.


Renal impairment
Since renal clearance is the major route of elimination of LuNET-SRY, the administered activity should be carefully considered in patients with impaired renal function, to avoid increased total body radiation exposure. The pharmacokinetic profile and safety of [177Lu]DOTA-TATE in patients with severe renal impairment or end-stage renal disease have not been studied. LuNET-SRY treatment is contraindicated in severe kidney failure (CrCL <30 mL/min), and is not recommended in patients with CrCL <50 mL/min at baseline. No dose adjustment is recommended for renally impaired patients with CrCL ≥50 mL/min; however, renal function should be frequently monitored as these patients may be at a greater risk of nephrotoxicity.

Hepatic impairment
No studies have been reported on patients with hepatic impairment, therefore such patients should only be treated withLuNET-SRY after careful benefit-risk assessment. There might be increased risk for hepatotoxicity in patients with a high hepatic disease-burden. As a general recommendation, no dose adjustment is required for patients with mild or moderate hepatic impairment. For additional details about the treatment of patient with mild to moderate hepatic impairment, see sections 4.2 and 4.4.

Pediatric population
LuNET-SRY is not authorized for use in pediatric patients. The safety and efficacy of LuNET-SRY in pediatric patients have not been established yet.

Method of administration
Precautions to be taken before manipulating or administering the product LuNET-SRY is a radioactive medicinal product and should be kept away from pregnant women. Its handling by pregnant healthcare professionals is forbidden.
Special precautions for handling of the medicinal product and its associated disposables are described in the following section, and should be done in accordance with the institutional radiation protection guidelines.

LuNET-SRY is a ready-to-use radioactive medicinal product for single use. It must be administered by slow intravenous infusion over approximately 30 min, concomitantly with the administration of a contralateral intravenous infusion of an amino acid solution. It is forbidden to inject this medicinal product as bolus.
Premedication with antiemetics should be started at least 30 min prior to the start of amino acid infusion, according to the respective product information.
The recommended infusion method for administering LuNET-SRY is the gravity method described below.
Throughout the entire process, the recommended radiation safety precaution measures should be undertaken (see section 6.6).

LuNET-SRY should be infused directly from its original container. The vial must not be opened nor the solution be transferred to another container, and only disposable materials should be used for handling it.
The medicinal product should be infused through an intravenous catheter placed in the vein exclusively for LuNET- SRY infusion.


Transport and storage of the vial
LuNET-SRY solution is supplied in a pre-sealed sterile 20 mL clear borosilicate glass bottle, stored inside two radioprotective containers:
1. An inner container made of poly(methyl methacrylate) (PMMA), which attenuates the emitted betta minus particles, and
2. An outer lead container, which attenuates the emitted gamma photons and x-rays. Prior to transport, the lead container is placed within a polyoxymethylene (POM) case stored within a shielded box.

Room and equipment preparation:
Administration room:
The floor and furniture should be covered with sufficient absorbent paper to avoid contamination. Dedicated waste bags indicated with a radioactive sign should be used for discarding all the disposables.

Care supplies and equipment:
Two infusion poles (for LuNET-SRY and for the amino acid infusion)
Two gravity intravenous infusion sets with a clamp for regulating the flow One Long needle (recommended 90 – 100 mm, 18 gauge)
One Short needle (recommended 25 mm, 20 gauge)
Two peripheral intravenous plastic catheters
One sterile tubing line with a clamp to regulate or stop the flow
A pair of long forceps for handling the vial of the radiopharmaceutical A calibrated radioactivity measurement system and a dosimeter for monitoring radioactivity 
Administration procedure (gravity method)
Throughout the infusion, the flow of saline solution for injection into the LuNET SRY vial increases the pressure inside the vial, facilitating the flow of the entirety of the drug product into the catheter inserted in the patient’s peripheral vein.
Careful monitoring of vital signs during the infusion is recommended.

1.    Two intravenous plastic catheters should be inserted into the patient’s peripheral veins, one in each arm unless contraindicated. These catheters are eventually connected to two infusion sets: one for LuNET-SRY administration and one for infusing the amino acid solution.
2.    Antiemetic premedication should be administered at least 30 min prior to the start of aminoacid solution infusion (see section 4.2).
3.    The amino acid solution should be administered over 4 hours, beginning 30 min prior to LuNET-SRY infusion, and proceeding for an additional 3 hours after the cessation of LuNET-SRY infusion.
4.    Before connecting the LuNET-SRY vial with the infusion system, measure its radioactive content using a calibrated radioactivity measurement system.
5.    LuNET-SRY vial tubing connection (Figure 1):
5.1   The tubing line for administering the radiopharmaceutical should be pre-filled with sodium chloride 9 mg/mL (saline) solution for injection and then connected with the venous catheter previously inserted to the patient’s arm.
5.2   The infusion set should be connected to a bag of saline solution for injection and pre-filled by opening the clamp.
5.3   The septum of the LuNET-SRY vial should be poked with the short needle. Care should be taken to position the needle without touching the radioactive solution. This step equilibrates the pressure between the vial content and the ambient pressure, and reduces the risk of leakage. Subsequently, the short needle should be connected to the pre-filled saline infusion set (described in step 5.2).
5.4   The long needle should be connected to the pre-filled tubing line (described in step 5.1) and then inserted into the LuNET-SRY vial, so that it reaches the bottom of the vial, allowing complete transfer of the radiopharmaceutical solution.
6.      It is advised to administer LuNET-SRY infusion over 30 ± 10 min, starting 30 min after the initiation of the amino acid infusion. The pressure within the LuNET-SRY vial should be maintained constant during the infusion. For recommendations in case of extravasation, refer to section 4.4.

Figure 1. LuNET-SRY and amino acid solution tubing connection scheme 


7.    LuNET-SRY administration should be initiated by opening first the tubing line connected to the patient’s peripheral vein, followed by opening the infusion set connected to the bag of saline solution for injection.
Refrain from moving the position of the patient’s arm.
8.    The flow of LuNET-SRY solution from the vial to the patient’s vein should be monitored during the entire infusion. Soon after starting the infusion, the radioactivity emission over the patient’s thorax should be measured using a dosimeter to confirm the presence of LuNET-SRY in the bloodstream. Subsequent 5-6 additional follow-up checks of radioactivity emission should be performed at the level of the patient’s thorax and at the level of the vial during LuNET-SRY infusion. Throughout this time, the radioactivity emitted from the patient’s thorax should steadily increase, with a concomitant decrease in the emitted activity from the LuNET-SRYvial.
9.    To ensure administration of the entire drug product, the LuNET-SRY solution inside the vial should be kept under constant pressure. The level of solution in the vial should remain constant during the entire infusion time. Visual control of the solution level should be repeated during the infusion by direct visual inspection, using a pair of dedicated tongs to handle the vial.
10.   The infusion should be stopped once the radioactivity emitted from the vial becomes stable for several min.
The volume of saline solution for injection necessary to complete the infusion may vary between treatments.
11.   The total administered activity equals the measured activity in the vial before infusion minus the remaining activity in the vial after the infusion. Measurements should be performed using the same calibrated system.


Table 2 summarizes the treatment-related procedures during a single administration of LuNET-SRY using the gravity method:
Table 2.         Summary of antiemetic, amino acid and LuNET-SRY administration 
Administered agent           Relative start time (min)                           Duration Antiemetic                    At least 30 min prior to the amino acid solution   As per prescribing information Amino acid solution           0                                                  4 hours LuNET-SRY infusion            30                                                 30 ± 10 min