Posology : מינונים

4.2    Posology and method of administration

Important safety instructions
Lutathera 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.

Patient identification

Before starting treatment with Lutathera, somatostatin receptor imaging (scintigraphy or positron emission tomography [PET]) must confirm the overexpression of these receptors in the tumour tissue with the tumour uptake at least as high as normal liver uptake (tumour uptake score ≥ 2).

Posology

Adults
The recommended treatment regimen of Lutathera in adults consists of 4 infusions of 7 400 MBq each. The recommended interval between each administration is 8 weeks (±1 week).

Information on dose modifications to manage severe or intolerable adverse drug reactions is given in the respective section below.

Amino acid solution
For renal protection purposes, an amino acid solution containing L-lysine and L-arginine must be administered intravenously over 4 hours (see composition in Tables 1 and 2). The infusion of the amino acid solution should start 30 minutes prior to start of Lutathera infusion. Infusion of the amino acid solution and Lutathera through a separate venous access in each of the patient’s arms is the preferred method. However, if two intravenous lines are not possible due to poor venous access or institutional/clinical preference, the amino acid solution and Lutathera may be infused through the same line via a three-way valve, taking into consideration flow rate and maintenance of venous access.
The dose of the amino acid solution should not be decreased even if a reduced dose of Lutathera is administered.

An amino acid solution containing just L-lysine and L-arginine in the amounts specified in Table 1 is considered the medicinal product of choice, due to the lower total volume to be infused and lower osmolality.

The amino acid solution can be prepared as a compounded product, in compliance with the hospital’s good preparation practices for sterile medicinal products 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 for injection, or      1L water for injections
*equivalent to 20.0 g L-lysine
** equivalent to 20.7 g L-arginine

Alternatively, commercially available amino acid solutions can be used if compliant with the specification described in Table 2.

Table 2 Specification of commercially available amino acid solutions

Characteristic                   Specification
L-lysine HCl                     Between 18 and 25 g*
L-arginine HCl                   Between 18 and 25 g**
Volume                           1 to 2 L
Osmolality                       < 1 200 mOsmol/kg
*equivalent to 14.4-20 g L-lysine
**equivalent to 14.9-20.7 g L-arginine


Treatment monitoring
Before each administration and during the treatment with Lutathera, laboratory tests are required to assess the patient’s condition and adapt the therapeutic protocol as necessary (dose, infusion interval, number of infusions) (see Table 3).

The minimum laboratory tests needed before each infusion are:
•    Haematology (haemoglobin [Hb], white blood cell count with differential counts, platelet count)
•    Kidney function (serum creatinine and creatinine clearance by Cockcroft-Gault formula)
•    Liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], serum albumin, international normalised ratio [INR] and bilirubin)

These laboratory tests should be performed at least once in the 2 to 4 weeks prior to administration and shortly before administration. It is also recommended to perform these tests every 4 weeks for at least 3 months after the last infusion of Lutathera and every 6 months thereafter, in order to be able to detect possible delayed adverse reactions (see section 4.8). Dosing may need to be modified based on the test results (see Table 3).

Dose modification
Management of severe or intolerable adverse drug reactions may require temporary dose interruption (extension of the dosing interval from 8 weeks up to 16 weeks), dose reduction, or permanent discontinuation of treatment with Lutathera (see Table 3Error! Reference source not found. and Figure 1).

Table 3 Recommended dose modifications of Lutathera for adverse drug reactions 
Adverse drug           Severity of adverse drug                      Dose modification reaction                     reaction
Withhold dose until complete or partial resolution (Grade 0 to 1).
First occurrence of:
Grade 2 (platelets <75-50 x        Resume Lutathera at 3 700 MBq (100 mCi) in 109/L)                             patients with complete or partial resolution. If reduced dose does not result in Grade 2, 3 or
Thrombocytopenia        Grade 3 (platelets <50-25 x        4 thrombocytopenia, administer Lutathera at 109/L)                             7 400 MBq (200 mCi) as next dose.

Grade 4 (platelets <25 x 109/L)    Permanently discontinue Lutathera for Grade 2 or higher thrombocytopenia requiring a dosing interval beyond 16 weeks
Recurrent Grade 2, 3 or 4          Permanently discontinue Lutathera.
First occurrence of anaemia:       Withhold dose until complete or partial Grade 3 (Hb <8.0g/dL);             resolution (Grade 0, 1, or 2).
transfusion indicated
Resume Lutathera at 3 700 MBq (100 mCi) in
Grade 4 (life-threatening          patients with complete or partial resolution. If consequences)                      reduced dose does not result in Grade 3 or 4 Anaemia and                                                anaemia or neutropenia, administer Lutathera neutropenia                                                at 7 400 MBq (200 mCi) as next dose.
First occurrence of neutropenia:
Grade 3 (absolute neutrophil count [ANC] <1.0-0.5 x 109/L)      Permanently discontinue Lutathera for Grade 3 or higher anaemia or neutropenia
Grade 4 (ANC <0.5 x 109/L)         requiring a dosing interval beyond 16 weeks.
Recurrent Grade 3 or 4             Permanently discontinue Lutathera.


Adverse drug              Severity of adverse drug                     Dose modification reaction                         reaction
First occurrence of:                Withhold dose until resolution or return to • Creatinine clearance less than    baseline.
40 mL/min; calculated using
Cockcroft-Gault formula with        Resume Lutathera at 3 700 MBq (100 mCi) in actual body weight, or              patients with resolution or return to baseline.
If reduced dose does not result in renal
• 40% increase from baseline        toxicity, administer Lutathera at 7 400 MBq Renal toxicity serum creatinine, or                (200 mCi) as next dose.

• 40% decrease from baseline        Permanently discontinue Lutathera for renal creatinine clearance; calculated    toxicity requiring a dosing interval beyond using Cockcroft-Gault formula       16 weeks.
with actual body weight.
Recurrent renal toxicity            Permanently discontinue Lutathera.
Withhold dose until resolution or return to baseline.

First occurrence of:
Resume Lutathera at 3 700 MBq (100 mCi) in
• Bilirubinaemia greater than patients with resolution or return to baseline.
3 times the upper limit of normal
(Grade 3 or 4), or                  If reduced Lutathera dose does not result in Hepatotoxicity                                               hepatotoxicity, administer Lutathera at 7 400 MBq (200 mCi) as next dose.
• Albuminaemia less than
30 g/L with INR >1.5
Permanently discontinue Lutathera for hepatotoxicity requiring a dosing interval beyond 16 weeks.
Recurrent hepatotoxicity            Permanently discontinue Lutathera.
Any other CTCAE*                                             Withhold dose until complete or partial Grade 3 or Grade 4                                           resolution (Grade 0 to 2).
adverse drug reaction1
Resume Lutathera at 3 700 MBq (100 mCi) in patients with complete or partial resolution.
First occurrence of Grade 3 or 4    If reduced dose does not result in Grade 3 or 4 toxicity, administer Lutathera at 7 400 MBq
(200 mCi) as next dose.

Permanently discontinue Lutathera for
Grade 3 or higher adverse drug reaction requiring a dosing interval beyond 16 weeks.
Recurrent Grade 3 or 4               Permanently discontinue Lutathera.
1
No dose modification required for haematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.
* CTCAE: Common Terminology Criteria for Adverse Events, National Cancer Institute 

Figure 1 Overview of instructions for dose modifications



DMT: Dose-modifying toxicity

Other reasons to consider temporary dose interruption of Lutathera include occurrence of an intercurrent disease (e.g. urinary tract infection) which the physician considers could increase the risks associated with Lutathera administration and which should be resolved or stabilised for treatment to resume, or major surgery, in the event of which treatment should be withheld for 12 weeks after the date of surgery.

Special populations
Elderly
No dose adjustment is required in patients aged 65 years or above as clinical experience has not identified differences in responses between the elderly and younger patients. However, since increased risk of presenting with haematotoxicity has been described in elderly patients (≥70 years old), close follow-up allowing for prompt dose adaptation (DMT) in this population is advisable.

Renal impairment
Careful consideration of the activity to be administered to patients with renal impairment is required since an increased radiation exposure is possible in these patients. The pharmacokinetic profile and safety of lutetium (177Lu) oxodotreotide in patients with baseline severe renal impairment (creatinine clearance <30 mL/min by Cockcroft-Gault formula) or end-stage renal disease )have not been studied.
Treatment with Lutathera in patients with kidney failure with creatinine clearance < 30 mL/min is contraindicated (see section 4.3). Treatment with Lutathera in patients with baseline creatinine clearance <40 mL/min (using Cockcroft-Gault formula) is not recommended. No dose adjustment is recommended for renally impaired patients with baseline creatinine clearance ≥40 mL/min. However, as this medicinal product is known to be substantially excreted by the kidneys, renal function should be more frequently monitored during treatment as these patients may be at greater risk of toxicity.
For additional details about the treatment of patients with renal toxicity, see Table 3 in section 4.2 and section 4.4.

Hepatic impairment
Careful consideration of the activity to be administered to patients with hepatic impairment is required since an increased radiation exposure is possible in these patients. The pharmacokinetic profile and safety of lutetium (177Lu) oxodotreotide in patients with baseline severe hepatic impairment (total bilirubin >3 times upper limit of normal, regardless of AST level) have not been studied. Patients with baseline hepatic impairment with either total bilirubin >3 times the upper limit of normal or albuminaemia <30 g/L and INR >1.5 should only be treated with Lutathera after careful benefit-risk assessment. No dose adjustment is recommended for patients with baseline mild or moderate hepatic impairment.

For additional details about the treatment of patients with hepatotoxicity, see Table 3 in section 4.2 and section 4.4.

Paediatric population
Lutathera is not indicated for paediatric population.
There is no relevant use of Lutathera in the paediatric population in the indication of treatment of GEP-NETs (excluding neuroblastoma, neuroganglioblastoma and phaeochromocytoma).


Method of administration
Lutathera is for intravenous use. It is a ready-to-use radiopharmaceutical medicinal product for single use only.

Lutathera must be administered by slow intravenous infusion over approximately 30 minutes, concomitantly with amino acid solution administered by contralateral intravenous infusion. This medicinal product must not be injected as a bolus.
Premedication with an antiemetic should be injected 30 minutes before the start of amino acid solution infusion.

The recommended infusion method for administration of Lutathera is the gravity method. During administration the recommended precaution measures should be taken (see section 6.6).

Lutathera should be infused directly from its original container. The vial must not be opened or the solution transferred to another container. During the administration only disposable materials should be used.
The medicinal product should be infused through an intravenous catheter placed in the vein exclusively for its infusion.

Requirements
Storage of the vial
•     Either in a container made of polymethyl methacrylate (PMMA), a transparent radioprotection container that allows a direct visual inspection of the vial,
•     Or in the lead container in which Lutathera is supplied.

Room and equipment preparation
•    Administration room:
     The floor and furniture should be covered with tissue paper to avoid any accidental contamination.

•     Medicinal products to be administered:
    One vial of Lutathera
    One bag of sodium chloride 9 mg/mL (0.9%) solution for injection (500 mL)     Amino acid solution bag(s)
    Antiemetic

•     Care supplies and equipment:
     Two infusion poles
     One long needle (90–100 mm)
     One short needle
 Two gravity intravenous infusion sets with a clamp to regulate or stop the flow (one for Lutathera, one for amino acid solution administration)
     Two peripheral intravenous plastic catheters
     One sterile tubing line with a clamp to regulate or stop the flow      A pair of tongs (for Lutathera vial handling)
 Calibrated radioactivity measurement system and Geiger counter to monitor the radioactivity of Lutathera

Lutathera vial tubing connection procedure (see also Figure 2)
•     The tubing line should be pre-filled with sodium chloride 9 mg/mL (0.9%) solution for injection and then connected with a venous catheter already inserted into the patient’s arm.
•     The infusion set should be connected to the bag of sodium chloride 9 mg/mL (0.9%) solution for injection and pre-filled by opening the clamp.
•     The short needle should be inserted into the Lutathera vial, so that it does not touch the radiopharmaceutical solution. This will equilibrate pressure thus reducing any risk of leakage.
•     The short needle should be then connected to the pre-filled infusion set.
•     The long needle should be connected to the pre-filled tubing line and then inserted into the Lutathera vial, so that it touches the bottom of the vial. This will allow for the complete extraction of the radiopharmaceutical solution.
•     The flow of the radiopharmaceutical solution should be regulated with the clamps.

Figure 2 Gravity method - overview of tubing connection procedure



Administration procedure (gravity method)
During the infusion, the flow of sodium chloride 9 mg/mL (0.9%) solution for injection increases the pressure in the Lutathera vial, facilitating the flow of Lutathera 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.
2.    The catheters should be connected to the infusion sets (one for Lutathera, one for amino acid solution).
3.    Antiemetic premedication should be administered 30 minutes before start of amino acid solution infusion (see section 4.2).
4.    Administration of the amino acid solution should be initiated 30 minutes before Lutathera infusion, with an infusion rate of 250 to 550 mL/h (depending on the solution type). Amino acid solution should be administered over a 4-hour time span. Rates lower than 320 mL/h are not recommended for commercial solutions. In case of severe nausea or vomiting during amino acid solution infusion, an antiemetic of a different pharmacological class can be administered.
5.    Radioactivity in the Lutathera vial should be measured immediately before infusion using a calibrated radioactivity measurement system.
6.    The Lutathera infusion should start 30 minutes after the beginning of the amino acid solution infusion, with an infusion rate of approximately 400 mL/h (this infusion rate is the reference rate and can be adapted depending on the patient’s venous status). Lutathera should be administered over 20 to 30 minute time span. Constant intra-vial pressure should be maintained throughout the infusion.
7.    Lutathera administration should be initiated by first opening the tubing line connected to the patient’s peripheral vein, and then, opening the infusion set connected to the bag of sodium chloride 9 mg/mL (0.9%) solution for injection. The pole height should be adjusted in order to compensate any increase or reduction of pressure inside the vial. Moving the patient’s arm position should be avoided if possible (extreme flexion or extension could lead to vein compression).
8.      The flow of Lutathera from the vial to the patient should be monitored throughout the infusion.
Shortly after the start of the infusion, the radioactivity emission over the patient’s thorax should be measured using a Geiger counter to verify the presence of Lutathera in the bloodstream.
Subsequent checks of the radioactivity emission should be performed approximately every 5 minutes at the level of the patient’s thorax and vial. During the infusion, the radioactivity emission from the patient’s thorax should steadily increase while that from the Lutathera vial should decrease.
9.      To ensure complete administration, the Lutathera vial should be kept under even pressure. The level of solution in the vial should remain constant throughout the infusion.
Visual controls of the solution levels should be repeated during administration by direct visual control (when PMMA container is used) or by using a pair of tongs to handle the vial (when the lead shipping container is used).
10.     The infusion should be stopped once the radioactivity emission from the vial has been stable for several minutes (or over two consecutive measurements). This is the only parameter that can be used to determine completion of the procedure. The volume of sodium chloride 9 mg/mL (0.9%) solution for injection necessary to complete the infusion may vary.
11.     Total activity administered is equal to the activity in the vial before infusion minus the activity remaining in the vial after infusion. The measurements should be performed using a calibrated system.

The following table summarises the whole administration procedures for Lutathera as required with the gravity method:

Table 4 Procedure for administration of antiemetic amino acid solution and Lutathera 
Administered agents                          Start time     Infusion rate               Duration (min)          (mL/h)
Antiemetic                                   At least       As per prescribing          As per 30 minutes     information                 prescribing prior to                                   information amino acid solution
Amino acid solution, either
250-500 depending on extemporaneously compounded (1 L) or         0                                          4 hours volume commercial (1 to 2 L)
Lutathera with sodium chloride 9 mg/mL                                                  20 to 30 30             Up to 400
(0.9%) solution for injection                                                           minutes 
For instructions on preparation of the medicinal product before administration, see section 10.
For recommendations in case of extravasation, see section 4.4.