LUTATHERA Solution for infusion Ref.[10985] Active ingredients: Lutetium ¹⁷⁷Lu oxodotreotide

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.

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.

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.

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

For renal protection purpose, an amino acid solution must be administered intravenously during 4 hours. The infusion of the amino acid solution should start 30 minutes prior to start of Lutathera infusion.

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:

^* equivalent to 20.0 g lysine
^** equivalent to 20.7 g arginine

Alternatively, some 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:

^* equivalent to 14.4-20 g lysine
^** equivalent to 14.9-20.7 g arginine

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

Treatment monitoring

Before each administration and during the treatment, biological tests are required to re-assess the patient’s condition and adapt the therapeutic protocol if necessary (dose, infusion interval, number of infusions).

The minimum laboratory tests needed before each infusion are:

• Haematology (Haemoglobin [Hb], white blood cell count, platelet count)
• Kidney function (serum creatinine and creatinine clearance)
• Liver function (alanine aminotransferase [ALAT], aspartate aminotransferase [ASAT], albumin, bilirubin)

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 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.

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 Lutathera (see Table 3 and Figure 1).

Table 3. Recommended dose modifications of Lutathera for Adverse Drug Reactions:

Figure 1. Scheme 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 according to the physician could increase the risks associated to Lutathera administration, and which should be resolved or stabilized for treatment to resume; and major surgery, in which case treatment should be withheld for 12 weeks after the date of surgery.

Special populations

Elderly

No dosage adjustment is required in patients 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 haematotoxicity has been described in elderly patients (≥ 70 years old), a close follow up allowing for prompt dose adaptation (DMT) in this population is advisable.

Renal impairment

Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients. The pharmacokinetic profile and safety of lutetium (¹⁷⁷Lu) oxodotreotide in patients with severe renal impairment or end-stage renal disease has not been studied. Treatment with Lutathera in patients with severe kidney failure with creatinine clearance <30 mL/min is contraindicated (see section 4.3). Treatment with Lutathera in patients with creatinine clearance <40 mL/min at baseline (using Cockcroft Gault) is not recommended. No dose adjustment is recommended for renally impaired patients with 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 the treatment as these patients may be at a greater risk of toxicity. For additional details about the treatment of patient with renal impairment see Table 3 in section 4.2 and section 4.4.

Hepatic impairment

No dose adjustment is recommended for patients with mild or moderate 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 of lutetium (¹⁷⁷Lu) oxodotreotide in patients with severe hepatic impairment has not been studied (total bilirubin >3 times upper limit of normal and any ASAT), therefore those patients should only be treated with Lutathera after careful benefit-risk assessment. For additional details about the treatment of patient with mild to moderate hepatic impairment, see Table 3 and section 4.4.

Paediatric population

There is no relevant use of Lutathera in the paediatric population in the indication of treatment of GEP-NETs (excluding neuroblastoma, neuroganglioblastoma, 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 antiemetics should be injected at least 30 minutes prior to the start of amino acid solution infusion to reach the full antiemetic efficacy of the selected product, according to the respective product information.

The recommended infusion method for administration of Lutathera is the gravity method, described in more detail in this section. Treating physicians may use other methods deemed appropriate and safe, including the use of infusion pumps, particularly when dose reduction is required. During the administration the recommended radiation safety precaution measures should be undertaken regardless of the infusion method (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 delivered.

Room and equipment preparation:

• Administration room:
  • The floor and the 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)
  • Antiemetics
• Care supplies and equipment:
  • Two infusion poles
  • One Long needle (recommended 90–100 mm, 18 gauge)
  • One Short needle (recommended 25 mm, 20 gauge)
  • 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 connections procedure (see 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 previously inserted to 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 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 infusion method – tubing connection scheme:

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 the vital signs during the infusion is recommended.

1. Two intravenous plastic catheters should be inserted into patient’s peripheral veins, one on 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 at least 30 minutes prior to the 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 500 mL/h (depending on volume). Amino acid solution should be administered over 4 hour time span. 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. Lutathera infusion should start 30 minutes after the beginning of the amino acid solution infusion, with the infusion rate of approximately 400 mL/h (this infusion rate is the reference rate; the infusion should start at a lower rate of <100mL/h for the first 5 to 10 minutes and should then be increased depending on the patient’s venous status). Lutathera should be administered over 30 ± 10 minute time span. Constant intra-vial pressure should be maintained during the entire infusion.
7. Lutathera administration should be initiated by opening first the tubing line connected to the patient’s peripheral vein, and then, by 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 which could lead to vein compression).
8. The flow of Lutathera from the vial to the patient should be monitored during the entire infusion. Soon after the start of the infusion, the radioactivity emission over the patient’s thorax should be measured using 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 the one 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 during the entire infusion. Visual controls of the solution levels should be repeated during the administration by direct visual control (when PMMA container is used) or 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 becomes stable for several minutes (or during two consecutive measurements). This is the only parameter to determine the procedure completion. 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 the infusion. The measurements should be performed using a calibrated system.

The following table summarises the required procedures during a treatment course with Lutathera using the gravity method:

Table 4. Administration procedure of antiemetic, amino acid solution and Lutathera:

For instructions on the medicinal product before administration, see section 12.

For patient preparation, see section 4.4.

For recommendations in case of extravasation, see section 4.4.

Overdose is unlikely with Lutathera as this medicinal product is supplied as a “single dose” and “ready to use” product containing a predefined amount of radioactivity. In the case of overdose, an increase in the frequency of the adverse reactions related to radiotoxicity is expected.

In the event of administration of a radiation overdose with Lutathera, 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 during the first 48 hours after infusion. It is helpful to estimate the effective dose that was applied.

The following checking should be carried out every week, for the next 10 weeks:

• Hematologic monitoring: white blood cells, platelets, and haemoglobin
• Blood chemistry monitoring: serum creatinine and glycaemia.

72 hours from the date and time of calibration.

Store below 25°C.

Store in the original package to protect from ionizing radiation (lead shielding).

Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.

Clear colourless Type I glass vial, closed with a bromobutyl rubber stopper and aluminium seal.

Each vial contains a volume varying from 20.5 to 25.0 mL of solution corresponding to an activity of 7,400 MBq at date and time of infusion.

The vial is enclosed within a lead container for protective shielding.

For single use only.

General warning

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 instruction 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 this container and 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. It is necessary to wear waterproof gloves and suitable aseptic techniques when handling the medicinal product.

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 injected with Lutathera. The use of television monitor systems to monitor the patients is recommended. Given the half-life of ¹⁷⁷Lu 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 7,400 MBq 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, hence radioprotection rules should be followed (section 4.4). Suitable precautions in accordance with national regulations should be taken concerning the activity eliminated by the patients in order to avoid any contaminations.

Any unused medicinal product or waste material should be disposed according to local requirements.