Lutathera Dosage/Direction for Use

Lutathera should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings (see Special precautions for disposal and other handling under Cautions for Usage) 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 as follows.
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 6. (See Table 6.)

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Alternatively, some commercially available amino acid solutions can be used if compliant with the specification described in Table 7. (See Table 7.)

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An amino acid solution containing just lysine and arginine in the amounts specified in Table 6 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 thereof, in order to be able to detect possible delayed adverse reactions (see Adverse Reactions). Dosing may need to be modified based on the tests 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 8 and Figure 3).

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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 Contraindications). 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 8 and Precautions.
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 8 and Precautions.
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 Special precautions for disposal and other handling under Cautions for Usage).
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: 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 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.
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.
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 < 100 mL/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: See Table 9.

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For instructions on the medicinal product before administration, see Instructions for preparation of radiopharmaceuticals under Cautions for Usage.
For patient preparation, see Precautions.
For recommendations in case of extravasation, see Precautions.