LuNet-SRY

/ S.R.Y. (Medical Services) LTD, Israel

This medicinal product should be administered only by persons authorized to handle radiopharmaceuticals in designated clinical settings and after evaluation of the patient by a qualified physician.
Before starting the treatment, overexpression of somatostatin receptor in the tumor tissue must be confirmed by medical imaging, such as positron-emission tomography (PET), wherein tumor uptake is higher than that of the normal liver parenchyma.
Adults:  The recommended treatment regimen 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). See prescribing information for full details.
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, 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. The 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 with the product 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. See prescribing information for full details.
Pediatric population: This medicinal product is not authorized for use in pediatric patients. The safety and efficacy in pediatric patients have not been established yet.

Treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults.

– Hypersensitivity to the active substance or to any of the excipients.
– Established or suspected pregnancy or when pregnancy has not been excluded.
– Kidney failure with creatinine clearance <30 mL/min.

Individual benefit/risk justification: For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required therapeutic effect. See prescribing information for full details.
Myelosuppression: Because of the potential for undesirable effects, blood counts must be monitored at baseline and during treatment and until resolution of any eventual toxicity. Treatment initiation is not recommended in patients with severely impaired hematological function at baseline (except lymphopenia). See prescribing information for full details.
Myelodysplastic syndrome and acute leukaemia: Late-onset myelodysplastic syndrome (MDS) and acute leukaemia (AL) have been observed after treatment with [¹⁷⁷Lu]DOTA-TATE, occurring approximately 29 months (9–45) for MDS and 55 months (32-125) for AL after the first infusion. The etiology of these therapy-related secondary myeloid neoplasms (t-MNs) is unclear. Factors such as age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior exposure to chemotherapeutic agents (specifically alkylating agents), and prior radiotherapy are suggested as potential risks and/or predictive factors for MDS/AL.
Renal toxicity: Because [¹⁷⁷Lu]DOTA-TATE is almost exclusively eliminated through the renal system, it is mandatory to concomitantly administer an amino acid solution containing the amino acids L-lysine and L-arginine. It is not recommended to decrease the amount of amino acid solution in case of dose adjustment. Patients should be encouraged to empty their bladder as frequently as possible during the administration of amino acid solution and in the hours after administration. Renal function as determined by serum creatinine and calculated creatinine clearance must be assessed at baseline, during and for at least the first year after treatment. Treatment in patients with creatinine clearance <40 mL/min at baseline is not recommended. More frequent monitoring of renal function is recommended in renally impaired patients with creatinine clearance ≥40 mL/min. For patients with creatinine clearance <50 mL/min, an increased risk for transient hyperkalemia due to the amino acid solution should also be taken into consideration. See prescribing information for full details.
Hepatic toxicity: Since many of the patients have hepatic metastasis, it may be common to observe patients with altered baseline liver function. Patients with hepatic metastasis or pre-existing advanced hepatic impairment may be at increased risk of hepatotoxicity due to radiation exposure. Therefore, it is recommended to monitor ALT, AST, bilirubin and serum albumin during treatment. Patients with baseline liver impairment with either total bilirubin >3 times the upper limit of normal or albuminemia <30 g/L and INR >1.5, should only be treated after careful benefit-risk assessment.
Nausea and vomiting: To avoid treatment-related nausea and vomiting, an intravenous bolus of an antiemetic medicinal product should be injected at least 30 minutes prior to the start of amino acid solution infusion to reach the full antiemetic efficacy.
Concomitant use of somatostatin analogues: Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with the product efficacy. See prescribing information for full details.
Neuroendocrine hormonal crises: Crises due to excessive release of hormones or bioactive substances may occur following the treatment, therefore observation of patients by overnight hospitalization should be considered in some cases (e.g. patients with poor pharmacological control of symptoms). In case of hormonal crises, recommended treatments are: intravenous high-dose somatostatin analogues, intravenous fluids, corticosteroids, and correction of electrolyte disturbances in patients with diarrhea and/or vomiting.
Tumor lysis syndrome: Tumor lysis syndrome has been reported following therapy with medicines containing lutetium-177. Patients with a history of renal insufficiency and high tumor burden may be at greater risk and should be treated with increased caution. Renal function and electrolyte balance should be assessed at baseline and during treatment.
Radioprotection rules: This medicinal product should always be infused through an intravenous catheter placed exclusively for its infusion. The correct positioning of the catheter should be checked before and during infusion.
Patients should be kept away from others during administration and until the radiation emission limits stipulated by the applicable laws are reached, usually within the 4-5 hours following medicinal product administration. The nuclear medicine physician should determine when the patient can leave the controlled area of the hospital.
Patients should be encouraged to urinate as much as possible after administration. They should be instructed to drink substantial quantities of water (1 glass every hour) on the day of infusion and the day after to facilitate elimination. They should also be encouraged to defecate every day and to use a laxative if needed. Urine and feces should be disposed of according to the national regulations.
It is recommended that when conducting standard care or examinations with medical devices or other instruments which come into contact with the skin, basic protection measures should be observed such as wearing gloves, etc.
Close contact (less than 1 meter) with other people should be limited for 7 days following each administration of this product. For children and/or pregnant women, close contact (less than 1 meter) should be limited to less than 15 minutes per day for 7 days. Patients should sleep in a separate bedroom from other people for 7 days following each administration. Patients should sleep in a separate bedroom from children and/or pregnant women for 15 days. See prescribing information for full details.
Recommended measures in case of extravasation: Disposable waterproof gloves should be worn. The infusion of the medicinal product must be immediately ceased and the administration device (catheter, etc.) removed. The nuclear medicine physician and the radiopharmacist should be informed.
All the administration device materials should be kept in order to measure the residual radioactivity and the activity actually administered and the absorbed dose should be determined. The extravasation area should be delimited with an indelible pen and a picture should be taken if possible. It is also recommended to record the time of extravasation and the estimated volume extravasated.
To continue infusion, it is mandatory to use a new catheter, possibly placing it in a contralateral venous access.
No additional medicinal product can be administered to the same side where the extravasation occurred.
In order to accelerate medicinal product dispersion and to prevent its stagnation in tissue, it is recommended to increase blood flow by elevating the affected arm.
Symptoms, especially inflammation and/or pain, should be treated.
The extravasation area must be monitored until the patient is discharged from the hospital .See prescribing information for full details.
Patients with urinary incontinence: During the first 2 days following administration, special precautions should be taken with patients with urinary incontinence to avoid spread of radioactive contamination. See prescribing information for full details.
Patients with brain metastases: There are no efficacy data in patients with known brain metastases, therefore individual benefit-risk must be assessed in these patients.
Secondary malignant neoplasms: Exposure to ionizing radiation is linked with cancer induction and a potential for development of hereditary defects. The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiation exposure are less than from the disease itself.
Other patients with risk factors: Patients presenting with bone metastasis, previous oncological radiometabolic therapies with 131I compounds or any other therapy using unshielded radioactive sources or with history of other malignant tumors unless the patient is considered to have been in remission for at least 5 years, are more prone to develop adverse reactions. Therefore, it is recommended to monitor such patients more frequently during the treatment. See prescribing information for full details.
Sodium content: This medicinal product contains up to 2.7 mmol (55 mg) sodium per dose, equivalent to 2.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Specific warnings and precautions regarding the co-administered renal protective amino acid solution:
Hyperkalemia: A transient increase in serum potassium levels may occur in patients receiving arginine and lysine, usually returning to normal levels within 24 hours from the start of the amino acid solution infusion. Serum potassium levels must be tested before each administration of amino acid solution. In case of hyperkalemia, the patient’s history of hyperkalemia and concomitant medication should be checked. Hyperkalemia must be corrected accordingly before starting the infusion.
In case of pre-existing clinically significant hyperkalemia, a second monitoring prior to amino acid solution infusion must confirm that hyperkalemia has been successfully corrected. The patient should be monitored closely for signs and symptoms of hyperkalemia. An electrocardiogram (ECG) should be performed prior to discharging the patient.Vital signs should be monitored during the infusion regardless of baseline serum potassium levels. Patients should be instructed to drink substantial quantities of water (at least 1 glass every hour) on the day of infusion to remain hydrated and facilitate excretion of excess serum potassium.
In case hyperkalemia symptoms develop during amino acid solution infusion, appropriate corrective measures must be taken. In case of severe symptomatic hyperkalemia, discontinuation of amino acid solution infusion should be considered, taking into consideration the risk-benefit of renal protection versus acute hyperkalemia. See prescribing information for full details.
Heart failure: Due to potential for clinical complications related to volume overload, care should be taken with use of arginine and lysine in patients with severe heart failure defined as class III or class IV in the NYHA classification. Patients with severe heart failure should only be treated after careful benefit-risk assessment, taking into consideration the volume and osmolality of the amino acid solution.
Metabolic acidosis: Metabolic acidosis has been observed with complex amino acid solutions administered as part of total parenteral nutrition (TPN) protocols. Shifts in acid-base balance alter the balance of extracellular- intracellular potassium and the development of acidosis may be associated with rapid increases in plasma potassium.

Very common: Nausea, vomiting, thrombocytopenia, lymphopenia, anemia, pancytopenia, fatigue, decreased appetite.
Common: Refractory cytopenia with multilineage dysplasia (myelodysplastic syndrome), leukopenia, neutropenia, secondary hypothyroidism, hyperglycemia, dehydration, hypomagnesaemia, hyponatremia, sleep disorders, dizziness, dysgeusia, headache, lethargy, syncope, electrocardiogram qt prolonged, hypertension, flushing, hot flush, hypotension, dyspnea, abdominal distension, diarrhea, abdominal pain constipation, abdominal pain upper, dyspepsia, gastritis, hyperbilirubinaemia, alopecia, musculoskeletal pain, muscle spasms, acute kidney injury, hematuria, renal failure, proteinuria, injection site reaction, edema peripheral, administration site pain, chills, influenza like illness, blood creatinine increased, GGT increased, ALT  increased, AST increased, blood ALP increased, transfusion.
See prescribing information for full details.

Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with the efficacy of this product. Therefore, administration of long-acting somatostatin analogues should be avoided within 30 days prior to the administration of this medicinal product. If necessary, patients may be treated with short-acting somatostatin analogues up to 24 hours preceding administration of the product.
There is some evidence that corticosteroids can induce down-regulation of SST2 receptors. Therefore, as a matter of cautiousness, repeated administration of high-doses of glucocorticoids should be avoided during the treatment. Patients with a history of chronic use of glucocorticoids should be carefully evaluated for sufficient somatostatin receptor expression. It is not known if there is of interaction between glucocorticoids used intermittently for the prevention of nausea and vomiting during the product administration. Therefore, glucocorticoids should be avoided as preventive anti-emetic treatment. In the case where the treatments previously provided for nausea and vomiting are insufficient, a single dose of corticosteroids can be used, as long as it is not given before initiating or within one hour after the end of the product infusion.
The absence of inhibition or significant induction of the human CYP450 enzymes, and the absence of specific interaction with P-glycoprotein (efflux transporter) or OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 and BCRP transporters in pre-clinical studies, suggest that [¹⁷⁷Lu]DOTA-TATE has a low probability of causing significant other drug-drug interactions.

Women of childbearing potential:
When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in any doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionizing radiation (if there are any) should be offered to the patient. Before the use of this medicinal product, pregnancy should be excluded using an adequate/validated test.
Contraception in males and females:
This medicinal product can cause fetal harm when administered to a pregnant woman. During treatment with the product and for a minimum of 6 months after the end of the treatment, appropriate measures must be taken to avoid pregnancy; this applies to both male and female patients.
Pregnancy:
No studies on animal reproductive function have been conducted with [¹⁷⁷Lu]oxodotreotide. Radionuclide procedures carried out on pregnant women also involve a radiation dose to the fetus. The use is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded due to the risk associated with the ionizing radiation. Pregnant women should be advised of the risk to a fetus.
Breast-feeding:
It is unknown whether [¹⁷⁷Lu]DOTA-TATE is excreted in breast milk. A risk to the breast-fed child associated with ionizing radiation cannot be excluded. Breast-feeding should be avoided during treatment with this medicinal product. If during breast-feeding is necessary, the child must be weaned.
Fertility:
No animal studies have been performed to determine the effects of [¹⁷⁷Lu]DOTA-TATE on male and female fertility. Ionizing radiation of [¹⁷⁷Lu]DOTA-TATE may potentially have temporary toxic effects on female and male gonads. Genetic consultation is recommended if the patient wishes to have children after treatment. Cryopreservation of sperm or eggs can be discussed as an option for patients before treatment.

Overdose is unlikely as this medicinal product is supplied as a single-dose and ready-to-use product containing a predefined amount of radioactivity. In the event 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, 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 might be helpful to estimate the effective dose that was applied.
The following laboratory tests should be carried out every week, for the next 10 weeks:
– Hematologic monitoring: white blood cells, platelets and hemoglobin
– Blood chemistry monitoring: serum creatinine and glycemia.

Radiopharmaceuticals should be received, stored, transferred, administered and disposed of only by authorized personnel and in accordance with the regulations and appropriate licenses of the medical center.
Appropriate aseptic precautions should be taken, and adequate aseptic techniques should be used while handling the product.
Radiopharmaceuticals should be handled in line with radiation safety and pharmaceutical quality requirements. Waterproof gloves and suitable personal protective equipment should be used. Use adequate shielding and minimize the exposure to ionizing radiation as low as reasonably achievable. Healthcare personnel are advised to limit the time of close contact with patients injected with the product.