Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

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.
Given the mechanism of action and the tolerance profile of Lutathera, it is not recommended to start treatment with Lutathera in patients with somatostatin receptor-negative or mixed visceral lesions according to somatostatin receptor imaging.

Myelosuppression

Because of the potential for undesirable haematological effects, blood counts must be monitored at baseline and prior to each dose of Lutathera during treatment and until resolution of any eventual toxicity (see section 4.2). Patients with impaired bone marrow function and patients who have received prior chemotherapy or external beam radiotherapy (involving more than 25% of the bone marrow) may be at higher risk of haematological toxicity during Lutathera treatment. Treatment of patients with severely impaired haematological function at baseline and during treatment (e.g. Hb <4.9 mmol/L or 8 g/dL, platelets <75 x 109/L, or leukocytes <2 x 109/L) is not recommended unless solely due to lymphopenia.

Myelodysplastic syndrome and acute leukaemia

Late-onset myelodysplastic syndrome (MDS) and acute leukaemia (AL) have been observed after treatment with Lutathera (see section 4.8), occurring approximately 29 months (9-45) for MDS and 55 months (32-125) for AL after the first Lutathera infusion. The aetiology 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 lutetium (177Lu) oxodotreotide 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. The amino acid solution will help to decrease reabsorption of lutetium (177Lu) oxodotreotide through the proximal tubules, resulting in a significant reduction in the kidney absorbed dose (see section 4.2). When the recommended concomitant amino acid solution infusion is delivered over a 4-hour time span, a mean reduction in kidney radiation exposure of about 47% has been reported.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of and the day after administration of Lutathera (e.g. 1 glass of water every hour).

Renal function as determined by serum creatinine and calculated creatinine clearance using Cockcroft-Gault formula must be assessed at baseline, during and for at least the first year after treatment (see section 4.2).

Patients with renal impairment at baseline or with renal or urinary tract abnormalities, may be at increased risk of toxicity due to increased radiation exposure (see section 4.2).
For patients with creatinine clearance <50 mL/min, an increased risk for transient hyperkalaemia due to the amino acid solution should also be taken into consideration (see Warning and precaution regarding the co-administered renal protective amino acid solution).

Hepatotoxicity

Since many patients referred for Lutathera therapy 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, serum albumin and INR during treatment (see section 4.2).

Hypersensitivity

Cases of hypersensitivity reactions (including isolated angioedema events) have been reported in the post-marketing setting in patients treated with Lutathera (see section 4.8). In the event of serious hypersensitivity reactions, the ongoing Lutathera infusion should be discontinued immediately.
Appropriate medicinal products and equipment to manage such reactions should be available for immediate use.

Nausea and vomiting

To prevent 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 (see section 4.2).

Concomitant use of somatostatin analogues

Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with the efficacy of Lutathera (see section 4.5).

Neuroendocrine hormonal crises

Crises due to excessive release of hormones or bioactive substances may occur following treatment with Lutathera, therefore observation of patients by overnight hospitalisation 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 diarrhoea and/or vomiting.

Tumour lysis syndrome

Tumour lysis syndrome has been reported following therapy with medicinal products containing lutetium-177. Patients with a history of renal insufficiency and high tumour 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

Patients under treatment with Lutathera 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 healthcare professional should determine when the patient can leave the controlled area of the hospital, i.e. when the radiation exposure to third parties does not exceed regulatory thresholds.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of and the day after administration of Lutathera (e.g. 1 glass of water every hour) to facilitate elimination.
They should also be encouraged to defecate every day and to use a laxative if needed. Urine and faeces should be disposed of according to the national regulations.

Provided the patient’s skin is not contaminated, such as from the leakage of the infusion system or because of urinary incontinence, radioactivity contamination is not expected on the skin and in the vomited mass. However, it is recommended that when conducting standard care or examinations with medical devices or other instruments which come into contact with the skin (e.g. electrocardiogram [ECG]), basic protection measures should be observed such as wearing gloves, installing the material/electrode before the start of radiopharmaceutical infusion, changing the material/electrode after measurement, and eventually monitoring the radioactivity of equipment after use.

Before being discharged, the patient should be instructed in the necessary radioprotection rules for interacting with other members of the same household and the general public, and the general precautions the patient must follow during daily activities after treatment (as given in the next paragraph) to minimise radiation exposure to others.

After each administration, the following general recommendations can be considered along with national, local and institutional procedures and regulations:
• Close contact (less than 1 metre) with other people should be limited for 7 days.
• For children and/or pregnant women, close contact (less than 1 metre) 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.
• Patients should sleep in a separate bedroom from children and/or pregnant women for 15 days.

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 Lutathera 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. Depending on the case, aspiration of extravasation fluid, flush injection of sodium chloride 9 mg/mL (0.9%) solution for injection, or application of warm compresses or a heating pad to the infusion site to accelerate vasodilation should be considered.

Symptoms, especially inflammation and/or pain, should be treated. Depending on the situation, the nuclear medicine physician should inform the patient about the risks linked to extravasation injury and give advice about potential treatment and necessary follow-up requirements. The extravasation area must be monitored until the patient is discharged from the hospital. Depending on its severity, this event should be declared as an adverse reaction.

Patients with urinary incontinence

During the first 2 days following administration of this medicinal product, special precautions should be taken with patients with urinary incontinence to avoid spread of radioactive contamination. This includes the handling of any materials possibly contaminated with urine.

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 ionising 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 any of the conditions below are more prone to develop adverse reactions.
Therefore, it is recommended to monitor such patients more frequently during the treatment. Please see Table 3 in case of dose modifying toxicity.
•     Bone metastasis;
•     Previous oncological radiometabolic therapies with 131I compounds or any other therapy using unshielded radioactive sources;
•     History of other malignant tumours unless the patient is considered to have been in remission for at least 5 years.

Contraception in males and females

Female patients of reproductive potential should be advised to use effective contraception during treatment and for 7 months after the last dose of Lutathera (see section 4.6).

Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment and for 4 months after the last dose of Lutathera (see section 4.6).

Specific warnings and precautions regarding the co-administered renal protective amino acid solution 
Hyperkalaemia
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.
Patients with reduced creatinine clearance may be at increased risk for transient hyperkalaemia (see “Renal toxicity” in section 4.4).

Serum potassium levels must be tested before each administration of amino acid solution. In case of hyperkalaemia, the patient’s history of hyperkalaemia and concomitant medicinal product should be checked. Hyperkalaemia must be corrected accordingly before starting the infusion.

In case of pre-existing clinically significant hyperkalaemia, a second monitoring prior to amino acid solution infusion must confirm that hyperkalaemia has been successfully corrected. The patient should be monitored closely for signs and symptoms of hyperkalaemia, e.g. dyspnoea, weakness, numbness, chest pain and cardiac manifestations (conduction abnormalities and cardiac arrhythmias). 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 encouraged to remain hydrated and to urinate frequently before, on the day of and the day after administration (e.g. 1 glass of water every hour) to facilitate elimination of excess serum potassium.

In case hyperkalaemia symptoms develop during amino acid solution infusion, appropriate corrective measures must be taken. In case of severe symptomatic hyperkalaemia, discontinuation of amino acid solution infusion should be considered, taking into consideration the benefit-risk of renal protection versus acute hyperkalaemia.

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 (New York Heart Association) classification. Patients with severe heart failure defined as class III or class IV in the NYHA classification 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.

Specific warnings

Sodium content
This medicinal product contains up to 3.5 mmol (81.1 mg) sodium per vial, equivalent to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Precautions with respect to environmental hazard see section 6.6.

Effects on Driving

4.7    Effects on ability to drive and use machines

Lutathera has no or negligible influence on the ability to drive and use machines. Nevertheless, the general condition of the patient and the possible adverse reactions to treatment must be taken into account before driving or using machines.