Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Advanced Accelerator Applications, 20 rue Diesel, 01630 Saint Genis Pouilly, France
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.
Because of the potential for undesirable effects, blood counts must be monitored at baseline and during treatment and until resolution of any eventual toxicity (see section 4.2). Patients with impaired haematological 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 initiation is not recommended in patients with severely impaired haematological function at baseline (e.g. Hb <4.9 mmol/L or 8 g/dL, platelets <75 g/L or 75 × 103/mm³, or leukocytes <2 g/L or 2000/mm³) (except lymphopenia).
Late-onset myelodisplastic syndrome (MDS) and acute leukaemia (AL) have been observed after treatment with Lutathera (see section 4.8), occurring approximately 28 months (9-41) for MDS and 55 months (32-125) for AL after the end of treatment. Etiology of this 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.
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 acids solution will help to decrease reabsorption of lutetium (177Lu) oxodotreotide through the proximal tubules, resulting in a significant reduction in the kidney radiation dose (see section 4.2). When the recommended concomitant amino acids infusion is delivered over a 4 hour time span, a mean reduction in kidney radiation exposure of about 47% has been reported. It is not recommended to decrease the amount of amino acid solution in case of Lutathera dose adaptation.
Patients should be encouraged to empty their bladder as frequently as possible during the administration of amino acids and the hours after administration. Renal function as determined by serum creatinine and calculated creatinine clearance must be assessed at baseline, during and at least for the first year after treatment (see section 4.2).
Patients with renal impairment at baseline, or with renal or urinary tract morphological abnormalities may be at greater risk of toxicity. Treatment with Lutathera in patients with creatinine clearance <40 mL/min (using Cockcroft Gault) at baseline is not recommended. More frequent monitoring of renal function is recommended in renally impaired patients with creatinine clearance >40 mL/min (see section 4.2).
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 Warning and precaution regarding the co-administered renal protective amino acid solution).
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 ALAT, ASAT, bilirubin and albumin serum during treatment (see section 4.2).
Patients with baseline liver impairment with either total bilirubinemia >3 times the upper limit of normal or albuminemia <30 g/L and prothrombin ratio decreased <70%, should only be treated with Lutathera after careful benefit-risk assessment (see section 4.2).
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 (see section 4.2).
Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with the efficacy of Lutathera (see section 4.5).
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 pharmacologic 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 has been reported following therapy with medicines containing lutetium (177Lu). 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 as well as electrolyte balance should be assessed at baseline and during treatment.
Lutathera should always be infused through an intravenous catheter placed exclusively for its infusion. The adequate position of the catheter should be checked before and during infusion.
The patient treated with Lutathera should be kept away from others during the administration and up to reaching the radiation emission limits stipulated by applicable laws, 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, i.e. when the radiation exposure to third parties does not exceed regulatory thresholds.
The patient should be encouraged to urinate as much as possible after Lutathera administration. Patients 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. The patient should also be encouraged to defecate every day and to use laxative if needed. Urine and faeces should be disposed according to the national regulations.
As long as 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 exams with medical devices or other instruments which contact 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 the patient is released, the nuclear physician should explain the necessary radioprotection rules of interacting with family members and third parties, and the general precautions the patient must follow during daily activities after treatment (as given in next paragraph and the package leaflet) to minimize radiation exposure to others.
Close contact (less than 1 meter) with other people should be limited for 7 days following an administration of Lutathera. 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 an administration of Lutathera. Patients should sleep in separate bedrooms from children and/or pregnant women for 15 days.
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 eventually 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, sodium chloride 9 mg/mL (0.9%) solution for injection flush injection, or applying 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 upon its seriousness, this event should be declared as an adverse reaction.
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.
There is no efficacy data in patients with known brain metastases therefore individual benefit-risk must be assessed in these patients.
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.
A patient presenting with any of the conditions below is more prone to develop adverse reactions. Therefore, it is recommended to monitor those patients more frequently during the treatment. Please see Table 3 in case of dose modifying toxicity.
This medicinal product contains up to 3.5 mmol (81.1 mg) sodium per dose, 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.
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 infusion. Serum potassium levels must be tested before each treatment with amino acid solutions. In case of hyperkalemia, 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 infusion must confirm that hyperkalemia has been successfully corrected. The patient should be monitored closely for signs and symptoms of hyperkalemia, e.g. dyspnea, 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 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 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.
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 (New York Heart Association). 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 volume and osmolality of the amino acid solution.
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 extracellularintracellular potassium and the development of acidosis may be associated with rapid increases in plasma potassium.
Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with the efficacy of Lutathera. 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 until at least 24 hours preceding Lutathera administration.
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 glucocorticosteroids should be avoided during Lutathera treatment. Patients with a history of chronic use of glucocorticosteroids should be carefully evaluated for sufficient somatostatin receptor expression. It is not known if there is of interaction between glucocorticosteroids used intermittently for the prevention of nausea and vomiting during Lutathera administration. Therefore, glucocorticosteroids 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 Lutathera infusion.
The absence of inhibition or significant induction of the human CYP450 enzymes, the absence of specific interaction with P-glycoprotein (efflux transporter) as well as OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 and BCRP transporters in pre-clinical studies suggest that Lutathera has a low probability of causing significant other drug-drug interactions.
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 ionising radiation (if there are any) should be offered to the patient. Before the use of Lutathera, pregnancy should be excluded using an adequate/validated test.
Lutathera can cause fetal harm when administered to a pregnant woman. During treatment with Lutathera and for a minimum of the following 6 months after the end of the treatment, appropriate measures must be taken to avoid pregnancy; this applies to patients of both genders.
No studies on animal reproductive function have been conducted with lutetium (177Lu) oxodotreotide. Radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus. The use of Lutathera is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded due to the risk associated with the ionizing radiation (see section 4.3). Pregnant women should be advised of the risk to a foetus.
It is unknown whether lutetium (177Lu) oxodotreotide is excreted in breast milk. A risk to the suckling child associated with ionising radiation cannot be excluded. Breast-feeding should be avoided during treatment with this medicinal product. If treatment with Lutathera during breast-feeding is necessary, the child must be weaned.
No animal studies have been performed to determine the effects of lutetium (177Lu) oxodotreotide on the fertility of either gender. Ionizing radiations of lutetium (177Lu) oxodotreotide 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 to patients before the treatment.
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.
The overall safety profile of Lutathera is based on pooled data from patients from clinical trials (NETTER-1 phase III and Erasmus phase I/II Dutch patients) and from compassionate use programs.
The most common adverse reactions in patients receiving Lutathera treatment were nausea and vomiting which occurred at the beginning of the infusion in 58.9% and 45.5% of patients, respectively. The causality of nausea/vomiting is confounded by the emetic effect of the concomitant amino acids infusion administered for renal protection.
Due to the bone marrow toxicity of Lutathera, the most expected adverse reactions were related to haematological toxicity: thrombocytopenia (25%), lymphopenia (22.3%), anaemia (13.4%), pancytopenia (10.2%).
Other very common adverse reactions reported include fatigue (27.7%) and decreased appetite (13.4%).
The adverse reactions are listed in Table 5 according to the frequency and the MedDRA System Organ Class (SOC). The frequencies are categorized as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Table 5. Frequency of adverse reactions reported from clinical trials and from post-marketing surveillance:
| MedDRA System Organ Class (SOC) | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Conjunctivitis Respiratory tract infection Cystitis Pneumonia Herpes zoster Ophthalmic herpes zoster Influenza Staphylococcal infections Streptococcal bacteraemia | ||
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Refractory cytopenia with multilineage dysplasia (Myelodysplastic syndrome) | Acute myeloid leukaemia Acute leukaemia Chronic myelomonocytic leukaemia | |
| Blood and lymphatic system disorders | Thrombocytopenia2 Lymphopenia3 Anaemia4Pancytopenia | Leukopenia5 Neutropenia6 | Refractory cytopenia with unilineage dysplasia Nephrogenic anaemia Bone marrow failure Thrombocytopenic purpura |
| Immune system disorders | Hypersensitivity | ||
| Endocrine disorders | Secondary hypothyroidism | Hypothyroidism Diabetes mellitus Carcinoid crisis Hyperparathyroidism | |
| Metabolism and nutrition disorders | Decreased appetite | Hyperglycaemia Dehydration Hypomagnesaemia Hyponatremia | Hypoglycaemia Hypernatremia Hypophosphatemia Tumor lysis syndrome Hypercalcaemia Hypocalcaemia Hypoalbuminaemia Metabolic acidosis |
| Psychiatric disorders | Sleep disorders | Anxiety Hallucination Disorientation | |
| Nervous system disorders | Dizziness Dysgeusia Headache10 Lethargy Syncope | Formication Hepatic encephalopathy Paraesthesia Parosmia Somnolence Spinal cord compression | |
| Eye disorders | Eye disorders | ||
| Ear and labyrinth disorders | Vertigo | ||
| Cardiac disorders | Electrocardiogram QT prolonged | Atrial fibrillation Palpitations Myocardial infarction Angina pectoris Cardiogenic shock | |
| Vascular disorders | Hypertension7 Flushing Hot flush Hypotension | Vasodilatation Peripheral coldness Pallor Orthostatic hypotension Phlebitis | |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Oropharyngeal pain Pleural effusion Sputum increased Choking sensation | |
| Gastrointestinal disorders | Nausea Vomiting | Abdominal distension Diarrhoea Abdominal pain Constipation Abdominal pain upper Dyspepsia Gastritis | Dry mouth Flatulence Ascities Gastrointestinal pain Stomatitis Haematochezia Abdominal discomfort Intestinal obstruction Colitis Pancreatitis acute Rectal haemorrhage Melaena Abdominal pain lower Haematemesis Haemorrhagic ascites Ileus |
| Hepatobiliary disorders | Hyperbilirubinaemia9 | Pancreatic enzymes decreased Hepatocellular injury Cholestasis Hepatic congestion Hepatic failure | |
| Skin and subcutaneous tissue disorders | Alopecia | Rash Dry skin Swelling face Hyperhidrosis Pruritus generalized | |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain8 Muscle spasms | ||
| Renal and urinary disorders | Acute kidney injury Haematuria Renal failure Proteinuria | Leukocyturia Urinary incontinence Glomerular filtration rate decreased Renal disorder Acute prerenal failure Renal impairment | |
| General disorders and administration site conditions | Fatigue1 | Injection site reaction11 Oedema peripheral Administration site pain Chills Influenza like illness | Injection site mass Chest discomfort Chest pain Pyrexia Malaise Pain Deaths Feeling abnormal |
| Investigations | Blood creatinine increased GGT* increased ALAT** increased ASAT*** increased Blood ALP**** increased | Blood potassium decreased Blood urea increased Glycosylated haemoglobin increased Haematocrit decreased Protein urine Weight decreased Blood creatine phosphokinase increased Blood lactate dehydrogenase increased Blood catecholamines c-reactive protein increased | |
| Injury, poisoning and procedural complications | Clavicle fracture | ||
| Surgical and medical procedures | Transfusion | Abdominal cavity drainage Dialysis Gastrointestinal tube insertion Stent placement Abscess drainage Bone marrow harvest Polypectomy | |
| Social circumstances | Physical disability |
1 Includes Asthenia and Fatigue
2 Includes Thrombocytopenia and Platelet count decreased
3 Includes Lymphopenia and Lymphocyte count decreased
4 Includes Anaemia and Haemoglobin decreased
5 Includes Leukopenia and White blood cell count decreased
6 Includes Neutropenia and Neutrophil count decreased
7 Includes Hypertension and Hypertensive crisis
8 Includes Arthralgia, Pain in extremity, Back pain, Bone pain, Flank pain, Musculoskeletal chest pain and Neck pain
9 Includes Blood bilirubin increased and Hyperbilirubinaemia
10 Includes Headache and migraine
11 Includes injection site reaction, injection site hypersensibility, injection site induration, injection site swelling
* Gamma-glutamyltransferase
** Alanine amino transferase
*** Aspartate amino transferase
**** Alkaline phosphatase
Bone marrow toxicity (myelo-/hematotoxicity) manifested with reversible/transient reductions in blood counts affecting all lineages (cytopenias in all combinations, i.e., pancytopenia, bicytopenias, isolated monocytopenias – anemia, neutropenia, lymphocytopenia, and thrombocytopenia). In spite of an observed significant selective B-cell depletion, no increase in the rate of infectious complications occurs after PRRT. Cases of irreversible hematological pathologies, i.e., premalignant and malignant blood neoplasms (i.e., myelodysplastic syndrome and acute myeloid leukemia, respectively) have been reported following Lutathera treatment.
Lutetium (177Lu) oxodotreotide is excreted by the kidney. The long-term trend of progressive glomerular filtration function deterioration demonstrated in the clinical studies confirms that Lutathera-related nephropathy is a chronic kidney disease that develops progressively over months or years after exposure. An individual benefit-risk assessment is recommended prior to treatment with Lutathera in patients with mild and moderate renal impairment, for additional details see section 4.2 (Table 3) and section 4.4. The use of Lutathera is contraindicated in patients with severe kidney failure (see section 4.3).
Hormonal crises related to bioactive substances release (probably due to lysis of the neuroendocrine tumour cells) have rarely been observed and resolved after appropriate medical treatment (section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 4.2.
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