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  • Lutathera 370 MBq/mL Solution for Infusion
    / Marshall Isotope


    Active Ingredient

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    20.5 to 25.0 ml

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    Dosage

    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 which could be extended up to 16 weeks in case of dose modifying toxicity (DMT) (see Table 5 at the attached doctor’s leaflet).
    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 at the attached doctor’s leaflet.
    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:
    • Liver function (alanine aminotransferase [ALAT], aspartate aminotransferase [ASAT], albumin, bilirubin)
    • Kidney function (creatinine and creatinine clearance)
    • Haematology (Haemoglobin [Hb], white blood count, platelet count)
    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. Dosing may need to be modified based on the
    tests results.
    Dose modification: In some circumstances, it might be necessary to temporarily discontinue treatment with Lutathera, adapt the dose after the first administration or even discontinue the treatment (see Table 3 – Table 5 and Figure 1 at the attached doctor’s leaflet).
    Elderly: 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 of lutetium (177Lu) oxodotreotide in patients with severe renal impairment (creatinine clearance < 30 mL/min) has not been studied, therefore treatment with Lutathera in those patients is contraindicated. As this medicinal product is known to be substantially excreted by the kidneys, patients with mild to moderate impaired renal function should be more frequently monitored during the treatment.
    For additional details about the treatment of patient with renal impairment see prescribing information.
    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, therefore treatment with Lutathera in those patients is not recommended.
    For additional details about the treatment of patient with mild to moderate hepatic impairment, see prescribing information.
    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).
    See prescribing information for full details.


    Indications

    Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults.


    Contra-Indications

    Hypersensitivity to the active substance, to any of the excipients listed in section 6.1.
    • Established or suspected pregnancy or when pregnancy has not been excluded (see section 4.6).
    • Kidney failure with creatinine clearance < 30 mL/min.


    Special Precautions

    Patients with risk factors: 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 5 at the attached doctor’s leaflet in case of dose modifying toxicity.
    • Renal or urinary tract morphological abnormalities;
    • Urinary incontinence;
    • Mild to moderate chronic kidney disease with creatinine clearance ≥ 50 mL/min;
    • Previous chemotherapy;
    • Hematologic toxicity greater or equal to grade 2 (CTCAE) before treatment other than lymphopenia;
    • Bone metastasis;
    • Previous oncologic radiometabolic therapies with 131I-compounds or any other therapy using unshielded radioactive sources;
    • History of other malignant tumours unless the patient is considered to be in remission for at least 5 years.
    Given the mechanism of action and the tolerance profile of Lutathera, it is not
    recommended to start treatment in the following cases:
    • Previous external beam radiotherapy involving more than 25% of the bone marrow;
    • Severe heart failure defined as class III or IV in the NYHA classifications;
    • Kidney failure with creatinine clearance < 50 mL/min;
    • Impaired haematological function with either Hb < 4.9 mmol/L (8 g/dL), platelets < 75 G/L (75×10³/mm³), or leucocytes < 2 G/L (2,000/mm³) (except lymphopenia);
    • Liver impairment with either total bilirubinemia > 3 times the upper limit of normal or albuminemia < 30 g/L and prothrombin ratio decreased < 70%;
    • Patients with somatostatin receptor negative or mixed visceral lesions (tumour uptake score < 2) according to somatostatin receptor imaging.
    Nevertheless, if the physician decides to start the treatment, clear information should be given to the patient regarding the risks associated with the administration of Lutathera. The posology can be adapted according to the patient’s status at the discretion of the physician.
    See prescribing information for full details.


    Side Effects

    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%).


    Drug interactions

    Somatostatin and its analogues competitively bind to somatostatin receptors. 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
    during the 4 weeks until 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
    11
    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, OCT2,
    OATP1B1, OATP1B3, OCT1 and BCRP transporters in pre-clinical studies suggest that Lutathera has
    a low probability of causing significant other drug-drug interactions.


    Pregnancy and Lactation

    Pregnancy
    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).
    Breast-feeding
    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.


    Overdose

    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.


    Important notes

    Shelf life: 72 hours from the date and time of calibration.
    Storage: 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.


    Manufacturer
    Advanced Accelerator Applications, France
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