Lutathera · 4.6 Fertility, pregnancy and lactation · 1

HOS-097705 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The overall safety profile of Lutathera is based on pooled data from patients from clinical studies (NETTER-1 phase III and Erasmus phase I/II Dutch patients), as well as data from the NETTER-P phase II study and from compassionate use programmes. 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 acid solution 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%). At the time of the NETTER-1 final analysis, after a median follow-up duration of 76 months in each study arm, the safety profile remained consistent with that previously reported. Tabulated list of adverse reactions The adverse reactions are listed in Table 5 according to frequency and MedDRA System Organ Class (SOC). The frequencies are categorised 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). 13 Table 5 Frequency of adverse reactions reported from clinical studies and post-marketing surveillance MedDRA System Very common Common Uncommon Not known Organ Class (SOC) Infections and Conjunctivitis infestations Respiratory tract infection Cystitis Pneumonia Herpes zoster Ophthalmic herpes zoster Influenza

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HOS-097701 · has-contraindication-information · PDF-Seite 7

• Hypersensitivity to the active substance or 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.

HOS-097700 · has-indication-information · PDF-Seite 2

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.

HOS-097703 · has-interaction-information · PDF-Seite 12

Somatostatin analogues 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 up to 24 hours preceding Lutathera administration. Glucocorticoids There is some evidence that glucocorticoids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Therefore, as a matter of caution, repeated administration of high doses of glucocorticoids should be avoided during Lutathera treatment. Patients with a history of chronic use of glucocorticoids should be carefully evaluated for sufficient somatostatin receptor expression. It is not known whether the intermittent use of glucocorticoids for the prevention of nausea and vomiting during Lutathera administration could induce SSTR2 down-regulation. As a matter of caution, glucocorticoids should also be avoided as preventive antiemetic treatment. In the event that the treatment administered for the prevention of nausea and vomiting before the amino acid solution infusion proves insufficient, a single glucocorticoid dose can be used, provided it is not given before initiating or within one hour after the end of Lutathera infusion.

HOS-097704 · has-pregnancy-information · PDF-Seite 12

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 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. Contraception in males and females Lutathera can cause foetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised to use effective contraception during treatment and for 7 months after the last dose of Lutathera. 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. Pregnancy No studies on animal reproductive function have been conducted with lutetium (177Lu) oxodotreotide. Radionuclide procedures carried out on pregnant women also involve a 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 ionising radiation (see section 4.3). Pregnant women should be advised of the risk to a foetus. Breast-feeding It is unknown whether lutetium (177Lu) oxodotreotide is excreted in breast milk. A risk to the breast- fed child associated with ionising radiation cannot be excluded. Breast-feeding should be avoided 12 during treatment with this medicinal product. If treatment with Lutathera during breast-feeding is necessary, the child must be weaned. Fertility No animal studies have been performed to determine the effects of lutetium (177Lu) oxodotreotide on male and female fertility. Ionising 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 for patients before treatment.

HOS-097702 · has-warning-information · PDF-Seite 7

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. 7 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

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