Selpercatinib in the first-line treatment of RET fusion-positive NSCLC

December 2022 Pharma News Jolien Blokken

Based on the results of the LIBRETTO-001 trial, selpercatinib was approved and reimbursed in Belgium for the treatment of patients with RET fusion-positive advanced NSCLC who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. Updated results of this trial now led to the broadening of the EMA-approval to also include previously untreated advanced, RET fusion-positive NSCLC.1,2

Oncogenic RET-fusions, resulting in a constitutive activation of RET, are found in approximately 1-2% of patients with non-small cell lung cancer (NSCLC), with a predominance for younger, non-smoking patients and an adenocarcinomatous histology.3 Selpercatinib is a first-in-class, highly selective and potent RET-inhibitor with established central nervous system (CNS) activity.4,5 Based on the results of the LIBRETTO-001 trial, selpercatinib was approved for the treatment of patients with RET fusion-positive advanced NSCLC who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy and is also reimbursed in Belgium in this setting.6,7

LIBRETTO-001

In the open-label, phase I-II LIBRETTO-001 trial, patients with RET-altered advanced or metastatic solid tumours were treated with selpercatinib until disease progression, death, unacceptable toxicity, or withdrawal of consent. To be eligible for the study, patients had to have an ECOG performance status of 0-2. Interestingly, patients with previously treated or untreated brain metastases who were either asymptomatic or had been in neurologically stable condition for at least 2 weeks were also eligible for LIBRETTO-001.8 Of the 796 patients that were enrolled in the study, 356 patients were diagnosed with RET fusion-positive NSCLC.1

Among the 355 patients included in the efficacy population, 69 patients were treatment-naïve, 247 patients were previously treated with platinum-based chemotherapy and 39 patients received other prior therapy. In total, 106 patients had measurable and non-measurable CNS metastases, including 26 patients with measurable CNS metastases. Among the patients previously treated with platinum chemotherapy, the confirmed objective response rate (ORR) was reported at 61.1%. Importantly, in treatment-naïve patients, the ORR mounted to an impressive 84.1%. Despite a median follow-up of approximately two years in the pre-treated and treatment-naïve population, both the median DoR as the median PFS were still not mature. Nonetheless, the median DoR was estimated at 20.2 months for treatment-naïve patients, with an estimated median PFS of 22.0 months. Corresponding values for the platinum-chemotherapy pre-treated population were 28.6 and 24.9 months, respectively.1 Among the 26 patients with measurable CNS disease at baseline, an intracranial ORR of 84.6% was noted with selpercatinib, with a median duration of intracranial response of 9.4 months. Of these patients, seven (26.9%) obtained a complete intracranial response, 15 (57.7%) had a partial response and an additional four (15.4%) had disease stabilization. After a median follow-up of 22.1 months, the intracranial PFS among the 106 patients with measurable or non-measurable CNS disease at baseline was 19.4 months.1 In the safety population (NSCLC patients with ≥1 dose, N=356), the most common treatment-related grade ≥3 adverse events were hypertension (13.8%) and increased ALT (11.5%) or AST (6.7%) levels. Of the 34 (9.6%) patients who discontinued selpercatinib due to an adverse event, 11 (3.1%) were deemed to be treatment-related according to the investigator.1

New EMA-approval for treatment-naïve RET fusion-positive NSCLC patients

Based on these positive results in the first line setting, the EMA extended the label of selpercatinib to include all advanced RET fusion-positive NSCLC patients who were not previously treated with a RET inhibitor.2 As such, selpercatinib can now also be used as first-line therapy in this setting. Given the EMA-approval of selpercatinib, it has become key to also include a test for RET-fusions in the routine biomarker testing protocol. For advanced non-squamous NSCLC, level I alterations (i.e., the alterations that should be screened on a routine basis) include EGFR, ALK, MET, BRAFV600E, ROS, NTRK and RET.9 Of note, since January 1st 2021, RNA NGS testing for RET-fusions in advanced NSCLC is reimbursed in Belgium.10,11

References

1. Drilon A, et al. J Clin Oncol, published online on Sept 19, 2022.

2. https://www.ema.europa.eu/en/medicines/human/EPAR/retsevmo

3. Drusbosky L, et al. J Hematol Oncol. 2021;14:50.

4. Subbiah V, et al. J Clin Oncol. 2020;38(11):1209-21.

5. Subbiah V, et al. Clin Cancer Res. 2021;27(15):4160-7.

6. Retsevmo® Summary of product characteristics, latest approved version via www.fagg-afmps.be/

7. RIZIV/INAMI reimbursement criteria Selpercatinib.

8. Drilon A, et al. N Engl J Med. 2020;383(9):813-24.

9. Mosele F, et al. Ann Oncol. 2020;31(11):1491-1505. 10

10. https://www.compermed.be/cms/public/uploads/compermed/originals/

eee5b4f1-a067-4d46-a1c3-92a41faede1e.pdf

11. https://www.riziv.fgov.be/nl/professionals/verzorgingsinstellingen/laboratoria/

Paginas/oncologie-terugbetaling-moleculair-biologische-ngs.aspx-

#Welke_prestaties_van_NGS_en_voor_welk_bedrag_vergoedt_de_ziekteverzekering


Retsevmo® (selpercatinib) as monotherapy is indicated for the treatment of adults with: • advanced RET fusion-positive non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor. • advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinib. Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC).

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

METHOD OF DELIVERY: Medicinal product subject to restricted medical prescription. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

This material is meant only for individuals allowed by law to prescribe or deliver

PP-SE-BE-0096-NOVEMBER 2022


ProductPackageHospital Price (€)
Retsevmo® 80mg112 caps.9 520,00
Retsevmo® 40mg168 caps.7 224,00

MINIMAL INFORMATIONS OF THE SPC ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Retsevmo 40 mg hard capsules Retsevmo 80 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Retsevmo 40 mg hard capsules Each hard capsule contains 40 mg selpercatinib. Retsevmo 80 mg hard capsules Each hard capsule contains 80 mg selpercatinib. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsules. Retsevmo 40 mg hard capsules Grey opaque capsule, 6 x 18 mm (size 2), imprinted with “Lilly”, “3977” and “40 mg” in black ink. Retsevmo 80 mg hard capsules Blue opaque capsule, 8 x 22 mm (size 0), imprinted with “Lilly”, “2980” and “80 mg” in black ink. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Retsevmo as monotherapy is indicated for the treatment of adults with: advanced RET fusionpositive nonsmall cell lung cancer (NSCLC) not previously treated with a RET inhibitor advanced RET fusionpositive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinib Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RETmutant medullary thyroid cancer (MTC). 4.2 Posology and method of administration Retsevmo therapy should be initiated and supervised by physicians experienced in the use of anticancer therapies. RET testing The presence of a RET gene fusion (NSCLC and nonmedullary thyroid cancer) or mutation (MTC) should be confirmed by a validated test prior to initiation of treatment with Retsevmo. Posology The recommended dose of Retsevmo based on body weight is: Less than 50 kg: 120 mg twice daily. 50 kg or greater: 160 mg twice daily. If a patient vomits or misses a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken. Treatment should be continued until disease progression or unacceptable toxicity. The current selpercatinib dose should be reduced by 50% if coadministering with a strong CYP3A inhibitor. If the CYP3A inhibitor is discontinued, the selpercatinib dose should be increased (after 35 halflives of the inhibitor) to the dose that was used before starting the inhibitor. Dose adjustments Management of some adverse reactions may require dose interruption and/or dose reduction. Retsevmo dose modifications are summarised in Table 1 and Table 2. Table 1 Recommended dose modifications for Retsevmo for adverse reactions based on body weight Starting dose Adults and adolescents ≥50 Kg 160 mg orally twice daily Adults and adolescents <50 Kg 120 mg orally twice daily First dose reduction Adults and adolescents ≥50 Kg 120 mg orally twice daily Adults and adolescents <50 Kg 80 mg orally twice daily Second dose reduction Adults and adolescents ≥50 Kg 80 mg orally twice daily Adults and adolescents <50 Kg 40 mg orally twice daily Third dose reduction Adults and adolescents ≥50 Kg 40 mg orally twice daily Adults and adolescents <50 Kg Not applicable Table 2 Recommended dose modifications for adverse reactions Increased ALT or AST Grade 3 or Grade 4 Suspend dose until toxicity resolves to baseline (see sections 4.4 and 4.8). Resume at a dose reduced by 2 levels. If after at least 2 weeks selpercatinib is tolerated without recurrent increased ALT or AST, increase dosing by 1 dose level. If selpercatinib is tolerated without recurrence for at least 4 weeks, increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. Permanently discontinue selpercatinib if Grade 3 or 4 ALT or AST increases recur despite dose modifications. Hypersensitivity All Grades Suspend dose until toxicity resolves and begin corticosteroids at a dose of 1 mg/kg (see sections 4.4 and 4.8). Resume selpercatinib at 40 mg twice daily while continuing steroid treatment. Discontinue selpercatinib for recurrent hypersensitivity. If after at least 7 days, selpercatinib is tolerated without recurrent hypersensitivity, incrementally increase the selpercatinib dose by 1 dose level each week, until the dose taken prior to the onset of hypersensitivity is reached. Taper steroid dose after selpercatinib has been tolerated for at least 7 days at the final dose. QT interval prolongation Grade 3 Suspend dose for QTcF intervals >500 ms until the QTcF returns to <470 ms or baseline (see section 4.4). Resume selpercatinib treatment at the next lower dose level. Grade 4 Permanently discontinue selpercatinib if QT prolongation remains uncontrolled after two dose reductions or if the patient has signs or symptoms of serious arrhythmia. Hypertension Grade 3 Patient blood pressure should be controlled before starting treatment. Selpercatinib should be suspended temporarily for medically significant hypertension until controlled with antihypertensive therapy. Dosing should be resumed at the next lower dose if clinically indicated (see sections 4.4 and 4.8). Grade 4 Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled. Haemorrhagic events Grade 3 or Grade 4 Selpercatinib should be suspended until recovery to baseline. Discontinue selpercatinib for severe or life-threatening haemorrhagic events. Other adverse reactions Grade 3 or Grade 4 Selpercatinib should be suspended until recovery to baseline. Discontinue selpercatinib for severe or life-threatening eventsc Special populations Elderly No dose adjustment is required based on age (see section 5.2). No overall differences were observed in the treatment emergent adverse events or effectiveness of selpercatinib between patients who were ≥65 years of age and younger patients. Limited data are available in patients ≥75 years. Renal impairment Dose adjustment is not necessary in patients with mild, moderate or severe renal impairment. There are no data in patients with end stage renal disease, or in patients on dialysis (section 5.2). Hepatic impairment Close monitoring of patients with impaired hepatic function is important. No dose adjustment is required for patients with mild (ChildPugh class A) or moderate (ChildPugh class B) hepatic impairment. Patients with severe (ChildPugh class C) hepatic impairment should be dosed with 80 mg selpercatinib twice daily (section 5.2). Paediatric population Retsevmo should not be used in children aged less than 12 years. There is no data in children or adolescents with RET fusionpositive NSCLC or thyroid cancer. Retsevmo is intended to be used from the age of 12 years for the treatment of patients with RETmutant MTC (see section 5.1). In RETmutant MTC, there are very limited data available in children or adolescents aged less than 18 years. Patients should be dosed according to body weight (see section 4.2). Based on results from a preclinical study (see section 5.3), open growth plates in adolescent patients should be monitored. Dose interruption or discontinuation should be considered based on the severity of any growth plate abnormalities and an individual riskbenefit assessment. Method of administration Retsevmo is for oral use. The capsules should be swallowed whole (patients should not open, crush, or chew the capsule before swallowing) and can be taken with or without food. Patients should take the doses at approximately the same time every day. Retsevmo must be accompanied by a meal if used concomitantly with a proton pump inhibitor (see section 4.5). Retsevmo should be administered 2 hours before or 10 hours after H2 receptor antagonists (see section 4.5). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.8 Undesirable effects Summary of the safety profile The most common serious adverse drug reactions (ADRs) are abdominal pain (2.5%), hypersensitivity (2.0%), diarrhoea (1.9%), ALT increased (1.5%) and AST increased (1.5%). Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 8.0% of patients. ADRs resulting in permanent discontinuation (2 or more patients) included increased ALT (0.6%), fatigue (0.6%), increased AST (0.5%), hypersensitivity (0.3%), and thrombocytopenia (0.3%). Tabulated list of adverse drug reactions The ADRs reported in the 796 patients treated with selpercatinib are shown in Table 3. The ADRs are classified according to MedDRA the system organ class. Frequency groups are defined by the following convention: 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 available data). Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Median time on treatment with selpercatinib was 21.3 months. Table 3 Adverse drug reactions in patients receiving single agent selpercatinib (LIBRETTO001) Selpercatinib (N=796) Immune system disordersa Common Hypersensitivityc All grades toxicity (%) 5.9 Grade 3, 4 toxicity (%) 1.9* Metabolism and nutrition disorders Very common Decreased appetite All grades toxicity (%) 18.8 Grade 3, 4 toxicity (%) 0.4* Nervous system disorders Very common Headached All grades toxicity (%) 27.6 Grade 3, 4 toxicity (%) 1.4* Dizzinesse All grades toxicity (%) 19.1 Grade 3, 4 toxicity (%) 0.3* Cardiac disorders Very common Electrocardiogram QT prolonged,f All grades toxicity (%) 21.1 Grade 3, 4 toxicity (%) 4.8* Vascular disorders Very common Hypertensiong All grades toxicity (%) 41.0 Grade 3, 4 toxicity (%) 19.7 Gastrointestinal disorders Very common Abdominal painh All grades toxicity (%) 33.7 Grade 3, 4 toxicity (%) 2.5* Diarrhoeai All grades toxicity (%) 47.0 Grade 3, 4 toxicity (%) 5.0* Nausea All grades toxicity (%) 31.2 Grade 3, 4 toxicity (%) 1.1* Vomiting All grades toxicity (%) 22.4 Grade 3, 4 toxicity (%) 1.8* Constipation All grades toxicity (%) 32.8 Grade 3, 4 toxicity (%) 0.8* Dry Mouthj All grades toxicity (%) 43.2 Grade 3, 4 toxicity (%) 0 Skin and subcutaneous tissue disorders Very common Rashk All grades toxicity (%) 32.8 Grade 3, 4 toxicity (%) 0.6* General disorders and administration site conditions Very common Pyrexia All grades toxicity (%) 17.0 Grade 3, 4 toxicity (%) 0.1* Fatiguel All grades toxicity (%) 45.9 Grade 3, 4 toxicity (%) 3.1* Oedemam All grades toxicity (%) 48.5 Grade 3, 4 toxicity (%) 0.8* Investigations b Very common AST increased All grades toxicity (%) 58.9 Grade 3, 4 toxicity (%) 10.6 ALT increased All grades toxicity (%) 55.5 Grade 3, 4 toxicity (%) 11.8 Platelets decreased All grades toxicity (%) 37.4 Grade 3, 4 toxicity (%) 3.2 Lymphocyte count decreased All grades toxicity (%) 51.8 Grade 3, 4 toxicity (%) 19.5 Magnesium decreased All grades toxicity (%) 32.9 Grade 3, 4 toxicity (%) 0.6 Creatinine increased All grades toxicity (%) 47.3 Grade 3, 4 toxicity (%) 2.4 Blood and lymphatic system Very common Haemorrhagen All grades toxicity (%) 22.0 Grade 3, 4 toxicity (%) 2.6 * Only includes a grade 3 adverse reaction. a Hypersensitivity reactions were characterised by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient’s first cycle of treatment (typically between Days 721). b Based on laboratory assessments. Percentage is calculated based on the number of patients with baseline assessment and at least one postbaseline assessment as the denominator, which was 765 for lymphocyte count decrease, 787 for magnesium decreased and 791 for the others. c Hypersensitivity includes drug hypersensitivity and hypersensitivity d Headache includes headache, sinus headache and tension headache. e Dizziness includes dizziness, vertigo, presyncope and dizziness postural. f Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and Electrocardiogram QT interval abnormal. g Hypertension includes hypertension and blood pressure increased. h Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain. i Diarrhoea includes diarrhoea, anal incontinence, defaecation urgency, frequent bowel movements and gastrointestinal hypermotility. j Dry mouth includes dry mouth and mucosal dryness. k Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash pruritic, rash papular, rash morbilliform. l Fatigue includes fatigue, asthenia and malaise. m Oedema includes oedema peripheral, face oedema, periorbital oedema, swelling face, peripheral swelling, localised oedema, eyelid oedema, eye swelling, lymphoedema, orbital oedema, eye oedema, oedema, swelling, scrotal oedema and scrotal swelling. n Haemorrhage includes epistaxis, haematuria, contusion, haemoptysis, rectal haemorrhage, haematochezia, ecchymosis, petechiae, vaginal haemorrhage, blood urine present, gastric haemorrhage, traumatic haematoma, cerebral haemorrhage, gingival bleeding, mouth haemorrhage, purpura, blood blister, haemorrhage intracranial, spontaneous haematoma, subarachnoid haemorrhage, subdural haemorrhage, abdominal wall haematoma, anal haemorrhage, angina bullosa haemorrhagica, conjunctival haemorrhage, disseminated intravascular coagulation, diverticulum intestinal haemorrhagic, eye haemorrhage, gastrointestinal haemorrhage, haematemesis, haemorrhage, haemorrhage subcutaneous, haemorrhagic stroke, haemorrhoidal haemorrhage, hepatic haematoma, hepatic haemorrhage, intra-abdominal haemorrhage, laryngeal haemorrhage, lower gastrointestinal haemorrhage, melaena, occult blood positive, pelvic haematoma, periorbital haematoma, periorbital haemorrhage, pharyngeal haemorrhage, post procedural haemorrhage, postmenopausal haemorrhage, pulmonary contusion, retinal haemorrhage, retroperitoneal haematoma, scleral haemorrhage, skin haemorrhage, upper gastrointestinal haemorrhage, uterine haemorrhage and vessel puncture site haematoma. Description of selected adverse reactions Aminotransferase elevations (AST / ALT increased) Based on laboratory assessment, ALT and AST elevations were reported in 55.5% and 58.9% patients, respectively. Grade 3 or 4 ALT or AST elevations were reported in 11.8% and 10.6% patients respectively. The median time to first onset was: AST increase 4.3 weeks (range: 0.7, 151.7), ALT increase 4.3 weeks (range: 0.9, 144.0). Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see section 4.2). QT interval prolongation In the 792 patients who had ECGs, review of data showed 7.3% of patients had >500 msec maximum postbaseline QTcF value, and 19.8% of patients had a >60 msec maximum increase from baseline in QTcF intervals. At the time of the last post-baseline measurement, increase in QTc value >60 msec was reported in 2.1% of patients. There were no reports of Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, or ventricular flutter related to selpercatinib. No patient discontinued treatment due to QT prolongation. Retsevmo may require dose interruption or modification (see sections 4.2 and 4.4). Hypertension In the 793 patients who had blood pressure measurements, the median maximum increase from baseline systolic pressure was 31 mm Hg (range: –12, +96). Only 10.8% of patients retained their baseline grade during treatment, 42.2% had an increasing shift of 1 grade, 37.1% of 2 grades, and 9.3% of 3 grades. A treatment emergent adverse event of hypertension was reported in 43.9% patients with history of hypertension (28.2% with grade 3, 4) and 38.8% of patients without history of hypertension (13.7% with grade 3, 4). Overall, a total of 19.6% displayed treatmentemergent Grade 3 hypertension (defined as maximum systolic blood pressure greater than 160 mm Hg). Grade 4 treatment emergent hypertension was reported in 0.1% of patients. Diastolic blood pressure results were similar, but the increases were of lesser magnitude. One patient was permanently discontinued due to hypertension. Dose modification is recommended in patients who develop hypertension (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy (see section 4.4). Hypersensitivity Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or increased aminotransferase. In study LIBRETTO001, 24.7% (197/796) of patients treated with selpercatinib had previously received antiPD1/PDL1 immunotherapy. Hypersensitivity occurred in a total of 5.9% (47/796) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.9% (15/796) of patients. Of the 47 patients with hypersensitivity, 55.3% (26/47) had NSCLC and had received prior antiPD1/PDL1 immunotherapy. Grade 3 hypersensitivity occurred in 3.6% (7/197) of the patients previously treated with antiPD1/PDL1 immunotherapy. The median time to onset was 1.9 weeks (range: 0.7 to 112.1 weeks): 1.7 weeks in patients with previous antiPD1/PDL1 immunotherapy and 4.4 weeks in patients who were antiPD1/PDL1 immunotherapy naïve. Retsevmo may require dose interruption or modification (see section 4.2). Haemorrhages Grade ≥3 haemorrhagic events occurred in 3.1% of patients treated with selpercatinib, including 4 (0.5%) patients with fatal haemorrhagic events, two cases of cerebral haemorrhage, and one case each of tracheostomy site haemorrhage, and haemoptysis. The median time to onset was 24.3 weeks (range: 0.1 week to 147.6 weeks). Selpercatinib should be discontinued permanently in patients with severe or lifethreatening haemorrhage (see section 4.2). Additional information on special populations Paediatric patients There were 3 patients < 18 years (range: 1517) of age in LIBRETTO001. The safety of selpercatinib in children aged less than 18 years has not been established. Elderly In patients receiving selpercatinib, 24.4% were ≥6574 years of age, 8.3% were 7584 years of age, and 1.0% ≥ 85 years of age. The frequency of serious adverse events reported was higher in patients ≥6574 years (51.5%), 7584 years (56.1%), and ≥85 years (100.0%), than in patients <65 years (39.4%) of age. The frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥6574 years (7.2%), 7584 years (18.2%), and ≥85 years (25.0%), than in patients <65 years of age (6.8%). Reporting of suspected adverse reactions 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: Belgium : Agence fédérale des médicaments et des produits de santé, Division Vigilance, Boîte Postale 97, B- 1000 Bruxelles Madou, Site internet: www.notifieruneffetindesirable.be, e-mail: adr@afmps.be. Luxembourg : Centre Régional de Pharmacovigilance de Nancy, Bâtiment de Biologie Moléculaire et de Biopathologie (BBB), CHRU de Nancy – Hôpitaux de Brabois, Rue du Morvan, 54 511 VANDOEUVRE LES NANCY CEDEX, Tél : (+33) 3 83 65 60 85 / 87, E-mail : crpv@chru-nancy.fr ou Direction de la Santé, Division de la Pharmacie et des Médicaments, 20, rue de Bitbourg, L-1273 Luxembourg-Hamm, Tél. : (+352) 2478 5592, E-mail : pharmacovigilance@ms.etat.lu. Link pour le formulaire : https://guichet.public.lu/fr/entreprises/sectoriel/sante/medecins/notification-effets-indesirables-medicaments.html 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83 3528BJ Utrecht The Netherlands 8. MARKETING AUTHORISATION NUMBER(S) EU/1/20/1527/001 EU/1/20/1527/002 EU/1/20/1527/003 EU/1/20/1527/004 EU/1/20/1527/005 EU/1/20/1527/006 EU/1/20/1527/007 EU/1/20/1527/008 EU/1/20/1527/009 EU/1/20/1527/010 EU/1/20/1527/011 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 11 February 2021 Date of latest renewal: 16 December 2021 10. DATE OF REVISION OF THE TEXT 02 September 2022. METHOD OF DELIVERY Medicinal product subject to restricted medical prescription. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

X