Selpercatinib▼ reaffirmed as the standard of care first line treatment for patients with RET-fusion positive advanced non-small cell lung cancer

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 solid tumours, when treatment options not targeting RET provide limited clinical benefit, or have been exhausted (see sections 4.4 and 5.1) Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with: advanced RET fusionpositive thyroid cancer who are radioactive iodine-refractory (if radioactive iodine is appropriate) 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 mutation (MTC) or fusion (all other tumour types) 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 Dose modificationStarting 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 Adverse drug reaction (ADR)/Dose modification 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 Selpercatinib should be suspended until recovery to baseline. Resume at a reduced dose. If Grade 3 events reoccur following dose modification, permanently discontinue selpercatinib. Grade 4 Permanently discontinue selpercatinib. Interstitial lung disease (ILD)/Pneumonitis Grade 2 Withhold selpercatinib until resolution. Resume at a reduced dose. Discontinue selpercatinib for recurrent ILD/ pneumonitis Grade 3 or Grade 4 Discontinue selpercatinib. Other adverse reactions Grade 3 or Grade 4 Selpercatinib should be suspended until recovery to baseline. Resume at a reduced dose. If Grade 4 events reoccur following dose modification, permanently discontinue selpercatinib. 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 tumours except RET fusion-positive thyroid cancer. Retsevmo is intended to be used from the age of 12 years for the treatment of patients with RETmutant MTC and RET fusionpositive thyroid cancer (see section 5.1). In RETmutant MTC and RET fusionpositive thyroid cancer, 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 integrated frequency of ADRs reported in patients treated with selpercatinib from an open-label, multicentre, dose-escalation phase 1/2 study (LIBRETTO-001) and from two open-label, multicentre, randomised phase 3 comparative studies (LIBRETTO-431 and LIBRETTO-531) are summarised. The most common (≥ 1.0%) serious adverse drug reactions (ADRs) are pneumonia (5.3%), haemorrhage (2.4%), abdominal pain (2.1%), blood sodium decreased (2.0%), diarrhoea (1.5%), hypersensitivity (1.4%), vomiting (1.3%), blood creatinine increased (1.3%), pyrexia (1.3%), urinary tract infections (1.3%), ALT increased (1.0%) and AST increased (1.0%). Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 8.8% of patients. The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.7%), fatigue (0.5%), increased AST (0.4%), blood bilirubin increased (0.3%),pneumonia (0.3%), thrombocytopenia (0.3%), haemorrhage (0.3%), and hypersensitivity (0.3%). Tabulated list of adverse drug reactions The integrated frequency and severity of ADRs reported in patients treated with selpercatinib in Study LIBRETTO-001, Study LIBRETTO-431, and Study LIBRETTO-531 are shown in Table 3. The ADRs are classified according to the MedDRA system organ class and frequency. 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). Median time on treatment with selpercatinib was 30.09 months (Study LIBRETTO-001), 16.7 months (Study LIBRETTO-431), and 14.9 months (Study LIBRETTO-531). Table 3 Adverse drug reactions in patients receiving selpercatinib (N=1188) MedDRA system organ class/MedDRA preferred term Infections and infestations Urinary tract infectionsa Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Pneumoniab Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Immune system  disordersc Hypersensitivityd Frequency of all Grades Common Frequency of Grade ≥ 3 Common Endocrine disorders Hypothyroidism Frequency of all Grades Very common Metabolism and nutrition disorders Decreased appetite Frequency of all Grades Very common Frequency of Grade ≥ 3 Uncommon Nervous system disorders Headachee Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Dizzinessf Frequency of all Grades Very common Frequency of Grade ≥ 3 Uncommon Cardiac disorders Electrocardiogram QT prolongedg Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Vascular disorders Hypertensionh Frequency of all Grades Very common Frequency of Grade ≥ 3 Very common Haemorrhagei Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Respiratory, thoracic and mediastinal disorders Interstitial lung disease/pneumonitisj Frequency of all Grades Common Frequency of Grade ≥ 3 Uncommon Chylothorax Frequency of all Grades Common Frequency of Grade ≥ 3 Uncommon Gastrointestinal disorders Diarrhoeak Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Dry Mouthl Frequency of all Grades Very common Frequency of Grade ≥ 3 Uncommon Abdominal painm Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Constipation Frequency of all Grades Very common Frequency of Grade ≥ 3 Uncommon Nausea Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Vomitingn Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Stomatitiso Frequency of all Grades Very common Frequency of Grade ≥ 3 Uncommon Chylous ascitesp Frequency of all Grades Common Frequency of Grade ≥ 3 Uncommon Skin and subcutaneous tissue disorders Rashq Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Musculoskeletal and connective tissue disorders Epiphysiolysis of the femoral headr Frequency of all Grades Common Frequency of Grade ≥ 3 Common General disorders and administration site conditions Oedemas Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Fatiguet Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Pyrexia Frequency of all Grades Very common Frequency of Grade ≥ 3 Uncommon Investigationsu AST increased Frequency of all Grades Very common Frequency of Grade ≥ 3 Very common ALT increased Frequency of all Grades Very common Frequency of Grade ≥ 3 Very common Calcium decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Lymphocyte count decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Very common White blood cell count decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Albumin decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Creatinine increased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Sodium decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Very common Alkaline phosphatase increased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Platelets decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Total bilirubin increased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Neutrophil count decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Haemoglobin decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Magnesium decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common Potassium decreased Frequency of all Grades Very common Frequency of Grade ≥ 3 Common a Urinary tract infections includes urinary tract infection, cystitis, urosepsis, escherichia urinary tract infection, escherichia pyelonephritis,kidney infection, nitrite urine present, pyelonephritis, urethritis, urinary tract infection bacterial and urogenital infection fungal. b Pneumonia includes pneumonia, lung infection, pneumonia aspiration, empyema, lung consolidation, pleural infection, pneumonia bacterial, pneumonia staphylococcal, atypical pneumonia, lung abscess, pneumocystis jirovecii pneumonia, pneumonia pneumococcal, pneumonia respiratory syncytial viral, infectious pleural effusion, and pneumonia viral. c 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). d Hypersensitivity includes drug hypersensitivity and hypersensitivity. e Headache includes headache, sinus headache and tension headache. f Dizziness includes dizziness, vertigo, presyncope and dizziness postural. g Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and Electrocardiogram QT interval abnormal. h Hypertension includes hypertension and blood pressure increased. i Haemorrhage includes epistaxis, haemoptysis, contusion, haematuria, rectal haemorrhage, vaginal haemorrhage, cerebral haemorrhage, traumatic haematoma, blood urine present, conjunctival haemorrhage, ecchymosis, gingival bleeding, haematochezia, petechiae, blood blister, spontaneous haematoma, abdominal wall haematoma, anal haemorrhage, angina bullosa haemorrhagica, disseminated intravascular coagulation, eye haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haemorrhage intracranial, haemorrhage subcutaneous, haemorrhoidal haemorrhage, hepatic haematoma, intra-abdominal haemorrhage, mouth haemorrhage, oesophageal haemorrhage, pelvic haematoma, periorbital haematoma, periorbital haemorrhage, pharyngeal haemorrhage, pulmonary contusion, purpura, retroperitoneal haematoma, skin haemorrhage, subarachnoid haemorrhage, diverticulum intestinal haemorrhagic, eye haematoma, haematemesis, haemorrhage, haemorrhagic stroke, hepatic haemorrhage, laryngeal haemorrhage, lower gastrointestinal haemorrhage, melaena, menorrhagia, occult blood positive, post procedural haemorrhage, postmenopausal haemorrhage, retinal haemorrhage, scleral haemorrhage, subdural haemorrhage, traumatic haemothorax, tumour haemorrhage, upper gastrointestinal haemorrhage, uterine haemorrhage, vessel puncture site haematoma, haemarthrosis and haematoma. j Interstitial lung disease/pneumonitis includes interstitial lung disease, pneumonitis, radiation pneumonitis, restrictive pulmonary disease, acute respiratory distress syndrome, alveolitis, bronchiolitis, langerhans’ cell histiocytosis, pulmonary radiation injury, cystic lung disease, lung infiltration and lung opacity. k Diarrhoea includes diarrhoea, anal incontinence, defaecation urgency, frequent bowel movements and gastrointestinal hypermotility. l Dry mouth includes dry mouth and mucosal dryness. m Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain. n Vomiting includes vomiting, retching and regurgitation. o Stomatitis includes stomatitis, mouth ulceration,mucosal inflammation and oral mucosal blistering. p Chylous ascites includes chylous ascites and ascites chylous (MedDRA LLTs). q Rash includes rash, rash maculo-papular, dermatitis, skin exfoliation, rash macular, rash erythematous, urticaria, dermatitis allergic, exfoliative rash, rash papular, rash morbilliform, rash pruritic, rash vesicular, butterfly rash, rash follicular, rash generalised, rash pustular and skin reaction. r Epiphysiolysis of the femoral head has been commonly observed (6.4%) in paediatric patients (<18 years of age) treated with selpercatinib (n=47). s Oedema includes oedema peripheral, face oedema, periorbital oedema, swelling face, localised oedema, peripheral swelling, generalised oedema, eyelid oedema, eye swelling, lymphoedema,oedema genital, scrotal swelling, angioedema, eye oedema, oedema, scrotal oedema, skin oedema, swelling, orbital oedema, testicular swelling, vulvovaginal swelling, orbital swelling, penile oedema, periorbital swelling and swelling of eyelid. t Fatigue includes fatigue, asthenia and malaise. u 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. Description of selected adverse reactions in patients receiving selpercatinib Aminotransferase elevations (AST / ALT increased) Based on laboratory assessment, ALT and AST elevations were reported in 59.4% and 61% patients, respectively. Grade 3 or 4 ALT or AST elevations were reported in 14.1% and 9.5% patients respectively. The median time to first onset was: AST increase 4.7 weeks (range: 0.7, 227.9), ALT increase 4.4 weeks (range: 0.9, 186.1) in LIBRETTO-001, AST increase 5.1 weeks (range: 0.7, 88.1), ALT increase 5.1 weeks (range: 0.7, 110.9) in LIBRETTO-431, and AST increase 6.1 weeks (range: 0.1, 85.1), ALT increase 6.1 weeks (range: 0.1, 85.1) in LIBRETTO-531. 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 837 patients in study LIBRETTO-001 who had ECGs, review of data showed 8.1% of patients had >500 msec maximum postbaseline QTcF value, and 21.6% of patients had a >60 msec maximum increase from baseline in QTcF intervals. In the 156 patients in LIBRETTO-431 who had ECGs, 5.1% of patients had >500 msec maximum post-baseline QTcF value, and 16.7% of patients had a >60 msec maximum increase from baseline in QTcF intervals. In the 191 patients in LIBRETTO-531 who had ECGs, 3.7% of patients had >500 msec maximum post-baseline QTcF value, and 17.8% of patients had a >60 msec maximum increase from baseline in QTcF intervals. In LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531 studies, there were no reports of torsades de pointes, events of Grade ≥3 or clinically significant treatment-emergent arrhythmias, ventricular tachycardia, ventricular fibrillation, or ventricular flutter. Fatal events of sudden death and cardiac arrest were reported in patients with significant cardiac history. Across all studies, two patients (0.2%) discontinued selpercatinib treatment due to QT prolongation. Retsevmo may require dose interruption or modification (see sections 4.2 and 4.4). Hypertension In the 837 patients who had blood pressure measurements in study LIBRETTO-001, the median maximum increase from baseline systolic pressure was 32 mm Hg (range: –15, +100). Diastolic blood pressure results were similar, but the increases were of lesser magnitude. In LIBRETTO-001, only 10.3% of patients retained their baseline grade during treatment, 40.7% had an increasing shift of 1 grade, 38.5% of 2 grades, and 9.8% of 3 grades. A treatment emergent adverse event of hypertension was reported in 44.8% patients with history of hypertension (28.2% with grade 3, 4) and 41.7% of patients without history of hypertension (14.1% with grade 3, 4). In the 154 patients treated with selpercatinib who had blood pressure measurements in LIBRETTO-431, 23.4% of patients treated with selpercatinib retained their baseline grade during treatment, 49.4% had an increasing shift of 1 grade, 22.7% had an increasing shift of 2 grades, and 3.3% had an increasing shift of 3 grades. In the 192 patients treated with selpercatinib who had blood pressure measurements in LIBRETTO-531, 20.8% of patients treated with selpercatinib retained their baseline grade during treatment, 43.8% had an increasing shift of 1 grade, 27.6% had an increasing shift of 2 grades, and 6.8% had an increasing shift of 3 grades. Overall, a total of 19.8% of patients in LIBRETTO-001, 20.3% of patients in LIBRETTO-431, and 19.2% of patients in LIBRETTO-531 displayed treatment-emergent 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 in LIBRETTO-001, and no reports in LIBRETTO-431 and LIBRETTO-531. Two patients (0.2%) permanently discontinued treatment due to hypertension in LIBRETTO-001, and no patients in LIBRETTO-431 and LIBRETTO-531. 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, 24.0% (201/837) of patients treated with selpercatinib had previously received antiPD1/PDL1 immunotherapy. Hypersensitivity occurred in a total of 5.7% (48/837) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.9% (16/837) of patients. Of the 48 patients with hypersensitivity in LIBRETTO-001, 54.2% (26/48) had NSCLC and had received prior antiPD1/PDL1 immunotherapy. Grade 3 hypersensitivity occurred in 3.5% (7/201) of the patients previously treated with antiPD1/PDL1 immunotherapy in LIBRETTO-001. In LIBRETTO-001, the median time to onset was 1.9 weeks (range: 0.7 to 203.9 weeks): 1.7 weeks in patients with previous antiPD1/PDL1 immunotherapy and 4.4 weeks in patients who were antiPD1/ PDL1 immunotherapy naïve. Study LIBRETTO-431 enrolled patients with advanced or metastatic NSCLC. Hypersensitivity occurred in a total of 1.9% (3/158) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 0.6% (1/158) of patients. In an integrated analysis of patients with NSCLC receiving selpercatinib who were previously treated with anti-PD-1/PD-L1 therapy based on studies LIBRETTO-001 and LIBRETTO-431 (N=205), hypersensitivity occurred in 16.6% of patients, including ≥Grade 3 hypersensitivity in 5.9% of patients. Study LIBRETTO-531 enrolled patients with advanced or metastatic MTC. Hypersensitivity occurred in 1 patient (0.5% [1/193]) receiving selpercatinib. This 1 patient experienced Grade 3 hypersensitivity. Retsevmo may require dose interruption or modification (see section 4.2). Haemorrhages Grade ≥3 haemorrhagic events occurred in 2.5% of patients treated with selpercatinib across studies LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531. In LIBRETTO-001 this included 4 (0.5%) patients with fatal haemorrhagic events, two cases of cerebral haemorrhage, and one case each of tracheostomy site haemorrhage, and haemoptysis. No fatal haemorrhagic events were reported in patients treated with selpercatinib in LIBRETTO-431 or LIBRETTO-531. The median time to onset was 34.1 weeks (range: 0.1 week to 234.6 weeks) in LIBRETTO-001, 16.8 weeks (range: 1.1 to 94.1 weeks) in LIBRETTO-431, and 10.7 weeks (range: 1.0 to 124.1 weeks) in LIBRETTO-531. Selpercatinib should be discontinued permanently in patients with lifethreatening or recurrent severe haemorrhage (see section 4.2). Additional information on special populations Paediatric patients There were 3 patients < 18 years (range: 1517) of age with RETmutant MTC in LIBRETTO001. There were 8 patients < 18 years (range 1217) of age with RET fusionpositive thyroid cancer in LIBRETTO121. There was 1 patient 12 years of age with RET-mutant MTC in LIBRETTO-531. Cases of epiphysiolysis of the femoral head have been reported in patients < 18 years of age treated with selpercatinib (see section 4.4). No other unique safety findings in children aged less than 18 years have been identified. Elderly In patients receiving selpercatinib, 24.7% were ≥6574 years of age, 8.6% were 7584 years of age, and 1.0% ≥ 85 years of age in study LIBRETTO-001. In study LIBRETTO-431, 26.6% of patients receiving selpercatinib were ≥6574 years of age, 9.5% were 7584 years of age and 1.3% were ≥85 years of age. In study LIBRETTO-531, 20.2% of patients receiving selpercatinib were ≥6574 years of age, 5.2% were 7584 years of age and none were ≥85 years of age. The frequency of serious adverse events reported was higher in patients ≥6574 years (58.0%), 7584 years (62.5%), and ≥85 years (100.0%), than in patients <65 years (46.7%) of age in LIBRETTO-001 and in LIBRETTO-431, ≥6574 years (38.1%), 7584 years (46.7%), ≥85 years (50.0%), than in patients <65 years (31.3%) of age. In LIBRETTO-531 the frequency of serious adverse events reported was higher in patients 7584 years (50%) than in patients <65 years (20.8%) and 65-74 years (17.9%). In study LIBRETTO-001 the frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥6574 years (10.1%), 7584 years (19.4%), and ≥85 years (37.5%), than in patients <65 years of age (7.6%). In study LIBRETTO-431, the frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥6574 years (14.3%), 7584 years (20.0%) than in patients <65 years (7.1%) of age. No patients ≥85 years of age discontinued selpercatinib due to AE. In LIBRETTO-531, the frequency of AE leading to discontinuation of selpercatinib was higher in patients 75-84 years (10%), and ≥6574 years (7.7%) than in patients <65 years (3.5%). 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, www.afmps.be, Division Vigilance: Site internet: www.notifieruneffetindesirable.be, e-mail: adr@fagg-afmps.be. Luxembourg : Centre Régional de Pharmacovigilance de Nancy ou Division de la pharmacie et des médicaments de la Direction de la santé Site internet : www.guichet.lu/pharmacovigilance. 7. MARKETING AUTHORISATION HOLDER Eli Lilly Nederland B.V. Papendorpseweg 83 3528BJ Utrecht The Netherlands 8. MARKETING AUTORISATION 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: 05 January 2024 10. DATE OF REVISION OF THE TEXT 11 July 2024. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. METHOD OF DELIVERY Medicinal product subject to restricted medical prescription.