RETSEVMO 80mg capsules medication leaflet

Retsevmo 40 mg hard capsules

Retsevmo 80 mg hard capsules

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.

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.

Retsevmo as monotherapy is indicated for the treatment of adults with:

- advanced RET fusion-positive non-small cell lung cancer (NSCLC) not previously treated witha RET inhibitor- advanced RET fusion-positive solid tumours, when treatment options not targeting RET providelimited 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 olderwith:- advanced RET fusion-positive thyroid cancer who are radioactive iodine-refractory (ifradioactive iodine is appropriate)- advanced RET-mutant medullary thyroid cancer (MTC)

Retsevmo therapy should be initiated and supervised by physicians experienced in the use ofanti-cancer therapies.

RET testing

The presence of a RET gene mutation (MTC) or fusion (all other tumour types) should be confirmedby a validated test prior to initiation of treatment with Retsevmo.

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 itsscheduled 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 co-administering with a strong CYP3Ainhibitor. If the CYP3A inhibitor is discontinued, the selpercatinib dose should be increased (after3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.

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 bodyweight

Dose modification Adults and adolescents Adults and adolescents≥50 Kg <50 Kg

Starting dose 160 mg orally twice daily 120 mg orally twice daily

First dose reduction 120 mg orally twice daily 80 mg orally twice daily

Second dose reduction 80 mg orally twice daily 40 mg orally twice daily

Third dose reduction 40 mg orally twice daily Not applicable

Table 2 Recommended dose modifications for adverse reactions

Adverse drug Dose modificationreaction (ADR)

Increased ALT or Grade 3 or Grade 4 * Suspend dose until toxicity resolves

AST to baseline (see sections 4.4 and 4.8).

Resume at a dose reduced by2 levels.

* If after at least 2 weeks selpercatinibis tolerated without recurrentincreased ALT or AST, increasedosing by 1 dose level.

* If selpercatinib is tolerated withoutrecurrence for at least 4 weeks,increase to dose taken prior to theonset of Grade 3 or 4 increased ASTor ALT.

* Permanently discontinueselpercatinib if Grade 3 or 4 ALT or

AST increases recur despite dosemodifications.

Hypersensitivity All Grades * Suspend dose until toxicity resolvesand begin corticosteroids at a dose of1 mg/kg (see sections 4.4 and 4.8).

Resume selpercatinib at 40 mg twicedaily while continuing steroidtreatment. Discontinue selpercatinibfor recurrent hypersensitivity.

* If after at least 7 days, selpercatinibis tolerated without recurrenthypersensitivity, incrementallyincrease the selpercatinib dose by1 dose level each week, until thedose taken prior to the onset ofhypersensitivity is reached. Tapersteroid dose after selpercatinib hasbeen tolerated for at least 7 days atthe final dose.

QT interval Grade 3 * Suspend dose for QTcF intervalsprolongation >500 ms until the QTcF returns to<470 ms or baseline (see section4.4).

* Resume selpercatinib treatment atthe next lower dose level.

Grade 4 * Permanently discontinueselpercatinib if QT prolongationremains uncontrolled after two dosereductions or if the patient has signsor symptoms of serious arrhythmia.

Hypertension Grade 3 * Patient blood pressure should becontrolled before starting treatment.

* Selpercatinib should be suspendedtemporarily for medically significanthypertension until controlled withantihypertensive therapy. Dosingshould be resumed at the next lowerdose if clinically indicated (seesections 4.4 and 4.8).

Grade 4 * Selpercatinib should be discontinuedpermanently if medically significanthypertension cannot be controlled.

Haemorrhagic Grade 3 * Selpercatinib should be suspendedevents until recovery to baseline. Resume ata reduced dose.

If Grade 3 events reoccur followingdose modification, permanentlydiscontinue selpercatinib.

Grade 4 * Permanently discontinueselpercatinib.

Interstitial lung Grade 2 * Withhold selpercatinib untildisease resolution.(ILD)/Pneumonitis * Resume at a reduced dose.

* Discontinue selpercatinib forrecurrent ILD/pneumonitis

Grade 3 or Grade 4 * Discontinue selpercatinib.

Other adverse Grade 3 or Grade 4 * Selpercatinib should be suspendedreactions until recovery to baseline. Resume ata reduced dose.

* If Grade 4 events reoccur followingdose modification, permanentlydiscontinue selpercatinib.

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 ofselpercatinib between patients who were ≥65 years of age and younger patients. Limited data areavailable in patients ≥75 years.

Dose adjustment is not necessary in patients with mild, moderate or severe renal impairment. Thereare no data in patients with end stage renal disease, or in patients on dialysis (section 5.2).

Close monitoring of patients with impaired hepatic function is important. No dose adjustment isrequired for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepaticimpairment. Patients with severe (Child-Pugh class C) hepatic impairment should be dosed with80 mg selpercatinib twice daily (section 5.2).

Retsevmo should not be used in children aged less than 12 years.

There is no data in children or adolescents with RET fusion-positive 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

RET-mutant MTC and RET fusion-positive thyroid cancer (see section 5.1). In RET-mutant MTC and

RET fusion-positive thyroid cancer, there are very limited data available in children or adolescentsaged less than 18 years. Patients should be dosed according to body weight (see section 4.2). Based onresults from a preclinical study (see section 5.3), open growth plates in adolescent patients should bemonitored. Dose interruption or discontinuation should be considered based on the severity of anygrowth plate abnormalities and an individual risk-benefit assessment.

Retsevmo is for oral use.

The capsules should be swallowed whole (patients should not open, crush, or chew the capsule beforeswallowing) 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 (seesection 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Efficacy across tumour types

The benefit of selpercatinib has been established in single arm trials encompassing a relatively smallsample of patients whose tumours exhibit RET gene fusions. Favourable effects of selpercatinib havebeen shown on the basis of objective response rate and response duration in a limited number oftumour types. The effect may be quantitatively different depending on tumour type, as well as onconcomitant genomic alterations (see section 5.1). For these reasons, selpercatinib should only be usedif there are no treatment options for which clinical benefit has been established, or where suchtreatment options have been exhausted (i.e., no satisfactory treatment options).

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal cases of ILD/pneumonitis have been reported in patients treated withselpercatinib (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of

ILD/pneumonitis. Selpercatinib should be withheld, and patients should be promptly investigated for

ILD if they present with acute or worsening of respiratory symptoms which may be indicative of ILD(e.g., dyspnoea, cough, and fever), and treated as medically appropriate. Based on the severity of

ILD/pneumonitis, the dose of selpercatinib should be interrupted, reduced, or permanentlydiscontinued (see section 4.2).

Increased alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)

Grade ≥3 increased ALT and Grade ≥3 increased AST were reported in patients receivingselpercatinib (see section 4.8). ALT and AST should be monitored prior to the start of selpercatinibtherapy, every 2 weeks during the first 3 months of treatment, monthly for the next 3 months oftreatment, and otherwise as clinically indicated. Based on the level of ALT or AST elevations,selpercatinib may require dose modification (see section 4.2).

Hypertension was reported in patients receiving selpercatinib (see section 4.8). Patient blood pressureshould be controlled before starting selpercatinib treatment, monitored during selpercatinib treatmentand treated as needed with standard anti-hypertensive therapy. Based on the level of increased bloodpressure, selpercatinib may require dose modification (see section 4.2). Selpercatinib should bediscontinued permanently if medically significant hypertension cannot be controlled withantihypertensive therapy.

QT interval prolongation

QT interval prolongation was reported in patients receiving selpercatinib (see section 5.1).

Selpercatinib should be used with caution in patients with such conditions as congenital long QTsyndrome or acquired long QT syndrome or other clinical conditions that predispose to arrhythmias.

Patients should have a QTcF interval of ≤470 ms and serum electrolytes within normal range beforestarting selpercatinib treatment. Electrocardiograms and serum electrolytes should be monitored in allpatients after 1 week of selpercatinib treatment, at least monthly for the first 6 months and otherwise,as clinically indicated, adjusting frequency based upon risk factors including diarrhoea, vomiting,and/or nausea. Hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior toinitiating selpercatinib and during treatment. Monitor the QT interval with ECGs more frequently inpatients who require treatment with concomitant medicinal products known to prolong the QTinterval.

Selpercatinib may require dose interruption or modification (see section 4.2).

Hypothyroidism has been reported in patients receiving selpercatinib (see section 4.8). Baselinelaboratory measurement of thyroid function is recommended in all patients. Patients with pre-existinghypothyroidism should be treated as per standard medical practice prior to the start of selpercatinibtreatment. All patients should be observed closely for signs and symptoms of thyroid dysfunctionduring selpercatinib treatment. Thyroid function should be monitored periodically throughouttreatment with selpercatinib. Patients who develop thyroid dysfunction should be treated as perstandard medical practice, however patients could have an insufficient response to substitution withlevothyroxine (T4) as selpercatinib may inhibit the conversion of levothyroxine to triiodothyronine(T3) and supplementation with liothyronine may be needed (see section 4.5).

Concomitant use of strong CYP3A4 inducers should be avoided due to the risk of decreased efficacyof selpercatinib (see section 4.5).

Women of childbearing potential/Contraception in females and males

Women of childbearing potential must use highly effective contraception during treatment and for atleast one week after the last dose of selpercatinib. Men with female partners of childbearing potentialshould use effective contraception during treatment and for at least one week after the last dose ofselpercatinib (see section 4.6).

Based on nonclinical safety findings, male and female fertility may be compromised by treatment with

Retsevmo (see sections 4.6 and 5.3). Both men and women should seek advice on fertility preservationbefore treatment.

Hypersensitivity was reported in patients receiving selpercatinib with a majority of events observed inpatients with NSCLC previously treated with anti-PD-1/PD-L1 immunotherapy (see section 4.8).

Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias withconcurrent decreased platelets or elevated aminotransferases.

Suspend selpercatinib if hypersensitivity occurs, and begin steroid treatment. Based on the grade ofhypersensitivity reactions, selpercatinib may require dose modification (see section 4.2). Steroidsshould be continued until patient reaches target dose and then tapered. Permanently discontinueselpercatinib for recurrent hypersensitivity.

Haemorrhages

Serious including fatal haemorrhagic events were reported in patients receiving selpercatinib (seesection 4.8).

Permanently discontinue selpercatinib in patients with life-threatening or recurrent severehaemorrhage (see section 4.2).

Cases of TLS have been observed in patients treated with selpercatinib. Risk factors for TLS includehigh tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, andacidic urine. These patients should be monitored closely and treated as clinically indicated, andappropriate prophylaxis including hydration should be considered.

Epiphysiolysis of the femoral head in Paediatric Patients

Epiphysiolysis of the femoral head has been reported in paediatric patients (<18 years of age)receiving selpercatinib (see section 4.8). Patients should be monitored for symptoms indicative ofepiphysiolysis of the femoral head and treated as medically and surgically appropriate.

Effects of other medicinal products on the pharmacokinetics of selpercatinib

Selpercatinib metabolism is through CYP3A4. Therefore, medicinal products that can influence

CYP3A4 enzyme activity may alter the pharmacokinetics of selpercatinib.

Selpercatinib is a substrate for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) invitro, however these transporters do not appear to limit the oral absorption of selpercatinib, as its oralbioavailability is 73% and its exposure was increased minimally by co-administration of the P-gpinhibitor rifampicin (increase of approximately 6.5% and 19% in selpercatinib AUC0-24 and Cmax,respectively).

Agents that may increase selpercatinib plasma concentrations

Co-administration of a single 160 mg selpercatinib dose with itraconazole, a strong CYP3A inhibitor,increased the Cmax and AUC of selpercatinib by 30% and 130%, respectively, compared toselpercatinib given alone. If strong CYP3A and/or P-gp inhibitors, including, but not limited to,ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole andnefazodone, have to be co-administered, the dose of selpercatinib should be reduced (see section 4.2).

Agents that may decrease selpercatinib plasma concentrations

Co-administration of rifampicin, a strong CYP3A4 inducer resulted in a decrease of approximately87% and 70% in selpercatinib AUC and Cmax, respectively, compared to selpercatinib alone, thereforethe concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine,phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), shouldbe avoided.

Effects of selpercatinib on the pharmacokinetics of other medicinal products (increase in plasmaconcentration)

Sensitive CYP2C8 substrates

Selpercatinib increased the Cmax and AUC of repaglinide (a substrate of CYP2C8) by approximately91% and 188% respectively. Therefore, co-administration with sensitive CYP2C8 substrates (e.g.,odiaquine, cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone,buprenorphine, selexipag, dasabuvir and montelukast), should be avoided.

Sensitive CYP3A4 substrates

Selpercatinib increased Cmax and AUC of midazolam (a CYP3A4 substrate) by approximately 39%and 54%, respectively. Therefore, concomitant use with sensitive CYP3A4 substrates, (e.g., alfentanil,avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, lomitapide, lovastatin, midazolam,naloxegol, nisoldipine, saquinavir, simvastatin, tipranavir, triazolam, vardenafil), should be avoided.

Co-administration with medicinal products that affect gastric pH

Selpercatinib has pH-dependent solubility, with decreased solubility at higher pH. No clinicallysignificant differences in selpercatinib pharmacokinetics were observed when co-administered withmultiple daily doses of ranitidine (H2 receptor antagonist) given 2 hours after the selpercatinib dose.

Co-administration with medicinal products that are proton pump inhibitors

Co-administration with multiple daily doses of omeprazole (a proton pump inhibitor) decreasedselpercatinib AUC0-INF and Cmax when selpercatinib was administered fasting. Co-administration withmultiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmaxwhen Retsevmo was administered with food.

Co-administration with medicinal products that are substrates of transporters

Selpercatinib inhibits the renal transporter multidrug and toxin extrusion protein 1 (MATE1). In vivointeractions of selpercatinib with clinically relevant substrates of MATE1, such as creatinine, mayoccur (see section 5.2).

Selpercatinib is an in vitro inhibitor of P-gp and BCRP. In vivo, selpercatinib increased Cmax and AUCof dabigatran, a P-gp substrate, by 43% and 38%, respectively. Therefore, caution should be usedwhen taking a sensitive P-gp substrate (e.g., fexofenadine, dabigatran etexilate, colchicine,saxagliptin), and particularly those with a narrow therapeutic index (e.g., digoxin) (see section 5.2).

Medicinal products that may be less effective when given with selpercatinib

Selpercatinib could inhibit D2 deiodinase and thereby decrease the conversion of levothyroxine (T4)to triiodothyronine (T3). Patients could therefore have an insufficient response to substitution withlevothyroxine and supplementation with liothyronine may be needed (see section 4.4).

Interaction studies have only been performed in adults.

Women of childbearing potential/Contraception in females and males

Women of childbearing potential have to use highly effective contraception during treatment and for atleast one week after the last dose of selpercatinib. Men with female partners of childbearing potentialshould use effective contraception during treatment and for at least one week after the last dose ofselpercatinib.

There are no available data from the use of selpercatinib in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Retsevmo is not recommended during pregnancy and inwomen of childbearing potential not using contraception. It should only be used during pregnancy ifthe potential benefit justifies the potential risk to the foetus.

It is unknown whether selpercatinib is excreted in human milk. A risk to breast-fed newborns/infantscannot be excluded. Breast-feeding should be discontinued during treatment with Retsevmo and for atleast one week after the last dose.

No human data on the effect of selpercatinib on fertility are available. Based on findings from animalstudies, male and female fertility may be compromised by treatment with Retsevmo (see section 5.3).

Both men and women should seek advice on fertility preservation before treatment.

Retsevmo may have minor influence on the ability to drive and use machines. Patients should beadvised to be cautious when driving or using machines in case they experience fatigue or dizzinessduring treatment with Retsevmo (see section 4.8).

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. Themost 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 ofattribution occurred in 8.8% of patients. The most common ADRs resulting in permanentdiscontinuation (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 (≥ 1/100to < 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 MedDRA preferred term Frequency of all Frequency of Gradeorgan class Gra des ≥ 3

Infections and infestations Urinary tract infectionsa Very common Common

Pneumoniab Very common Common

Immune system disordersc Hypersensitivityd Common Common

Endocrine disorders Hypothyroidism Very common -

Metabolism and nutrition Decreased appetite Very common Uncommondisorders

Nervous system disorders Headachee Very common Common

Dizzinessf Very common Uncommon

Cardiac disorders Electrocardiogram QT Very common Commonprolongedg

Vascular disorders Hypertensionh Very common Very common

Haemorrhagei Very common Common

Respiratory, thoracic and Interstitial lung Common Uncommonmediastinal disorders disease/pneumonitisj

Chylothorax Common Uncommon

Gastrointestinal disorders Diarrhoeak Very common Common

Dry Mouthl Very common Uncommon

Abdominal painm Very common Common

Constipation Very common Uncommon

Nausea Very common Common

Vomitingn Very common Common

Stomatitiso

Very common Uncommon

Chylous ascitesp Common Uncommon

Skin and subcutaneous Rashq Very common Commontissue disorders

Musculoskeletal and Epiphysiolysis of Common Commonconnective tissue the femoraldisorders headr

Reproductive system and Erectile dysfunctions Very common Uncommonbreast disorders

General disorders and Oedemat Very common Commonadministration site Fatigueu Very common Commonconditions Pyrexia Very common Uncommon

Investigationsv AST increased Very common Very common

ALT increased Very common Very common

Calcium decreased Very common Common

Lymphocyte count decreased Very common Very common

White blood cell count Very common Commondecreased

Albumin decreased Very common Common

Creatinine increased Very common Common

Sodium decreased Very common Very common

Alkaline phosphatase increased Very common Common

Platelets decreased Very common Common

Total bilirubin increased Very common Common

Neutrophil count decreased Very common Common

MedDRA system MedDRA preferred term Frequency of all Frequency of Gradeorgan class Gra des ≥ 3

Haemoglobin decreased Very common Common

Magnesium decreased Very common Common

Potassium decreased Very common Commona Urinary tract infections includes urinary tract infection, cystitis, urosepsis, escherichia urinary tract infection,escherichia pyelonephritis, kidney infection, nitrite urine present, pyelonephritis, urethritis, urinary tractinfection bacterial and urogenital infection fungal.

b Pneumonia includes pneumonia, lung infection, pneumonia aspiration, empyema, lung consolidation, pleuralinfection, pneumonia bacterial, pneumonia staphylococcal, atypical pneumonia, lung abscess, pneumocystisjirovecii pneumonia, pneumonia pneumococcal, pneumonia respiratory syncytial viral, infectious pleuraleffusion, and pneumonia viral.

c Hypersensitivity reactions were characterised by a maculopapular rash often preceded by a fever withassociated arthralgias/myalgias during the patient’s first cycle of treatment (typically between Days 7-21).

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, vaginalhaemorrhage, cerebral haemorrhage, traumatic haematoma, blood urine present, conjunctival haemorrhage,ecchymosis, gingival bleeding, haematochezia, petechiae, blood blister, spontaneous haematoma, abdominalwall haematoma, anal haemorrhage, angina bullosa haemorrhagica, disseminated intravascular coagulation,eye haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haemorrhage intracranial, haemorrhagesubcutaneous, haemorrhoidal haemorrhage, hepatic haematoma, intra-abdominal haemorrhage, mouthhaemorrhage, 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 gastrointestinalhaemorrhage, melaena, menorrhagia, occult blood positive, post procedural haemorrhage, postmenopausalhaemorrhage, retinal haemorrhage, scleral haemorrhage, subdural haemorrhage, traumatic haemothorax,tumour haemorrhage, upper gastrointestinal haemorrhage, uterine haemorrhage, vessel puncture sitehaematoma, 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’ cellhistiocytosis, pulmonary radiation injury, cystic lung disease, lung infiltration and lung opacity.

k Diarrhoea includes diarrhoea, anal incontinence, defaecation urgency, frequent bowel movements andgastrointestinal hypermotility.

l Dry mouth includes dry mouth and mucosal dryness.m Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal painlower 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 ofage) treated with selpercatinib (n=47).

s Erectile dysfunction has been very commonly observed (12.4%) in male patients treated with selpercatinib inclinical trials (n=986)t Oedema includes oedema peripheral, face oedema, periorbital oedema, swelling face, localised oedema,peripheral swelling, generalised oedema, eyelid oedema, eye swelling, lymphoedema, oedema genital, scrotalswelling, angioedema, eye oedema, oedema, scrotal oedema, skin oedema, swelling, orbital oedema,testicular swelling, vulvovaginal swelling, orbital swelling, penile oedema, periorbital swelling and swellingof eyelid.

u Fatigue includes fatigue, asthenia and malaise.v Based on laboratory assessments. Percentage is calculated based on the number of patients with baselineassessment and at least one post-baseline 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% patientsrespectively.

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 5.1weeks (range: 0.7, 110.9) in LIBRETTO-431, and AST increase 6.1 weeks (range: 0.1, 85.1), ALTincrease 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 (seesection 4.2).

QT interval prolongation

In the 837 patients in study LIBRETTO-001 who had ECGs, review of data showed 8.1% of patientshad >500 msec maximum post-baseline QTcF value, and 21.6% of patients had a >60 msec maximumincrease 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 msecmaximum 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 hada >60 msec maximum increase from baseline in QTcF intervals.

In LIBRETTO-001, LIBRETTO-431 and LIBRETTO-531 studies, there were no reports of torsades depointes, events of Grade ≥3 or clinically significant treatment-emergent arrhythmias, ventriculartachycardia, ventricular fibrillation, or ventricular flutter. Fatal events of sudden death and cardiac arrestwere 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 interruptionor modification (see sections 4.2 and 4.4).

In the 837 patients who had blood pressure measurements in study LIBRETTO-001, the medianmaximum increase from baseline systolic pressure was 32 mm Hg (range: -15, +100). Diastolic bloodpressure results were similar, but the increases were of lesser magnitude. In LIBRETTO-001, only10.3% of patients retained their baseline grade during treatment, 40.7% had an increasing shift of1 grade, 38.5% of 2 grades, and 9.8% of 3 grades. A treatment emergent adverse event of hypertensionwas reported in 44.8% patients with history of hypertension (28.2% with grade 3, 4) and 41.7% ofpatients 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 anincreasing 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 anincreasing shift of 3 grades.

Overall, a total of 19.8% of patients in LIBRETTO-001, 20.3% of patients in LIBRETTO-431, and19.2% of patients in LIBRETTO-531 displayed treatment-emergent Grade 3 hypertension (defined asmaximum systolic blood pressure greater than 160 mm Hg). Grade 4 treatment emergent hypertensionwas 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, andno patients in LIBRETTO-431 and LIBRETTO-531. Dose modification is recommended in patientswho develop hypertension (see section 4.2). Selpercatinib should be discontinued permanently ifmedically significant hypertension cannot be controlled with antihypertensive therapy (see section4.4).

Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias withconcurrent decreased platelets or increased aminotransferase.

In study LIBRETTO-001, 24.0% (201/837) of patients treated with selpercatinib had previouslyreceived anti-PD-1/PD-L1 immunotherapy. Hypersensitivity occurred in a total of 5.7% (48/837) ofpatients 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 hadreceived prior anti-PD-1/PD-L1 immunotherapy.

Grade 3 hypersensitivity occurred in 3.5% (7/201) of the patients previously treated withanti-PD-1/PD-L1 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 inpatients with previous anti-PD-1/PD-L1 immunotherapy and 4.4 weeks in patients who wereanti-PD-1/PD-L1 immunotherapy naïve.

Study LIBRETTO-431 enrolled patients with advanced or metastatic NSCLC. Hypersensitivityoccurred in a total of 1.9% (3/158) of patients receiving selpercatinib, including Grade 3hypersensitivity in 0.6% (1/158) of patients. In an integrated analysis of patients with NSCLCreceiving 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 occurredin 1 patient (0.5% [1/193]) receiving selpercatinib. This 1 patient experienced Grade 3hypersensitivity.

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 included4 (0.5%) patients with fatal haemorrhagic events, two cases of cerebral haemorrhage, and one caseeach of tracheostomy site haemorrhage, and haemoptysis. No fatal haemorrhagic events were reportedin patients treated with selpercatinib in LIBRETTO-431 or LIBRETTO-531. The median time to onsetwas 34.1 weeks (range: 0.1 week to 234.6 weeks) in LIBRETTO-001, 16.8 weeks (range: 1.1 to 94.1weeks) 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 life-threatening or recurrent severehaemorrhage (see section 4.2).

Additional information on special populations

There were 3 patients < 18 years (range: 15-17) of age with RET-mutant MTC in LIBRETTO-001.

There were 8 patients < 18 years (range 12-17) of age with RET fusion-positive thyroid cancer in

LIBRETTO-121. 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 treatedwith selpercatinib (see section 4.4). No other unique safety findings in children aged less than 18 yearshave been identified.

In patients receiving selpercatinib, 24.7% were ≥65-74 years of age, 8.6% were 75-84 years of age,and 1.0% ≥ 85 years of age in study LIBRETTO-001. In study LIBRETTO-431, 26.6% of patientsreceiving selpercatinib were ≥65-74 years of age, 9.5% were 75-84 years of age and 1.3% were ≥85years of age. In study LIBRETTO-531, 20.2% of patients receiving selpercatinib were ≥65-74 years ofage, pct. 5.2% were 75-84 years of age and none were ≥85 years of age. The frequency of serious adverseevents reported was higher in patients ≥65-74 years (58.0%), 75-84 years (62.5%), and ≥85 years(100.0%), than in patients <65 years (46.7%) of age in LIBRETTO-001 and in LIBRETTO-431,≥65-74 years (38.1%), 75-84 years (46.7%), ≥85 years (50.0%), than in patients <65 years (31.3%) ofage. In LIBRETTO-531 the frequency of serious adverse events reported was higher in patients75-84 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 higherin patients ≥65-74 years (10.1%), 75-84 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 ofselpercatinib was higher in patients ≥65-74 years (14.3%), 75-84 years (20.0%) than in patients <65years (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 inpatients 75-84 years (10%), and ≥65-74 years (7.7%) than in patients <65 years (3.5%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms of overdose have not been established. In the event of suspected overdose, supportive careshould be provided.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents,protein kinase inhibitors, ATC code: L01EX22

Selpercatinib is an inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase.

Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and

VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinibalso inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In abinding assay at the concentration of 1 µM selpercatinib, significant antagonist binding activity(>50%) was observed for the 5-HT (serotonin) transporter (70.2% antagonist) and α2C adrenoreceptor(51.7% antagonist). The concentration of 1 µM is approximately 7-fold higher than the maximumunbound plasma concentration of at the efficacious dose of selpercatinib.

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RETwith various partners can result in constitutively activated chimeric RET fusion proteins that can act asoncogenic drivers by promoting cell proliferation of tumour cell lines. In in vitro and in vivo tumourmodels, selpercatinib demonstrated anti-tumour activity in cells harboring constitutive activation of

RET protein resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET,

RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumour activity in miceintracranially implanted with a patient-derived RET fusion-positive tumour.

Pharmacodynamic properties

In a thorough QT study with positive control in 32 healthy subjects, no large change (that is, >20 ms)in the QTcF interval was detected at selpercatinib concentrations similar to those observed with atherapeutic dosing schedule. An exposure-response analysis indicated that supra therapeuticconcentrations, could lead to an increase in QTc > 20 ms.

In patients receiving selpercatinib, QT interval prolongation was reported. Therefore, dose interruptionor modification may be required in patients (see sections 4.2 and 4.4).

The efficacy of Retsevmo was evaluated in adult patients with advanced RET fusion-positive NSCLC,

RET fusion-positive thyroid cancer, other RET fusion-positive solid tumours, and in adult andadolescent patients with RET-mutant MTC enrolled in a phase 1/2, multicenter, open-label, single-armclinical study: Study LIBRETTO-001. Efficacy of Retsevmo in RET fusion-positive NSCLC wasconfirmed in the Phase 3 Study LIBRETTO-431 (see section Treatment-naïve RET fusion-positive

NSCLC). Efficacy of Retsevmo in RET-mutant MTC was confirmed in the Phase 3 Study

LIBRETTO-531 (see section Vandetanib and cabozantinib naïve RET-mutant medullary thyroidcancer (MTC)).

Study LIBRETTO-001 included two parts: phase 1 (dose escalation) and phase 2 (dose expansion).

The primary objective of the phase 1 portion was to determine the recommended phase 2 dose ofselpercatinib. The primary objective of the phase 2 part was to evaluate the anti-tumour activity ofselpercatinib by determining ORR, as assessed by independent review committee. Patients withmeasurable or non-measurable disease as determined by RECIST 1.1, with evidence of a RET genealteration in tumour were enrolled. Patients with CNS metastases were eligible if stable, while patientswith symptomatic primary CNS tumour, metastases, leptomeningeal carcinomatosis or spinal cordcompression were excluded. Patients with known primary driver alteration other than RET, clinicallysignificant active cardiovascular disease or history of myocardial infarction, QTcF interval > 470 msecwere excluded.

Patients in the phase 2 portion of the study received Retsevmo 160 mg orally twice daily untilunacceptable toxicity or disease progression. Identification of a RET gene alteration was prospectivelydetermined in local laboratories using next generation sequencing (NGS), polymerase chain reaction(PCR), or fluorescence in situ hybridization (FISH). The primary efficacy outcome measure wasobjective response rate (ORR) according to RECIST v1.1 as evaluated by a Blinded Independent

Review Committee (IRC). Secondary efficacy outcomes included duration of response (DOR),progression free survival (PFS) and overall survival (OS).

Treatment-naïve RET fusion-positive NSCLC

LIBRETTO-431

The efficacy of Retsevmo in RET fusion-positive NSCLC was confirmed in LIBRETTO-431, a phase3 multicentre, randomised, open-label comparator study, comparing selpercatinib to platinum-basedand pemetrexed therapy with or without pembrolizumab in patients with advanced or metastatic RETfusion-positive NSCLC. Adult patients with histologically confirmed, unresectable, locally advancedor metastatic NSCLC with no previous systemic therapy for metastatic disease were eligible. Patientswho received adjuvant or neoadjuvant therapy if the last dose of systemic treatment was completed atleast 6 months prior to randomisation were also eligible. Patients received 160 mg of selpercatinibtwice daily (starting dose) or platinum-based and pemetrexed therapy with or without pembrolizumab.

Patients were stratified according to geographic region (East Asia vs. elsewhere), status with respect toinvestigator assessed brain metastases at baseline (absent or unknown vs present), and whether theinvestigator had intended (before randomisation) to treat the patient with or without pembrolizumab.

The primary efficacy outcome measure was PFS per RECIST 1.1 by BICR. Secondary efficacyoutcomes included OS, ORR/DOR/DCR by BICR, intracranial ORR/DOR by BICR, and time todeterioration in pulmonary symptoms by NSCLC-SAQ.

Of the 261 patients enrolled and randomized in Study LIBRETTO-431 intention to treat (ITT)population, 212 were stratified according to whether the investigator would intend for the patient toreceive pembrolizumab (before randomisation), to form the ITT-Pembrolizumab population. In the

ITT-Pembrolizumab population, 129 patients received selpercatinib while 83 received platinum-basedpemetrexed chemotherapy with pembrolizumab. The median age of patients in the ITT-

Pembrolizumab population was 61.5 years (range 31 to 84 years). 53.3% of patients were female.41.3% of patients were White, 56.3% were Asian, 1% were Black. 67.9% were never smokers. In the

ITT Pembrolizumab population, 93% had metastatic disease, and 20.3% of patients had CNSmetastases at baseline. ECOG performance status was reported as 0-1 (96.7%) or 2 (3.3%). The mostcommon fusion partner was KIF5B (44.8%), followed by CCDC6 (9.9%). The study met its primaryendpoint of improving PFS in both the ITT-Pembrolizumab and ITT populations. Primary efficacyresults for the ITT-Pembrolizumab population for treatment naïve patients with RET fusion-positive

NSCLC are summarised in Table 4 and Figure 1.

Table 4 LIBRETTO-431: Summary of efficacy data (BICR assessment, ITT-Pembrolizumabpopulation)

Selpercatinib Control (platinum-based pemetrexedchemotherapy withpembrolizumab)

Progression-free survival N = 129 N = 83

Median [months] (95% CI) 24.84 (16.89, NE) 11.17 (8.77, 16.76)

Hazard ratio (95% CI) 0.465 (0.309, 0.699)

Stratified log rank p-value 0.000224 months PFS rate (%) (95% CI) 54.2 (43.6, 63.6) 31.6 (20.1, 43.7)

Objective response (CR + PR)% (95% CI) 83.7 (76.2, 89.6) 65.1 (53.8, 75.2)

Complete response n (%) 9 (7.0) 5 (6.0)

Partial response n (%) 99 (76.7) 49 (59.0)

Duration of response*

Median [months] (95% CI) 24.18 (17.94, NE) 11.47 (9.66, 23.26)

Rate (%) of patients with duration of response24 months (95% CI) 59.6 (47.5, 69.8) 22.8 (6.3, 45.5)

NE = not estimable

*Median duration of follow-up was 17.97 months (25th, 75th percentile: 12.32, 21.03) in theselpercatinib arm and 14.55 months (25th, 75th percentile: 9.69, 20.73) in the control arm.

Data Cut-off date: 01 May 2023.

Figure 1. LIBRETTO-431: Kaplan-Meier plot of progression-free survival (BICR assessment,

ITT-Pembrolizumab population)

Data Cut-off date: 01 May 2023

OS was not mature at the time of the primary PFS analysis. At the time of an updated descriptiveinterim analysis of OS (43% of prespecified OS events needed for the final analysis, with a data lockof 1 May 2024), in the ITT population, 75 events were observed across the two arms and the HR was1.259 ([95% CI: 0.777, 2.040]; p=0.3496). At 30 months the estimated overall survival was 71% (95%

CI: 63, 78) and 76% (95% CI: 66, 84) in the selpercatinib arm and the control arm, respectively. OSmay be affected by the imbalance in post-progression therapies. Of 68 control arm patients who haddisease progression, 50 patients (74%) received selpercatinib at progression. Of 71 selpercatinib armpatients who had disease progression, 16 (23%) received chemotherapy and/or immune checkpointinhibitor therapy, and 44 (62%) continued receiving selpercatinib.

In the ITT-Pembrolizumab population, selpercatinib significantly delayed time to worsening ofpatient-reported NSCLC symptoms, as measured by the NSCLC-Symptom Assessment Questionnairetotal score (≥ 2-point increase) compared with the control (HR: 0.34 [95% CI: 0.20, 0.55]; mediantime was not reached for selpercatinib arm versus 1.9 months [95% CI: 0.7, 6.6]) for the control arm.

In addition, selpercatinib significantly delayed time to confirmed deterioration of physical functionand maintained overall quality of life over time.

LIBRETTO-001

Of the 362 RET fusion-positive NSCLC patients enrolled in LIBRETTO-001, 69 were treatmentnaïve. The median age was 63 years (range 23 years to 92 years). 62.3% of patients were female.69.6% of patients were White, 18.8% were Asian, 5.8% were Black and 69.6% were never smokers.

Most patients (98.6%) had metastatic disease at enrolment and 23.2% had CNS metastasis at baselineas assessed by investigator. ECOG performance status was reported as 0-1 (94.2%) or 2 (5.8%). Themost common fusion partner was KIF5B (69.6%), followed by CCDC6 (14.5%) and then NCOA4(1.4%). Efficacy results for treatment-naive RET fusion-positive NSCLC patients are summarised in

Table 5.

Table 5 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients

IRC assessment

N 69

Objective response (CR + PR)% (95% CI) 82.6 (71.6, 90.7)

Complete response n (%) 5 (7.2)

Partial response n (%) 52 (75.4)

Duration of response (months)*

Median, 95% CI 20.23 (15.4, 29.5)

Rate (%) of patients with duration of response≥ 6 months (95% CI) 87.5 (75.5, 93.8)≥ 12 months (95% CI) 66.7 (52.4, 77.6)

*Median duration of follow-up was 37.09 months (25th, 75th percentile: 24.0, 45.1)

Data Cut-off date: 13 January 2023.

Previously treated RET fusion-positive NSCLC

A total of 247 patients had received prior platinum-based chemotherapy in Study LIBRETTO-001.

The median age was 61 years (range 23 years to 81 years). 56.7% of patients were female. 43.7% ofpatients were White, 47.8% were Asian, 4.9% were Black, and 66.8% were never smokers. Mostpatients (98.8%) had metastatic disease at enrolment and 31.2% had CNS metastasis at baseline asassessed by investigator. ECOG performance status was reported as 0-1 (97.1%) or 2 (2.8%). Themost common fusion partner was KIF5B (61.9%), followed by CCDC6 (21.5%) and then NCOA4(2.0%). The median number of prior systemic therapies was 2 (range 1-15) and 43.3% (n = 107/247)received 3 or more prior systemic regimens; prior treatments included anti PD1/PD-L1 therapy(58.3%), multi-kinase inhibitor (MKI) (31.6%) and taxanes (34.8%); 41.3% had other systemictherapy. Efficacy results for previously treated RET fusion-positive NSCLC patients are summarisedin Table 6.

Table 6 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients

IRC assessment

N 247

Objective response (CR + PR)% (95% CI) 61.5 (55.2, 67.6)

Complete response n (%) 20 (8.1)

Partial response n (%) 132 (53.4)

Duration of response (months)*

Median (95% CI) 31.6 (20.4, 42.3)

Rate (%) of patients with duration of response≥ 6 months (95% CI) 87.0 (80.4, 91.5)≥ 12 months (95% CI) 73.0 (65.0, 79.5)

*Median duration of follow-up was 39.52 months (25th, 75th percentile: 24.6, 45.0)

Data Cut-off date: 13 January 2023.

CNS response in RET fusion-positive NSCLC

In Study LIBRETTO-431 the CNS ORR assessed by BICR was 82.4% (14/17 95% CI: 56.6, 96.2) inthe 17 patients with measurable brain metastases at baseline treated with selpercatinib, versus 58.3%(7/12 95% CI: 27.7 to 84.4) in the 12 patients in the control arm of the ITT-Pembrolizumabpopulation. CR was observed in 6/17 (35.3%) of patients in the selpercatinib arm versus 2/12 (16.7%)patients in the control arm. With a median follow up time for DOR of 9.92 months (95% CI: 7.66,18.10) in the selpercatinib arm and 12.68 months (95% CI: 2.79, NE) in the control arm, the median

DOR was not reached for selpercatinib (95% CI: 7.62, NE) compared to 13.4 months (95% CI: 3.45,

NE) with control. In 192 patients with intracranial baseline scans available, the cause-specific hazardratio for the time to CNS progression, as assessed by BICR, was 0.28; 95% CI: 0.12, 0.68 (HR of 0.17;95% CI: 0.04, 0.69 for 150 patients without baseline intracranial metastases, and HR of 0.61; 95% CI:0.19, 1.92 for 42 patients with baseline intracranial metastases). 8 patients (6.7%) in the selpercatinibarm had a first event of CNS progression compared to 13 patients (18.1%) in the control arm.

The CNS ORR assessed by IRC was 84.6% (22/26; 95% CI: 65.1, 95.6) in 26 patients withmeasurable disease in Study LIBRETTO-001. CR was observed in 7 (26.9%) patients and PR in 15(57.5%) patients. The median CNS DOR was 9.36 months (95% CI: 7.4, 15.3).

Systemic treatment-naive RET fusion-positive thyroid cancer

Of the RET fusion-positive thyroid cancer patients naive to systemic therapy other than radioactiveiodine, and enrolled in LIBRETTO-001, 24 patients had the opportunity to be followed for at least6 months and were considered efficacy eligible. The median age was 60.5 years (range 20 to 84 years).58.3% of patients were male. 75% of patients were White. ECOG performance status was reported as0-1 (95.8%) or 2 (4.2%). 100% of patients had a history of metastatic disease. 22 out of the 24 patients(91.7%) received radioactive iodine prior to enrolment and therefore were considered radioactiveiodine refractory. The different histologies represented in the 24 patients included: papillary (n=23)and poorly differentiated (n=1). The most common fusion partner was CCDC6 (62.5%) followed by

NCOA4 (29.2%). Efficacy results for systemic treatment-naive RET fusion-positive thyroid cancerpatients are summarised in Table 7.

Table 7 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients

IRC assessment

N 24

Objective response (CR + PR)% (95% CI) 95.8 (78.9, 99.9)

Complete response n (%) 5 (20.8)

Partial response n (%) 18 (75.0)

Duration of response (months)*

Median (95% CI) NE (42.8, NE)

Rate (%) of patients with duration ofresponse≥ 12 months (95% CI) 100.0 (NE, NE)≥ 24 months (95% CI) 90.9 (50.8, 98.7)

NE = not estimable

*Median duration of follow-up was 17.81 months (25th, 75th percentile: 9.2, 42.3)

Data Cut-off date: 13 January 2023

Previously treated RET fusion-positive thyroid cancer

Of the RET fusion-positive thyroid cancer patients previously treated with systemic therapy other than

Radioactive iodine, and enrolled in LIBRETTO-001, 41 patients had the opportunity to be followedfor at least 6 months and were considered efficacy eligible. The median age was 58 years (range 25 to88 years). 43.9% of patients were male. 58.5% of patients were White while 29.3% were Asian and7.3% were Black. ECOG performance status was reported as 0-1 (92.7%) or 2 (7.3%). 100% ofpatients had metastatic disease. Patients had received a median of 3 prior systemic therapies (range:1-7). The most common prior therapies included radioactive iodine (73.2%), MKI (85.4%). 9.8% hadother systemic therapy. The different histologies represented in the 41 patients included: papillary(n = 31), poorly differentiated (n = 5), anaplastic (n = 4), and Hurthle cell (n = 1). The most commonfusion partner was CCDC6 (61.0%) followed by NCOA4 (19.5%).

Efficacy results for previously treated RET fusion-positive thyroid cancer are summarised in Table 8.

Table 8 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients IRC assessment

N 41

Objective response (CR + PR)% (95% CI) 85.4 (70.8, 94.4)

Complete response n (%) 5 (12.2)

Partial response n (%) 30 (73.2)

Duration of response (months)*

Median (95% CI) 26.7 (12.1, NE)

Rate (%) of patients with duration ofresponse≥ 12 months (95% CI) 71.7 (52.4, 84.2)≥ 24 months (95% CI) 50.7 (30.4, 67.8)

NE = not estimable

*Median duration of follow-up was 33.87 months (25th, 75th percentile: 12.9, 44.8)

Data Cut-off date: 13 January 2023.

Vandetanib and cabozantinib naïve RET-mutant medullary thyroid cancer (MTC)

LIBRETTO-531

The efficacy of Retsevmo in RET-mutant MTC was confirmed in LIBRETTO-531, a phase 3multicenter, randomised, open-label comparator study, comparing selpercatinib to physician’s choiceof cabozantinib or vandetanib in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant MTC. Adult or adolescent patients with histologically confirmed, unresectable, locallyadvanced, or metastatic MTC with no previous treatment with a kinase inhibitor were eligible. Patientsreceived 160 mg of selpercatinib twice daily (starting dose) or physician’s choice of cabozantinib (140mg once daily) or vandetanib (300 mg once daily). Patients were stratified according to RET mutation(M918T vs. other), and the intended treatment if randomised to control arm (cabozantinib vsvandetanib). The primary efficacy outcome measure was PFS per RECIST 1.1 by BICR. Keysecondary efficacy outcomes included treatment failure-free survival (TFFS) and comparativetolerability, and other secondary efficacy outcomes included OS and ORR/DOR by BICR.

Of the 291 patients enrolled and randomised in LIBRETTO-531 to form the ITT population, 193 wererandomised to the selpercatinib arm, and 98 were randomised to the control arm. Of the 98 patientsrandomised to the control arm, 73 were stratified to cabozantinib, and 25 were stratified to vandetanib.

The median age of patients in the ITT population was 55 years (range: 12 to 84 years). 37.1% ofpatients were female. 69.4% of patients were White, 27.7% were Asian, 2.9% were Black. Mostpatients (77%) had metastatic disease at enrolment. ECOG performance status was reported as 0-1(98.3%) or 2 (1%). The most common mutation was M918T (62.5%). The study met its primaryendpoint of improving PFS in the ITT population. Efficacy results for the ITT population aresummarized in Table 9 and Figure 2.

Table 9 LIBRETTO-531: Summary of efficacy data (BICR assessment, ITT population)

Selpercatinib Control (Cabozantinib or

Vandetanib)

Progression-free survival N = 193 N = 98

Median [months] (95% CI) NE (NE, NE) 16.76 (12.22, 25.10)

Hazard ratio (95% CI) 0.280 (0.165, 0.475)

Stratified log rank p-value <0.000130 months PFS rate (%) 95% CI 76.4 (66.5, 83.8) 24.8 (6.9, 48.3)

Treatment failure-free survival* N = 193 N=98

Median [months] (95% CI) NE (NE, NE) 13.93 (11.27, 25.10)

Hazard ratio (95% CI) 0.254 (0.153, 0.423)

Stratified log rank p-value <0.000130 months TFFS rate (%) 95% CI 75.8 (65.9, 83.2) 25.3 (7.2, 48.8)

Objective response (CR + PR)% (95% CI) 69.4 (62.4, 75.8) 38.8 (29.1, 49.2)

Complete response n (%) 23 (11.9) 4 (4.1)

Partial response n (%) 111 (57.5) 34 (34.7)

Duration of response#

Median [months] (95% CI) NE (NE, NE) 16.56 (10.41, NE)

Rate (%) of patients with duration ofresponse≥24 months (95% CI) 79.1 (66.9, 87.2) NE (NE, NE)

NE = not estimable

*Treatment failure-free survival is defined as the time from randomization to the first occurrence of:documented radiographic disease progression per RECIST 1.1, or unacceptable toxicity leading totreatment discontinuation as assessed by the investigator, or death due to any cause.#Median duration of follow-up was 11.14 months (25th, 75th percentile: 5.62, 16.62) in the selpercatinibarm and 12.81 months (25th and 75th percentile: 6.34, 15.51) in the control arm.

Data Cut-off date: 22 May 2023

Figure 2. LIBRETTO-531: Kaplan-Meier plot of progression-free survival (BICR assessment,

ITT population)

Data cut off: 22 May 2023

At the time of the primary PFS analysis, 18 OS events were observed across the two arms. In the ITTpopulation, the OS HR was 0.374 ([95% CI: 0.147, 0.949]). The censoring rate was 95.9% in theselpercatinib arm and 89.8% in the control arm.

Comparative tolerability was evaluated in 242 patients (selpercatinib arm, N=161; control arm, N=81).

The selpercatinib arm had a statistically significantly lower proportion of time on treatment wherepatients reported “high side effect bother” (8%) than the control arm (24%) (95% CI: -23%, -10%,p<0.0001) as assessed by Functional Assessment of Cancer Therapy item GP5 response 3 “Quite abit” or 4 “Very much”.

At a later OS analysis, with a data lock of 11 March 2024, 26 events were observed across the twoarms and the HR was 0.275 (95% CI: 0.124, 0.608). The PFS HR for this analysis was 0.202 (95% CI:0.128, 0.320) and the ORR for selpercatinib was 82.4% compared to 43.9% for the control arm.

LIBRETTO-001

Of the 324 RET-mutant MTC patients enrolled in LIBRETTO-001, 143 were naïve to treatment withcabozantinib and vandetanib. Of these 116 were treatment naïve to other systemic therapy and 27 hadpreviously received other systemic therapy. Among patients naïve to cabozantinib and vandetanib, themedian age was 57 years (range 15 to 87 years). 2 patients (1.4%) were < 18 years of age. 58.0% ofpatients were male. 86.7% of patients were White, 5.6% were Asian, 1.4% were Black. Most patients(97.9%) had metastatic disease at enrolment. ECOG performance status was reported as 0-1 (95.9%)or 2 (4.2%). The most common mutation was M918T (60.1%), followed by extracellular cysteinemutations (23.8%). Efficacy results for cabozantinib and vandetanib treatment-naive RET-mutant

MTC patients are summarised in Table 10.

Table 10 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients

IRC assessment

N 143

Objective response (CR + PR)% (95% CI) 82.5 (75.3, 88.4)

Complete response n (%) 34 (23.8)

Partial response n (%) 84 (58.7)

Duration of response (months)*

Median, 95% CI NE (51.3, NE)

Rate (%) of duration of response≥ 12 months (95% CI) 91.4 (84.6, 95.3)≥ 24 months (95% CI) 84.1 (75.9, 89.7)

NE = not estimable,

*Median duration of follow-up was 39.4 months (25th, 75th percentile: 32.3, 45.4).

Data cut-off date 13 January 2023.

Previously treated RET-mutant medullary thyroid cancer

Of the RET-mutant MTC patients enrolled in LIBRETTO-001, 152 were previously treated withcabozantinib and/or vandetanib, and considered efficacy eligible. The median age was 58 years (range17 years to 90 years); 1 patient (0.7%) was < 18 years of age. 63.8% of patients were male. 90.1% ofpatients were White while 1.3% were Asian, and 1.3% were Black. ECOG performance status wasreported as 0-1 (92.7%) or 2 (7.2%). 98.0% of patients had metastatic disease. The most commonmutation was M918T (65.1%), followed by extracellular cysteine mutations (15.8%). 100% (n = 152)of patients received prior systemic therapy with a median of 2 prior systemic regimens and 27.6%(n = 42) received 3 or more prior systemic regimens.

Efficacy results for previously treated RET-mutant MTC are summarised in Table 11.

Table 11 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients

IRC assessment

N 152

Objective response (CR + PR)% (95% CI) 77.6 (70.2, 84.0)

Complete response n (%) 19 (12.5)

Partial response n (%) 99 (65.1)

Duration of response (months)*

Median (95% CI) 45.3 (33.6, NE)

Rate (%) of duration of response≥ 12 months (95% CI) 83.0 (74.6, 88.8)≥ 24 months (95% CI) 66.4 (56.3, 74.7)

NE = not estimable

*Median duration of follow-up was 38.3 months (25th, 75th percentile: 23.0, 46.1).

Data cut-off date 13 January 2023.

Other RET Fusion-Positive Solid Tumours

Efficacy was evaluated in 52 patients with RET fusion-positive tumours other than NSCLC andthyroid cancer with disease progression on or following prior systemic treatment or who had nosatisfactory alternative treatment options. The median age was 54 years (range 21 to 85); 51.9% werefemale; 67.3% were White, 25.0% were Asian, and 5.8% were Black; ECOG performance status was0-1 (92.3%) or 2 (7.7%) and 96.2% of patients had metastatic disease. Forty-seven patients (90.4%)received prior systemic therapy with a median of 2 prior systemic therapies (range 0 to 9) and 28.8%received 3 or more prior systemic therapies. No patients had been previously treated with a selective

RET inhibitor. The most common cancers were pancreatic (25%), colon (25%), and salivary (7.7%).

The most common fusion partners were NCOA4 (34.6%), CCDC6 (17.3%), and KIF5B (11.5%).

Efficacy results for RET fusion-positive solid tumours other than NSCLC and thyroid cancer aresummarized in Table 12 and Table 13.

Table 12 LIBRETTO-001: Objective response and duration of response

Efficacy eligible patients

IRC assessment

N 52

Objective response (CR+PR)% (95% CI) 44.2 (30.5, 58.7)

Complete response n (%) 3 (5.8)

Partial response n (%) 20 (38.5)

Duration of Response (months)*

Median (95% CI) 37.19 (13.3, NE)

Rate (%) of duration of response≥ 6 months (95% CI) 84.7 (59.5, 94.8)≥ 12 months (95% CI) 79 (53.1, 91.6)

*Median duration of follow-up was 28.55 months (25th, 75th percentile: 11.2, 40.9)

NE = not estimable

Data cut-off date 13 January 2023

Table 13 LIBRETTO-001: Objective response and duration of response by Tumour Type

Patients ORR (IRC assessment) DOR(N = 52) n (%) 95% CI Range

Tumour Type (months)

Pancreatic 13 7 (53.8) 25.1, 80.8 2.50, 52.14

Colorectal 13 4 (30.8) 9.1, 61.4 1.84+, 13.31

Salivary 4 2 (50.0) 6.8, 93.2 5.72, 37.19

Cholangiocarcinoma 3 1 (33.3) 0.8, 90.6 14.82

Unknown primary 3 1 (33.3) 0.8, 90.6 9.23

Sarcoma 3 1 (33.3) 0.8, 90.6 31.44+

Breast 2 PR, CR NA 2.30+, 17.28

Xanthogranuloma 2 NE, NE a NA NA

Carcinoma of the skin 2 NE, PR NA 14.82+

Carcinoid 1 PR NA 40.94+

Ovarian 1 PR NA 28.55+

Pulmonarycarcinosarcoma 1 NE NA NA

Rectal neuroendocrine 1 NE NA NA

Small intestine 1 CR NA 24.54

Neuroendocrine 1 PR NA 3.54+

Small cell lung cancer 1 SD NA NA+ denotes ongoing response.a One xanthogranuloma patient had disease that could not be evaluated by IRC due to skin being theonly site of disease. Based on investigator assessment, this patient had a CR.

CI = confidence interval, CR = complete response, DOR = duration of response, NA = not applicable,

NE = not evaluable, ORR = objective response rate, PR = partial response, SD = stable disease.

Data cut-off date 13 January 2023

Due to the rarity of RET fusion-positive cancer, patients were studied across multiple tumour typeswith a limited number of patients in some tumour types, causing uncertainty in the ORR estimate pertumour type. The ORR in the total population may not reflect the expected response in a specifictumour type.

As of 13 January 2023, 10 patients with RET fusion-positive thyroid cancer aged 12 to ≤21 years havebeen treated in LIBRETTO-121, an ongoing Phase 1/2 study in paediatric patients with an advancedsolid or primary CNS tumour harbouring an activating RET alteration. Of these 10 patients, 8 patientswere less than 18 years of age. Of the 10 patients, 4 were previously treated with radioactive iodineonly, 2 had received prior systemic therapy that did not include radioactive iodine and 4 were notpreviously treated with any systemic therapy. For all 10 patients, per IRC, objective response rate was60.0% (95% CI: 26.2, 87.8). 3 patients had confirmed complete response whilst 3 patients hadconfirmed partial response.

The European Medicines Agency has waived the obligation to submit the results of studies withselpercatinib in patients aged 6 months and below in solid tumours (see section 4.2 for information onpaediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies withselpercatinib in one or more subsets of the paediatric population in relapsed/refractory solid tumours,including RET fusion-positive solid tumours, RET-mutant medullary thyroid cancer, and othertumours with RET alteration/activation (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastaticsolid tumours administered 160 mg twice daily unless otherwise specified. Steady-state selpercatinib

AUC and Cmax increased in a linear to supra-dose proportional manner over the dose range of 20 mgonce daily to 240 mg twice daily.

Steady-state was reached by approximately 7 days and the median accumulation ratio afteradministration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient ofvariation (CV%)] Cmax was 2 980 (53%) ng/mL and AUC0-24h was 51 600 (58%) ng*h/mL.

In vivo studies indicate that selpercatinib is a mild inhibitor of P-gp.

In vitro studies indicate that selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9,

CYP2C19, or CYP2D6 at clinically relevant concentrations.

In vitro studies indicate that selpercatinib inhibits MATE1, and BCRP, but does not inhibit OAT1,

OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevantconcentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion ofcreatinine via inhibition of MATE1.

The hard capsule and film-coated tablet dosage forms of selpercatinib are bioequivalent.

After an oral dose of 160 mg, Retsevmo was rapidly absorbed, with Tmax of approximately 2 hours.

Geometric mean absolute oral bioavailability was 73.2% (range: 60.2-81.5%).

Compared to selpercatinib AUC and Cmax in the fasted state, selpercatinib AUC was increased by 9%and Cmax was reduced by 14% after oral administration of a single 160 mg dose to healthy subjectstaken with a high-fat meal. These changes were not considered to be clinically relevant. Therefore,selpercatinib can be taken with or without food.

Selpercatinib mean (CV%) volume of distribution (Vss/F), estimated by Population PK analysis, is203.1 (69%) L following oral administration of selpercatinib in adult patients. Selpercatinib is 96%bound to human plasma proteins in vitro and binding is independent of concentration. Theblood-to-plasma concentration ratio is 0.7.

Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single[14C] radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinibconstituted 86% of the measured radioactive components in plasma.

The mean (CV%) clearance (CL/F) of selpercatinib is 5.5 (45%) L/h and the half-life is 26.5 hoursfollowing oral administration of selpercatinib in adult patients. Following oral administration of asingle [14C] radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% (14% unchanged) ofthe administered radioactivity was recovered in faeces and 24% (11.5% unchanged) was recovered inurine.

Age, gender and body weight

Age (range: 12 years to 92 years) or gender had no clinically meaningful effect on thepharmacokinetics of Retsevmo. Patients with a body weight < 50 kg should start Retsevmo treatmentwith a dose of 120 mg twice daily, while patients ≥ 50 kg should start Retsevmo treatment with a doseof 160 mg twice daily.

Selpercatinib AUC0-∞ increased by 7% in subjects with mild, 32% in subjects with moderate

Child-Pugh classification. Thus, selpercatinib exposure (AUC) in subjects with mild and moderatehepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when adose of 160 mg is administered.

Selpercatinib AUC0-∞ increased by 77% in subjects with severe hepatic impairment (Child-Pugh class

C). There is limited clinical data on the safety of selpercatinib in patients with severe hepaticimpairment. Therefore, dose modification is recommended for patients with severe hepatic impairment(section 4.2).

In a clinical pharmacology study using single dose selpercatinib 160 mg, exposure (AUC) wasunchanged in subjects with mild, moderate, or severe renal impairment. End stage renal disease (eGFR<15 ml/min) and dialysis patients have not been studied.

Based on limited pharmacokinetic data, the Cmax and AUC was similar in adolescent patients,12-18 years of age, and in adults.

Repeat-dose studies were conducted in juvenile and adolescent/adult rats and adolescent/adultminipigs to characterize toxicity. Target organs of toxicity common to the rat and minipig werehematopoietic system, lymphoid tissues, tongue, pancreas, gastro-intestinal tract, epiphyseal growthplate, and male reproductive tissues. In general, toxicities in these organs were reversible; theexceptions were the testicular toxicity in adolescent/adult and juvenile animals, and changes in growthplates in juvenile rats. Reversible toxicity was observed in the ovaries in minipigs only. At high doses,gastrointestinal toxicity caused morbidity at exposures in minipigs that were generally lower thanexposures determined in humans at the recommended dose. In one minipig study, females exhibited aslight, reversible increase in QTc prolongation of approximately 12% compared to controls and 7 %compared to pre-dose values. Target organs of toxicity observed only in rats were incisor tooth, liver,vagina, lungs, Brunner’s gland, and multi-tissue mineralization associated with hyperphosphatemia.

These toxicities only occurring in these organs in rats were reversible.

Juvenile toxicity

Selpercatinib exposure approximately 0.5-2 times the exposure in adult humans caused mortality inrats younger than 21 days old. Comparable exposure was tolerated in rats aged 21 days and older.

Juvenile and adolescent/adult rats and adolescent/adult minipigs with open growth plates administeredselpercatinib exhibited microscopic changes of hypertrophy, hyperplasia, and dysplasia of growthplate cartilage (physis). In juvenile rats, the dysplasia at the growth plates was irreversible andassociated with decreased femur length and reductions in bone mineral density. Skeletal changes wereobserved at exposure levels equivalent to those seen in adult patients taking the recommended dose of160 mg BID.

Juvenile male rats administered selpercatinib and allowed to reach reproductive age after cessation ofadministration, exhibited decreased reproductive performance when mated with untreated female rats.

Decreased fertility and copulation indices, increased pre- and post-implantation losses, and decreasednumber of viable embryos, were observed at an exposure approximately 3.4 times the efficaciousexposure in adults.

Selpercatinib is not genotoxic at therapeutic doses. In an in vivo micronucleus assay in rats,selpercatinib was positive at concentrations >7 times the Cmax at the human dose of 160 mg twicedaily. In an in vitro micronucleus assay in human peripheral blood lymphocytes, an equivocalresponse was observed at a concentration approximately 485 times the Cmax at the human dose.

Selpercatinib did not cause mutations in a bacterial mutagenicity assay.

In a 2-year carcinogenicity study of selpercatinib in rats, vaginal tumours were observed in somefemales at plasma exposure levels similar to levels observed in adult patients treated with the dose of160 mg twice daily. No pre-neoplastic changes were observed in the reproductive tract of female rats.

The clinical relevance of these findings is unknown. Selpercatinib was not carcinogenic in male rats inthis study.

Selpercatinib was not carcinogenic in male and female mice in a 6-month study.

Embryotoxicitiy/Teratogenicity

Based on data from animal reproduction studies and its mechanism of action, selpercatinib can causefoetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant ratsduring organogenesis at maternal exposures that were approximately equal to those observed at therecommended human dose of 160 mg twice daily resulted in embryolethality and malformations.

Reproduction toxicity

Results of studies conducted in rats and minipigs suggest that selpercatinib could impair fertility inmales and females.

In a fertility study in male rats, dose-dependent germ cell depletion and spermatid retention wereobserved at subclinical AUC-based exposure levels (0.2 times the clinical exposure at therecommended human dose). These effects were associated with reduced organ weights, reduced spermmotility, and an increase in the number of abnormal sperm at AUC-based exposure levelsapproximately twice the clinical exposure at the recommended human dose. Microscopic findings inthe fertility study in male rats were consistent with effects in repeat dose studies in rats and minipigs,in which dose-dependent, non-reversible testicular degeneration was associated with reduced luminalsperm in the epididymis at subclinical AUC-based exposure levels (0.1 to 0.4 times the clinicalexposure at the recommended human dose).

In a fertility and early embryonic study in female rats, a reduction in the number of estrous cycles aswell as embryolethality were observed at AUC-based exposure levels approximately equal to clinicalexposure at the recommended human dose. In repeat-dose studies in rats, reversible vaginalmucification with individual cell cornification and altered estrous cycles were noted at clinicallyrelevant AUC-based exposure levels. In minipigs, decreased corpora lutea and/or corpora luteal cystswere observed at subclinical AUC-based clinical exposure levels (0.07 to 0.3 times the clinicalexposure at the recommended human dose).

Cellulose, microcrystalline

Silica, colloidal anhydrous

Retsevmo 40 mg hard capsules

Gelatin

Titanium dioxide (E171)

Iron Oxide (E172)

Retsevmo 80 mg hard capsules

Gelatin

Titanium dioxide (E171)

Brilliant Blue FCF (E133)

Capsules black ink composition

Shellac

Ethanol (96 per cent),

Isopropyl alcohol

Butanol

Water, purified

Ammonia solution, concentrated

Potassium hydroxide

Iron oxide black

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Plastic bottle

Each pack contains 1 HDPE bottle with a plastic screw cap.

Retsevmo 40 mg hard capsules

Retsevmo 40 mg hard capsules is supplied as a 60 count HDPE bottle.

Retsevmo 80 mg hard capsules

Retsevmo 80 mg hard capsules is supplied as 60 count HDPE bottle or 120 count HDPE bottle.

Blister pack

Retsevmo 40 mg hard capsules

Supplied as PCTFE/PVC blisters sealed with an aluminium foil in a blister card, in packs of 14, 42, 56or 168 hard capsules.

Retsevmo 80 mg hard capsules

Supplied as PCTFE/PVC blisters sealed with an aluminium foil in a blister card, in packs of 14, 28, 56or 112 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V.

Papendorpseweg 833528BJ Utrecht

The Netherlands

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

Date of first authorisation: 11 February 2021

Date of latest renewal: 13 January 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.