RETSEVMO Hard capsule Ref.[28022] Active ingredients: Selpercatinib

Efficacy across tumour types

The benefit of selpercatinib has been established in single arm trials encompassing a relatively small sample of patients whose tumours exhibit RET gene fusions. Favourable effects of selpercatinib have been shown on the basis of objective response rate and response duration in a limited number of tumour types. The effect may be quantitatively different depending on tumour type, as well as on concomitant genomic alterations (see section 5.1). For these reasons, selpercatinib should only be used if there are no treatment options for which clinical benefit has been established, or where such treatment 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 with selpercatinib (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 permanently discontinued (see section 4.2).

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

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

Hypertension

Hypertension was reported in patients receiving selpercatinib (see section 4.8). Patient blood pressure should be controlled before starting selpercatinib treatment, monitored during selpercatinib treatment and treated as needed with standard anti-hypertensive therapy. Based on the level of increased blood pressure, selpercatinib may require dose modification (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive 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 QT syndrome 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 before starting selpercatinib treatment. Electrocardiograms and serum electrolytes should be monitored in all patients 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 to initiating selpercatinib and during treatment. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medicinal products known to prolong the QT interval. Selpercatinib may require dose interruption or modification (see section 4.2).

Hypothyroidism

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

Strong CYP3A4 inducers

Concomitant use of strong CYP3A4 inducers should be avoided due to the risk of decreased efficacy of 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 at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib (see section 4.6).

Fertility

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 preservation before treatment.

Hypersensitivity

Hypersensitivity was reported in patients receiving selpercatinib with a majority of events observed in patients 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 with concurrent decreased platelets or elevated aminotransferases.

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

Haemorrhages

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

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

Tumour lysis syndrome (TLS)

Cases of TLS have been observed in patients treated with selpercatinib. Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely and treated as clinically indicated, and appropriate 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 of epiphysiolysis 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) in vitro, however these transporters do not appear to limit the oral absorption of selpercatinib, as its oral bioavailability is 73% and its exposure was increased minimally by co-administration of the P-gp inhibitor rifampicin (increase of approximately 6.5% and 19% in selpercatinib AUC_0-24 and C_max, 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 C_max and AUC of selpercatinib by 30% and 130%, respectively, compared to selpercatinib given alone. If strong CYP3A and/or P-gp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, have to be coadministered, 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 approximately 87% and 70% in selpercatinib AUC and C_max, respectively, compared to selpercatinib alone, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided.

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

Sensitive CYP2C8 substrates

Selpercatinib increased the C_max and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% and 188% respectively. Therefore, coadministration 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 C_max 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 clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H₂ receptor antagonist) given 2 hours after the selpercatinib dose.

Co-administration with medicinal products that are proton pump inhibitors

Coadministration with multiple daily doses of omeprazole (a proton pump inhibitor) decreased selpercatinib AUC_0-INF and C_max when selpercatinib was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC_0-INF and C_max when 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 vivo interactions of selpercatinib with clinically relevant substrates of MATE1, such as creatinine, may occur (see section 5.2).

Selpercatinib is an in vitro inhibitor of P-gp and BCRP. In vivo, selpercatinib increased C_max and AUC of dabigatran, a P-gp substrate, by 43% and 38%, respectively. Therefore, caution should be used when 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 liothyronine (T3). Patients could therefore have an insufficient response to substitution with levothyroxine and supplementation with liothyronine may be needed (see section 4.4).

Paediatric population

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 at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib.

Pregnancy

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

Breast-feeding

It is unknown whether selpercatinib is excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Retsevmo and for at least one week after the last dose.

Fertility

No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, 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 be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with Retsevmo (see section 4.8).

Summary of the safety profile

The integrated frequency of ADRs reported in patients treated with selpercatinib from an open-label, multicentre, dose-escalation phase ½ 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):

^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 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, 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.
° 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 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% 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 post-baseline 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 LIBRETTO-001, 24.0% (201/837) of patients treated with selpercatinib had previously received anti-PD-1/PD-L1 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 anti-PD-1/PD-L1 immunotherapy. Grade 3 hypersensitivity occurred in 3.5% (7/201) of the patients previously treated with anti-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 in patients with previous anti-PD-1/PD-L1 immunotherapy and 4.4 weeks in patients who were anti-PD-1/PD-L1 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 15 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 life-threatening or recurrent severe haemorrhage (see section 4.2).

Additional information on special populations

Paediatric patients

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 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 ≥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 patients receiving selpercatinib were ≥65-74 years of age, 9.5% were 75-84 years of age and 1.3% were ≥85 years of age. In study LIBRETTO-531, 20.2% of patients receiving selpercatinib were ≥65-74 years of age, 5.2% were 75-84 years of age and none were ≥85 years of age. The frequency of serious adverse events 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%) of age. In LIBRETTO-531 the frequency of serious adverse events reported was higher in patients 75-84 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 higher in 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 of selpercatinib was higher in patients ≥65-74 years (14.3%), 75-84 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 ≥65-74 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 the national reporting system listed in Appendix V.

Not applicable.