Retsevmo 40 mg hard capsules

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

– advanced RET fusion-positive non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor

– advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinib Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC).

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

RET testing

The presence of a RET gene fusion (NSCLC and non-medullary thyroid cancer) or mutation (MTC) should be confirmed by a validated test prior to initiation of treatment with Retsevmo.

Posology

The recommended dose of Retsevmo based on body weight is:

- Less than 50 kg: 120 mg twice daily.

- 50 kg or greater: 160 mg twice daily.

If a patient vomits or misses a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.

Treatment should be continued until disease progression or unacceptable toxicity.

The current selpercatinib dose should be reduced by 50% if co-administering with a strong CYP3A inhibitor. If the CYP3A inhibitor is discontinued, the selpercatinib dose should be increased (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.

Dose adjustments

Management of some adverse reactions may require dose interruption and/or dose reduction. Retsevmo dose modifications are summarised in Table 1 and Table 2.

Table 1 Recommended dose modifications for Retsevmo for adverse reactions based on body weight

Table 2 Recommended dose modifications for adverse reactions

Special populations

Elderly

No dose adjustment is required based on age (see section 5.2).

No overall differences were observed in the treatment emergent adverse events or effectiveness of selpercatinib between patients who were ≥ 65 years of age and younger patients. Limited data are available in patients ≥ 75 years.

Renal impairment

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

Hepatic impairment

Close monitoring of patients with impaired hepatic function is important. No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Patients with severe (Child-Pugh class C) hepatic impairment should be dosed with 80 mg selpercatinib twice daily (section 5.2).

Paediatric population

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

There is no data in children or adolescents with RET fusion-positive NSCLC or thyroid cancer.

Retsevmo is intended to be used from the age of 12 years for the treatment of patients with RET-mutant MTC (see section 5.1). In RET-mutant MTC, there are very limited data available in children or adolescents aged less than 18 years. Patients should be dosed according to body weight (see section 4.2). Based on results from a preclinical study (see section 5.3), open growth plates in adolescent patients should be monitored. Dose interruption or discontinuation should be considered based on the severity of any growth plate abnormalities and an individual risk-benefit assessment.

Method of administration

Retsevmo is for oral use.

The capsules should be swallowed whole (patients should not open, crush, or chew the capsule before swallowing) and can be taken with or without food.

Patients should take the doses at approximately the same time every day.

Retsevmo must be accompanied by a meal if used concomitantly with a proton pump inhibitor (see section 4.5).

Retsevmo should be administered 2 hours before or 10 hours after H₂ receptor antagonists (see section 4.5).

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

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 medications 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.

Coadministration 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.

Coadministration 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.

Coadministration 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 triiodothyronine (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 1/2 study (LIBRETTO-001) and from an open-label, multicentre, randomised phase 3 study (LIBRETTO-431) are summarised. The most common (≥ 1.0%) serious adverse drug reactions (ADRs) are pneumonia (6.0%), haemorrhage (2.8%), blood sodium decreased (2.4%), abdominal pain (2.5%), diarrhoea (1.7%), hypersensitivity (1.7%), vomiting (1.5%), chylous ascites (1.5%), blood creatinine increased (1.4%), pyrexia (1.3%), renal and urinary tract infections (1.3%), ALT increased (1.2%), AST increased (1.2%), fatigue (1.1%) and nausea (1.0%).

Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 9.6% of patients. The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.8%), fatigue (0.6%), increased AST (0.4%), blood bilirubin increased (0.4%), pneumonia (0.3%), thrombocytopenia (0.3%), haemorrhage (0.3%), chylous ascites (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 and Study LIBRETTO-431 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 for Study LIBRETTO-001, and 16.7 months for Study LIBRETTO-431.

Table 3 Adverse drug reactions in patients receiving selpercatinib (N=995)

^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, 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 and pneumonia respiratory syncytial 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 and vessel puncture site haematoma.

^j Interstitial lung disease/pneumonitis includes pneumonitis, radiation pneumonitis, restrictive pulmonary disease, acute respiratory distress syndrome, alveolitis, bronchiolitis, langerhans' cell histiocytosis and pulmonary radiation injury.

^k Diarrhoea includes diarrhoea, anal incontinence, defaecation urgency, frequent bowel movements and gastrointestinal hypermotility.

^l Dry mouth includes dry mouth and mucosal dryness.

^m Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain.

ⁿ Vomiting includes vomiting, retching and regurgitation.

^o Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation, 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, and rash pustular.

^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 and vulvovaginal swelling.

^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, across both LIBRETTO-001 and LIBRETTO-431 studies, ALT and AST elevations were reported in 60.5% and 63.7% patients, respectively. Grade ≥ 3 ALT or AST elevations were reported in 13.6% and 10.3% 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, and AST increase 5.1 weeks (range: 0.7, 88.1), ALT increase 5.1 weeks (range: 0.7, 110.9) in LIBRETTO-431.

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. At the time of the last post-baseline measurement, increase in QTc value >60 msec was reported in 2.0% of patients in LIBRETTO-001. 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 LIBRETTO-001 and LIBRETTO-431 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 LIBRETTO-001 and LIBRETTO-431, 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.

Overall, a total of 19.8% displayed treatment-emergent Grade 3 hypertension in LIBRETTO-001 (defined as maximum systolic blood pressure greater than 160 mm Hg), and a total of 20.3% displayed treatment-emergent Grade 3 hypertension in LIBRETTO-431. Grade 4 treatment emergent hypertension was reported in 0.1% of patients in LIBRETTO-001, and no reports in LIBRETTO-431.

Two patients (0.2%) permanently discontinued treatment due to hypertension in LIBRETTO-001, and no patients in LIBRETTO-431. 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 naï ve.

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.

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

Haemorrhages

Grade ≥ 3 haemorrhagic events occurred in 2.9% of patients treated with selpercatinib across both LIBRETTO-001 and LIBRETTO-431 studies. 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 evens were reported in LIBRETTO-431. The median time to onset was 34.1 weeks (range: 0.1 week to 234.6 weeks) in LIBRETTO-001 and 16.8 weeks (range 1.1 to 94.1 weeks) in LIBRETTO-431.

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 in LIBRETTO-001. Cases of epiphysiolysis of the femoral head have been reported in patients < 18 years of age treated with selpercatinib (see section 4.4). The safety of selpercatinib in children aged less than 18 years has not been established.

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, and 26.6% 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-431. 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%), <65 years (31.3%) of age.

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.

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 Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

Mechanism of action

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, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In a binding assay at the concentration of 1 µ M selpercatinib, significant antagonist binding activity (>50%) was observed for the 5-HT (serotonin) transporter (70.2% antagonist) and α 2C adrenoreceptor (51.7% antagonist). The concentration of 1 µ M is approximately 7-fold higher than the maximum unbound plasma concentration of at the efficacious dose of selpercatinib.

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor 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-tumor activity in mice intracranially implanted with a patient-derived RET fusion-positive tumor.

Pharmacodynamic properties

Cardiac electrophysiology

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 a therapeutic dosing schedule. An exposure-response analysis indicated that supra therapeutic concentrations, could lead to an increase in QTc > 20 ms.

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

Clinical efficacy and safety

The efficacy of Retsevmo was evaluated in adult patients with advanced RET fusion-positive NSCLC and RET fusion-positive thyroid cancer and in adult and adolescent patients with RET-mutant MTC enrolled in a phase 1/2, multicenter, open-label, single-arm clinical study: Study LIBRETTO-001. Efficacy of Retsevmo in RET fusion-positive NSCLC was confirmed in the Phase 3 Study LIBRETTO-431 (see section Treatment-naï ve RET fusion-positive NSCLC).

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 of selpercatinib. The primary objective of the phase 2 part was to evaluate the anti-tumour activity of selpercatinib by determining ORR, as assessed by independent review committee. Patients with measurable or non-measurable disease as determined by RECIST 1.1, with evidence of a RET gene alteration in tumour were enrolled. Patients with CNS metastases were eligible if stable, while patients with symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis or spinal cord compression were excluded. Patients with known primary driver alteration other than RET, clinically significant active cardiovascular disease or history of myocardial infarction, QTcF interval > 470 msec were excluded.

Patients in the phase 2 portion of the study received Retsevmo 160 mg orally twice daily until unacceptable toxicity or disease progression. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescence in situ hybridization (FISH). The primary efficacy outcome measure was overall 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-naive RET fusion-positive NSCLC

LIBRETTO-431

The efficacy of Retsevmo in RET fusion-positive NSCLC was confirmed in LIBRETTO-431, a phase 3 multicentre, randomised, open-label comparator study, comparing selpercatinib to platinum-based and pemetrexed therapy with or without pembrolizumab in patients with advanced or metastatic RET fusion-positive NSCLC. Adult patients with histologically confirmed, unresectable, locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease were eligible. Patients who received adjuvant or neoadjuvant therapy if the last dose of systemic treatment was completed at least 6 months prior to randomisation were also eligible. Patients received 160 mg of selpercatinib twice 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 to investigator assessed brain metastases at baseline (absent or unknown vs present), and whether the investigator 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 efficacy outcomes included OS, ORR/DOR/DCR by BICR, intracranial ORR/DOR by BICR, and time to deterioration 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 to receive pembrolizumab (before randomisation), to form the ITT-Pembrolizumab population. In the ITT-Pembrolizumab population, 129 patients received selpercatinib while 83 received platinum-based pemetrexed 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 CNS metastases at baseline. ECOG performance status was reported as 0-1 (96.7%) or 2 (3.3%). The most common fusion partner was KIF5B (44.8%), followed by CCDC6 (9.9%). The study met its primary endpoint of improving PFS in both the ITT-Pembrolizumab and ITT populations. Primary efficacy results for the ITT-Pembrolizumab population for treatment naï ve 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-Pembrolizumab population)

NE = not estimable

*Median duration of follow-up was 17.97 months (25^th, 75^th percentile: 12.32, 21.03) in the selpercatinib arm and 14.55 months (25^th, 75^th 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 (40 events observed across the two arms). The censoring rate was 80.6% in the selpercatinib arm and 81.9% in the control arm and results may be confounded due to cross over. In the ITT-Pembrolizumab population the OS HR was 0.961 ([95% CI: 0.503, 1.835]; p=0.9033).

In the ITT-Pembrolizumab population, selpercatinib significantly delayed time to worsening of patient-reported NSCLC symptoms, as measured by the NSCLC-Symptom Assessment Questionnaire total score (≥ 2-point increase) compared with the control (HR: 0.34 [95% CI: 0.20, 0.55]; median time 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 function and maintained overall quality of life over time.

LIBRETTO-001

Of the 362 RET fusion-positive NSCLC patients enrolled in LIBRETTO-001, 69 were treatment naï ve. 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 baseline as assessed by investigator. ECOG performance status was reported as 0-1 (94.2%) or 2 (5.8%). The most 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

*Median duration of follow-up was 37.09 months (25^th, 75^th 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% of patients were White, 47.8% were Asian, 4.9% were Black, and 66.8% were never smokers. Most patients (98.8%) had metastatic disease at enrolment and 31.2% had CNS metastasis at baseline as assessed by investigator. ECOG performance status was reported as 0-1 (97.1%) or 2 (2.8%). The most 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 systemic therapy. Efficacy results for previously treated RET fusion-positive NSCLC patients are summarised in Table 6.

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

*Median duration of follow-up was 39.52 months (25^th, 75^th 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) in the 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-Pembrolizumab population. 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 hazard ratio 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 selpercatinib arm 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 with measurable 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).

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 followed for at least 6 months and were considered efficacy eligible. The median age was 58 years (range 25 to 88 years). 43.9% of patients were male. 58.5% of patients were White while 29.3% were Asian and 7.3% were Black. ECOG performance status was reported as 0-1 (92.7%) or 2 (7.3%). 100% of patients 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% had other 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 common fusion partner was CCDC6 (61.0%) followed by NCOA4 (19.5%).

Efficacy results for previously treated RET fusion-positive thyroid cancer are summarised in Table 7.

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

NE = not estimable

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

Data Cut-off date: 13 January 2023.

Vandetanib and cabozantinib naï ve RET-mutant medullary thyroid cancer

Of the 324 RET-mutant MTC patients enrolled in LIBRETTO-001, 143 were naï ve to treatment with cabozantinib and vandetanib. Of these 116 were treatment naï ve to other systemic therapy and 27 had previously received other systemic therapy. Among patients naï ve to cabozantinib and vandetanib, the median age was 57 years (range 15 to 87 years). 2 patients (1.4%) were < 18 years of age. 58.0% of patients 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 cysteine mutations (23.8%). Efficacy results for cabozantinib and vandetanib treatment-naive RET-mutant MTC patients are summarised in Table 8.

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

NE = not estimable,

*Median duration of follow-up was 39.4 months (25^th, 75^th 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 with cabozantinib and/or vandetanib, and considered efficacy eligible. The median age was 58 years (range 17 years to 90 years); 1 patient (0.7%) was < 18 years of age. 63.8% of patients were male. 90.1% of patients were white while 1.3% were Asian, and 1.3% were Black. ECOG performance status was reported as 0-1 (92.7%) or 2 (7.2%). 98.0% of patients had metastatic disease. The most common mutation 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 9.

Table 9 LIBRETTO-001: Objective response and duration of response

NE = not estimable

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

Data cut-off date 13 January 2023.

Paediatric population

The licensing authority has waived the obligation to submit the results of studies with selpercatinib in patients aged 6 months and below in solid tumours (see section 4.2 for information on paediatric use).

The licensing authority has deferred the obligation to submit the results of studies with selpercatinib 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 other tumours with RET alteration/activation (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The licensing authority will review new information on this medicinal product at least every year and this SmPC will be updated as necessary

The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady-state selpercatinib AUC and C_max increased in a linear to supra-dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily.

Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] C_max 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 relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1.

Absorption

After an oral dose of 160 mg, Retsevmo was rapidly absorbed, with T_max of approximately 2 hours. Geometric mean absolute oral bioavailability was 73.2% (range: 60.2-81.5%).

Effect of food

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

Distribution

Selpercatinib mean (CV%) volume of distribution (V_ss/F), estimated by Population PK analysis, is 191 (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. The blood-to-plasma concentration ratio is 0.7.

Biotransformation

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

Elimination

The mean (CV%) clearance (CL/F) of selpercatinib is 6.0 (49%) L/h and the half-life is 22 hours following oral administration of selpercatinib in adult patients. Following oral administration of a single [¹⁴C] radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% (14% unchanged) of the administered radioactivity was recovered in faeces and 24% (11.5% unchanged) was recovered in urine.

Special populations

Age, gender and body weight

Age (range: 15 years to 90 years) or gender had no clinically meaningful effect on the pharmacokinetics of Retsevmo. Patients with a body weight < 50 kg should start Retsevmo treatment with a dose of 120 mg twice daily, while patients ≥ 50 kg should start Retsevmo treatment with a dose of 160 mg twice daily.

Hepatic impairment

Selpercatinib AUC_0-∞ increased by 7% in subjects with mild, 32% in subjects with moderate Child-Pugh classification. Thus, selpercatinib exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 160 mg is administered.

Selpercatinib AUC_0-∞ 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 hepatic impairment. Therefore, dose modification is recommended for patients with severe hepatic impairment (section 4.2).

Renal impairment

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

Paediatric population

Based on limited pharmacokinetic data, the C_max 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/adult minipigs to characterize toxicity. Target organs of toxicity common to the rat and minipig were hematopoietic system, lymphoid tissues, tongue, pancreas, gastro-intestinal tract, epiphyseal growth plate, and male reproductive tissues. In general, toxicities in these organs were reversible; the exceptions were the testicular toxicity in adolescent/adult and juvenile animals, and changes in growth plates 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 than exposures determined in humans at the recommended dose. In one minipig study, females exhibited a slight, 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 in rats 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 administered selpercatinib exhibited microscopic changes of hypertrophy, hyperplasia, and dysplasia of growth plate cartilage (physis). In juvenile rats, the dysplasia at the growth plates was irreversible and associated with decreased femur length and reductions in bone mineral density. Skeletal changes were observed at exposure levels equivalent to those seen in adult patients taking the recommended dose of 160 mg BID.

Juvenile male rats administered selpercatinib and allowed to reach reproductive age after cessation of administration, exhibited decreased reproductive performance when mated with untreated female rats. Decreased fertility and copulation indices, increased pre- and post-implantation losses, and decreased number of viable embryos, were observed at an exposure approximately 3.4 times the efficacious exposure in adults.

Genotoxicity

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

Mutagenesis

Selpercatinib did not cause mutations in a bacterial mutagenicity assay.

Carcinogenesis

Long-term studies to assess the carcinogenic potential of selpercatinib have not been performed.

Embryotoxicitiy / Teratogenicity

Based on data from animal reproduction studies and its mechanism of action, selpercatinib can cause foetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended 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 in males and females.

In a fertility study in male rats, dose-dependent germ cell depletion and spermatid retention were observed at subclinical AUC-based exposure levels (0.2 times the clinical exposure at the recommended human dose). These effects were associated with reduced organ weights, reduced sperm motility, and an increase in the number of abnormal sperm at AUC-based exposure levels approximately twice the clinical exposure at the recommended human dose. Microscopic findings in the 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 luminal sperm in the epididymis at subclinical AUC-based exposure levels (0.1 to 0.4 times the clinical exposure at the recommended human dose).

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

Capsule content

Cellulose, microcrystalline

Silica, colloidal anhydrous

Capsule shell

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

Propylene glycol

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, 56 or 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, 56 or 112 hard capsules.

Not all pack sizes may be marketed.

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