4.1. Therapeutic indications

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

Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with:

– advanced RET fusion‑positive thyroid cancer who are radioactive iodine-refractory (if radioactive iodine is appropriate)

– advanced RET‑mutant medullary thyroid cancer (MTC)

4.2. Posology and method of administration

Retsevmo therapy should be initiated and supervised by physicians experienced in the use of 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

Dose modification

Adults and adolescents ≥50 Kg

Adults and adolescents <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 reaction (ADR)

Dose modification

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

Grade 3 or Grade 4

• Suspend dose until toxicity resolves to baseline (see sections 4.4 and 4.8). Resume at a dose reduced by 2 levels.

• If after at least 2 weeks selpercatinib is tolerated without recurrent increased ALT or AST, increase dosing by 1 dose level.

• If selpercatinib is tolerated without recurrence for at least 4 weeks, increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT.

• Permanently discontinue selpercatinib if Grade 3 or 4 ALT or AST increases recur despite dose modifications.

Hypersensitivity

All Grades

• Suspend dose until toxicity resolves and begin corticosteroids at a dose of 1 mg/kg (see sections 4.4 and 4.8). Resume selpercatinib at 40 mg twice daily while continuing steroid treatment. Discontinue selpercatinib for recurrent hypersensitivity.

• If after at least 7 days, selpercatinib is tolerated without recurrent hypersensitivity, incrementally increase the selpercatinib dose by 1 dose level each week, until the dose taken prior to the onset of hypersensitivity is reached. Taper steroid dose after selpercatinib has been tolerated for at least 7 days at the final dose.

QT interval prolongation

Grade 3

• Suspend dose for QTcF intervals >500 ms until the QTcF returns to <470 ms or baseline (see section 4.4).

• Resume selpercatinib treatment at the next lower dose level.

Grade 4

• Permanently discontinue selpercatinib if QT prolongation remains uncontrolled after two dose reductions or if the patient has signs or symptoms of serious arrhythmia.

Hypertension

Grade 3

• Patient blood pressure should be controlled before starting treatment.

• Selpercatinib should be suspended temporarily for medically significant hypertension until controlled with antihypertensive therapy. Dosing should be resumed at the next lower dose if clinically indicated (see sections 4.4 and 4.8).

Grade 4

• Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled.

Haemorrhagic events

Grade 3

• Selpercatinib should be suspended until recovery to baseline. Resume at a reduced dose.

If Grade 3 events reoccur following dose modification, permanently discontinue selpercatinib.

Grade 4

• Permanently discontinue selpercatinib.

Interstitial lung disease (ILD)/Pneumonitis

Grade 2

• Withhold selpercatinib until resolution.

• Resume at a reduced dose.

• Discontinue selpercatinib for recurrent ILD/pneumonitis

Grade 3 or Grade 4

• Discontinue selpercatinib.

Other adverse reactions

Grade 3 or Grade 4

• Selpercatinib should be suspended until recovery to baseline. Resume at a reduced dose.

• If Grade 4 events reoccur following dose modification, permanently discontinue selpercatinib.

Special populations

Elderly

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

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

Renal impairment

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

Hepatic impairment

Close monitoring of patients with impaired hepatic function is important. No dose adjustment is required for patients with mild (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.

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 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 tablets should be swallowed whole to ensure consistent performance (patients should not crush, chew, or split the tablet before swallowing), and can be taken with or without food. In case of difficulty swallowing the larger tablets whole, patients may consider taking multiple units of the smaller tablets to achieve the required dose.

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

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

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

Severe cutaneous adverse reactions (SCARs)

Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported in association with selpercatinib treatment (see section 4.8). Patients should be advised of the signs of the severe cutaneous adverse reactions and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. If signs and symptoms suggestive of these reactions appear, selpercatinib should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a severe cutaneous adverse reaction such as SJS with the use of selpercatinib, treatment with selpercatinib must not be restarted in this patient at any time.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 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 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 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 approximately 87% and 70% in selpercatinib AUC and Cmax, 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 Cmax and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% 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 clinically significant differences in selpercatinib pharmacokinetics were observed when co-administered 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

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

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

Summary of the safety profile

The integrated frequency of adverse drug reactions (ADRs) reported in patients treated with selpercatinib from an open-label, multicentre, dose-escalation phase 1/2 study (LIBRETTO-001) and from two open-label, multicentre, randomised phase 3 comparative studies (LIBRETTO-431 and LIBRETTO-531) are summarised. The most common (≥ 1.0%) serious ADRs are pneumonia (5.3%), haemorrhage (2.4%), abdominal pain (2.1%), blood sodium decreased (2.0%), diarrhoea (1.5%), hypersensitivity (1.4%), vomiting (1.3%), blood creatinine increased (1.3%), pyrexia (1.3%), urinary tract infections (1.3%), ALT increased (1.0%) and AST increased (1.0%).

Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 8.8% of patients. The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.7%), fatigue (0.5%), increased AST (0.4%), blood bilirubin increased (0.3%), pneumonia (0.3%), thrombocytopenia (0.3%), haemorrhage (0.3%), and hypersensitivity (0.3%).

Tabulated list of adverse drug reactions

The integrated frequency and severity of ADRs reported in patients treated with selpercatinib in Study LIBRETTO-001, Study LIBRETTO-431, and Study LIBRETTO-531 are shown in Table 3.

The ADRs are classified according to the MedDRA system organ class and frequency.

Frequency groups are defined by the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), and not known (cannot be estimated from available data).

Median time on treatment with selpercatinib was 30.09 months (Study LIBRETTO-001), 16.7 months (Study LIBRETTO-431), and 14.9 months (Study LIBRETTO-531).

Table 3 Adverse drug reactions in patients receiving selpercatinib (N=1188)

MedDRA system organ class

MedDRA preferred term

Frequency of all Grades

Frequency of Grade ≥ 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 disorders

Decreased appetite

Very common

Uncommon

Nervous system disorders

Headachee

Very common

Common

Dizzinessf

Very common

Uncommon

Cardiac disorders

Electrocardiogram QT prolongedg

Very common

Common

Vascular disorders

Hypertensionh

Very common

Very common

Haemorrhagei

Very common

Common

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease/pneumonitisj

Common

Uncommon

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 tissue disorders

Rashq

Very common

Common

Stevens-Johnson Syndromer

Not known

Not known

Musculoskeletal and connective tissue disorders

Epiphysiolysis of the femoral heads

Common

Common

Reproductive system and breast disorders

Erectile dysfunctiont

Very common

Uncommon

General disorders and administration site conditions

Oedemau

Very common

Common

Fatiguev

Very common

Common

Pyrexia

Very common

Uncommon

Investigationsw

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 decreased

Very common

Common

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

Haemoglobin decreased

Very common

Common

Magnesium decreased

Very common

Common

Potassium decreased

Very common

Common

a Urinary tract infections includes urinary tract infection, cystitis, urosepsis, escherichia urinary tract infection, escherichia pyelonephritis, kidney infection, nitrite urine present, pyelonephritis, urethritis, urinary tract infection bacterial and urogenital infection fungal.

b Pneumonia includes pneumonia, lung infection, pneumonia aspiration, empyema, lung consolidation, pleural infection, pneumonia bacterial, pneumonia staphylococcal, atypical pneumonia, lung abscess, pneumocystis jirovecii pneumonia, pneumonia pneumococcal, pneumonia respiratory syncytial viral, infectious pleural effusion, and pneumonia viral.

c Hypersensitivity reactions were characterised by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient's first cycle of treatment (typically between Days 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.

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 From post-marketing data.

s Epiphysiolysis of the femoral head has been commonly observed (6.4%) in paediatric patients (<18 years of age) treated with selpercatinib (n=47).

t Erectile dysfunction has been very commonly observed (12.4%) in male patients treated with selpercatinib in clinical trials (n=986).

u 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.

v Fatigue includes fatigue, asthenia and malaise.

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

4.9. Overdose

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