Retsevmo

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 mutation (MTC) or fusion (all other tumour types) should be confirmed by a validated test prior to initiation of treatment with Retsevmo.

Posology The recommended dose of Retsevmo based on body weight is: - Less than 50 kg: 120 mg twice daily. - 50 kg or greater: 160 mg twice daily. If a patient vomits or misses a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.

Treatment should be continued until disease progression or unacceptable toxicity. The current selpercatinib dose should be reduced by 50% if 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. 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.

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. 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.

5 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. 8).

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.

0%). 8% of patients. 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).

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 12 MedDRA system organ class MedDRA preferred term Frequency of all Grades Frequency of Grade ≥ 3 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.

Efficacy across tumour types The benefit of selpercatinib has been established in single arm trials encompassing a relatively small sample of patients whose tumours exhibit RET gene fusions. Favourable effects of selpercatinib have been shown on the basis of objective response rate and response duration in a limited number of tumour types.

1). , no satisfactory treatment options). 8). Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. , dyspnoea, cough, and fever), and treated as medically appropriate. 2). 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.

2). 8). Patient blood pressure should be controlled before starting selpercatinib treatment, monitored during selpercatinib treatment and treated as needed with standard anti-hypertensive therapy. 2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy.

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.

1.