Active Ingredient: Selpercatinib
Selpercatinib as monotherapy is indicated for the treatment of adults and paediatric patients 2 years of age and older with advanced RET fusion-positive solid tumours, when treatment options not targeting RET provide limited clinical benefit, or have been exhausted.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Regimen A, in the case that patient weight is < 50 kg :
Oral, 120 milligrams selpercatinib, 2 times daily.
Regimen B, in the case that patient weight is ≥ 50 kg :
Oral, 160 milligrams selpercatinib, 2 times daily.
The recommended dose of selpercatinib for patients 12 years of age and older based on body weight is:
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.
Management of some adverse reactions may require dose interruption and/or dose reduction. Selpercatinib dose modifications are summarised in Table 1 and Table 2.
Table 1. Recommended dose modifications for selpercatinib 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 |
* Permanently discontinue selpercatinib in patients unable to tolerate three dose reductions
Dose modifications in paediatric patients for adverse reactions should be determined based on the current dose and step wise dose-level modification approach as that described for adults in the adverse reactions discussed below (Table 2) except where stated otherwise.
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. 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. 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 ≤440 ms for patients under 12 years of age) or baseline. • 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. |
| 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. |
No dose adjustment is required based on age.
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.
Patients should take the doses at approximately the same time every day.
Selpercatinib must be accompanied by a meal if used concomitantly with a proton pump inhibitor.
Selpercatinib should be administered 2 hours before or 10 hours after H2 receptor antagonists.
For:
Regimen A, in the case that patient age in years is ≥ 2 and patient body surface area is ≥ 0.45 m² and patient body surface area is ≤ 0.65 m² :
Oral, 40 milligrams selpercatinib, 3 times daily.
Regimen B, in the case that patient age in years is ≥ 2 and patient body surface area is ≥ 0.66 m² and patient body surface area is ≤ 1.08 m² :
Oral, 80 milligrams selpercatinib, 2 times daily.
Regimen C, in the case that patient age in years is ≥ 2 and patient body surface area is ≥ 1.09 m² and patient body surface area is ≤ 1.52 m² :
Oral, 120 milligrams selpercatinib, 2 times daily.
Regimen D, in the case that patient age in years is ≥ 2 and patient body surface area is ≥ 1.53 m² :
Oral, 160 milligrams selpercatinib, 2 times daily.
The recommended dose of selpercatinib for paediatric patients 2 to less than 12 years of age is based on the following body surface area (BSA) categories:
Table 1. Recommended dose for paediatric patients 2 to less than 12 years of age:
| Body surface area (BSA) | Recommended dose |
| 0.45 to 0.65 m² | 40 mg three times daily |
| 0.66 to 1.08 m² | 80 mg twice daily |
| 1.09 to 1.52 m² | 120 mg twice daily |
| ≥1.53 m² | 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.
Management of some adverse reactions may require dose interruption and/or dose reduction. Selpercatinib dose modifications are summarised in Table 2 and Table 3.
Table 2. Recommended dose modifications for selpercatinib 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 |
* Permanently discontinue selpercatinib in patients unable to tolerate three dose reductions
Dose modifications in paediatric patients for adverse reactions should be determined based on the current dose and step wise dose-level modification approach as that described for adults in the adverse reactions discussed below (Table 3) except where stated otherwise.
Table 3. 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. 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. 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 ≤440 ms for patients under 12 years of age) or baseline. • 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. |
| 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. |
Patients should take the doses at approximately the same time every day.
Selpercatinib must be accompanied by a meal if used concomitantly with a proton pump inhibitor.
Selpercatinib should be administered 2 hours before or 10 hours after H2 receptor antagonists.
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