Active Ingredient: Entrectinib
Entrectinib as monotherapy is indicated for the treatment of adult and paediatric patients older than 1 month with solid tumours that have a NTRK gene fusion,
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 600 milligrams entrectinib, once daily.
A validated assay is required for the selection of patients with NTRK gene fusion-positive solid tumours. NTRK gene fusion-positive status must be established prior to initiation of entrectinib therapy.
The recommended dose for adults is 600 mg entrectinib once daily.
No dose adjustment is required in patients ≥65 years of age.
It is recommended that patients are treated with entrectinib until disease progression or unacceptable toxicity.
If a planned dose of entrectinib is missed, patients can make up that dose unless the next dose is due within 12 hours. If vomiting occurs immediately after taking a dose of entrectinib, patients may repeat that dose.
When entrectinib is administered by individuals other than the healthcare professional (e.g., caregivers or parents) and partial or total vomiting/spitting occurs immediately after taking an administered dose, caregivers should consult the healthcare professional for the next steps.
Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with entrectinib, in case of specified adverse reactions (see Table 1) or based on the prescriber’s assessment of the patient’s safety or tolerability.
For adults, the dose of entrectinib may be reduced up to 2 times, based on tolerability (see Table 1). Entrectinib treatment should be permanently discontinued if patients are unable to tolerate a dose of 200 mg once daily.
Table 1. Dose reduction schedule for adult patients:
| Starting dose once daily | First dose reduction | Second dose reduction | |
|---|---|---|---|
| 250 mg/m² | Reduce the once daily dose to two thirds of the starting dose* | Reduce the once daily dose to one third of the starting dose* | Permanently discontinue entrectinib in patients who are unable to tolerate entrectinib after two dose reductions. |
| 100 mg | 50 mg or 100 mg once daily, according to schedule** | 50 mg once daily | |
| 200 mg | 150 mg once daily | 100 mg once daily | |
| 300 mg | 200 mg once daily | 100 mg once daily | |
| 400 mg | 300 mg once daily | 200 mg once daily | |
| 600 mg | 400 mg once daily | 200 mg once daily |
* To enable dosing increments of 10 mg, capsules prepared as an oral suspension may be used.
** Monday (100 mg), Tuesday (50 mg), Wednesday (100 mg), Thursday (50 mg), Friday (100 mg), Saturday (50 mg), and Sunday (100 mg).
Recommendations for entrectinib dose modifications for adult patients in case of specific adverse reactions are provided in Table 2.
Table 2. Recommended entrectinib dose modifications for adverse reactions in adult patients:
| Adverse reaction | Severity* | Dosage modification |
|---|---|---|
| Congestive heart failure | Symptomatic with middle to moderate activity or exertion, including where intervention is indicated (Grade 2 or 3) | • Withhold entrectinib until recovered to less than or equal to Grade 1 • Resume at reduced dose |
| Severe with symptoms at rest, minimal activity, or exertion or where intervention is indicated (Grade 4) | • Withhold entrectinib until recovered to less than or equal to Grade 1 • Resume at reduced dose or discontinue as clinically appropriate | |
| Cognitive disorders | Intolerable, but moderate changes interfering with activities of daily living (Intolerable Grade 2) | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at same dose or reduced dose, as clinically needed |
| Severe changes limiting activities of daily living (Grade 3) | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at reduced dose | |
| Urgent intervention indicated for event (Grade 4) | • For prolonged, severe, or intolerable events, discontinue entrectinib as clinically appropriate | |
| Hyperuricemia | Symptomatic or Grade 4 | • Initiate urate-lowering medication • Withhold entrectinib until improvement of signs or symptoms • Resume entrectinib at same or reduced dose |
| QT interval prolongation | QTc 481 to 500 ms | • Withhold entrectinib until recovered to baseline • Resume treatment at same dose |
| QTc greater than 500 ms | • Withhold entrectinib until QTc interval recovers to baseline • Resume at same dose if factors that cause QT prolongation are identified and corrected • Resume at reduced dose if other factors that cause QT prolongation are not identified | |
| Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia | • Permanently discontinue entrectinib | |
| Transaminase elevations | Grade 3 | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at same dose if resolution occurs within 4 weeks • Permanently discontinue if adverse reaction does not resolve within 4 weeks • Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks |
| Grade 4 | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at reduced dose if resolution occurs within 4 weeks • Permanently discontinue if adverse reaction does not resolve within 4 weeks • Permanently discontinue for recurrent Grade 4 events | |
| ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 2 times ULN (in the absence of cholestasis or haemolysis) | • Permanently discontinue entrectinib | |
| Anaemia or neutropenia | Grade 3 or 4 | • Withhold entrectinib until recovery to less than or equal to Grade 2 or to baseline • Resume at the same dose or reduced dose, as clinically needed |
| Other clinically relevant adverse reactions | Grade 3 or 4 | • Withhold entrectinib until adverse reaction resolves or improves to recovery or improvement to Grade 1 or baseline • Resume at the same or reduced dose, if resolution occurs within 4 weeks • Consider permanent discontinuation if adverse reaction does not resolve within 4 weeks • Permanently discontinue for recurrent Grade 4 events |
* Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
Entrectinib can be taken with or without food but should not be taken with grapefruit or grapefruit juice.
For:
Regimen A: In case that patient age in months is ≥ 1 and patient age in months is ≤ 6, oral, 250 milligrams entrectinib per square meter of body surface, once daily.
Regimen B: In case that patient age in years is ≥ 6 and patient body surface area is ≤ 0.42 m², oral, 250 milligrams entrectinib per square meter of body surface, once daily.
Regimen C: In case that patient age in years is ≥ 6 and patient body surface area is ≥ 0.43 m² and patient body surface area is ≤ 0.50 m², oral, 100 milligrams entrectinib, once daily.
Regimen D: In case that patient age in years is ≥ 6 and patient body surface area is ≥ 0.51 m² and patient body surface area is ≤ 0.80 m², oral, 200 milligrams entrectinib, once daily.
Regimen E: In case that patient age in years is ≥ 6 and patient body surface area is ≥ 0.81 m² and patient body surface area is ≤ 1.10 m², oral, 300 milligrams entrectinib, once daily.
Regimen F: In case that patient age in years is ≥ 6 and patient body surface area is ≥ 1.11 m² and patient body surface area is ≤ 1.50 m², oral, 400 milligrams entrectinib, once daily.
Regimen G: In case that patient age in years is ≥ 6 and patient body surface area is ≥ 1.51 m², oral, 600 milligrams entrectinib, once daily.
A validated assay is required for the selection of patients with NTRK gene fusion-positive solid tumours. NTRK gene fusion-positive status must be established prior to initiation of entrectinib therapy.
The recommended dose for paediatric patients >6 months of age is based on body surface area (BSA) (see Table 1).
Table 1. Recommended dosing for paediatric patients >6 months:
| Body surface area (BSA)* | Once daily dose |
|---|---|
| ≤0.42 m² | 250 mg/m² |
| 0.43 m² to 0.50 m² | 100 mg |
| 0.51 m² to 0.80 m² | 200 mg |
| 0.81 m² to 1.10 m² | 300 mg |
| 1.11 m² to 1.50 m² | 400 mg |
| ≥1.51 m² | 600 mg |
* BSA categories and recommended dosing in Table 1 are based on closely matching exposures to a target dose of 300 mg/m²
The recommended dose for paediatric patients >1 month to ≤6 months of age is 250 mg/m² BSA entrectinib once daily.
The daily dose to be administered should be rounded to the nearest 10 mg increment.
It is recommended that patients are treated with entrectinib until disease progression or unacceptable toxicity.
If a planned dose of entrectinib is missed, patients can make up that dose unless the next dose is due within 12 hours. If vomiting occurs immediately after taking a dose of entrectinib, patients may repeat that dose.
When entrectinib is administered by individuals other than the healthcare professional (e.g., caregivers or parents) and partial or total vomiting/spitting occurs immediately after taking an administered dose, caregivers should consult the healthcare professional for the next steps.
Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with entrectinib, in case of specified adverse reactions (see Table 1) or based on the prescriber’s assessment of the patient’s safety or tolerability.
For paediatric patients older than 1 month, the dose of entrectinib may be reduced up to 2 times, based on tolerability (see Table 2).
Table 2. Dose reduction schedule for paediatric patients:
| Starting dose once daily | First dose reduction | Second dose reduction | |
|---|---|---|---|
| 250 mg/m² | Reduce the once daily dose to two thirds of the starting dose* | Reduce the once daily dose to one third of the starting dose* | Permanently discontinue entrectinib in patients who are unable to tolerate entrectinib after two dose reductions. |
| 100 mg | 50 mg or 100 mg once daily, according to schedule** | 50 mg once daily | |
| 200 mg | 150 mg once daily | 100 mg once daily | |
| 300 mg | 200 mg once daily | 100 mg once daily | |
| 400 mg | 300 mg once daily | 200 mg once daily | |
| 600 mg | 400 mg once daily | 200 mg once daily |
* To enable dosing increments of 10 mg, capsules prepared as an oral suspension may be used.
** Monday (100 mg), Tuesday (50 mg), Wednesday (100 mg), Thursday (50 mg), Friday (100 mg), Saturday (50 mg), and Sunday (100 mg).
Recommendations for entrectinib dose modifications for paediatric patients in case of specific adverse reactions are provided in Table 3.
Table 3. Recommended entrectinib dose modifications for adverse reactions in paediatric patients:
| Adverse reaction | Severity* | Dosage modification |
|---|---|---|
| Congestive heart failure | Symptomatic with middle to moderate activity or exertion, including where intervention is indicated (Grade 2 or 3) | • Withhold entrectinib until recovered to less than or equal to Grade 1 • Resume at reduced dose |
| Severe with symptoms at rest, minimal activity, or exertion or where intervention is indicated (Grade 4) | • Withhold entrectinib until recovered to less than or equal to Grade 1 • Resume at reduced dose or discontinue as clinically appropriate | |
| Cognitive disorders | Intolerable, but moderate changes interfering with activities of daily living (Intolerable Grade 2) | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at same dose or reduced dose, as clinically needed |
| Severe changes limiting activities of daily living (Grade 3) | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at reduced dose | |
| Urgent intervention indicated for event (Grade 4) | • For prolonged, severe, or intolerable events, discontinue entrectinib as clinically appropriate | |
| Hyperuricemia | Symptomatic or Grade 4 | • Initiate urate-lowering medication • Withhold entrectinib until improvement of signs or symptoms • Resume entrectinib at same or reduced dose |
| QT interval prolongation | QTc 481 to 500 ms | • Withhold entrectinib until recovered to baseline • Resume treatment at same dose |
| QTc greater than 500 ms | • Withhold entrectinib until QTc interval recovers to baseline • Resume at same dose if factors that cause QT prolongation are identified and corrected • Resume at reduced dose if other factors that cause QT prolongation are not identified | |
| Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia | • Permanently discontinue entrectinib | |
| Transaminase elevations | Grade 3 | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at same dose if resolution occurs within 4 weeks • Permanently discontinue if adverse reaction does not resolve within 4 weeks • Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks |
| Grade 4 | • Withhold entrectinib until recovery to less than or equal to Grade 1 or to baseline • Resume at reduced dose if resolution occurs within 4 weeks • Permanently discontinue if adverse reaction does not resolve within 4 weeks • Permanently discontinue for recurrent Grade 4 events | |
| ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 2 times ULN (in the absence of cholestasis or haemolysis) | • Permanently discontinue entrectinib | |
| Anaemia or neutropenia | Grade 3 or 4 | • Withhold entrectinib until recovery to less than or equal to Grade 2 or to baseline • Resume at the same dose or reduced dose, as clinically needed |
| Other clinically relevant adverse reactions | Grade 3 or 4 | • Withhold entrectinib until adverse reaction resolves or improves to recovery or improvement to Grade 1 or baseline • Resume at the same or reduced dose, if resolution occurs within 4 weeks • Consider permanent discontinuation if adverse reaction does not resolve within 4 weeks • Permanently discontinue for recurrent Grade 4 events |
* Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
Entrectinib can be taken with or without food but should not be taken with grapefruit or grapefruit juice.
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