Active Ingredient: Tovorafenib
Tovorafenib is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.
This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 380 milligrams tovorafenib per square meter of body surface, once weekly.
Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation prior to initiation of treatment with tovorafenib.
Before initiating tovorafenib, evaluate liver function tests, including ALT, AST and bilirubin.
The recommended dosage of tovorafenib based on body surface area (BSA) is 380 mg/m² orally once weekly (the maximum recommended dosage is 600 mg orally once weekly) with or without food until disease progression or intolerable toxicity. A recommended dosage for patients with BSA less than 0.3 m² has not been established.
Recommended dosage for tovorafenib based on Body Surface Area:
| Body Surface Area (m²) | Dosage |
|---|---|
| 0.30-0.35 | 125 mg once weekly |
| 0.36-0.42 | 150 mg once weekly |
| 0.43-0.48 | 175 mg once weekly |
| 0.49-0.54 | 200 mg once weekly |
| 0.55-0.63 | 225 mg once weekly |
| 0.64-0.77 | 275 mg once weekly |
| 0.78-0.83 | 300 mg once weekly |
| 0.84-0.89 | 350 mg once weekly |
| 0.90-1.05 | 375 mg once weekly |
| 0.90-1.12 | 400 mg once weekly |
| 1.06-1.25 | 450 mg once weekly |
| 1.13-1.39 | 500 mg once weekly |
| 1.26-1.39 | 525 mg once weekly |
| ≥1.40 | 600 mg once weekly |
Continue once weekly dosing until disease progression or intolerable toxicity.
If a dose is missed by:
If vomiting occurs immediately after taking a dose, repeat that dose.
The recommended dosage reductions for adverse reactions for tovorafenib are provided in the following table.
Recommended dosage reductions for adverse reactions:
| BSA (m²) | First dosage reduction | Second dosage reduction |
|---|---|---|
| Dose (mg) | Dose (mg) | |
| 0.30-0.35 | 100 mg once weekly | 75 mg once weekly |
| 0.36-0.42 | 125 mg once weekly | 100 mg once weekly |
| 0.43-0.48 | 150 mg once weekly | 125 mg once weekly |
| 0.49-0.54 | 175 mg once weekly | 150 mg once weekly |
| 0.55-0.63 | 200 mg once weekly | 150 mg once weekly |
| 0.64-0.77 | 225 mg once weekly | 200 mg once weekly |
| 0.78-0.83 | 250 mg once weekly | 200 mg once weekly |
| 0.84-0.89 | 300 mg once weekly | 250 mg once weekly |
| 0.90-1.05 | 325 mg once weekly | 275 mg once weekly |
| 1.06-1.25 | 375 mg once weekly | 325 mg once weekly |
| 1.26-1.39 | 450 mg once weekly | 375 mg once weekly |
| ≥1.40 | 500 mg once weekly | 400 mg once weekly |
The recommended dosage modifications of tovorafenib for adverse reactions are in the table below.
Recommended dosage modifications for adverse reactions:
| Severity of ADRa | Dosage modificationb |
|---|---|
| Hemorrhage | |
| • Intolerable Grade 2 • Any Grade 3 | Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. • If not improved, consider permanent discontinuation of tovorafenib. |
| • First occurrence of any Grade 4 | Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. OR • Permanently discontinue tovorafenib. |
| • Recurrent Grade 4 | Permanently discontinue tovorafenib. |
| Skin Toxicity including Photosensitivity | |
| • Intolerable Grade 2 • Grade 3 or 4 | Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. • If not improved, consider permanent discontinuation of tovorafenib. |
| Hepatotoxicity | |
| • Grade 3 AST or ALT • Grade 3 bilirubin | Withhold tovorafenib. If improved to Grade ≤ 2 or baseline, resume as follows: • If laboratory abnormality resolves within 8 days, resume tovorafenib at the same dose. • If laboratory abnormality does not resolve within 8 days, resume tovorafenib at lower dosage. |
| • First occurrence of any Grade 4 | Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. OR • Permanently discontinue tovorafenib. |
| • Recurrent Grade 4 | Permanently discontinue tovorafenib. |
| Other Adverse Reactions | |
| • Intolerable Grade 2 • Any Grade 3 | Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. • If not improved, consider permanent discontinuation of tovorafenib. |
| • First occurrence of any Grade 4 | Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. OR • Permanently discontinue tovorafenib. |
| • Recurrent Grade 4 | Permanently discontinue tovorafenib. |
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
b See Table 3 and Table 4 for recommended dosage reductions.
Take tovorafenib at a regularly scheduled time once weekly.
Tovorafenib may be taken with or without food.
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