Dose Adjustments for Specific Adverse Reactions of Binimetinib
1. Cardiomyopathy
(1) Asymptomatic decrease in left ventricular ejection fraction (LVEF) of >10% from baseline and below the lower limit of normal (LLN): Interrupt treatment for up to 4 weeks; assess LVEF every 2 weeks. If LVEF returns to ≥ LLN, with an absolute decrease from baseline of ≤10%, and the patient is asymptomatic, resume at a reduced dose. If LVEF does not recover within 4 weeks, permanently discontinue.
(2) Symptomatic congestive heart failure or absolute decrease in LVEF of >20% from baseline and below LLN: Permanently discontinue.
2. Venous Thromboembolism
(1) Uncomplicated deep vein thrombosis (DVT) or pulmonary embolism (PE): Interrupt treatment. If improved to Grade 0 or 1, resume at a reduced dose. If no improvement, permanently discontinue.
(2) Life‑threatening pulmonary embolism: Permanently discontinue.
3. Serous Retinopathy
Symptomatic serous retinopathy/retinal pigment epithelial detachment: Interrupt treatment for up to 10 days. If improved and asymptomatic, resume at the same dose. If not improved, resume at a reduced dose or permanently discontinue.
4. Retinal Vein Occlusion (RVO)
Any grade: Permanently discontinue.
5. Uveitis
(1) Grade 1, 2, or 3: If Grade 1 or 2 does not respond to specific ophthalmologic treatment, or if Grade 3 uveitis occurs, interrupt treatment for up to 6 weeks. If improved, resume at the same or reduced dose. If not improved, permanently discontinue.
(2) Grade 4: Permanently discontinue.
6. Interstitial Lung Disease
(1) Grade 2: Interrupt treatment for up to 4 weeks. If improved to Grade 0 or 1, resume at a reduced dose. If not resolved within 4 weeks, permanently discontinue.
(2) Grade 3 or 4: Permanently discontinue.
7. Hepatotoxicity
(1) Grade 2 AST or ALT elevation: Maintain dose. If no improvement within 2 weeks, interrupt until improved to Grade 0 or 1 or to pre‑treatment/baseline level, then resume at the same dose.
(2) First occurrence of Grade 3 AST or ALT elevation: Interrupt for up to 4 weeks. If improved to Grade 0 or 1 or baseline, resume at a reduced dose. If no improvement, permanently discontinue.
(3) Recurrent Grade 3 AST or ALT elevation: Consider permanent discontinuation.
(4) First occurrence of Grade 4 AST or ALT elevation: Permanently discontinue, or interrupt for up to 4 weeks. If improved to Grade 0 or 1 or baseline, resume at a reduced dose. If no improvement, permanently discontinue.
(5) Recurrent Grade 4 AST or ALT elevation: Permanently discontinue.
8. Rhabdomyolysis or Creatine Phosphokinase (CPK) Elevation
Grade 4 asymptomatic CPK elevation, or any grade of CPK elevation with symptoms or with renal impairment: Interrupt treatment for up to 4 weeks. If improved to Grade 0 or 1, resume at a reduced dose. If not resolved within 4 weeks, permanently discontinue.
9. Skin Adverse Reactions
(1) Grade 2: If no improvement within 2 weeks, interrupt until improved to Grade 0‑1. If first occurrence, resume at the same dose; if recurrent, resume at a reduced dose.
(2) Grade 3: Interrupt until improved to Grade 0 or 1. If first occurrence, resume at the same dose; if recurrent, resume at a reduced dose.
(3) Grade 4: Permanently discontinue.
10. Other Adverse Reactions (including bleeding)
(1) Recurrent Grade 2 or first occurrence of any Grade 3: Interrupt for up to 4 weeks. If improved to Grade 0 or 1, resume at a reduced dose. If not resolved within 4 weeks, permanently discontinue.
(2) First occurrence of any Grade 4: Permanently discontinue, or interrupt for up to 4 weeks. If improved to Grade 0 or 1 or to pre‑treatment/baseline level, resume at a reduced dose. If no improvement, permanently discontinue.
Precautions for Binimetinib
1. Contraindications: No clear contraindications.
2. Pediatric use: Not recommended for use in children.
3. Dialysis: Binimetinib is 95% bound to plasma proteins; therefore, it is unlikely to be removed by hemodialysis.
Storage of Binimetinib
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F).
