Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: PIERRE FABRE MEDICAMENT, Les Cauquillous, 81500 Lavaur, France
Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600E mutation.
Binimetinib treatment in combination with encorafenib should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products.
Before taking binimetinib in combination with encorafenib, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used.
The efficacy and safety of binimetinib in combination with encorafenib have been established only in patients with melanoma tumours expressing BRAF V600E and V600K mutations, or NSCLC expressing a BRAF V600E mutation. Binimetinib in combination with encorafenib should not be used in patients with wild type BRAF malignant melanoma or wild type BRAF NSCLC.
The recommended dose of binimetinib is 45 mg (three 15 mg tablets or one 45 mg tablet) twice daily approximately 12 hours apart, corresponding to a total daily dose of 90 mg.
The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation (see below, Table 1 and Table 2).
For patients receiving 45 mg binimetinib twice daily, the recommended reduced dose of binimetinib is 30 mg twice daily. Dose reduction below 30 mg twice daily is not recommended. Therapy should be discontinued if the patient is not able to tolerate 30 mg orally twice daily.
If the adverse reaction that resulted in a dose reduction is under effective management, dose re-escalation to 45 mg twice daily may be considered. Dose re-escalation to 45 mg twice daily is not recommended if the dose reduction is due to left ventricular dysfunction (LVD) or any Grade 4 toxicity.
Dose modifications recommendations in case of adverse reactions are presented below and in Tables 1 and 2.
If treatment-related toxicities occur when binimetinib is used in combination with encorafenib, then both treatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions where dose reductions are necessary for encorafenib only (adverse reactions primarily related to encorafenib) are: palmar-plantar erythrodysaesthesia syndrome (PPES), uveitis including iritis and iridocyclitis and QTc prolongation.
If one of these toxicities occurs, see section 4.2 of encorafenib Summary of Product Characteristics (SmPC) for dose modification instructions for encorafenib.
If binimetinib is temporarily interrupted, encorafenib should be reduced to 300 mg once daily during the time of binimetinib dose interruption (see Tables 1 and 2) as encorafenib is not well-tolerated at the dose of 450 mg as a single agent. If binimetinib is permanently discontinued, encorafenib should be discontinued.
If encorafenib is temporarily interrupted (see section 4.2 of encorafenib SmPC), binimetinib should be interrupted. If encorafenib is permanently discontinued, then binimetinib should be discontinued. For information on the posology and recommended dose modifications of encorafenib, see section 4.2 of encorafenib SmPC.
Table 1. Recommended dose modifications for binimetinib (used in combination with encorafenib) for selected adverse reaction:
| Severity of adverse reactiona | Binimetinib |
|---|---|
| Cutaneous reactions | |
| • Grade 2 | Binimetinib should be maintained. If rash worsens or does not improve within 2 weeks with treatment, binimetinib should be withheld until improved to Grade 0 or 1 and then resumed at the same dose if first occurrence or resumed at a reduced dose if recurrent Grade 2. |
| • Grade 3 | Binimetinib should be withheld until improved to Grade 0 or 1 and resumed at the same dose if first occurrence or resumed at a reduced dose if recurrent Grade 3. |
| • Grade 4 | Binimetinib should be permanently discontinued. |
| Ocular events | |
| • Symptomatic retinal pigment epithelial detachments (RPED) (Grade 2 or 3) | Binimetinib should be withheld for up to 2 weeks and ophthalmic monitoring should be repeated including visual acuity assessment. • If improved to Grade 0 or 1, binimetinib should be resumed at same dose. • If improved to Grade 2, binimetinib should be resumed at a lower dose. • If not improved to Grade 2, binimetinib should be permanently discontinued. |
| • Symptomatic RPED (Grade 4) associated with reduced visual acuity (Grade 4) | Binimetinib should be permanently discontinued. |
| • Retinal vein occlusion (RVO) | Binimetinib should be permanently discontinued. |
| Cardiac events | |
| • Grade 2 Left ventricular ejection fraction (LVEF) decrease or asymptomatic, absolute decrease in LVEF of greater than 10% from baseline that is below lower limit of normal (LLN) | LVEF should be evaluated every 2 weeks. • If asymptomatic: Binimetinib should be withheld for up to 4 weeks. Binimetinib should be resumed at a reduced dose if all of the following are present within 4 weeks: o LVEF is at or above the LLN o Absolute decrease from baseline is 10% or less. • If the LVEF does not recover within 4 weeks, binimetinib should be permanently discontinued. |
| • Grade 3 or 4 LVEF decrease or symptomatic left ventricular dysfunction (LVD) | Binimetinib should be permanently discontinued. LVEF should be evaluated every 2 weeks until recovery. |
| Rhabdomyolysis/Creatine phosphokinase (CK) elevation | |
| • Grade 3 (CK >5 – 10x upper limit of normal (ULN)) asymptomatic | Binimetinib dose should be maintained and it should be ensured that patient is adequately hydrated. |
| • Grade 4 (CK >10x ULN) asymptomatic | Binimetinib should be withheld until improved to Grade 0 or 1. It should be ensured that patient has adequate hydration. |
| • Grade 3 or grade 4 (CK >5x ULN) with muscle symptoms or renal impairment | Binimetinib should be withheld until improved to Grade 0 or 1. • If resolved within 4 weeks, binimetinib should be resumed at a reduced dose, or • Binimetinib should be permanently discontinued. |
| Venous thromboembolism (VTE) | |
| • Uncomplicated deep vein thrombosis (DVT) or pulmonary embolism (PE) ≤ Grade 3 | Binimetinib should be withheld. • If improved to Grade 0 or 1, binimetinib should be resumed at a reduced dose, or • If not improved, binimetinib should be permanently discontinued. |
| • Grade 4 PE | Binimetinib should be permanently discontinued. |
| Liver laboratory abnormalities | |
| • Grade 2 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x – ≤5x upper limit of normal (ULN) | Binimetinib dose should be maintained. If no improvement within 2 weeks, binimetinib should be withheld until improved to Grade 0 or 1 or to baseline levels, and then resumed at the same dose. |
| • First occurrence of Grade 3 (AST or ALT >5x ULN and blood bilirubin >2x ULN) | Binimetinib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1 or baseline level, binimetinib should be resumed at reduced dose, or • If not improved, binimetinib should be permanently discontinued. |
| • First occurrence of Grade 4 (AST or ALT >20 ULN) | Binimetinib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1 or baseline levels, binimetinib should be resumed at a reduced dose level, or • If not improved, binimetinib should be permanently discontinued. Or, binimetinib should be permanently discontinued. |
| • Recurrent Grade 3 (AST or ALT >5x ULN and blood bilirubin >2x ULN) | It should be considered to permanently discontinue binimetinib. |
| • Recurrent Grade 4 (AST or ALT >20 ULN) | Binimetinib should be permanently discontinued. |
| Interstitial lung disease (ILD)/pneumonitis | |
| • Grade 2 | Binimetinib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1, binimetinib should be resumed at reduced dose, or • If not resolved within 4 weeks, binimetinib should be permanently discontinued. |
| • Grade 3 or Grade 4 | Binimetinib should be permanently discontinued. |
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03
Table 2. Recommended dose modifications for binimetinib (used in combination with encorafenib) for other adverse reactions:
| Severity of adverse reaction | Binimetinib |
|---|---|
| • Recurrent or intolerable Grade 2 adverse reactions • First occurrence of Grade 3 adverse reactions | Binimetinib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1 or baseline level, binimetinib should be resumed at reduced dose, or • If not improved, binimetinib should be permanently discontinued. |
| • First occurrence of Grade 4 adverse reactions | Binimetinib should be withheld for up to 4 weeks. • If improved to Grade 0 or 1 or baseline levels, binimetinib should be resumed at a reduced dose level, or • If not improved, binimetinib should be permanently discontinued. Or, binimetinib should be permanently discontinued binimetinib. |
| • Recurrent Grade 3 adverse reactions | It should be considered to permanently discontinue binimetinib. |
| • Recurrent Grade 4 adverse reactions | Binimetinib should be permanently discontinued. |
Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity.
If a dose of binimetinib is missed, it should not be taken if it is less than 6 hours until the next dose is due.
In case of vomiting after administration of binimetinib, the patient should not re-take the dose and should take the next scheduled dose.
No dose adjustment is required for patients aged 65 years and older (see section 5.2).
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh A).
As encorafenib is not recommended in patients with moderate (Child Pugh B) or severe hepatic impairment (Child-Pugh C), administration of binimetinib is not recommended in these patients. (see section 4.2 of encorafenib SmPC).
No dose adjustment is recommended for patients with renal impairment (see section 5.2).
The safety and efficacy of binimetinib in children and adolescents have not yet been established. No data are available.
Mektovi is for oral use.
The tablets are to be swallowed whole with water. They may be taken with or without food.
The highest dose of binimetinib evaluated as single agent in clinical studies was 80 mg administered orally twice daily and was associated with ocular (chorioretinopathy) and skin toxicities (dermatitis acneiform).
There is no specific treatment of overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Since binimetinib is highly bound to plasma proteins, haemodialysis is likely to be ineffective in the treatment of overdose with binimetinib.
3 years.
This medicinal product does not require any special storage conditions.
Mektovi 15 mg film-coated tablets:
PVC/PVDC/Alu blister containing 12 tablets. Each pack contains either 84 or 168 tablets.
Not all pack sizes may be marketed.
Mektovi 45 mg film-coated tablets:
PVC/PVDC/Alu blister containing 14 tablets. Each pack contains either 28 or 56 tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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