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Mektovi is a brand name for Binimetinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Melanoma Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Non-small cell lung cancer (NSCLC) Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with advanced…
Verbatim from this product's EMA label. Tap a section to expand.
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. 3 BRAF mutation testing 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. Posology 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.
Dose modification 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.
Summary of safety profile The safety of binimetinib (45 mg orally twice daily) in combination with encorafenib (450 mg orally once daily) has been evaluated in the integrated safety population (ISP) of 372 patients including patients with BRAF V600 mutant unresectable or metastatic melanoma and BRAF V600E mutant advanced NSCLC (hereafter referred to as Combo 450 ISP).
1). The most common adverse reactions (> 25 %) occurring in patients treated with binimetinib administered with encorafenib were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy/muscular disorders and arthralgia. The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the Combo 300 population), based on the Phase III study (CMEK162B2301, Part 2).
The most common adverse reactions (>25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea. Tabulated list of adverse reactions Adverse reactions are listed below by MedDRA body system organ class and the following frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 3:
Adverse reactions occurring in patients receiving binimetinib in combination with encorafenib at the recommended dose (n = 372) System Organ Class Adverse reaction Frequency (All grades) Neoplasms benign, malignant and unspecified Cutaneous squamous cell carcinomaa Common Skin papilloma* Common Basal cell carcinoma* Uncommon Blood and lymphatic system disorders Anaemia Very common Immune system disorders Hypersensitivityb Common Metabolism and nutrition disorders Tumour lysis syndrome Not known Nervous system disorders Neuropathy peripheral* Very common Dizziness* Very common Headache* Very common 12 Dysgeusia Common Facial paresisc Uncommon Eye disorders Visual impairment* Very common RPED* Very common Uveitis* Common Cardiac disorders Left ventricular dysfunctiond Common Vascular disorders Haemorrhagee Very common Hypertension* Very common Venous thromboembolismf Common Gastrointestinal disorders Abdominal pain* Very common Diarrhoea* Very common Vomiting* Very common Nausea Very common Constipation Very common Colitisg Common Pancreatitis* Uncommon Skin and subcutaneous tissue disorders Hyperkeratosis * Very common Rash * Very common Dry skin* Very common Pruritus* Very common Alopecia* Very common Photosensitivity* Common Dermatitis acneiform* Common Palmar-plantar erythrodysaesthesia syndrome (PPES) Common Erythema* Common Panniculitis* Common Musculoskeletal and connective tissue disorders Arthralgia* Very common Myopathy/Muscular disorderh Very common Back pain* Very common Pain in extremity Very common Rhabdomyolysis Uncommon Renal and urinary disorders Renal failure* Common General disorders and administration site conditions Pyrexia* Very common Peripheral oedema i Very common Fatigue* Very common Investigations Blood creatine phosphokinase increased Very Common Transaminase increased* Very Common Gamma-glutamyl transferase increased* Very Common Blood creatinine increased* Common Blood alkaline phosphatase increased Common Amylase increased Common Lipase increased Common *composite terms which included more than one preferred term a includes keratoacanthoma, squamous cell carcinoma and squamous cell carcinoma of skin b includes, but not limited to, angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis, and urticaria c includes facial nerve disorder, facial paralysis, facial paresis, Bell's palsy d includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction abnormal 13 e includes haemorrhage at various sites including, but not limited to, cerebral haemorrhage, intracranial haemorrhage, vaginal haemorrhage, heavy menstrual bleeding, intermenstrual bleeding, haematochezia, haemoptysis, haemothorax, gastrointestinal haemorrhage and haematuria f includes, but not limited to, pulmonary embolism, deep vein thrombosis, embolism, thrombophlebitis, thrombophlebitis superficial, thrombosis, phlebitis, superior vena cava syndrome, mesenteric vein thrombosis and vena cava thrombosis g includes colitis, colitis ulcerative, enterocolitis and proctitis h includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis i includes, but not limited to, fluid retention, peripheral oedema, localised oedema, generalised oedema and swelling When encorafenib was used at a dose of 300 mg once daily in combination with binimetinib 45 mg twice daily (Combo 300) in study CMEK162B2301-Part 2, the frequency category was lower compared to the pooled Combo 450 population for the following adverse reactions: anaemia, peripheral neuropathy, haemorrhage, hypertension, pruritus (common) and colitis, increased amylase and increased lipase (uncommon).
Binimetinib is to be given in combination with encorafenib. 4 of encorafenib SmPC. Binimetinib in combination with encorafenib in patients who have progressed on a BRAF inhibitor There are limited data for use of the combination of binimetinib with encorafenib in patients who have progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastatic melanoma with BRAF V600 mutation.
These data show that the efficacy of the combination would be lower in these patients. 1). Left ventricular dysfunction (LVD) LVD defined as symptomatic or asymptomatic decreases in ejection fraction can occur when binimetinib is administered.
It is recommended that LVEF is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of binimetinib, 1 month after initiation, and then at approximately 3-month intervals or more frequently as clinically indicated, while on treatment.
2). The safety of binimetinib in combination with encorafenib has not been established in patients with a baseline LVEF that is either below 50 % or below the institutional LLN. Therefore, in these patients, binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, Grade 3-4 LVEF, or absolute decrease of LVEF from baseline of ≥ 10 %, binimetinib should be discontinued and LVEF should be evaluated every 2 weeks until recovery.
8). The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet therapy. The occurrence of Grade ≥ 3 haemorrhagic events should be managed with dose . 2) and as clinically indicated. Ocular toxicities Ocular toxicities including RPED and RVO can occur when binimetinib is administered.
8). Binimetinib is not recommended in patients with a history of RVO. The safety of binimetinib has not been established in patients with predisposing factors for RVO including uncontrolled glaucoma, ocular hypertension, uncontrolled diabetes mellitus or a history of hyperviscosity or hypercoagulability syndromes.
1.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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. 2 of encorafenib SmPC), binimetinib should be interrupted. If encorafenib is permanently discontinued, then binimetinib should be discontinued. 2 of encorafenib SmPC.
4 Table 1: Recommended dose modifications for binimetinib (used in combination with encorafenib) for selected adverse reaction Severity of adverse reactiona Binimetinib Cutaneous reactions • Grade2 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 Grade2.
• 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. 5 Severity of adverse reactiona Binimetinib • 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 […]
8 of encorafenib SmPC). 3% (83/372) of patients. 6 % (6/372) of patients. Most […]
Therefore, binimetinib should be used with caution in these patients. Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. If symptoms of new or worsening visual disturbances including diminished central vision, blurred vision or loss of vision are identified, a prompt ophthalmologic examination is recommended.
2). 2). 2 of encorafenib SmPC for guidance. 8), and, rhabdomyolysis was uncommonly reported. Special attention should be paid to patients with neuromuscular conditions associated with CK elevation and rhabdomyolysis. CK and creatinine levels should be monitored monthly during the first 6 months of treatment and as clinically indicated.
The patient should be advised to maintain an adequate fluid intake during treatment. 2). Hypertension Hypertension, or worsening of pre-existing hypertension, can occur with the use of binimetinib. Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate.
2). 8). Binimetinib should be used with caution in patients who are at risk for, or who have a history of VTE. 2). Pneumonitis/Interstitial lung disease Pneumonitis/ILD can occur with binimetinib. 2). Binimetinib should be permanently discontinued in patients diagnosed with treatment related pneumonitis or ILD.
8). Cutaneous malignancies Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma has been observed in patients treated with binimetinib […]