Chemical formula: C₁₇H₁₅BrF₂N₄O₃ Molecular mass: 441.233 g/mol PubChem compound: 10288191
Binimetinib interacts in the following cases:
Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. The extent of drug interactions mediated by UGT1A1 is unlikely to be clinically relevant; however, as this has not been evaluated in a formal clinical study, UGT1A1 inducers (such as rifampicin and phenobarbital) and inhibitors (such as indinavir, atazanavir, sorafenib) should be co-administered with caution.
While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinib exposure have been observed clinically when binimetinib is co-administered with encorafenib.
Inducers of CYP1A2 enzymes (such as carbamazepine and rifampicin) may decrease binimetinib exposure, which could result in a decrease of efficacy.
Binimetinib is a potential inducer of CYP1A2, and caution should be taken when it is used with sensitive substrates (such as duloxetine or theophylline).
Inducers of Pgp transport (such as Saint John’s wort or phenytoin) may decrease binimetinib exposure, which could result in a decrease of efficacy.
Liver metabolism mainly via glucuronidation is the primary route of elimination of binimetinib. As encorafenib is not recommended in patients with moderate (Child Pugh B) and severe hepatic impairment (Child Pugh C), administration of binimetinib is not recommended in these patients.
Binimetinib is a weak inhibitor of OAT3, and caution should be taken when it is used with sensitive substrates (such as pravastatin or ciprofloxacin).
Pneumonitis/ILD can occur with binimetinib. Treatment with binimetinib should be withheld in patients with suspected pneumonitis or ILD, including patients presenting new or progressive pulmonary symptoms or findings such as cough, dyspnoea, hypoxia, reticular opacities or pulmonary infiltrates. Binimetinib should be permanently discontinued in patients diagnosed with treatment related pneumonitis or ILD.
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. In case of severe hypertension, temporary interruption of binimetinib is recommended until hypertension is controlled.
Venous thromboembolism can occur when binimetinib is administered. Binimetinib should be used with caution in patients who are at risk for, or who have a history of VTE. If during treatment patient develops VTE or pulmonary embolism, it should be managed with dose interruption, reduction or treatment discontinuation.
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. The occurrence of LVEF decrease can be managed with treatment interruption, dose reduction or with treatment discontinuation. 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.
There are no data from the use of binimetinb in pregnant women. Studies in animals have shown reproductive toxicity. Binimetinib is not recommended during pregnancy and in women of childbearing potential not using contraception. If binimetinib is used during pregnancy, or if the patient becomes pregnant while taking binimetinib, the patient should be informed of the potential hazard to the foetus.
It is unknown whether binimetinib or its metabolite are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue binimetinb therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
There are no data on the effect on fertility in humans for binimetinib.
Binimetinib has minor influence on the ability to drive or use machines. Visual disturbances have been reported in patients treated with binimetinib during clinical studies. Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse reaction that may affect their ability to drive and use machines.
The safety of binimetinib (45 mg orally twice daily) in combination with encorafenib (450 mg orally once daily) (hereafter referred to as Combo 450) was evaluated in 274 patients with BRAF V600 mutant unresectable or metastatic melanoma, based on two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1) (hereafter referred to as the pooled Combo 450 population). At the recommended dose (n=274) in patients with unresectable or metastatic melanoma, the most common adverse reactions (>25%) occurring in patients treated with binimetinib administered with encorafenib were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, blood CK increased and myalgia.
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.
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=274):
Common: Cutaneous squamous cell carcinomaa, Basal cell carcinoma*, Skin papilloma*
Very common: Anaemia
Common: Hypersensitivityb
Very common: Neuropathy peripheral*, Dizziness*, Headache*
Common: Dysgeusia
Uncommon: Facial paresisc
Very common: Visual impairment*, RPED*
Common: Uveitis*
Common: Left ventricular dysfunctiond
Very common: Haemorrhagee, Hypertension*
Common: Venous thromboembolismf
Very common: Abdominal pain*, Diarrhoea*, Vomiting*, Nausea, Constipation
Common: Colitisg
Uncommon: Pancreatitis*
Very common: Hyperkeratosis*, Rash*, Dry skin*, Pruritus*, Alopecia*
Common: Photosensitivity*, Dermatitis acneiform*, Palmar-plantar erythrodysaesthesia syndrome (PPES), Erythema*, Panniculitis*
Very common: Arthralgia*, Muscular disorders/Myalgiah, Back pain, Pain in extremity
Uncommon: Rhabdomyolysis
Common: Renal failure*
Very common: Pyrexia*, Peripheral oedemai, Fatigue*
Very common: Blood creatine phosphokinase increased, Transaminase increased*, Gamma-glutamyl transferase increased*
Common: Blood creatinine increased*, Blood alkaline phosphatase increased, Amylase increased, Lipase increased
==*==composite terms which included more than one preferred term
a includes keratoacanthoma, squamous cell carcinoma, lip squamous cell carcinoma and squamous cell carcinoma of skin
b includes angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis and urticaria
c includes facial nerve disorder, facial paralysis, facial paresis
d includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction abnormal
e includes haemorrhage at various sites including cerebral haemorrhage
f includes pulmonary embolism, deep vein thrombosis, embolism, thrombophlebitis, thrombophlebitis superficial and thrombosis
g includes colitis, colitis ulcerative, enterocolitis and proctitis
h includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis
i includes fluid retention, peripheral oedema, localised oedema
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: anemia, peripheral neuropathy, haemorrhage, hypertension, pruritus (common) and colitis, increased amylase and increased lipase (uncommon).
CuSCC was reported when binimetinib was used in combination with encorafenib.
In the pooled Combo 450 population, RPED was reported in 29.6% (81/274) of patients. RPED was Grade 1 (asymptomatic) in 21.2% (58/274) of patients, Grade 2 in 6.6% (18/274) of patients and Grade 3 in 1.8% (5/274) of patients. Most events were reported as retinopathy, retinal detachment, subretinal fluid, macular oedema, and chorioretinopathy and led to dose interruptions or dose modifications in 4.7% (13/274) of patients. The median time to onset of the first event of RPED (all grades) was 1.5 month (range 0.03 to 17.5 months).
Visual impairment, including vision blurred and reduced visual acuity, occurred in 21.5% (59/274) of patients. Visual impairment was generally reversible.
Uveitis was also reported when binimetinib was used in combination with encorafenib.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, RPED was observed in 12.5% (32/257) of patients with 0.4% (1/257) Grade 4 event.
In the pooled Combo 450 population, LVD was reported in 8.4% (23/274) of patients. Grade 3 events occurred in 1.1% (3/274) of patients. LVD led to treatment discontinuation in 0.4% (1/274) of patients and led to dose interruptions or dose reductions in 6.6% (18/274) of patients.
The median time to first occurrence of LVD (any grade) was 4.4 months (range 0.03 to 21.3 months) in patients who developed an LVEF below 50%. The mean LVEF value dropped by 5.9% in the pooled Combo 450 population, from a mean of 63.9% at baseline to 58.1%. LVD was generally reversible following dose reduction or dose interruption.
Haemorrhagic events were observed in 17.9% (49/274) of patients in the pooled Combo 450 population. Most of these cases were Grade 1 or 2 (14.6%) and 3.3% were Grade 3 or 4 events. Few patients requiring dose interruptions or dose reductions (0.7% or 2/274). Haemorrhagic events led to discontinuation of treatment in 1.1% (3/274) of patients. The most frequent haemorrhagic events were haematuria in 3.3% (9/274) of patients, rectal haemorrhage in 2.9% (8/274) and haematochezia in 2.9% (8/274) of patients. Fatal gastric ulcer haemorrhage with multiple organ failure as a concurrent cause of death, occurred in one patient. Cerebral haemorrhage occurred in 1.5% (4/274) of patients with fatal outcome in 3 patients. All events occurred in the setting of new or progressive brain metastases.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, haemorrhagic events were observed in 6.6% (17/257) of patients and were Grade 3-4 in 1.6% (4/257) of patients.
New onset elevated blood pressure or worsening of pre-existing hypertension were reported in 11.7% (32/274) of patients treated with the Combo 450. Hypertension events were reported as Grade 3 in 5.5% (15/274) of patients, including hypertensive crisis (0.4% (1/274)). Hypertension led to dose interruption or adjustment in 2.9% of patients. Hypertensive adverse reactions required additional therapy in 8.0% (22/274) of patients.
In patients treated with Combo 450, VTE occurred in 4.7% (13/274) of patients, including 2.2% (6/274) of patients who developed pulmonary embolism. In the pooled Combo 450 population, VTE was reported as Grade 1 or 2 in 3.6% (10/274) of patients and Grade 3 or 4 in 1.1% (3/274) of patients. VTE led to dose interruptions or dose modifications in 1.1% (3/274) patients and to additional therapy in 4.7% (13/274) of patients.
Pancreatitis was reported when binimetinib was used in combination with encorafenib.
Dermatologic reactions may occur when binimetinib is used in combination with encorafenib.
In the pooled Combo 450 population, rash occurred in 19.7% (54/274) of patients. Most events were mild, with Grade 3 or 4 events reported in 0.7% (2/274) of patients. Rash led to treatment discontinuation in 0.4% (1/274) of patients and to dose interruption or dose modification in 1.1% (3/274) of patients.
In patients treated with Combo 450, dermatitis acneiform occurred in 4.4% (12/274) of patients, was Grade 1 and 2 and no event led to treatment discontinuation. Dose modification was reported in 0.7% (2/274) of patients.
PPES can occur when binimetinib is used in combination with encorafenib.
In the pooled Combo 450 population, photosensitivity was observed in 4.0% (11/274) of patients. Most events were Grade 1-2, with Grade 3 reported in 0.4% (1/274) of patients and no event led to discontinuation. Dose interruption or dose modification was reported in 0.4% (1/274) of patients.
Facial paresis was reported when binimetinib was used in combination with encorafenib.
In the pooled Combo 450 population, mostly mild asymptomatic blood CK elevation was reported in 27.0% (74/274) of patients. The incidence of Grade 3 or 4 adverse reactions was 5.8% (16/274). The median time to onset of the first event was 2.7 months (range: 0.5 to 17.5 months).
Rhabdomyolysis was reported in 0.4% (1/274) of patients treated with encorafenib in combination with binimetinib. In this patient, rhabdomyolysis was observed with concomitant symptomatic Grade 4 CK elevation.
Blood creatinine elevation and renal failure occurred when binimetinib was used in combination with encorafenib.
The incidences of liver laboratory abnormalities reported in the pooled Combo 450 population are listed below:
In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidences of liver laboratory abnormalities are listed below:
In the pooled Combo 450 population, diarrhoea was observed in 38% (104/274) of patients and was Grade 3 or 4 in 3.3% (9/274) of patients. Diarrhoea led to dose discontinuation in 0.4% of patients and to dose interruption or dose modification in 4.4% of patients. Constipation occurred in 24.1% (66/274) of patients and was Grade 1 or 2. Abdominal pain was reported in 27.4% (75/274) of patients and was Grade 3 in 2.6% (7/274) patients. Nausea occurred in 41.6% (114/274) with Grade 3 or 4 observed in 2.6% (7/274) of patients. Vomiting occurred in 28.1% (77/274) of patients with Grade 3 or 4 reported in 2.2% (6/274) of patients.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, nausea was observed in 27.2% (70/257) of patients and was Grade 3 in 1.6% (4/257) of patients. Vomiting occurred in 15.2% (39/257) of patients with Grade 3 reported in 0.4% (1/257) of patients. Diarrhoea occurred in 28.4% (73/257) of patients with Grade 3 reported in 1.6% (4/257) of patients.
Gastrointestinal disorders were typically managed with standard therapy.
In the pooled Combo 450 population, anaemia was reported in 19.7% (54/274) of patients; 4.7% (13/274) of patients had Grade 3 or 4. No patients discontinued treatment due to anaemia, 1.5% (4/274) required dose interruption or dose modification.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, anaemia was observed in 9.7% (25/257) of patients with Grade 3-4 reported in 2.7% (7/257) patients.
In the pooled Combo 450 population, headache occurred in 21.5% (59/274) of patients including Grade 3 in 1.5% (4/274) of patients.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, headache was reported in 12.1% (31/257) of patients and was Grade 3 in 0.4% (1/257) of patients.
In the pooled Combo 450 population, fatigue occurred in 43.8% (120/274) of patients including Grade 3 in 2.9% (8/274) of patients.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, fatigue was observed in 33.5% (86/257) of patients with 1.6% (4/257) Grade 3-4 events.
In patients treated with Combo 450 (n=274), 194 patients (70.8%) were <65 years old, 65 patients (23.7%) were 65-74 years old and 15 patients (5.5%) were aged >75. No overall differences in safety or efficacy were observed between elderly patients (≥65) and younger patients. The proportion of patients experiencing adverse events and serious adverse events were similar in patients aged <65 years and those aged >65 years. The most common adverse events reported with a higher incidence in patients aged ≥65 years compared to patients aged <65 years included diarrhoea, pruritus, GGT and blood phosphatase alkaline elevation. In the small group of patients aged ≥75 years (n=15), patients were more likely to experience serious adverse events and adverse events leading to discontinuation of treatment.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
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