4.1. Therapeutic indications

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 non-small cell lung cancer with a BRAF V600E mutation.

4.2. Posology and method of administration

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.

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 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.

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

• 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.

• 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.

• Recurrent Grade 3 adverse reactions

It should be considered to permanently discontinue binimetinib.

• Recurrent Grade 4 adverse reactions

Binimetinib should be permanently discontinued.

Duration of treatment

Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity.

Missed doses

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.

Vomiting

In case of vomiting after administration of binimetinib, the patient should not re-take the dose and should take the next scheduled dose.

Special populations

Elderly patients

No dose adjustment is required for patients aged 65 years and older (see section 5.2).

Hepatic impairment

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).

Renal impairment

No dose adjustment is recommended for patients with renal impairment (see section 5.2).

Paediatric population

The safety and efficacy of binimetinib in children and adolescents have not yet been established. No data are available.

Method of administration

Mektovi is for oral use.

The tablets are to be swallowed whole with water. They may be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Binimetinib is to be given in combination with encorafenib. For additional information on warnings and precautions associated with encorafenib treatment, see section 4.4 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.

Binimetinib in combination with encorafenib in patients with brain metastases

There are limited efficacy data with the combination of binimetinib and encorafenib in patients with a BRAF V600 mutant melanoma or BRAF V600E mutant NSCLC which have metastasised to the brain (see section 5.1).

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. The occurrence of LVEF decrease can be managed with treatment interruption, dose reduction or with treatment discontinuation (see section 4.2).

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.

Haemorrhage

Haemorrhages, including major haemorrhagic events, can occur when binimetinib is administered (see section 4.8). 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 interruption, reduction or treatment discontinuation (see Table 2 in section 4.2) and as clinically indicated.

Ocular toxicities

Ocular toxicities including RPED and RVO can occur when binimetinib is administered. Uveitis including iridocyclitis and iritis have been reported in patients treated with binimetinib in combination with encorafenib (see section 4.8).

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. 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.

The occurrence of symptomatic RPED can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Table 1 in section 4.2).

Binimetinib should be permanently discontinued with the occurrence of RVO (see Table 1 in section 4.2).

If during treatment patient develops uveitis, see section 4.2 of encorafenib SmPC for guidance.

CK elevation and rhabdomyolysis

Asymptomatic CK elevations are seen in patients treated with binimetinib (see section 4.8), 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. Depending on the severity of symptoms, degree of CK elevation or creatinine elevation, dose reduction, dose interruption or permanent discontinuation of binimetinib may be required (see Table 1 in section 4.2).

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. In case of severe hypertension, temporary interruption of binimetinib is recommended until hypertension is controlled (see Table 2 in section 4.2).

Venous thromboembolism (VTE)

VTE can occur when binimetinib is administered (see section 4.8). 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 (see Table 1 in section 4.2).

Pneumonitis/Interstitial lung disease

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 (see Table 1 in section 4.2). Binimetinib should be permanently discontinued in patients diagnosed with treatment related pneumonitis or ILD.

New primary malignancies

New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur when binimetinib is administered in combination with encorafenib (see section 4.8).

Cutaneous malignancies

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma has been observed in patients treated with binimetinib when used in combination with encorafenib.

Dermatologic evaluations should be performed prior to initiation of therapy with binimetinib in combination with encorafenib, every 2 months while on therapy and for up to 6 months following discontinuation of the combination. Suspicious skin lesions should be managed with dermatological excision and dermatopathologic evaluation. Patients should be instructed to immediately inform their physicians if new skin lesions develop. Binimetinib and encorafenib should be continued without any dose modifications.

Non-cutaneous malignancies

Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Patients receiving binimetinib in combination with encorafenib should undergo a head and neck examination, chest/abdomen computerised tomography (CT) scan, anal and pelvic examinations (for women) and complete blood cell counts prior to initiation, during and at the end of treatment as clinically appropriate.

Permanent discontinuation of binimetinib and encorafenib should be considered in patients who develops RAS mutation-positive non-cutaneous malignancies. Benefits and risks should be carefully considered before administering binimetinib in combination with encorafenib to patients with a prior or concurrent cancer associated with RAS mutation.

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of binimetinib in association with encorafenib (see section 4.8). Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. These patients should be monitored closely and treated promptly as clinically indicated, and prophylactic hydration should be considered.

Liver laboratory abnormalities

Liver laboratory abnormalities including AST and ALT elevations can occur with binimetinib (see section 4.8). Liver laboratory values should be monitored before initiation of binimetinib and encorafenib and at least monthly during the 6 first months of treatment, and then as clinically indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see Table 1 in section 4.2).

Hepatic impairment

Liver metabolism mainly via glucuronidation is the primary route of elimination of binimetinib (see section 5.2). 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 (see sections 4.2 and 5.2).

Lactose intolerance

Mektovi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on binimetinib

Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. The extent of drug interactions mediated by UGT1A1 is unlikely to be clinically relevant (see section 5.2); 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 (see section 5.2).

Inducers of CYP1A2 enzymes (such as carbamazepine and rifampicin) and inducers of Pgp transport (such as Saint John's wort or phenytoin) may decrease binimetinib exposure, which could result in a decrease of efficacy.

Effects of binimetinib on other medicinal products

Binimetinib is a potential inducer of CYP1A2, and caution should be taken when it is used with sensitive substrates (such as duloxetine or theophylline).

Binimetinib is a weak inhibitor of OAT3, and caution should be taken when it is used with sensitive substrates (such as pravastatin or ciprofloxacin).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women of childbearing potential must use effective contraception during treatment with binimetinib and for at least 1 month following the last dose.

Pregnancy

There are no data from the use of binimetinb in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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.

Breast-feeding

It is unknown whether binimetinib or its metabolite are excreted in human milk. A risk to the breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Mektovi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

There are no data on the effect on fertility in humans for binimetinib.

4.7. Effects on ability to drive and use machines

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 (see sections 4.4 and 4.8).

4.8. Undesirable effects

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). In Combo 450 ISP, 274 patients received the combination for the treatment of BRAF V600 mutant unresectable or metastatic melanoma (in two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1), and 98 received the combination for the treatment of BRAF V600E mutant advanced NSCLC (in one non-randomized Phase II study (ARRAY-818-202)) (see section 5.1).

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

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

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).

Description of selected adverse reactions

Cutaneous malignancies

CuSCC was reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

Ocular events

In the Combo 450 ISP, RPED was reported in 22.3% (83/372) of patients. RPED was Grade 1 (asymptomatic) in 15.6% (58/372) of patients, Grade 2 in 5.1% (19/372) of patients and Grade 3 in 1.6 % (6/372) of patients. Most events were reported as retinopathy, retinal detachment, subretinal fluid, macular oedema, and central serous chorioretinopathy and led to dose interruptions or dose modifications in 3.8% (14/372) of patients. The median time to onset of the first event of RPED (all grades) was 1.4 months (range 0.00 to 17.5 months).

Visual impairment, including vision blurred and reduced visual acuity, occurred in 23.1% (86/372) of patients. Visual impairment was generally reversible.

Uveitis was also reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

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.

Left ventricular dysfunction

In the Combo 450 ISP, LVD was reported in 9.4 % (35/372) of patients. Grade 3 events occurred in 1.3 % (5/372) of patients. LVD led to treatment discontinuation in 0.8% (3/372) of patients and led to dose interruptions or dose reductions in 6.2 % (23/372) of patients.

The median time to first occurrence of LVD (any grade) was 5.2 months (range 0.0 to 25.7 months) in patients who developed an LVEF below 50 %. The mean LVEF value dropped by 5.3 % in the Combo 450 ISP, from a mean of 63.3 % at baseline to 58.0 %. LVD was generally reversible following dose reduction or dose interruption.

Haemorrhage

Haemorrhagic events were observed in 16.7% (62/372) of patients in the Combo 450 ISP. Most events were Grade 1 or 2: 13.2% (49/372) and 3.5% (13/372) were ≥Grade 3. Few patients required dose interruptions or dose reductions (2.4% or 9/372). Haemorrhagic events led to discontinuation of treatment in 0.8 % (3/372) of patients. The most frequent haemorrhagic events were haematuria in 2.7 % (10/372) of patients, haematochezia in 2.7% (10/372) and rectal haemorrhage in 2.2% (8/372) of patients. Fatal gastric ulcer haemorrhage with multiple organ failure as a concurrent cause of death, occurred in one patient. Cerebral haemorrhage/intracranial haemorrhage occurred in 1.6% (6/372) of patients with fatal outcome in 4 patients.

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.

Hypertension

New onset elevated blood pressure or worsening of pre-existing hypertension were reported in 11.0 % (41/372) of patients treated with the Combo 450 ISP. Hypertension events were reported as Grade 3 in 5.1 % (19/372) of patients, including hypertensive crisis (0.3 % (1/372). Hypertension led to dose interruption or adjustment in 2.2 % (8/372) of patients. Hypertensive adverse reactions required additional therapy in 7.5 % (28/372) of patients.

Venous thromboembolism

In the Combo 450 ISP, VTE occurred in 4.8% (18/372) of patients, including 1.9% (7/372) of patients who developed pulmonary embolism. VTE was reported as Grade 1 or 2 in 4.0 % (15/372) of patients and Grade 3 or 4 in 0.8 % (3/372) of patients. VTE led to dose interruptions or dose modifications in 1.1% (4/372) patients and to additional therapy in 4.6% (17/372) of patients.

Pancreatitis

Pancreatitis was reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

Dermatologic reactions

Dermatologic reactions may occur when binimetinib is used in combination with encorafenib.

Rash

In the Combo 450 ISP, rash occurred in 20.4% (76/372) of patients. Most events were mild, with Grade 3 or 4 events reported in 1.1% (4/372) of patients. Rash led to treatment discontinuation in 0.8% (3/372) of patients and to dose interruption or dose modification in 2.4% (9/372) of patients.

Dermatitis acneiform

In the Combo 450 ISP, dermatitis acneiform occurred in 4.0% (15/372) of patients. Dermatitis acneiform was reported as Grade 1 or 2 in 3.8% (14/372) of patients and Grade 3 in 0.3% (1/372) of patients. No event led to treatment discontinuation. Dose modification was reported in 0.5 % (2/372) of patients.

Palmar-plantar erythrodysaesthesia syndrome

PPES can occur when binimetinib is used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

Photosensitivity

In the Combo 450 ISP, photosensitivity was observed in 4.3% (16/372) of patients. Most events were Grade 1-2, with Grade 3 reported in 0.3% (1/372) of patients and no event led to discontinuation. Dose interruption or dose modification was reported in 0.3% (1/372) of patients.

Facial paresis

Facial paresis was reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

CK elevation/rhabdomyolysis

In the Combo 450 ISP, mostly mild asymptomatic blood CK elevation was reported in 23.9% (89/372) of patients. The incidence of Grade 3 or 4 adverse reactions was 5.1% (19/372). The median time to onset of the first event was 2.8 months (range: 0.5 to 26 months).

Rhabdomyolysis was reported in 0.3% (1/372) of patients treated with encorafenib in combination with binimetinib. In this patient, rhabdomyolysis was observed with concomitant symptomatic Grade 4 CK elevation.

Renal dysfunction

Blood creatinine elevation and renal failure occurred when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

Liver laboratory abnormalities

The incidences of liver laboratory abnormalities reported in the Combo 450 ISP are listed below:

• Increased transaminases: 16.4% (61/372) overall – 6.5% (24/372) Grade 3

• Increased GGT: 11.3% (42/372) overall – 6.7% (25/372) Grade 3-4

In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidences of liver laboratory abnormalities are listed below:

• Increased transaminases: 13.2% (34/257) overall – 5.4% (14/257) Grade 3-4

• Increased GGT: 14.0% (36/257) overall – 4.7% (12/257) Grade 3-4

Gastrointestinal disorders

In the Combo 450 ISP, diarrhoea was observed in 41.7% (155/372) of patients and was Grade 3 or 4 in 3.8% (14/372) of patients. Diarrhoea led to dose discontinuation in 0.8% of patients and to dose interruption or dose modification in 8.1% of patients. Constipation occurred in 24.7% (92/372) of patients and was Grade 1 or 2. Abdominal pain was reported in 28.5% (106/372) of patients and was Grade 3 in 2.2% (8/372) patients. Nausea occurred in 46.0% (171/372) with Grade 3 observed in 3.0% (11/372) of patients. Vomiting occurred in 31.2% (116/372) of patients with Grade 3 reported in 1.9% (7/372) 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.

Anaemia

In the Combo 450 ISP, anaemia was reported in 23.1% (86/372) of patients; 7.0% (26/372) of patients had Grade 3 or 4. No patients discontinued treatment due to anaemia, 3.2% (12/372) 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.

Headache

In the Combo 450 ISP, headache occurred in 18.8% (70/372) of patients including Grade 3 in 1.1% (4/372) 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.

Fatigue

In the Combo 450 ISP, fatigue occurred in 48.1% (179/372) of patients including Grade 3 or 4 in 4.3% (16/372) 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.

Special populations

Elderly

In patients treated with Combo 450 ISP (n = 372), 230 patients (61.8 %) were < 65 years old, 107 patients (28.8%) were 65-74 years old and 35 patients (9.4%) were aged > 75. No overall differences in safety or efficacy were observed between elderly patients (≥ 65) and younger patients except diarrhoea and pruritus that were more frequently reported in elderly patients.

In the age subgroup of patients aged ≥ 75 years, Grade ≥3 adverse reactions (62.9% vs 47.5%), adverse reactions (all grades) requiring dose modification of any study drug (60.0% vs 48.1%) or leading to treatment discontinuation (25.7% vs 7.4%) were more frequently reported than in patients <75 years. The most common adverse reactions reported with a higher incidence in patients aged ≥ 75 years compared to patients aged < 75 years included fatigue, nausea, diarrhoea, vomiting and anaemia.

Reporting of suspected adverse reactions

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: Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.