Binimetinib oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of binimetinib.
Drugs List
Therapeutic Indications
Uses
Treatment of unresectable or metastatic melanoma with BRAF V600 mutation
Unresectable or metastatic melanoma with a BRAF V600 mutation in adults, in combination with encorafenib.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
45mg (3 tablets) twice daily, taken approximately 12 hours apart.
Additional Dosage Information
Dose modifications
First dose reduction
Reduce dose to 30mg twice daily.
Further reductions
Binimetinib doses below 30mg twice daily are not recommended. If a patient is unable to tolerate 30mg twice daily, discontinue binimetinib.
Dose re-escalation (excludes left ventricular dysfunction, or any Grade 4 toxicity)
If the adverse reaction that lead to a dose reduction is successfully managed, consider re-escalating the dose to the recommended 45mg twice daily.
Management of cutaneous reactions
Grade 2: No initial adjustment. If cutaneous reaction worsens or persists for 2 weeks despite treatment, withhold binimetinib until Grade 1 or lower, then resume at the same dose (first occurrence), or a reduced dose (recurrence).
Grade 3: Withhold binimetinib until Grade 1 or lower, then resume at the same dose. If Grade 3 cutaneous reaction reoccurs withhold binimetinib until Grade 1 or lower, then resume at a reduced dose.
Grade 4: Permanently discontinue binimetinib.
Management of ocular events
Grade 2 or 3 symptomatic retinal pigment epithelial detachment (RPED): Withhold binimetinib and institute ophthalmic monitoring including visual acuity assessment. If RPED resolves to Grade 1 or lower, resume binimetinib at the same dose. If RPED resolves to Grade 2, resume binimetinib at a reduced dose. If RPED does not improve to Grade 2 or lower within 2 weeks, permanently discontinue binimetinib.
Grade 4 symptomatic retinal pigment epithelial detachment (RPED) associated with reduced visual acuity: Permanently discontinue binimetinib.
Management of cardiac events
Grade 2 left ventricular ejection fraction (LVEF) decrease (greater than 10% from baseline that is below lower limit of normal (LLN) without cardiac symptoms): Withhold binimetinib and re-evaluate LVEF every 2 weeks. If LVEF resolves to 10% or less from baseline and LVEF is at or above the lower limit of normal, resume binimetinib at a reduced dose. If LVEF does not resolve to these levels within 4 weeks, permanently discontinue binimetinib.
Grade 3 or 4 left ventricular ejection fraction (LVEF) decrease (with cardiac symptoms): Permanently discontinue binimetinib, and re-evaluate LVEF every 2 weeks until recovery.
Management of rhabdomyolysis/creatine phosphokinase (CK) elevations
Grade 3 asymptomatic elevations (CK above 5 and up to and including 10 times upper limit of normal): No initial adjustment. Ensure adequate hydration of patient.
Grade 3 with muscle symptoms or renal impairment: Withhold binimetinib until improved to Grade 1 or lower within 4 weeks, resume treatment at a reduced dose. If elevations do not resolve within 4 weeks, permanently discontinue binimetinib.
Grade 4 asymptomatic elevations (CK above 10 times upper limit of normal): Withhold binimetinib until improved to Grade 1 or lower. Patient requires adequate hydration.
Grade 4 elevations (CK above 5 times upper limit of normal) with muscle symptoms or renal impairment: Withhold binimetinib. If elevations improve to Grade 1 or lower within 4 weeks, resume treatment at a reduced dose. If elevations do not resolve within 4 weeks, permanently discontinue binimetinib.
Management of venous thromboembolism (VTE)
Uncomplicated deep vein thrombosis (DVT) or Grade 1 to 3 pulmonary embolism: Withhold binimetinib. If VTE resolves to Grade 0 or 1, resume treatment at a reduced dose. If VTE does not resolve, permanently discontinue binimetinib.
Grade 4 pulmonary embolism: Permanently discontinue binimetinib.
Management of liver laboratory abnormalities
Grade 2 aspartate aminotransferase or alanine aminotransferase elevations (above 3 and up to or equal to 5 times upper limit of normal): No initial dose adjustment. If Grade 2 abnormalities persist for 2 weeks, withhold binimetinib until abnormalities resolve to Grade 1 or lower (or to baseline levels), then resume treatment at the same dose.
Grade 3 aspartate aminotransferase or alanine aminotransferase elevations (above 5 and up to or equal to 20 times upper limit of normal), and blood bilirubin (above 2 times upper limit of normal): Withhold binimetinib. If abnormalities resolve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If abnormalities do not resolve within 4 weeks, permanently discontinue binimetinib. If Grade 3 abnormalities recur, consider permanently discontinuing binimetinib.
Grade 4 aspartate aminotransferase or alanine aminotransferase elevations (above 20 times upper limit of normal): Consider discontinuing binimetinib, otherwise withhold binimetinib. If abnormalities resolve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If abnormalities do not resolve within 4 weeks, permanently discontinue binimetinib. If Grade 4 abnormalities recur, permanently discontinue binimetinib.
Management of interstitial lung disease (ILD) or pneumonitis
Grade 2: Withhold binimetinib. If ILD/pneumonitis resolves to Grade 1 or lower, then resume treatment at a reduced dose. If ILD/pneumonitis do not resolve within 4 weeks, permanently discontinue binimetinib.
Grade 3 or 4: Permanently discontinue binimetinib.
Management of other adverse reactions
Recurrent/intolerable Grade 2 adverse reactions: Withhold binimetinib. If adverse reactions resolve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If adverse reactions do not resolve within 4 weeks, permanently discontinue binimetinib.
Grade 3 adverse reactions: Withhold binimetinib. If adverse reactions resolve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If adverse reactions do not resolve within 4 weeks, permanently discontinue binimetinib. If Grade 3 adverse reactions recur, consider permanently discontinuing binimetinib.
Grade 4 adverse reactions: Consider discontinuing binimetinib, otherwise withhold binimetinib. If adverse reactions resolve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If adverse reactions do not resolve within 4 weeks, permanently discontinue binimetinib. If Grade 4 adverse reactions recur, permanently discontinue binimetinib.
Missed dose
If a patient misses a dose, they should only take the missed dose provided it is more than 6 hours until the next scheduled dose.
Vomiting
If the patient vomits after taking a dose of binimetinib, the patient should wait until the next scheduled dose, and not take an additional dose to compensate.
Contraindications
Children under 18 years
Breastfeeding
Galactosaemia
History of retinal vein occlusion
Moderate hepatic impairment
Pregnancy
Precautions and Warnings
Females of childbearing potential
Predisposition to retinal vein occlusion
Predisposition to rhabdomyolysis
Predisposition to venous thromboembolism
Cerebral metastases
Gilbert's syndrome
Glucose-galactose malabsorption syndrome
History of venous thromboembolism
Hypertension
Interstitial lung disease
Lactose intolerance
Left ventricular ejection fraction value of 50% or less
RAS mutation associated cancer
Advise ability to drive/operate machinery may be affected by side effects
Confirm BRAF V600 mutation status of tumour prior to treatment
Treatment to be initiated and supervised by a specialist
Contains lactose
Consult local policy on the safe use of oral anti-cancer drugs
Ensure patient has adequate fluid intake
Staff: Not to be handled by pregnant staff
Anal examination advised before, during and at end of treatment
Assess LVEF before treatment, 1 month after starting, then every 3 months
Blood counts should be performed before and periodically during treatment
Monitor blood pressure pre-treatment and periodically thereafter
Pelvic examination advised before, during and at end of treatment
Perform chest/abdomen CT scans before, during and at end of treatment
Perform head and neck examinations before, during and at end of treatment
If visual disturbances occur, perform ophthalmic evaluation
Monitor CK and creatinine levels monthly during first 6 months of treatment
Monitor for skin lesions before, every 2 months during & for 6 months after
Monitor LFTs before treatment, then monthly for 6 months, then as required
Advise patient to immediately report new skin lesions
Advise patient to report new visual problems and symptoms
Consider rhabdomyolysis if creatine phosphokinase is elevated
Modify dose if adverse effects occur
Discontinue if retinal vein occlusion occurs
Consider dose modification in non-haematological toxicity
Advise patient not to take St John's wort concurrently
Female: Contraception required during and for 1 month after treatment
BRAF mutation testing
The efficacy and safety of binimetinib in combination with encorafenib have been established only in patients with tumours expressing BRAF V600E and V600K mutations and it should not be used in patients with wild type BRAF malignant melanoma.
Patients who have progressed on a BRAF inhibitor
Limited data indicates that the efficacy of binimetinib in combination with encorafenib may be lower in patients who have progressed on a prior BRAF inhibitor.
Binimetinib in combination with encorafenib
If patients experience treatment-related toxicities when taking binimetinib in combination with encorafenib, it should be considered if both drugs should be dose reduced, interrupted or discontinued simultaneously.
Dose reduction
For most adverse reactions it is necessary to reduce the dose of binimetinib and encorafenib simultaneously. If patients experience adverse reactions that primarily relate to encorafenib only, including palmar-plantar erythrodysaesthesia syndrome (PPES), uveitis and QTc prolongation, it is not necessary to reduce the dose of binimetinib. For these adverse reactions, dose reductions should apply to encorafenib only.
Dose interruption
If binimetinib is temporarily interrupted, the dose of encorafenib should be reduced to 300mg once daily during binimetinib's period of interruption. If encorafenib is temporarily interrupted, binimetinib should also be interrupted.
Discontinuation
If it is necessary to discontinue either binimetinib or encorafenib, both agents should be discontinued.
Pregnancy and Lactation
Pregnancy
Binimetinib is contraindicated during pregnancy.
There is limited data on the use of binimetinib during pregnancy. The manufacturer contraindicates the use of binimetinib during pregnancy and in women of childbearing potential not using contraception, citing animal studies that show reproductive toxicity in animals.
The effect of concurrent therapies on pregnancy should be considered.
Lactation
Binimetinib is contraindicated in breastfeeding.
There is limited data on the use of binimetinib in breastfeeding. The manufacturer contraindicates the use of binimetinib in breastfeeding, stating that it is unknown whether the drug is excreted in breast milk, and a risk to the nursing infant cannot be excluded.
LactMed (2018) suggests that the high plasma protein binding and the half-life of binimetinib may limit the amount of the drug present in breast milk. LactMed (2018) also indicates that for patients taking the combination with encorafenib the manufacturer recommends to discontinue breastfeeding during binimetinib therapy and for at least 2 weeks after the final dose.
The effect of concurrent therapies on lactation should be considered.
Side Effects
Abdominal pain
Alopecia
Anaemia
Angioedema
Arthralgia
Back pain
Basal cell carcinoma
Cardiac failure
Cerebral haemorrhage
Colitis
Constipation
Creatine phosphokinase increased
Decreased ejection fraction
Dermatitis acneiform
Detachment of the retinal pigment epithelium
Diarrhoea
Dizziness
Dry skin
Dysgeusia
Elevated amylase levels
Elevated serum lipase
Enterocolitis
Erythema
Facial muscle paresis
Facial nerve paresis
Facial paralysis
Fatigue
Fluid retention
Gamma glutamyl transferase (GGT) increased
Haemorrhage
Headache
Hyperkeratosis
Hypersensitivity reactions
Hypertension
Impaired vision
Increase in alkaline phosphatase
Iridocyclitis
Iritis
Keratoacanthoma
Left ventricular dysfunction
Localised oedema
Muscle injury
Muscle spasm
Muscle weakness
Myalgia
Myopathy
Myositis
Nausea
New primary malignancy
Painful extremities
Palmar-Plantar Erythrodysaesthesia syndrome
Pancreatitis
Panniculitis
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Proctitis
Pruritus
Pyrexia
Rash
Renal failure
Rhabdomyolysis
Serum creatinine increased
Skin papilloma
Squamous cell carcinoma
Superficial vein thrombophlebitis
Thromboembolism
Thrombophlebitis
Transaminases abnormal
Ulcerative colitis
Urticaria
Uveitis
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: February 2020.
Reference Sources
Summary of Product Characteristics: Mektovi 15mg film-coated tablets Pierre Fabre Limited. Revised October 2018.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/
Binimetnib Last revised: 03 December 2018.
Last accessed: 13 February 2020.
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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