Encorafenib oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of encorafenib.
Drugs List
Therapeutic Indications
Uses
Treatment of metastatic colorectal cancer with BRAF V600E mutation
Treatment of unresectable or metastatic melanoma with BRAF V600 mutation
Unresectable or metastatic melanoma with a BRAF V600 mutation in adults, in combination with binimetinib.
Metastatic colorectal cancer with BRAF V600E mutation in adults who have received prior systemic therapy, in combination with cetuximab.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
Melanoma
The recommended dose of encorafenib is 450mg, taken once daily.
Metastatic colorectal cancer
The recommended dose of encorafenib is 300mg, taken once daily.
Patients with Hepatic Impairment
Mild hepatic impairment
The recommended dose of encorafenib is 300mg, taken once daily.
Additional Dosage Information
Encorafenib in combination with binimetinib for melanoma treatment
If patients experience treatment-related toxicities when taking encorafenib in combination with binimetinib, 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 encorafenib and binimetinib 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
It is necessary to reduce the dose of encorafenib to 300mg once daily if binimetinib is temporarily interrupted, as encorafenib at a dose of 450mg as a single agent is not recommended. 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.
Dose modifications for melanoma treatment
First dose reduction: 300mg once daily.
Second dose reduction: 200mg once daily.
Further reductions: There are limited data for dose reduction to 100mg once daily. If the patient is unable to tolerate 100mg once daily, discontinue permanently encorafenib.
Encorafenib in combination with cetuximab for metastatic colorectal cancer treatment
If patients experience treatment-related toxicities when taking encorafenib in combination with cetuximab, 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 encorafenib and cetuximab 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 cetuximab. For these adverse reactions, dose reductions should apply to encorafenib only.
Discontinuation
If it is necessary to discontinue either cetuximab or encorafenib, both agents should be discontinued.
Dose modifications for metastatic colorectal cancer treatment
First dose reduction: 225mg once daily.
Second dose reduction: 150mg once daily.
Dose modifications of encorafenib for melanoma and metastatic colorectal cancer treatment
New primary cutaneous malignancies: No dose modification required for encorafenib.
New primary non-cutaneous RAS mutation-positive malignancies: Consider permanently discontinuing encorafenib.
Management of cutaneous reactions
Grade 2: No initial adjustment. If cutaneous reaction worsens or persists for 2 weeks despite treatment, withhold encorafenib until Grade 1 or lower, then resume at the same dose.
Grade 3: Withhold encorafenib until Grade 1 or lower, then resume at the same dose. If Grade 3 cutaneous reaction reoccurs withhold encorafenib until Grade 1 or lower, then resume at a reduced dose.
Grade 4: Permanently discontinue encorafenib.
Management of palmar-plantar erythrodysaesthesia syndrome (PPES)
Grade 2: No initial dose adjustment. Institute supportive measures (such as topical therapy). If PPES persists for 2 weeks despite treatment supportive measures, withhold encorafenib until Grade 1 or lower, then resume at either the same dose or a reduced dose.
Grade 3: Withhold encorafenib, institute supportive measures (such as topical therapy) and reassess patient weekly. Resume at either the same dose or a reduced dose when PPES improves to Grade 1 or lower.
Management of uveitis (including iritis and iridocyclitis)
Grade 1: No initial adjustment. Institute specific ocular therapy. If uveitis persists despite ocular therapy, withhold encorafenib and repeat ophthalmic monitoring within 2 weeks. If uveitis improves to Grade 0, resume treatment at the same dose. If uveitis persists for 6 weeks, repeat ophthalmic monitoring and permanently discontinue encorafenib.
Grade 2: No initial adjustment. Institute specific ocular therapy. If uveitis persists despite ocular therapy, withhold encorafenib and repeat ophthalmic monitoring within 2 weeks. If uveitis improves to Grade 1 or less, resume treatment at a reduced dose. If uveitis persists for 6 weeks, repeat ophthalmic monitoring and permanently discontinue encorafenib.
Grade 3: Withhold encorafenib and ophthalmic monitoring should be repeated within 2 weeks. If uveitis improves to Grade 1 or less, resume treatment at a reduced dose. If uveitis persists for 6 weeks, repeat ophthalmic monitoring and permanently discontinue encorafenib.
Grade 4: Permanently discontinue encorafenib and perform ophthalmic monitoring.
Management of QTc prolongation
QTcF above 500 milliseconds and a change of 60 milliseconds or less from baseline: Withhold encorafenib. If QTcF falls below 500 milliseconds, resume treatment at a reduced dose. Upon recurrence, permanently discontinue encorafenib.
QTcF above 500 milliseconds and an increase of greater than 60 milliseconds from baseline: Permanently discontinue encorafenib.
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 4 weeks, withhold encorafenib 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 times of the upper limit of normal), and blood bilirubin (above 2 times upper limit of normal): If first occurrence withhold encorafenib for up to 4 weeks. If abnormalities improve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If abnormalities do not improve within 4 weeks, permanently discontinue encorafenib. If Grade 3 abnormalities recur, consider permanently discontinuing encorafenib.
Grade 4 aspartate aminotransferase or alanine aminotransferase elevations (above 20 times upper limit of normal): Consider permanently discontinuing encorafenib, otherwise withhold encorafenib. If abnormalities resolve to Grade 1 or lower (or to baseline levels), then resume treatment at a reduced dose. If abnormalities do not improve within 4 weeks, permanently discontinue encorafenib. If Grade 4 abnormalities recur, permanently discontinue encorafenib.
Management of other adverse reactions
Recurrent/intolerable Grade 2 adverse reactions: Withhold encorafenib. 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 improve within 4 weeks, permanently discontinue encorafenib.
Grade 3 adverse reactions: If first occurrence withhold encorafenib for up to 4 weeks. 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 improve within 4 weeks, permanently discontinue encorafenib. If Grade 3 adverse reactions recur, consider permanently discontinuing encorafenib.
Grade 4 adverse reactions: Consider permanently discontinuing encorafenib, otherwise withhold encorafenib for up to 4 weeks. 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 improve within 4 weeks, permanently discontinue encorafenib. If Grade 4 adverse reactions recur, permanently discontinue encorafenib.
Missed doses
If a patient misses a dose, they should only take the missed dose provided it is more than 12 hours until the next scheduled dose.
Vomiting
If the patient vomits after taking a dose of encorafenib, the patient should wait until the next scheduled dose, and not take an additional dose to compensate.
Contraindications
Children under 18 years
Breastfeeding
Long QT syndrome
Moderate hepatic impairment
Pregnancy
Torsade de pointes
Precautions and Warnings
Family history of long QT syndrome
Females of childbearing potential
Cerebral metastases
Electrolyte imbalance
Hepatic impairment - Child-Pugh score between 5 and 6
History of torsade de pointes
Left ventricular ejection fraction value of 50% or less
RAS mutation associated cancer
Severe renal impairment
Correct electrolyte disorders before treatment
Reduce dose in patients with hepatic impairment
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
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
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
Increase LFT monitoring if hepatic impairment/signs of hepatic injury occur
Monitor ECG prior to and 1 month after initiation, then every 3 months
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
Monitor serum creatinine
Monitor serum electrolytes
Advise patient to report mucosal/skin reactions (blistering or peeling)
Advise patient to report new visual problems and symptoms
Modify dose if adverse effects occur
Discontinue if grade 4 toxicity occurs
Consider dose modification in non-haematological toxicity
Advise patient not to take St John's wort concurrently
Advise patient to avoid grapefruit products
May affect spermatogenesis
Female: Contraception required during and for 1 month after treatment
Female: Use barrier contraception during and for 1 month after treatment
Patients 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. Consider discontinuing encorafenib in patients that develop RAS mutation-positive non-cutaneous malignancies.
The efficacy of encorafenib in combination with binimetinib may be lower in patients who have previously progressed on a prior BRAF inhibitor.
Pregnancy and Lactation
Pregnancy
Encorafenib is contraindicated during pregnancy.
There is limited data on the use of encorafenib during pregnancy. The manufacturer contraindicates the use of encorafenib during pregnancy, citing animal studies that show reproductive toxicity in females.
Lactation
Encorafenib is contraindicated in breastfeeding.
There is limited data on the use of encorafenib in breastfeeding. The manufacturer contraindicates the use of encorafenib 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) recommends that patients do not breastfeed while being treated with encorafenib, and should not breastfeed for 2 weeks after the last dose of encorafenib.
Side Effects
Abdominal pain
Alopecia
Anaemia
Angioedema
Arthralgia
Arthritis
Back pain
Basal cell carcinoma
Cardiac failure
Cerebral haemorrhage
Colitis
Constipation
Creatine kinase increased
Creatine phosphokinase increased
Decreased appetite
Decreased ejection fraction
Deep vein thrombosis (DVT)
Dermatitis acneiform
Detachment of the retinal pigment epithelium
Diarrhoea
Dizziness
Dry skin
Dysgeusia
Elevated amylase levels
Elevated serum lipase
Embolism
Enterocolitis
Erythema
Exfoliative dermatitis
Exfoliative rash
Extrasystoles
Facial muscle paresis
Facial nerve paresis
Fatigue
Fluid retention
Gamma glutamyl transferase (GGT) increased
Gastro-intestinal obstruction/impaction
Haemorrhage
Headache
Hyperkeratosis
Hyperpigmentation of skin
Hypersensitivity reactions
Hypertension
Impaired vision
Increase in alkaline phosphatase
Insomnia
Iridocyclitis
Iritis
Keratoacanthoma
Left ventricular dysfunction
Melanocytic naevus
Muscle disorders
Muscle spasm
Muscle weakness
Myalgia
Myositis
Nausea
New primary malignancy
Painful extremities
Pancreatitis
Panniculitis
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Primary melanoma
Proctitis
Pruritus
Pulmonary embolism
Pyrexia
Rash
Renal failure
Retinal detachment
Rhabdomyolysis
Sinus tachycardia
Skin exfoliation
Skin papilloma
Squamous cell carcinoma
Supraventricular tachycardia
Tachyarrhythmia
Tachycardia
Thrombophlebitis
Thrombosis
Transaminases abnormal
Ulcerative colitis
Urticaria
Uveitis
Venous thrombosis
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: January 2020.
Reference Sources
Summary of Product Characteristics: Braftovi 50mg hard capsules, Pierre Fabre Limited. Revised June 2020.
Summary of Product Characteristics: Braftovi 75mg hard capsules, Pierre Fabre Limited. Revised June 2020.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/
Encorafenib Last revised: 03 December 2018.
Last accessed: 27 January 2020.
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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