Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
binimetinib
Binimetinib is a reversible inhibitor of mitogen-activated extracellular kinase (MEK1 and MEK2) activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promote cell proliferation and tumour growth.
In melanoma, MEK pathways are often activated by BRAF mutations. Binimetinib inhibits ERK phosphorylation and viability, and MEK-dependent phosphorylation of BRAF mutant cell lines.
| Bioavailability |
> 50% |
| T max |
1.6 hours |
| Effects with food |
A high-fat, high-calorie meal had no effect on drug exposure. |
| PPB |
97% (human plasma proteins) |
Binimetinib is primarily metabolized via UGT1A1 glucuronidation. Other metabolism pathways include N-dealkylation, amide hydrolysis, and loss of ethane-diol of the side chain.
| Active metabolites |
Yes |
| Feces |
62% (32% unchanged) |
| Urine |
31% (6.5% unchanged) |
| Half-life |
3.5 hours |
- Melanoma
Refer to the product monograph for a full list and details of approved indications.
Other Uses:
- Colorectal cancer
Emetogenic Potential:
The following adverse events were reported in > 10% of patients with unresectable or metastatic melanoma treated with binimetinib in combination with encorafenib in a randomized Phase 3 study. It also includes severe or life-threatening adverse effects from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (12%) (6% severe) | E | |||
| Left ventricular dysfunction (7%) (2% severe) | E D | ||||
| Venous thromboembolism (6%) | E | ||||
| Dermatological | Alopecia (14%) | E D | |||
| Dry skin (16%) | E | ||||
| Other (23%) (hyperkeratosis) | E D | ||||
| Rash, pruritus (22%) | E | ||||
| Gastrointestinal | Abdominal pain (28%) | E | |||
| Constipation (22%) | E | ||||
| Diarrhea (37%) (3% severe) | E | ||||
| Nausea, vomiting (41%) (2% severe) | I E | ||||
| General | Edema - limbs (13%) | E | |||
| Fatigue (43%) (3% severe) | E | ||||
| Fever (18%) (4% severe) | E | ||||
| Hematological | Hemorrhage (19%) (3% severe) | E | |||
| Hepatobiliary | ↑ LFTs (6%) (severe) | E | |||
| Pancreatitis (1%) | E | ||||
| Hypersensitivity | Hypersensitivity (1%) | I E | |||
| Musculoskeletal | Musculoskeletal pain (26%) | E | |||
| ↑CPK (58%) | E | ||||
| Rhabdomyolysis (<1%) | E | ||||
| Neoplastic | Secondary malignancy (3%) (cutaneous) | D L | |||
| Nervous System | Dizziness (15%) | E | |||
| Headache (22%) | E | ||||
| Other (1%) (facial paresis) | E | ||||
| Peripheral neuropathy (12%) | E | ||||
| Ophthalmic | Retinal vascular disorder (<1%) | E | |||
| Retinopathy (20%) (including retinal detachment) | E D | ||||
| Uveitis (4%) | E | ||||
| Respiratory | Pneumonitis (<1%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for binimetinib include increased CPK, fatigue, nausea, vomiting, diarrhea, abdominal pain, musculoskeletal pain, hyperkeratosis, constipation, headache, rash, pruritus and retinopathy.
Left ventricular dysfunction, with symptomatic or asymptomatic decreases in ejection fraction, has been reported with binimetinib. The median time to onset was ~4 months. Cardiomyopathy resolved in majority of patients. Hypertension, or worsening of pre-existing hypertension, can also occur.
Hemorrhagic events, mostly gastrointestinal, have occurred in patients treated with binimetinib in combination with encorafenib. Fatal cerebral hemorrhage has been reported in patients with new or progressive brain metastases.
Retinal vein occlusion (RVO) is a known adverse effect associated with MEK inhibitors and has been rarely reported with binimetinib. Perform ophthalmologic evaluation within 24 hours of acute vision loss or other visual disturbance. Serous retinopathy, retinal detachments, and uveitis have also occurred with binimetinib. The median time to onset for serous retinopathy was ~1 month.
Cutaneous malignancies, including cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma (KA), and basal cell carcinoma, have been reported. The median time to onset for cuSCC/KA was ~6 months.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
BRAF V600 mutation must be confirmed by a validated test prior to starting treatment.
Combination - Melanoma:
Oral: 45 mg BID
| Dose Level | Binimetinib Dose (mg, BID) |
| 0 | 45 |
| -1 | 30 |
| -2 | Discontinue |
| Toxicity/Severity | Action | |
|
Asymptomatic cardiomyopathy |
Hold for up to 4 weeks.
|
|
| Absolute ↓ LVEF >10% from baseline with LVEF < lower limit of normal (LLN) | ||
|
Symptomatic CHF |
Discontinue. | |
| Absolute ↓ LVEF >20% from baseline with LVEF < LLN | Discontinue. | |
| Uncomplicated DVT or PE |
Hold for up to 4 weeks. |
|
| Life-threatening PE | Discontinue. | |
| Acute vision loss or other visual disturbance | Refer to ophthalmologist within 24 hours. | |
| Symptomatic serous retinopathy / RPEDs |
Hold for up to 10 days. |
|
| Retinal Vein Occlusion | Discontinue. | |
| Uveitis | Grade 1 not responding to ocular therapy |
Hold for up to 6 weeks. |
| Grade 2 not responding to ocular therapy |
Hold for up to 6 weeks. |
|
| Grade 3 | ||
| Grade 4 | Discontinue. | |
| Pneumonitis | Grade 2 |
Hold for up to 4 weeks. |
| Grade 3 or 4 | Discontinue. | |
| Increase in AST or ALT |
Grade 2, without improvement for 2 weeks |
Hold until < Grade 1 or baseline. |
| Grade 3 or 4 | See Other Adverse Reactions below. | |
| Rhabdomyolysis or ↑ CPK | Grade 4 ↑ CPK (asymptomatic) |
Hold for up to 4 weeks. If improves to < Grade 1, resume at 1 dose level ↓. |
| Symptomatic or with renal impairment | ||
| Dermatologic* | Grade 2, without improvement for 2 weeks |
Hold until < Grade 1. |
| Grade 3 | ||
| Grade 4 | Discontinue. | |
| Other adverse reactions (including hemorrhage)* | Grade 2, recurrent | Hold for up to 4 weeks. If improves to < Grade 1 or baseline, resume at 1 dose level ↓. Discontinue if no improvement. |
| Grade 3, 1st occurrence | ||
| Grade 3, recurrent | Consider discontinuing. | |
|
Grade 4, 1st occurrence |
Discontinue. OR |
|
| Grade 4, recurrent | Discontinue. | |
*Excluding hand-foot syndrome, non-cutaneous RAS mutation-positive malignancies, and QTc prolongation. Refer to regimen monographs for dose modifications when given in combination.
For increased AST/ALT during treatment, refer to dose modifications table above.
| Bilirubin | AST | Binimetinib Dose | |
| ≤ ULN | and | > ULN | No dose adjustment |
| >1 to 1.5 × ULN | and | ANY | |
| >1.5 to 3 × ULN | and | ANY | Use not recommended |
| >3 × ULN | and | ANY |
No dose adjustment recommended in patients with renal impairment.
No dose adjustment required. No overall differences in the safety or efficacy observed in patients > 65 years on combination treatment with encorafenib compared to younger patients.
Higher incidences of diarrhea, pruritus, GGT and blood phosphatase alkaline elevation were reported in patients > 65 years.
Sex does not have a clinically relevant effect on binimetinib exposure.
The safety and efficacy of binimetinib have not been established in children < 18 years.
- Binimetinib tablets should be taken twice daily, approximately 12 hours apart.
- Tablets should be swallowed whole with water and may be taken with or without food.
- If a dose is missed, the dose may be taken if there are > 6 hours until the next dose. If there are < 6 hours until the next dose, the dose should be skipped and the next dose should be taken at the scheduled time. Patients should not take 2 doses at the same time to make up for a missed dose.
- If a dose is vomited, an additional dose should not be taken. The next dose should be continued as scheduled.
- Store between 15-30°C.
- Patients who have a hypersensitivity to this drug or any of its components
- Patients with a history of Gilbert’s syndrome, abnormal LVEF, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion were excluded from clinical trials. Consider benefits vs risks of using binimetinib in these patients.
- Patients should exercise caution when driving or operating a vehicle or potentially dangerous machinery as vision problems have been reported.
- Tablets contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
No
-
Fetotoxicity:
Yes
Binimetinib is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 1 month after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment and for at least 3 days after the last dose.
-
Fertility effects:
Unknown
No clinically relevant drug interactions have been observed.
UGT1A1 inducers or inhibitors should be used with caution with binimetinib as this interaction has not been formally evaluated.
Binimetinib is a P-gp and BCRP substrate.
Binimetinib is a weak OAT3 inhibitor. No clinically relevant effects of binimetinib on other transporters is expected.
No differences in binimetinib exposure have been observed when coadministered with encorafenib.
Binimetinib exposure was not affected by a gastric acid reducing agent (i.e. rabeprazole).
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline, monthly, and as clinically indicated |
Cardiac function tests (Echo or MUGA scans) |
Baseline, after 1 month, then every 2-3 months |
CBC |
Baseline and as clinically indicated |
Blood pressure |
Baseline and as clinically indicated |
CPK and creatinine levels (for rhabdomyolysis) |
Baseline, monthly and as clinically indicated |
Skin evaluation for any cutaneous malignancies |
Baseline, every 2 months during treatment and up to 6 months after the last dose |
Clinical toxicity assessment for fatigue, bleeding, thromboembolism, rhabdomyolysis, hypersensitivity, pneumonitis, pancreatitis, GI, ocular, and skin effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- binimetinib - For the treatment of patients with locally advanced unresectable or metastatic melanoma with a BRAF V600 mutation, according to clinical criteria.
Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615.
Dummer R, Flaherty KT, Robert C, et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol. 2022 Dec 20;40(36):4178-4188.
Encorafenib drug monograph. Ontario Health (Cancer Care Ontario).
eviQ Cancer Treatments Online. Clinical resources: Prevention of anti-cancer therapy induced nausea and vomiting (AINV). Cancer Institute NSW. May 2023.
Heinzerling L, Eigentler TK, Fluck M, et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open. 2019 May 23;4(3):e000491.
Product Monograph: Braftovi® (encorafenib). Pfizer Canada ULC. April 7, 2022.
Product monograph: Mektovi® (binimetinib). Pfizer Canada ULC. March 2, 2021.
July 2023 New drug monograph
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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