Binimetinib

(bin i ME ti nib)

• Antineoplastic Agent, MEK Inhibitor

There are no contraindications listed in the manufacturer's labeling.

Oral: Administer twice a day (~12 hours apart) with or without food.

Incidences of adverse reactions were defined during combination therapy with encorafenib.

>10%:

Cardiovascular: Peripheral edema (13%), hypertension (11%)

Central nervous system: Fatigue (43%), dizziness (15%)

Dermatologic: Skin rash (22%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (45%), hyponatremia (18%)

Gastrointestinal: Nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), constipation (22%)

Hematologic & oncologic: Anemia (36%, grades 3/4: 4%), hemorrhage (19%; grades 3/4:3%), leukopenia (13%), lymphocytopenia (13%, grades 3/4: 2%), neutropenia (13%, grades 3/4: 3%)

Hepatic: Increased serum alanine aminotransferase (29%), increased serum aspartate aminotransferase (27%), increased serum alkaline phosphatase (21%)

Neuromuscular & skeletal: Increased creatine phosphokinase (58%)

Ophthalmic: Visual impairment (20%), retinal pigment changes (≤20%, retinal pigment epithelial dystrophy), retinopathy (≤20%, serous including 8% retinal detachment and 6% macular edema)

Renal: Increased serum creatinine (93%)

Miscellaneous: Fever (18%)

1% to 10%:

Cardiovascular: Decreased left ventricular ejection fraction (7%), venous thromboembolism (6%), pulmonary embolism (3%)

Gastrointestinal: Colitis (<10%), hematochezia (3%), hemorrhoidal bleeding (1%)

Hematologic & oncologic: Rectal hemorrhage (4%)

Hypersensitivity: Hypersensitivity (<10%)

Neuromuscular & skeletal: Panniculitis (<10%)

Ophthalmic: Uveitis (4%)

Frequency not defined:

Cardiovascular: Left ventricular dysfunction

Central nervous system: Headache

<1%, postmarketing, and/or case reports: Interstitial pulmonary disease, pneumonitis, retinal vein occlusion, rhabdomyolysis

Concerns related to adverse effects:

• Cardiotoxicity: Cardiomyopathy (manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic ejection fraction decreases) has been reported in patients who received the combination of binimetinib and encorafenib. A decrease in LVEF below the institutional lower limit of normal (LLN) with an absolute decrease in LVEF ≥10% below baseline (detected by echocardiography or MUGA) has occurred. Grade 3 left ventricular dysfunction has been reported. The median time to first occurrence of any grade left ventricular dysfunction was 3.6 months (range: up to 21 months). Cardiomyopathy resolved in a majority of patients. Assess ejection fraction (by echocardiogram or MUGA scan) prior to treatment initiation, one month after initiation, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either <50% or below the institutional LLN. Monitor closely in patients with cardiovascular risk factors receiving binimetinib. Based on the severity, cardiomyopathy may require treatment interruption, dose reduction and/or permanent discontinuation.

• Hemorrhage: Hemorrhage may occur with the combination of binimetinib and encorafenib, including ≥ grade 3 hemorrhage. The most frequent hemorrhagic events were gastrointestinal in nature, including rectal hemorrhage, hematochezia, and hemorrhoidal hemorrhage. Fatal intracranial hemorrhage (in the setting of new or progressive brain metastases) was also reported. May require treatment interruption, dosage reduction, and/or permanent discontinuation based on the severity of the hemorrhage.

• Hepatotoxicity: Hepatotoxicity may occur with the combination of binimetinib and encorafenib; grade 3 or 4 elevations in ALT, AST, and/or alkaline phosphatase have been reported, although grade 3 or 4 total bilirubin elevations were not reported. Monitor liver function tests prior to treatment initiation, monthly during treatment, and as clinically indicated. May require treatment interruption, dose reduction, and/or permanent discontinuation, depending on the severity. Dosage reduction is recommended in patients with moderate or severe hepatic impairment at baseline.

• Ocular toxicity: Serous retinopathy (including retinal detachment and macular edema) has occurred with the combination of binimetinib and encorafenib, Symptomatic serous retinopathy has been reported, although blindness did not occur. In the clinical study, some patients required treatment interruption or dose reduction due to serous retinopathy, although discontinuation was not required. The median time to onset of the first serous retinopathy event (all grades) was 1.2 months (range: up to 17.5 months). Retinal vein occlusion (RVO) is a known (class-related) adverse reaction of MEK inhibitors, and may occur with the combination of binimetinib and encorafenib. The safety of binimetinib has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Uveitis, including iritis and iridocyclitis, has been reported in patients treated with the combination of binimetinib and encorafenib. Assess visual symptoms at each visit; perform an ophthalmologic examination at regular intervals and for new or worsening visual disturbances (and to follow new or persistent ophthalmologic findings). Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Based on the severity, ocular toxicity may require treatment interruption, dose reduction and/or permanent discontinuation. Permanently discontinue binimetinib in patients with documented RVO.

• Pulmonary toxicity: Cases of interstitial lung disease (ILD), including pneumonitis, developed in patients with BRAF mutation-positive melanoma receiving the combination of binimetinib and encorafenib. Evaluate new or progressive unexplained pulmonary symptoms/findings for possible ILD. Based on the severity, may require treatment interruption, dose reduction or permanent discontinuation.

• Rhabdomyolysis: Rhabdomyolysis may occur with the combination of binimetinib and encorafenib; CPK elevations may commonly occur. Monitor CPK and creatinine levels prior to treatment initiation, periodically during treatment, and as clinically indicated. Based on severity, may require treatment interruption, dosage reduction and/or permanent discontinuation.

• Thromboembolism: VTE, including PE, has occurred in patients receiving binimetinib in combination with encorafenib. Based on the severity, thromboembolism may require treatment interruption, dose reduction, and/or permanent discontinuation.

Concurrent drug therapy issues:

• Combination therapy with encorafenib: Additional toxicities may occur when used in combination with encorafenib (BRAF inhibitor). Refer to the encorafenib monograph for further information on warnings/precautions or encorafenib dosage modifications. If encorafenib is permanently discontinued, discontinue binimetinib.

Other warnings/precautions:

• Appropriate use: Prior to initiating therapy, confirm BRAF V600E or BRAF V600K mutation status with an approved test. Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/companiondiagnostics.

BRAFV600K or V600E mutation status (prior to treatment); monitor liver function tests prior to treatment initiation, monthly during treatment, and as clinically indicated; monitor CPK and creatinine levels prior to treatment initiation, periodically during treatment, and as clinically indicated. Verify pregnancy status in females of reproductive potential prior to treatment initiation. Assess ejection fraction (by echocardiogram or MUGA scan) prior to treatment initiation, one month after initiation, and then every 2 to 3 months during treatment; monitor closely in patients with cardiovascular risk factors. Evaluate visual symptoms at each visit; perform an ophthalmologic examination at regular intervals and for new or worsening visual disturbances (and to follow new or persistent ophthalmologic findings); perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Monitor for signs/symptoms of dermatologic toxicity, hemorrhage, interstitial lung disease (including new or progressive unexplained pulmonary symptoms/findings), ocular toxicity, rhabdomyolysis, and thromboembolism. Monitor adherence.

Based on its mechanism of action and on findings in animal reproduction studies, binimetinib may cause fetal harm if administered during pregnancy.

Verify pregnancy status in females of reproductive potential prior to initiating binimetinib therapy. Females of reproductive potential should use a highly effective contraceptive during therapy and for at least 30 days after the final binimetinib dose.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

Binimetinib comes as a tablet to take by mouth. It is usually taken with or without food twice daily, approximately 12 hours apart. Take binimetinib at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take binimetinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you vomit after taking the medication, do not take another dose. Continue your regular dosing schedule.

Your doctor may decrease or temporarily or permanently stop your treatment depending on if you experience any side effects. Be sure to tell your doctor how you are feeling during your treatment with binimetinib.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Before taking binimetinib,

• tell your doctor and pharmacist if you are allergic to binimetinib, any other medications, or any of the ingredients in binimetinib tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had heart or liver disease.
• tell your doctor if you are pregnant or plan to become pregnant. You will have to take a pregnancy test before starting treatment. You should use birth control to prevent pregnancy during your treatment with binimetinib and for 30 days after your final dose. Talk to your doctor about methods of birth control that will work for you. If you become pregnant while taking binimetinib, call your doctor immediately. Binimetinib may harm the fetus.
• tell your doctor if you are breastfeeding. Do not breastfeed while you are taking binimetinib and for 3 days after your final dose.

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.

• Mektovi^®

• If you have an allergy to binimetinib or any part of binimetinib.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take binimetinib and for at least 3 days after your last dose.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take binimetinib with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

Binimetinib is an antineoplastic agent.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For binimetinib, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to binimetinib or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of binimetinib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of binimetinib in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of binimetinib. Make sure you tell your doctor if you have any other medical problems, especially:

• Bleeding problems or
• Blood clots (eg, deep vein thrombosis, pulmonary embolism) or
• Eye or vision problems or
• Heart disease (eg, cardiomyopathy, heart failure) or
• Hypertension (high blood pressure) or
• Lung disease or breathing problems or
• Muscle problems—Use with caution. May make these conditions worse.

• Liver disease, moderate or severe—Use with caution. The effects may be increased because of the slower removal of the medicine from the body.