mirdametinib 2 MG Oral Capsule [Gomekli]

INDICATIONS AND USAGE GOMEKLI is indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection [see Clinical Studies (14) ]. GOMEKLI is a kinase inhibitor indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection. ( 1 )

DOSAGE AND ADMINISTRATION The recommended dosage of GOMEKLI is 2 mg/m 2 orally twice daily, with or without food, for the first 21 days of each 28-day cycle. Continue treatment with GOMEKLI until disease progression or unacceptable toxicity. ( 2 ) 2.1 Recommended Evaluation and Testing Before Initiating GOMEKLI Prior to administration of GOMEKLI: conduct comprehensive ophthalmic assessment [see Warnings and Precautions (5.1) ]. assess ejection fraction (EF) by echocardiogram [see Warnings and Precautions (5.2) ]. 2.2 GOMEKLI Dosage Form Overview GOMEKLI is available in 2 dosage forms: capsules or tablets for oral suspension. GOMEKLI capsules: must be swallowed whole, do not open, break or chew capsules. GOMEKLI tablets for oral suspension: can be swallowed whole or can be dispersed in drinking water and administered orally as a liquid [see Dosage and Administration (2.4) ]. 2.3 Recommended Dosage The recommended dosage of GOMEKLI is 2 mg/m 2 orally twice daily (approximately every 12 hours) with or without food for the first 21 days of each 28-day cycle. The maximum dose is 4 mg twice daily. Continue treatment with GOMEKLI until disease progression or unacceptable toxicity. The recommended dose of GOMEKLI is based on body surface area (BSA) as shown in Table 1. Table 1: Recommended Dosage for GOMEKLI Body Surface Area (m 2 ) * Recommended Dosage for Capsules or Tablets for Oral Suspension 0.40 to 0.69 1 mg twice daily 0.70 to 1.04 2 mg twice daily 1.05 to 1.49 3 mg twice daily ≥1.50 4 mg twice daily * The recommended dosage for patients with a BSA less than 0.40 m 2 has not been established. Missed dose: If the patient misses a dose of GOMEKLI, do not take an additional dose. Take the next scheduled dose at the prescribed time. Vomiting: If vomiting occurs after GOMEKLI administration, do not take an additional dose. Take the next scheduled dose at the prescribed time. 2.4 GOMEKLI Preparation and Administration Instructions GOMEKLI Capsules Swallow GOMEKLI capsules whole with or without food. If more than one capsule is required for a dose, swallow one capsule at a time. Do not open, break or chew capsules. Do not administer to patients who are unable to swallow a whole capsule [see GOMEKLI Tablets for Oral Suspension]. GOMEKLI Tablets for Oral Suspension GOMEKLI tablets for oral suspension can be swallowed whole with or without food. If more than one tablet is required for a dose, swallow one tablet at a time. For patients who are not able to swallow whole tablets, prepare GOMEKLI tablets for oral suspension dispersed in drinking water and administer orally as a liquid [see Instructions for Use ]. Preparation and Administration Add the prescribed number of tablets to a dosing cup containing approximately 5 mL to 10 mL of drinking water. Gently swirl the water and tablets until the tablets are fully dispersed and an oral suspension is obtained. It takes approximately two to four minutes to fully disperse the tablets. Once the tablets are dispersed, the oral suspension will appear white and cloudy. Administer the oral suspension immediately after preparation from a dosing cup or oral syringe. After administration of the prepared suspension, add approximately 5 mL to 10 mL of drinking water to the dosing cup and gently swirl to resuspend any remaining particles. Administer the suspension to ensure the full dose is taken. Discard the oral suspension if not administered within 30 minutes after preparation. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2 . Table 2: Recommended Dose Reductions for GOMEKLI for Adverse Reactions Body Surface Area (m 2 ) Reduced Dose * Morning Evening 0.40 to 0.69 1 mg once daily 0.70 to 1.04 2 mg 1 mg 1.05 to 1.49 2 mg 2 mg ≥1.50 3 mg 3 mg * Permanently discontinue GOMEKLI in patients unable to tolerate GOMEKLI after one dose reduction. The recommended dosage modifications for adverse reactions are provided in Table 3 . Table 3: Recommended Dosage Modifications and Management of Adverse Reactions for GOMEKLI Adverse Reaction Severity Dosage Modification Ocular Toxicity [see Warnings and Precautions (5.1) ] Grade ≤ 2 Continue GOMEKLI at current dose level. Consider ophthalmologic examinations every 2 to 4 weeks until resolution to ≤Grade 1 or baseline. Grade ≥ 3 Withhold GOMEKLI until ≤Grade 1 or baseline. If recovery occurs ≤14 days, resume GOMEKLI at the next lower dose. If recovery occurs in >14 days, consider permanent discontinuation of GOMEKLI. Symptomatic Retinal Pigment Epithelium Detachment (RPED) Withhold GOMEKLI until ≤Grade 1 or baseline. Resume GOMEKLI at the same dose. Retinal Vein Occlusion (RVO) Permanently discontinue GOMEKLI. Left Ventricular Dysfunction [see Warnings and Precautions (5.2) ] Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is less than the lower limit of normal Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Any absolute decrease in LVEF 20% or greater from baseline Permanently discontinue GOMEKLI. Adverse Reaction Severity Dosage Modification Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Intolerable Grade 2 or Grade 3 Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Grade 3 or 4 Dermatitis Acneiform or Non-Acneiform Rash Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Other Adverse Reactions [see Adverse Reactions (6.1) ] Intolerable Grade 2 or Grade 3 Withhold GOMEKLI until ≤Grade 1. Resume GOMEKLI at reduced dose. Grade 4 Consider permanent discontinuation of GOMEKLI. * Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v. 5.0).

WARNINGS AND PRECAUTIONS Ocular Toxicity : Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment and for new or worsening visual changes or blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity. ( 5.1 ) Left Ventricular Dysfunction : Assess ejection fraction by echocardiogram prior to initiating GOMEKLI, every 3 months during the first year, then as clinically indicated thereafter. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity. ( 5.2 ) Dermatologic Adverse Reactions : Initiate supportive care at first signs of dermatologic adverse reactions including rash. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity. ( 5.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.4 ) 5.1 Ocular Toxicity GOMEKLI can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision. In the pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 25% of patients treated with GOMEKLI: 20% were Grade 1 reactions, 3.8% were Grade 2 reactions, and 0.8% were Grade 3 reactions. Adult Patients In the adult pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 28% of patients treated with GOMEKLI: 21% were Grade 1 reactions, 5% were Grade 2 reactions and 1.3% were Grade 3 reactions. Retinal vein occlusion (RVO) occurred in 2.7% of adult patients, including one Grade 3 reaction which required permanent discontinuation of GOMEKLI. RPED occurred in one adult patient (1.3%). Blurred vision occurred in 9% of adult patients treated with GOMEKLI. Pediatric Patients In the pediatric pooled safety population [see Adverse Reactions (6.1) ], ocular toxicity occurred in 19% of patients: 17% were Grade 1 and 1.7% were Grade 2. Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes such as blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI as clinically indicated [see Dosage and Administration (2.5) ]. 5.2 Left Ventricular Dysfunction GOMEKLI can cause left ventricular dysfunction. Treatment with GOMEKLI has not been studied in patients with a history of clinically significant cardiac disease or LVEF <55% prior to initiation of treatment. In the ReNeu study, in adult and pediatric patients [see Adverse Reactions (6.1) ] , decreased LVEF of 10 to <20% occurred in 20%, and decreased LVEF of ≥20% occurred in 0.9% of patients treated with GOMEKLI. All patients with decreased LVEF were identified during routine echocardiography. Decreased LVEF resolved in 75% of these patients. Adult Patients In adult patients in the ReNeu study [see Adverse Reactions (6.1) ] , decreased LVEF of 10 to <20% occurred in 16% of adult patients treated with GOMEKLI. Of the adult patients with decreased LVEF, five patients (9%) required dose interruption, one patient (1.7%) required a dose reduction and one patient required permanent discontinuation of GOMEKLI. The median time to first onset of decreased LVEF in adult patients was 70 days. Pediatric Patients In pediatric patients in the ReNeu study [see Adverse Reactions (6.1) ] , decreased LVEF of 10 to <20% occurred in 25%, and decreased LVEF of ≥20% occurred in 1.8% of patients treated with GOMEKLI. Of the pediatric patients with decreased LVEF, one patient (1.8%) required dose interruption of GOMEKLI. The median time to first onset of decreased LVEF in pediatric patients was 132 days. Before initiating GOMEKLI, assess ejection fraction (EF) by echocardiogram. Monitor EF every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on the severity of adverse reaction [see Dosage and Administration (2.5) ]. 5.3 Dermatologic Adverse Reactions GOMEKLI can cause dermatologic adverse reactions including rash. In the pooled safety population [see Adverse Reactions (6.1) ], rash occurred in 84% of patients treated with GOMEKLI: 31% were Grade 2, and 6% were Grade 3. The most frequent rashes (≥2%) included dermatitis acneiform (65%), rash (11%), eczema (8%), maculo-papular rash (4.5%) and pustular rash (3.8%). Adult Patients In the pooled adult safety population [see Adverse Reactions (6.1) ], rash occurred in 92% of patients treated with GOMEKLI: 37% were Grade 2 and 8% were Grade 3 reactions. Rash requiring permanent discontinuation of GOMEKLI occurred in 11% of adult patients. Pediatric Patients In the pooled pediatric safety population [see Adverse Reactions (6.1) ] , rash occurred in 72% of patients treated with GOMEKLI: 22% were Grade 2 and 3.4% were Grade 3 reactions. Rash resulting in permanent discontinuation of GOMEKLI occurred in 3.4% of pediatric patients. Dermatitis acneiform occurred with a higher frequency in patients aged 12 to 17 years (77%) than those aged 2 to 11 years (16%), while non-acneiform rashes occurred with a higher frequency in patients aged 2 to 11 years (53%) than those aged 12 to 17 years (15%). Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction [see Dosage and Administration (2.5) ] . 5.4 Embryo-Fetal Toxicity Based on findings from clinical trials, animal studies and its mechanism of action, GOMEKLI can cause fetal harm when administered to a pregnant woman. In ReNeu, a pregnancy reported 31 days after the last dose of GOMEKLI resulted in a first trimester spontaneous abortion. In embryo-fetal development studies, oral administration of mirdametinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortality, structural abnormalities and alterations to growth at doses approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on body surface area (BSA). Verify the pregnancy status of females of reproductive potential prior to the initiation of GOMEKLI. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GOMEKLI and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3 ) ].

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Mirdametinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK. In a mouse model of NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.