Gomekli Drug Information

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.

Recommended Evaluation and Testing Before Initiating GOMEKLI Prior to administration of GOMEKLI: conduct comprehensive ophthalmic assessment. assess ejection fraction (EF) by echocardiogram.

• 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.

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 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.

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. GOMEKLI Tablets for Oral Suspension GOMEKLI tablets for oral suspension can be swallowed whole with or without food. 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.

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.

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 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 Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v. 5.0).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to GOMEKLI in 133 patients (75 adults and 58 pediatric patients) in the ReNeu study (n=114) and Study NF-106 (n=19). Patients received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Neurofibromatosis Type 1-Associated Plexiform Neurofibromas The safety of GOMEKLI was evaluated in the ReNeu study. Eligible patients were 2 years of age and older with neurofibromatosis type 1 (NF1) who had symptomatic plexiform neurofibromas (PN). Patients were excluded for abnormal left ventricular ejection fraction (LVEF), uncontrolled hypertension, alanine transaminase (ALT) value of >2 × upper limit of normal (ULN), any current or history of retinal vein occlusion (RVO) or retinal pigment epithelium detachment (RPED), intraocular pressure >21 mmHg (or upper limit of normal adjusted by age), and history of glaucoma.

For adult patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 0.4 to 46 months). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. Serious adverse reactions occurring in ≥1% of patients were COVID-19 (3.4%), nephrolithiasis (3.4%), and in 1 patient each: acute kidney injury, abdominal pain, ischemic colitis, urinary tract infection, retinal vein occlusion, scoliosis, squamous cell carcinoma of skin, cerebrovascular accident and chronic obstructive pulmonary disease.

One fatal adverse reaction occurred in an adult patient (1.7%) who received GOMEKLI, due to COVID-19. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 22% of adult patients. Adverse reactions which resulted in permanent discontinuation of GOMEKLI in ≥1% of adult patients were rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, RVO, dizziness, and vomiting.

Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 31% of adult patients. Adverse reactions which required dosage interruption in ≥5% of patients included left ventricular dysfunction and COVID-19. Dose reductions of GOMEKLI due to an adverse reaction occurred in 17% of adult patients.

Adverse reactions which required dose reductions in ≥5% of patients included rash. The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase.

For pediatric patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 1.6 to 40 months). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. Serious adverse reactions in ≥1% of patients included viral gastrointestinal infections (3.6%) and in 1 patient each: diplopia, musculoskeletal pain, seizure, fall, femoral neck fracture, dehydration and hypertension.

Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 9% of pediatric patients. Adverse reactions that required permanent discontinuation of GOMEKLI in ≥1% of patients were urticaria, rash, abdominal pain, constipation, and diarrhea. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 30% of pediatric patients.

Dose reductions of GOMEKLI due to an adverse reaction occurred in 13% of pediatric patients. Adverse reactions which required dosage reduction in ≥3% of pediatric patients were rash and decreased neutrophil count. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase.

Table 4: Adverse Reactions (≥20%) in Adult and Pediatric Patients with NF1- Associated PN Who Received GOMEKLI in ReNeu 0 a All reactions were Grade 3 except one fatal case of COVID-19 in an adult. b Rash includes dermatitis acneiform, eczema, maculo-papular rash, pustular rash, dermatitis, erythematous rash, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, skin exfoliation, pruritic rash, papule, papular rash and macular rash. c Diarrhea includes frequent bowel movements. d Abdominal pain includes upper abdominal pain, gastrointestinal pain and abdominal discomfort. e Stomatitis includes mouth ulceration, aphthous ulcer. f Musculoskeletal pain includes non-cardiac chest pain, back pain, pain in extremity, neck pain, musculoskeletal chest pain, myalgia, arthralgia, and bone pain. g Includes one fatal case in an adult. h Headache includes migraine. i Peripheral neuropathy includes paresthesia, hypoesthesia, neuralgia, peripheral sensory neuropathy. j Cough includes upper-airway cough syndrome. Clinically relevant adverse reactions that occurred in <20% of patients include: Skin and Subcutaneous Tissue Disorders: alopecia, hair color changes Gastrointestinal Disorders: constipation Eye Disorders: retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED) and blurred vision Table 5 summarizes the laboratory abnormalities in ReNeu. Table 5: Select Laboratory Abnormalities (≥15%) that Worsened from Baseline in Adult and Pediatric Patients with NF1-Associated PN Who Received GOMEKLI in ReNeu 0 9 0 a The denominator used to calculate the rate was 56 based on the number of patients with a baseline value and at least one post-treatment value. b The denominator used to calculate the rate varied from 55 to 56 based on the number of patients with a baseline value and at least one post-treatment value. c The denominator used to calculate the rate varied from 111 to 112 based on the number of patients with a baseline value and at least one post-treatment value. d Graded per NCI-CTCAE version 5.0. e No Grade 5 laboratory abnormalities were reported in the ReNeu study. f Calcium corrected for albumin (mmol/L).

Pregnancy Risk Summary Based on findings from clinical trials, animal studies, and its mechanism of action, GOMEKLI can cause fetal harm or loss of pregnancy when administered to a pregnant woman. In embryo-fetal development studies, oral administration of mirdametinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal mortality, structural abnormalities and alterations to growth at doses that were approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on BSA (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Human Data In ReNeu, a pregnancy reported 31 days after the last dose of GOMEKLI resulted in a first trimester spontaneous abortion. Animal Data In an embryo-fetal developmental toxicity study, mirdametinib was administered orally to pregnant rats during the period of organogenesis (gestation days 6 to 17) at doses of mg/kg/day.

Multiple malformations, including shortening of limbs and absence or shortening of digits, were observed in one fetus and another with hyperflexion variation at the dose of 3 mg/kg/day. In an embryo-fetal developmental toxicity study, mirdametinib was administered orally to pregnant rabbits during the period of organogenesis (gestation day 7 to 19) at doses of mg/kg/day. Two animals had spontaneous abortions at the 1 mg/kg dose on Days 20 and 23.

Mirdametinib caused post-implantation loss at doses ≥0.3 mg/kg/day (approximately equivalent to the human clinical dose of 2 mg/m 2 twice daily based on BSA).

Pediatric Use The safety and effectiveness of GOMEKLI have been established in pediatric patients 2 years of age and older with NF1-PN based on the results of the ReNeu study, a single-arm trial conducted in 58 pediatric patients age ≥2 years. The ReNeu study demonstrated improvement in overall response rate per REiNS criteria and duration of response. The safety and effectiveness of GOMEKLI have not been established in pediatric patients younger than 2 years old.

Animal Toxicity Data In a 3-month repeat-dose toxicology study in rats, oral administration of mirdametinib at doses ≥0.3 mg/kg/day (≥2 times the human exposure at the clinical dose of 2 mg/m2 twice daily based on AUC) resulted in dysplasia in femoral epiphyseal growth plate, metaphyseal hypocellularity of the bone marrow of long bones, and metaphyseal thickening of bone trabeculae of long bones; male rats were more sensitive to these effects.