Gomekli

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/m2 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.

*The recommended dosage for patients with a BSA less than 0.40 m2 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.

*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.

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

8.1        Pregnancy

Risk Summary

Based on findings from clinical trials, animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], 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/m2 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 2% to 4% and 15% to 20%, 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 0.3, 0.6, 3 or 5 mg/kg/day. Mirdametinib caused post-implantation loss and decreased fetal body weights at doses ≥3 mg/kg/day (≥5 times the human clinical dose of 2 mg/m2 twice daily based on BSA). 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 0.3, 1, 3, or 6 mg/kg/day. Maternal toxicity (decreased body weight and moribund condition) was observed at doses ≥1 mg/kg/day (≥3 times the human clinical dose of 2 mg/m2 twice daily based on BSA). 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/m2 twice daily based on BSA).

8.2        Lactation

Risk Summary

There are no data on the presence of mirdametinib or its metabolites in human milk or their effects on a breastfed child or on milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.

8.3        Females and Males of Reproductive Potential

GOMEKLI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating GOMEKLI.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with GOMEKLI and for 3 months after the last dose.

Infertility

Based on findings in animals, GOMEKLI may impair fertility in females of reproductive potential. The reversibility of the effects on female fertility in animals is unknown [see Nonclinical Toxicology (13.1)].

8.4        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 [see Clinical Studies (14.1)]. 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.

8.5        Geriatric Use

Of the 133 patients with neurofibromatosis type 1 (NF1) with symptomatic plexiform neurofibromas (PN) who received GOMEKLI 2 mg/m2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity, 2 (1.5%) were 65 years of age and older and none were 75 years of age and older. Clinical studies of GOMEKLI did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adult patients.

8.6        Renal Impairment

No dosage adjustment is required in patients with mild (creatinine clearance: 60-89 mL/min) or moderate (creatinine clearance: 30-59 mL/min) renal impairment. GOMEKLI has not been studied in patients with severe (creatinine clearance <30 mL/min) renal impairment [see Clinical Pharmacology (12.3)].

8.7        Hepatic Impairment

No dosage adjustment is required in patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or total bilirubin in 1-1.5 x ULN).

The pharmacokinetics of mirdametinib in patients with moderate (bilirubin >1.5 to 3 x ULN and any AST) or severe (bilirubin >3 x ULN and any AST) hepatic impairment has not been evaluated [see Clinical Pharmacology (12.3)].

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/m2 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)].