Mirdametinib

Acknowledgment
This article consists of drug labeling information developed under U.S. FDA guidance and excerpted from DailyMed. It was not reviewed by the MedLink Neurology Editorial Board. For the latest FDA-approved information about this drug, visit Drugs@FDA.com.

Highlights

Indications and usage
Mirdametinib (Gomekli®) is a kinase inhibitor indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection.
Dosage and administration
The recommended dosage of mirdametinib is 2 mg/m² orally twice daily, with or without food, for the first 21 days of each 28-day cycle. Continue treatment with mirdametinib until disease progression or unacceptable toxicity.
Dosage forms and strengths
	• Capsules: 1 and 2 mg.
	• Tablets for oral suspension: 1 mg.
Note: Mirdametinib was first approved by the U.S. FDA in 2025.

Contraindications
None.
Warnings and precautions
	• Ocular toxicity. Conduct comprehensive ophthalmic assessments before initiating mirdametinib, at regular intervals during treatment, and for new or worsening visual changes or blurred vision. Continue, withhold, reduce the dose, or permanently discontinue mirdametinib based on severity.
	• Left ventricular dysfunction. Assess ejection fraction by echocardiogram before initiating mirdametinib, every 3 months during the first year, then as clinically indicated thereafter. Withhold, reduce the dose, or permanently discontinue mirdametinib based on severity.
	• Dermatologic adverse reactions. Initiate supportive care at the first signs of dermatologic adverse reactions, including rash. Withhold, reduce the dose, or permanently discontinue mirdametinib based on severity.
	• Embryo-fetal toxicity. Can cause fetal harm. Advise patients of the reproductive potential of the potential risk to a fetus and to use effective contraception.
Adverse reactions
Adults
	• The most common adverse reactions (greater than 25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.
	• The most common Grade 3 or 4 laboratory abnormality (greater than 2%) was increased creatine phosphokinase.
Pediatric patients
	• The most common adverse reactions (greater than 25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
	• The most common Grade 3 or 4 laboratory abnormalities (greater than 2%) were decreased neutrophil count and increased creatine phosphokinase.
To report suspected adverse reactions, contact SpringWorks Therapeutics Inc. at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Use in specific populations.
	• Lactation. Advise not to breastfeed.
	• Infertility. May impair fertility in females.
	• See Patient counseling information and FDA-approved patient labeling.

Indications and usage

Mirdametinib is indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection.

Dosage and administration

Recommended evaluation and testing before initiating mirdametinib

Before administration of mirdametinib:

	• Conduct comprehensive ophthalmic assessment.
	• Assess ejection fraction by echocardiogram.

Mirdametinib dosage form overview

Mirdametinib is available in two dosage forms: capsules or tablets for oral suspension.

	• Mirdametinib capsules: must be swallowed whole; do not open, break, or chew capsules.
	• Mirdametinib 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 mirdametinib 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 mirdametinib until disease progression or unacceptable toxicity. The recommended dose of mirdametinib is based on body surface area as shown in Table 1.

Table 1. Recommended Dosage for Mirdametinib

Body surface area (m2)*	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 or more	4 mg twice daily
* The recommended dosage for patients with a body surface area of less than 0.40 m2 has not been established.

Missed dose. If the patient misses a dose of mirdametinib, do not take an additional dose. Take the next scheduled dose at the prescribed time.

Vomiting. If vomiting occurs after mirdametinib administration, do not take an additional dose. Take the next scheduled dose at the prescribed time.

Mirdametinib preparation and administration instructions

Mirdametinib capsules
	• Swallow mirdametinib 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.
Mirdametinib tablets for oral suspension
	• Mirdametinib 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 mirdametinib 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 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 2 to 4 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 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 Mirdametinib for Adverse Reactions

Body surface area (m2)	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 or more	3 mg	3 mg
* Permanently discontinue mirdametinib in patients unable to tolerate mirdametinib 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 Mirdametinib

Adverse reaction	Severity	Dosage modification
Ocular toxicity	Grade 2 or lower	• Continue mirdametinib at the current dose level. • Consider ophthalmologic examinations every 2 to 4 weeks until resolution to Grade 1 or lower or baseline.
	Grade 3 or higher	• Withhold mirdametinib until Grade 1 or lower or baseline. • If recovery occurs 14 days or less, resume mirdametinib at the next lower dose. • If recovery occurs in more than 14 days, consider permanent discontinuation of mirdametinib.
	Symptomatic retinal pigment epithelium detachment	• Withhold mirdametinib until Grade 1 or lower or baseline. • Resume mirdametinib at the same dose.
	Retinal vein occlusion	• Permanently discontinue mirdametinib.
Left ventricular dysfunction	Asymptomatic, absolute decrease in LVEF of 10% or more from baseline and less than the lower limit of normal	• Withhold mirdametinib until Grade 1 or lower. • Resume mirdametinib at reduced dose.
	Any absolute decrease in LVEF of 20% or more from baseline	• Permanently discontinue mirdametinib.
Dermatologic adverse reactions	Intolerable Grade 2 or 3	• Withhold mirdametinib until Grade 1 or lower. • Resume mirdametinib at reduced dose.
	Grade 3 or 4 dermatitis acneiform or non-acneiform rash	• Withhold mirdametinib until Grade 1 or lower. • Resume mirdametinib at reduced dose.
Other adverse reactions	Intolerable Grade 2 or 3	• Withhold mirdametinib until Grade 1 or lower. • Resume mirdametinib at reduced dose.
	Grade 4	• Consider permanent discontinuation of mirdametinib.
* Per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v. 5.0).

Dosage forms and strengths

Capsules
	• 1 mg: light green body and cap with “MIR 1 mg” printed on the cap in white ink.
	• 2 mg: white body and a blue-green cap with “MIR 2 mg” printed on the cap in white ink.
Tablets for oral suspension
	• 1 mg: white to off-white, oval, grape flavored tablet, debossed with “S” on one side.

Contraindications

None.

Warnings and precautions

Ocular toxicity

Mirdametinib can cause ocular toxicity, including retinal vein occlusion, retinal pigment epithelium detachment, and blurred vision.

In the pooled safety population, ocular toxicity occurred in 25% of patients treated with mirdametinib: 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, ocular toxicity occurred in 28% of patients treated with mirdametinib: 21% were Grade 1 reactions, 5% were Grade 2 reactions, and 1.3% were Grade 3 reactions. Retinal vein occlusion occurred in 2.7% of adult patients, including one Grade 3 reaction that required permanent discontinuation of mirdametinib. Retinal pigment epithelium detachment occurred in one adult patient (1.3%). Blurred vision occurred in 9% of adult patients treated with mirdametinib.

Pediatric patients. In the pediatric pooled safety population, ocular toxicity occurred in 19% of patients: 17% were Grade 1 and 1.7% were Grade 2.

Conduct comprehensive ophthalmic assessments before initiating mirdametinib, 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 mirdametinib as clinically indicated.

Left ventricular dysfunction

Mirdametinib can cause left ventricular dysfunction. Treatment with mirdametinib has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 55% before initiation of treatment.

In the ReNeu study, in adult and pediatric patients, decreased LVEF of 10% to less than 20% occurred in 20%, and decreased LVEF of 20% or more occurred in 0.9% of patients treated with mirdametinib. 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, decreased LVEF of 10% to less than 20% occurred in 16% of adult patients treated with mirdametinib. 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 mirdametinib. The median time to first onset of decreased LVEF in adult patients was 70 days.

Pediatric patients. In pediatric patients in the ReNeu study, decreased LVEF of 10% to less than 20% occurred in 25%, and decreased LVEF of 20% or more occurred in 1.8% of patients treated with mirdametinib. Of the pediatric patients with decreased LVEF, one patient (1.8%) required dose interruption of mirdametinib. The median time to first onset of decreased LVEF in pediatric patients was 132 days.

Before initiating mirdametinib, assess ejection fraction by echocardiogram. Monitor ejection fraction every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose, or permanently discontinue mirdametinib based on the severity of the adverse reaction.

Dermatologic adverse reactions

Mirdametinib can cause dermatologic adverse reactions, including rash.

In the pooled safety population, rash occurred in 84% of patients treated with mirdametinib: 31% were Grade 2, and 6% were Grade 3. The most frequent rashes (2% or more) 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, rash occurred in 92% of patients treated with mirdametinib: 37% were Grade 2 and 8% were Grade 3 reactions. Rash requiring permanent discontinuation of mirdametinib occurred in 11% of adult patients.

Pediatric patients. In the pooled pediatric safety population, rash occurred in 72% of patients treated with mirdametinib: 22% were Grade 2 and 3.4% were Grade 3 reactions.

Rash resulting in permanent discontinuation of mirdametinib 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%), whereas 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 the first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue mirdametinib based on the severity of adverse reactions.

Embryo-fetal toxicity

Based on findings from clinical trials, animal studies, and its mechanism of action, mirdametinib can cause fetal harm when administered to a pregnant woman. In ReNeu, a pregnancy reported 31 days after the last dose of mirdametinib 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.

Verify the pregnancy status of females of reproductive potential before the initiation of mirdametinib. 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 mirdametinib and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with mirdametinib and for 3 months after the last dose.

Adverse reactions

The following serious adverse reactions are described elsewhere in the labeling:

	• Ocular toxicity
	• Left ventricular dysfunction
	• Dermatologic adverse reactions
	• Embryo-fetal toxicity

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 mirdametinib in 133 patients (75 adults and 58 pediatric patients) in the ReNeu study (NCT02096471).

Patients received mirdametinib 2 mg/m² orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Among 133 patients who received mirdametinib, 62% were exposed for one year or longer, 38% were exposed for 2 years or longer, and 12% were exposed for 3 years or longer.

Neurofibromatosis type 1-associated plexiform neurofibromas. The safety of mirdametinib was evaluated in the ReNeu study. Eligible patients were 2 years of age and older with neurofibromatosis type 1 who had symptomatic plexiform neurofibromas. Patients were excluded for abnormal left ventricular ejection fraction, uncontrolled hypertension, alanine transaminase value of greater than two times the upper limit of normal, any history of retinal vein occlusion or retinal pigment epithelium detachment, intraocular pressure greater than 21 mmHg (or upper limit of normal adjusted by age), and history of glaucoma. Patients received mirdametinib 2 mg/m² orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Adult patients. The median age of adult patients (age 18 years or older) who received mirdametinib was 35 years (range: 18 to 69 years); 64% were female; 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races or race not reported; and 1.7% were Hispanic or Latino. For adult patients treated with mirdametinib, the median treatment duration was 22 months (range: 0.4 to 46 months).

Serious adverse reactions occurred in 17% of adult patients who received mirdametinib. Serious adverse reactions occurring in 1% or more of patients were COVID-19 (3.4%), nephrolithiasis (3.4%), and in one patient each: acute kidney injury, abdominal pain, ischemic colitis, urinary tract infection, retinal vein occlusion, scoliosis, squamous cell carcinoma of skin, cerebrovascular accident [stroke-ed.] and chronic obstructive pulmonary disease. One fatal adverse reaction occurred in an adult patient (1.7%) who received mirdametinib due to COVID-19.

Permanent discontinuation of mirdametinib due to an adverse reaction occurred in 22% of adult patients. Adverse reactions that resulted in permanent discontinuation of mirdametinib in 1% or more of adult patients were rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, retinal vein occlusion, dizziness, and vomiting.

Dosage interruptions of mirdametinib due to an adverse reaction occurred in 31% of adult patients. Adverse reactions that required dosage interruption in 5% or more of patients included left ventricular dysfunction and COVID-19.

Dose reductions of mirdametinib due to an adverse reaction occurred in 17% of adult patients. Adverse reactions that required dose reductions in 5% or more of patients included rash.

The most common adverse reactions (greater than 25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common Grade 3 or 4 laboratory abnormality (greater than 2%) was increased creatine phosphokinase.

Pediatric patients. The median age of pediatric patients (age 17 years or younger) who received mirdametinib was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races or race not reported, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. For pediatric patients treated with mirdametinib, the median treatment duration was 22 months (range: 1.6 to 40 months).

Serious adverse reactions occurred in 14% of pediatric patients who received mirdametinib. Serious adverse reactions in 1% or more of patients included viral gastrointestinal infections (3.6%) and in one patient each: diplopia, musculoskeletal pain, seizure, fall, femoral neck fracture, dehydration, and hypertension.

Permanent discontinuation of mirdametinib due to an adverse reaction occurred in 9% of pediatric patients. Adverse reactions that required permanent discontinuation of mirdametinib in 1% or more of patients were urticaria, rash, abdominal pain, constipation, and diarrhea.

Dosage interruptions of mirdametinib due to an adverse reaction occurred in 30% of pediatric patients. Adverse reactions that required dosage interruption in 5% or more of patients included COVID-19.

Dose reductions of mirdametinib due to an adverse reaction occurred in 13% of pediatric patients. Adverse reactions that required dosage reduction in 3% or more of pediatric patients were rash and decreased neutrophil count.

The most common adverse reactions (greater than 25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea. The most common Grade 3 or 4 laboratory abnormalities (greater than 2%) were decreased neutrophil count and increased creatine phosphokinase.

For detailed information about the adverse reactions and laboratory abnormalities in adult and pediatric patients with nf1-associated plexiform neurofibromas who received mirdametinib in ReNeu, see the relevant sections of the DAILYMED drug label information.

Use in specific populations

Pregnancy

Risk summary. Based on findings from clinical trials, animal studies, and its mechanism of action, mirdametinib 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 body surface area. 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 mirdametinib 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 of 3 mg/kg/day or more (five or more times the human clinical dose of 2 mg/m² twice daily based on body surface area). 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 or more (three or more times the human clinical dose of 2 mg/m² twice daily based on body surface area). Two animals had spontaneous abortions at the 1 mg/kg dose on Days 20 and 23. Mirdametinib caused post-implantation loss at doses of 0.3 mg/kg/day or more (approximately equivalent to the human clinical dose of 2 mg/m² twice daily based on body surface area).

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 mirdametinib and for 1 week after the last dose.

Females and males of reproductive potential

Mirdametinib can cause fetal harm when administered to a pregnant woman.

Pregnancy testing. Verify the pregnancy status of females of reproductive potential before initiating mirdametinib.

Contraception.

Females. Advise females of reproductive potential to use effective contraception during treatment with mirdametinib 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 mirdametinib and for 3 months after the last dose.

Infertility. Based on findings in animals, mirdametinib may impair fertility in females of reproductive potential. The reversibility of the effects on female fertility in animals is unknown.

Pediatric use

The safety and effectiveness of mirdametinib have been established in pediatric patients 2 years of age and older with NF1-plexiform neurofibromas based on the results of the ReNeu study, a single-arm trial conducted in 58 pediatric patients aged years or older. The ReNeu study demonstrated improvement in overall response rate per REiNS criteria and duration of response.

The safety and effectiveness of mirdametinib 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 or more (two or more 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.

Geriatric use

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

Renal impairment

No dosage adjustment is required in patients with mild (creatinine clearance: 60 to 89 mL/min) or moderate (creatinine clearance: 30 to 59 mL/min) renal impairment. Mirdametinib has not been studied in patients with severe (creatinine clearance less than 30 mL/min) renal impairment.

Hepatic impairment

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

The pharmacokinetics of mirdametinib in patients with moderate (bilirubin more than 1.5 to three times the upper limit of normal and any aspartate aminotransferase) or severe (bilirubin higher than three times the upper limit of normal and any aspartate aminotransferase) hepatic impairment has not been evaluated.

Clinical pharmacology

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 neurofibromatosis type 1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.

Pharmacodynamics

Mirdametinib exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.

Cardiac electrophysiology. At approximately six times the steady-state exposure associated with the recommended dose of 2 mg/m², clinically significant QTc interval prolongation was not observed.

Pharmacokinetics

For a summary of mirdametinib pharmacokinetic parameters, see the relevant sections of the DAILYMED drug label information.

Specific populations.

Effects of age, sex, and race. No clinically significant differences in mirdametinib pharmacokinetics were observed based on age (2 to 86 years), sex, and race (11% African American or Black, 12% Asian, 72% White). The effects of moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) on mirdametinib pharmacokinetics are unknown.

Drug interaction studies. No clinical drug-drug interaction studies have been conducted. The effect of concomitant strong CYP3A4 inducers (that also co-induce UGTs, P-gp, and CES enzymes) on mirdametinib PK is unknown.

In vitro studies.

CYP enzymes. Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4.

Transporter systems. Mirdametinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.

Mirdametinib is a substrate of BCRP and P-gp transporters.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day (approximately 15 times the human exposure at the clinical dose of 2 mg/m² twice daily based on AUC).

Mirdametinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.

In a dedicated fertility study, male rats were treated with mirdametinib for 28 days before mating with untreated females to Gestational Day 1. Female rats were treated with mirdametinib for 14 days before mating with untreated males to Gestational Day 7. No effects on mating performance or fertility in males or females were observed at doses up to 1 mg/kg/day (approximately two times the human clinical dose of 2 mg/m² twice daily based on body surface area). In a 3-month repeat-dose toxicology study in rats, mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated with decreases in the number of corpora lutea at doses 0.3 mg/kg/day or more (approximately two times the human exposure at the clinical dose of 2 mg/m² twice daily based on AUC). Findings in male rats included hypoplasia of the spermatogenic epithelium in the testis, decreased content in the epididymis, and inflammation of the prostate at 1 mg/kg (approximately eight times the human exposure at the clinical dose of 2 mg/m² based on AUC). The reversibility of effects on ovaries and male reproductive organs was not assessed.

Clinical studies

Neurofibromatosis Type 1 associated plexiform neurofibromas

The efficacy of mirdametinib was evaluated in the ReNeu study (NCT03962543), a multicenter, single-arm study in 114 patients aged 2 years or older with symptomatic, inoperable neurofibromatosis type 1-associated plexiform neurofibromas causing significant morbidity. An inoperable plexiform neurofibroma was defined as a plexiform neurofibroma that cannot be completely surgically removed without risk for substantial morbidity due to encasement of or close proximity to vital structures, invasiveness, or high vascularity of the plexiform neurofibroma. Patients received mirdametinib 2 mg/m² orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

The major efficacy outcome measure was confirmed overall response rate (ORR), defined as the percentage of patients with complete response (disappearance of the target plexiform neurofibroma) or partial response (20% or more reduction in plexiform neurofibroma volume). Responses were assessed by blinded independent central review using volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria modified to be confirmed at a subsequent tumor assessment within 2 to 6 months during the 24-cycle treatment phase. A secondary efficacy outcome measure was duration of response for patients who achieved a confirmed response.

Adults. A total of 58 adult patients received mirdametinib. The median age was 35 years (range 18 to 69 years); 64% were female, 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were of other races, and 1.7% were Hispanic or Latino. Approximately half of the patients (53%) had a progressing plexiform neurofibroma at study entry, 7% had prior treatment with a MEK inhibitor, and 69% had prior surgery. Morbidities reported in more than 25% of patients were pain (90%), disfigurement or major deformity (52%), and motor dysfunction (40%).

Pediatric patients. A total of 56 pediatric patients received mirdametinib. The median age was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. Most patients (63%) had a progressing plexiform neurofibroma at study entry, 11% had prior treatment with a MEK inhibitor, and 36% had prior surgery. Morbidities reported in more than 25% of patients were pain (70%), disfigurement or major deformity (50%), and motor dysfunction (27%).

Efficacy results are provided in Table 7. The median time to onset of response was 7.8 months (range: 4 to 19 months) for the adult cohort and 7.9 months (range: 4.1 months to 18.8 months) for the pediatric cohort.

Table 7. Efficacy Results by Blinded Independent Central Review from ReNeu

	Mirdametinib Adult (N=58)	Mirdametinib Pediatric (N=56)
Confirmed overall response rate^a,b,c n (%)	24 (41%)	29 (52%)
95% CI^d	(29, 55)	(38, 65)
Duration of response (DoR)
DoR 12 months or longer^e	21 (88%)	26 (90%)
DoR 24 months or longer^e	12 (50%)	14 (48%)
Abbreviations: CI: confidence interval. ^a Confirmed overall response was defined as two consecutive assessments of PR or CR assessed within 2 to 6 months during the treatment phase. ^b Patients who had no post-baseline MRI assessment or no confirmed overall response were treated as nonresponders. ^c All partial responses. ^d Obtained using the Clopper-Pearson approach. ^e Duration of response was assessed based on observed time.

How supplied/storage and handling

How supplied

Mirdametinib capsules are supplied as follows:
Capsule strength	Capsule description	Package configuration	NDC
1 mg	Light green body and cap with “MIR 1 mg” printed on the cap in white ink.	Bottle of 42 capsules	82448-130-42
2 mg	White body and a blue-green cap with “MIR 2 mg” printed on the cap in white ink.	Bottle of 42 capsules	82448-260-42
		Bottle of 84 capsules	82448-260-84
Mirdametinib tablets for oral suspension are supplied as follows:
Tablet strength	Tablet description	Package configuration	NDC
1 mg	White to off-white, oval, grape flavored tablet, debossed with “S” on one side.	Bottle of 42 tablets	82448-134-42
		Bottle of 84 tablets	82448-134-84

Storage and handling

Store capsules and tablets for oral suspension at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F). See USP Controlled Room Temperature. Protect from light.

Patient counseling information

Advise the patient or caregiver to read the FDA-approved patient labeling.

Ocular toxicity. Advise patients and caregivers that mirdametinib can cause serious ocular effects and to immediately contact their healthcare provider if they experience any changes in their vision.

Left ventricular dysfunction. Advise patients and caregivers that mirdametinib can cause decreased LVEF and to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider.

Dermatologic adverse reactions. Advise patients and caregivers that mirdametinib can cause severe dermatologic adverse reactions and to contact their healthcare provider if they experience any skin reactions. Advise patients and caregivers that mirdametinib can cause alopecia.

Embryo-fetal toxicity. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Contraception.

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

Males. Advise males with female partners of reproductive potential to use effective contraception during treatment with mirdametinib and for 3 months after the last dose.

Lactation. Advise women not to breastfeed during treatment with mirdametinib and for 1 week after the last dose.

Infertility. Advise females of reproductive potential that mirdametinib may impair fertility.

Administration. Advise patients to swallow mirdametinib capsules whole (do not open, break, or chew capsules).

Advise patients to either swallow mirdametinib tablets whole or to disperse mirdametinib tablets in water and administer orally as a liquid.

Evrysdi® is a trademark of SpringWorks Therapeutics, Inc.

Patient package insert and instructions for use

For the patient package insert and instructions of use, see the relevant sections of the DAILYMED drug label information.

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