Mirdametinib (Monograph)

Brand name: Gomekli
Drug class: Antineoplastic Agents

Introduction

Mirdametinib, a kinase inhibitor, is an antineoplastic agent.

Uses for Mirdametinib

Mirdametinib has the following uses:

Mirdametinib is indicated for the treatment of adults 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.

Mirdametinib Dosage and Administration

General

Mirdametinib is available in the following dosage form(s) and strength(s):

Capsules: 1 mg and 2 mg.
Tablets for oral suspension: 1 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults and Pediatric Patients ≥2 Years of Age

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.

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 recommended dosage based on body surface area (BSA) is shown in Table 1. The recommended dosage for patients with BSA less than 0.4 m² has not been established. The maximum dosage is 4 mg twice daily. Continue treatment with mirdametinib until disease progression or unacceptable toxicity.

Table 1: Recommended Dosage of 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	4 mg twice daily

See Full Prescribing Information for additional details on preparation and administration, and dosage modification recommendations for adverse reactions.

Cautions for Mirdametinib

Contraindications

None.

Warnings/Precautions

Ocular Toxicity

Mirdametinib can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), 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.

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. RVO occurred in 2.7% of adult patients, including one Grade 3 reaction which required permanent discontinuation of mirdametinib. RPED occurred in one adult patient (1.3%). Blurred vision occurred in 9% of adult patients treated with mirdametinib.

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 prior to 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 left ventricular ejection fraction (LVEF) <55% prior to initiation of treatment.

In the ReNeu study, in adult and pediatric patients, decreased LVEF of 10 to <20% occurred in 20%, and decreased LVEF of ≥20% 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.

In adult patients in the ReNeu study, decreased LVEF of 10 to <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.

In pediatric patients in the ReNeu study, decreased LVEF of 10 to <20% occurred in 25%, and decreased LVEF of ≥20% 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 (EF) by echocardiogram. Monitor EF 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 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%) included dermatitis acneiform (65%), rash (11%), eczema (8%), maculo-papular rash (4.5%) and pustular rash (3.8%).

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.

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 12 to 17 years of age (77%) than those 2 to 11 years of age (16%), while non-acneiform rashes occurred with a higher frequency in patients 2 to 11 years of age (53%) than those 12 to 17 years of age (15%).

Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue mirdametinib based on severity of adverse reaction.

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 the ReNeu study, 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 (BSA).

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

Specific Populations

Pregnancy

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 BSA. 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.

Lactation

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.

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

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

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.

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-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 mirdametinib have not been established in pediatric patients younger than 2 years of age.

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.

Geriatric Use

Of the 133 patients with neurofibromatosis type 1 (NF1) with symptomatic plexiform neurofibromas (PN) 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, 2 (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: 60-89 mL/min) or moderate (creatinine clearance: 30-59 mL/min) renal impairment. Mirdametinib has not been studied in patients with severe (creatinine clearance <30 mL/min) renal impairment.

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.

Common Adverse Effects

The most common adverse reactions (>25%) in adults were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.
The most common Grade 3 or 4 laboratory abnormality (>2%) in adults was increased creatine phosphokinase.
The most common adverse reactions (>25%) in pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
The most common Grade 3 or 4 laboratory abnormalities (>2%) in pediatric patients were decreased neutrophil count and increased creatine phosphokinase.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

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 (NF1), oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.

Advice to Patients

Advise the patient or caregiver to read the FDA-approved patient labeling.
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.
Advise patients and caregivers that mirdametinib can cause decreased left ventricular ejection fraction (LVEF) and to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider.
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.
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.
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.
Advise women not to breastfeed during treatment with mirdametinib and for 1 week after the last dose.
Advise females of reproductive potential that mirdametinib may impair fertility.
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.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.