Mirdametinib, an inhibitor of mitogen-activated extracellular signal-regulated kinases 1 and 2 (MEK1/2), is an antineoplastic agent.1
Mirdametinib is used 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.1, 4 Mirdametinib has been designated an orphan drug by FDA for the treatment of NF1.6
Efficacy of mirdametinib was evaluated in a multicenter, open-label, single-arm, phase IIb trial (ReNeu) in adults and pediatric patients with inoperable, radiologically measurable symptomatic NF1-associated plexiform neurofibromas (PNs) causing significant morbidity.1, 3, 4 Inoperable PN was defined as a PN that could not be completely removed surgically without the risk of substantial morbidity due to encasement of or close proximity to vital structures, invasiveness, or high vascularity.1 Pediatric patients (2 to 17 years of age) and adults (≥18 years of age) were enrolled in separate cohorts.3, 4 Mirdametinib was administered as a capsule or tablet for oral suspension, with or without food, at a dose of 2 mg/m2 (maximum dose of 4 mg) orally twice daily for the first 21 days of a 28-day cycle.1, 3, 4 Treatment was continued until disease progression or unacceptable toxicity occurred.1, 3 Age, lesion type, and prior MEK inhibitor treatment were considered as prognostic factors for 1:1 propensity score matching across cohorts.3
The primary efficacy end point was confirmed objective response rate (ORR), defined as the proportion of patients with complete response (disappearance of the target PN) or partial response (defined as ≥20% reduction in PN volume) on magnetic resonance imaging (MRI).1, 3, 4 Responses were assessed by blinded independent central review (BICR) using MRI analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria modified to be confirmed at a subsequent tumor assessment within 2‒6 months during the 24-cycle treatment phase.1, 3 Duration of response (DoR) was also assessed for patients who achieved a confirmed response.1, 3, 4 A total of 114 patients (58 adults and 56 pediatric patients) were enrolled in the study.1, 3, 4 The median age was 35 years (range: 18‒69) for adults and 10 years (range: 2‒17) for pediatric patients.1, 3 At baseline, 31 (53%) adults and 35 (63%) pediatric patients had investigator-determined progressive PN.1, 3 The most common NF1-PN-related morbidities were pain (90% of adults; 70% of pediatric patients), motor dysfunction (40% of adults; 27% of pediatric patients) and disfigurement or major deformity (52% of adults; 50% of pediatric patients).3
In the adult cohort, 7% received prior treatment with a MEK inhibitor and 69% had prior surgery.1 A confirmed objective response was achieved in 41% of adults.3 In responders, a DoR ≥12 months was achieved in 88% of patients and a DoR ≥24 months was achieved in 50% of patients.1 The median time to onset of confirmed response was 7.8 months (range: 4‒19 months) for adults.1, 3
In the pediatric cohort, 11% received prior treatment with a MEK inhibitor and 36% had prior surgery.1 A confirmed objective response was achieved in 52% of the pediatric patients.1, 3, 4 In responders, a DoR ≥12 months was achieved in 90% of patients and a DoR ≥24 months was achieved in 48% of patients.1, 4 The median time to onset of confirmed response was 7.9 months (range: 4.1‒18.8 months) in the pediatric cohort.1, 3
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome caused by loss of neurofibromin, the protein product of the NF1 gene.5 Patients diagnosed with NF1 are at risk of developing benign and malignant tumors including cutaneous neurofibromas, plexiform neurofibromas (PNs), and optic pathway or other low-grade gliomas.5 PNs develop in approximately 50% of patients with NF1.5 These tumors can result in significant morbidity, impacting a patient's appearance and/or function; PNs are also associated with a risk of malignant transformation.5 Treatment for PNs has historically been limited to surgical resection; however, resection may not be feasible due to tumor effects on adjacent tissue, nerves, and vasculature.4, 5 MEK inhibitors provide an alternative medical option to surgery in patients with NF1-associated PNs.4, 5 There are currently 2 available MEK inhibitors for the treatment of symptomatic inoperable NF1-PN: selumetinib and mirdametinib.4, 5
Administer mirdametinib orally twice daily with or without food.1 Mirdametinib is commercially available as capsules and tablets for oral suspension.1
Swallow mirdametinib capsules whole; do not open, break or chew.1, 4 If more than one capsule is required for a dose, swallow one capsule at a time.1 Do not administer to patients unable to swallow a whole capsule.1
If a patient misses a dose of mirdametinib, do not take an additional dose.1 Take the next scheduled dose at the prescribed time.1
If vomiting occurs after mirdametinib administration, do not take an additional dose.1 Take the next scheduled dose at the prescribed time.1
Store capsules at 20‒25°C.1 Excursions permitted between 15‒30°C.1 Protect from light.1
Swallow mirdametinib tablets for oral suspension whole or disperse the tablets in drinking water and administer as a liquid.1, 4 If more than one tablet is required for a dose, swallow one tablet at a time.1
To prepare the tablets for oral suspension, place the prescribed number of tablets into a dosing cup containing approximately 5‒10 mL of drinking water.1
Gently swirl the water and tablets until the tablets are fully dispersed and an oral suspension is obtained; full dispersion takes approximately 2‒4 minutes.1 Once the tablets are dispersed, the oral suspension will appear white and cloudy.1
Administer the oral suspension immediately after preparation from a dosing cup or oral syringe.1 After administration of the prepared suspension, add approximately 5‒10 mL of drinking water to the dosing cup and gently swirl to resuspend any remaining particles.1 Administer the suspension to ensure the full dose is taken.1 Discard the oral suspension if not administered within 30 minutes after preparation.1
If a patient misses a dose of mirdametinib, do not take an additional dose.1 Take the next scheduled dose at the prescribed time.1
If vomiting occurs after mirdametinib administration, do not take an additional dose.1 Take the next scheduled dose at the prescribed time.1
Store tablets for oral suspension at 20‒25°C.1 Excursions permitted between 15‒30°C.1 Protect from light.1
Neurofibromatosis Type 1-Associated Plexiform Neurofibroma
The recommended dosage of mirdametinib for the treatment of neurofibromatosis Type 1-associated plexiform neurofibroma in adults and pediatric patients 2 years of age and older is 2 mg/m2 orally twice daily (approximately every 12 hours) for the first 21 days of each 28-day cycle.1, 4 The maximum dosage is 4 mg twice daily.1 Continue mirdametinib until disease progression or unacceptable toxicity.1, 4 The recommended dose of mirdametinib is based on body surface area (BSA) as shown in Table 1.1
Body Surface Area (m2) | Recommended Dosage for Capsules or Tablets for Oral Suspension |
|---|---|
<0.4 | Not established |
0.4 to 0.69 | 1 mg twice a day |
0.7 to 1.04 | 2 mg twice a day |
1.05 to 1.49 | 3 mg twice a day |
≥1.5 | 4 mg twice a day |
Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are provided in Table 2.1
Body Surface Area (m2) | Reduced Dosage |
|---|---|
0.4 to 0.69 | 1 mg once daily |
0.7 to 1.04 | 2 mg in the morning and 1 mg in the evening |
1.05 to 1.49 | 2 mg in the morning and 2 mg in the evening |
≥1.5 | 3 mg in the morning and 3 mg in the evening |
Permanently discontinue mirdametinib in patients unable to tolerate the drug after one dose reduction.1
The recommended dosage modifications for adverse reactions are provided in Table 3.
Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
Ocular Toxicity | Grade ≤2 | Continue mirdametinib at current dose level. Consider ophthalmologic examinations every 2 to 4 weeks until resolution to Grade ≤1 or baseline. |
Ocular Toxicity | Grade ≥3 | Withhold mirdametinib until ≤Grade 1 or baseline. If recovery occurs in ≤14 days, resume mirdametinib at the next lower dose. If recovery occurs in >14 days, consider permanent discontinuation of mirdametinib. |
Ocular Toxicity | Symptomatic Retinal Pigment Epithelium Detachment (RPED) | Withhold mirdametinib until Grade ≤1 or baseline. Resume mirdametinib at the same dose. |
Ocular Toxicity | Retinal Vein Occlusion (RVO) | Permanently discontinue mirdametinib. |
Left Ventricular Dysfunction | Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) ≥10% from baseline and < the lower limit of normal | Withhold mirdametinib until Grade ≤1. Resume mirdametinib at reduced dose. |
Left Ventricular Dysfunction | Any absolute decrease in LVEF ≥20% from baseline | Permanently discontinue mirdametinib. |
Dermatologic Adverse Reactions | Intolerable Grade 2 or Grade 3 | Withhold mirdametinib until Grade ≤1. Resume mirdametinib at reduced dose. |
Dermatologic Adverse Reactions | Grade 3 or 4 Dermatitis | Withhold mirdametinib until Grade ≤1. |
Dermatologic Adverse Reactions | Acneiform or Non-Acneiform Rash | Resume mirdametinib at reduced dose. |
Other Adverse Reactions | Intolerable Grade 2 or Grade 3 | Withhold mirdametinib until Grade ≤1. Resume mirdametinib at reduced dose. |
Other Adverse Reactions | Grade 4 | Consider permanent discontinuation of mirdametinib. |
The manufacturer makes no specific dosage recommendations for hepatic impairment.1, 4
The manufacturer makes no specific dosage recommendations for renal impairment.1, 4
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Mirdametinib can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision.1
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.1
In adults, 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.1 RVO occurred in 2.7% of adult patients, including one Grade 3 reaction which required permanent discontinuation of mirdametinib.1 RPED occurred in one adult patient (1.3%).1 Blurred vision occurred in 9% of adult patients treated with mirdametinib.1
In the pediatric population, ocular toxicity occurred in 19% of patients; 17% were Grade 1 and 1.7% were Grade 2.1
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.1 Continue, withhold, reduce the dose, or permanently discontinue mirdametinib as clinically indicated.1
Mirdametinib can cause left ventricular dysfunction.1 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.1
In the ReNeu study, decreased LVEF of 10 to <20% occurred in 20%, and decreased LVEF of ≥20% occurred in 0.9% of adults and pediatreic patients treated with mirdametinib.1 Decreased LVEF resolved in 75% of these patients.1
In adult patients in the ReNeu study, decreased LVEF of 10 to <20% occurred in 16% of patients treated with mirdametinib.1 Of the adult patients with decreased LVEF, 5 patients (9%) required dose interruption, one patient (1.7%) required a dose reduction and one patient required permanent discontinuation of mirdametinib.1 The median time to first onset of decreased LVEF in adult patients was 70 days.1
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.1 Of the pediatric patients with decreased LVEF, one patient (1.8%) required dose interruption of mirdametinib.1 The median time to first onset of decreased LVEF in pediatric patients was 132 days.1
Assess ejection fraction (EF) by echocardiogram before initiating mirdametinib.1 Monitor EF every 3 months during the first year and then as clinically indicated.1 Withhold, reduce the dose, or permanently discontinue mirdametinib based on severity of the adverse reaction.1
Dermatologic Adverse Reactions
Mirdametinib can cause dermatologic adverse reactions including rash.1
In the pooled safety population, rash occurred in 84% of patients treated with mirdametinib; 31% were Grade 2, and 6% were Grade 3.1 Most frequent rashes (≥2%) included dermatitis acneiform (65%), rash (11%), eczema (8%), maculo-papular rash (4.5%), and pustular rash (3.8%).1
In adults, rash occurred in 92% of patients treated with mirdametinib; 37% were Grade 2 and 8% were Grade 3 reactions.1 Rash requiring permanent discontinuation of mirdametinib occurred in 11% of adult patients.1
In the pediatric population, rash occurred in 72% of patients treated with mirdametinib; 22% were Grade 2 and 3.4% were Grade 3 reactions.1 Rash resulting in permanent discontinuation of mirdametinib occurred in 3.4% of pediatric patients.1 Dermatitis acneiform occurred with a higher frequency in patients 12‒17 years of age (77%) than those 2‒ 11 years of age (16%), while non-acneiform rashes occurred with a higher frequency in patients 2‒ 11 years of age (53%) than those 12‒17 years of age (15%).1
Initiate supportive care at the first signs of dermatologic adverse reactions.1 Withhold, reduce the dose, or permanently discontinue mirdametinib based on severity of the adverse reaction.1
Fetal/Neonatal Morbidity and Mortality
Mirdametinib can cause fetal harm when administered to a pregnant woman.1 In the ReNeu study, a pregnancy reported 31 days after the last dose of mirdametinib resulted in spontaneous abortion in the first trimester.1
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 growth alterations at doses approximately equivalent to the human clinical dose of 2 mg/m2 twice daily based on body surface area (BSA).1
Verify the pregnancy status of females of reproductive potential prior to the initiation of mirdametinib.1 Advise patients of the potential risk to a fetus.1 Advise females of reproductive potential to use effective contraception during treatment with mirdametinib and for 6 weeks after the last dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment with mirdametinib and for 3 months after the last dose.1
Mirdametinib can cause fetal harm or loss of pregnancy when administered to a pregnant woman.1 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 growth alterations.1 Advise pregnant women of the potential risk to a fetus.1
There are no data on the presence of mirdametinib or its metabolites in human milk or their effects on a breastfed child or milk production.1 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.1
Females and Males of Reproductive Potential
Mirdametinib can cause fetal harm when administered to a pregnant woman.1 Verify the pregnancy status of females of reproductive potential prior to initiating mirdametinib.1
Advise females of reproductive potential to use effective contraception during treatment with mirdametinib and for 6 weeks after the last dose.1
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.1
Based on animal findings, mirdametinib may impair fertility in females of reproductive potential.1 The reversibility of these effects is unknown.1
Safety and effectiveness of mirdametinib have been established in pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) with symptomatic plexiform neurofibromas (PN) based on the results of the ReNeu study, a single-arm trial conducted in 58 pediatric patients ≥2 years of age.1 The ReNeu study demonstrated improvement in overall response rate per REiNS criteria and duration of response.1
Safety and effectiveness of mirdametinib have not been established in pediatric patients younger than 2 years of age.1
Of the 133 patients with NF1-PN who received mirdametinib in clinical studies, 2 (1.5%) were 65 years of age and older and no patients were 75 years of age and older.1 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.1
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).1 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 have not been evaluated.1, 4
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.1 Mirdametinib has not been studied in patients with severe (creatinine clearance <30 mL/min) renal impairment.1, 4
The most common adverse reactions (>25%) in adults were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.1, 4 The most common Grade 3 or 4 laboratory abnormality (>2%) in adults was increased creatine phosphokinase.1
The most common adverse reactions (>25%) in pediatric patients were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.1, 4 The most common Grade 3 or 4 laboratory abnormalities (>2%) in pediatric patients were decreased neutrophil count and increased creatine phosphokinase.1
No formal drug interaction studies have been performed to date with mirdametinib.1, 4 The effect of concomitant use of strong cytochrome P-450 (CYP) 3A4 inducers that also co-induce uridine diphosphate glucuronosyltransferases (UGTs), P-glycoprotein (P-gp), and carboxylesterase (CES) enzymes on mirdametinib pharmacokinetics is unknown.1, 4
Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.1 Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4.1 Mirdametinib has no detectable or limited (<50%) inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15.4 Mirdametinib does not inhibit breast cancer resistance protein (BCRP), P-gp, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 2 (OCT2), OAT1, OAT3, multidrug and toxin extrusion 1 (MATE1), or MATE2K transporters.1, 4 Mirdametinib is a substrate of BCRP and P-gp transporters.1, 4
Mirdametinib is an inhibitor of mitogen-activated extracellular signal-regulated protein kinases 1 and 2 (MEK1/2).1 MEK1/2 proteins are upstream regulators of extracellular signal-related kinase (ERK) pathway.1, 4 Activation of this signaling pathway leads to cell proliferation and is involved in various types of cancer.4 In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK.1 In a mouse model of neurofibromatosis type 1 (NF1), oral administration of mirdametinib inhibited phosphorylation of ERK and reduced neurofibroma tumor volume and proliferation.1
The bioavailability of mirdametinib is unknown.1 The time to peak plasma concentration following oral administration of mirdametinib (as the tablet or capsule formulation) is 0.8 or 1.1 hours, respectively.1, 4 Time to steady state concentrations is approximately 6 days.1 Plasma protein binding of mirdametinib is >99%.1, 4 Peak plasma concentrations of mirdametinib are decreased when administered with food; however, the change is not substantial.4 Mirdametinib is widely distributed into tissues, including the brain.4 Mirdametinib primarily undergoes glucuronidation and oxidation of the parent compound.4 Uridine diphosphate glucuronosyltransferase (UGT) 1A6 and UGT2B7 are involved in the metabolism of the drug.4 PD-0315209 (a carboxylic acid metabolite) and M22 (a glucuronide conjugate) have been identified as major metabolites (>10%).4 Both metabolites are pharmacologically active, although activity is significantly lower than the parent drug.4 The half-life of mirdametinib is 28 hours.4 The drug is excreted in the urine (68%; 0.7% unchanged) and feces (27%); 9% of unchanged mirdametinib is excreted in urine and feces.1, 4
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Mirdametinib is obtained through designated distributors.2 Contact the manufacturer for specific availability information.2
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 1 mg | Gomekli® | SpringWorks Therapeutics |
2 mg | Gomekli® | SpringWorks Therapeutics | ||
Tablets, for oral suspension | 1 mg | Gomekli® | SpringWorks Therapeutics |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. SpringWorks Therapeutics, Inc. Mirdametinib ®(mirdametinib) ORAL prescribing information. 2025 Feb.
2. SpringWorks Therapeutics, Inc. Product fact sheet and ordering guide. From SpringWorks Therapeutics, Inc. website. Accessed 2025 March 11.
3. Moertel CL, Hirbe AC, Shuhaiber HH, Bielamowicz K, Sidhu A, Viskochil D, et al. ReNeu: A pivotal, Phase IIb tiral of mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma. J Clin Oncol 2024;43:716-29.
4. Center for Drug Evaluation and Research. Mutli-Discipline Review. Revised 2022 June. From FDA website.
5. Klesse LJ, Jordan JT, Radtke HB, Rosser T, Schorry E, Ullrich N, et al.The use of MEK inhibitors in neurofibromatosis type-1 associated tumors and management of toxicities. The Oncologist 2020;25:e1109-e1116.
6. Food and Drug Administration. Search orphan drug designations and approvals. Silver Spring MD. From FDA website.