Mirdametinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]
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Overview
Mirdametinib is a kinase inhibitor that is FDA approved 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.. Common adverse reactions include Ocular Toxicity, Left Ventricular Dysfunction, Dermatologic Adverse Reactions, and Embryo-Fetal Toxicity..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
FDA-labeled Indication
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.
Doasage
- 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.
- If the patient misses a dose of GOMEKLI, do not take an additional dose. Take the next scheduled dose at the prescribed time.
- If vomiting occurs after GOMEKLI administration, do not take an additional dose. Take the next scheduled dose at the prescribed time.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mirdametinib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mirdametinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Mirdametinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mirdametinib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mirdametinib in pediatric patients.
Contraindications
None
Warnings
Ocular Toxicity
- GOMEKLI can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision.
- 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.
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.
- 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.
Dermatologic Adverse Reactions
- GOMEKLI can cause dermatologic adverse reactions including rash.
- The most frequent rashes (≥2%) included dermatitis acneiform (65%), rash (11%), eczema (8%), maculo-papular rash (4.5%) and pustular rash (3.8%).
- Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction.
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.
Adverse Reactions
Clinical Trials Experience
Clinical Trial Experience
Patients received GOMEKLI 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 GOMEKLI, 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 GOMEKLI was evaluated in the ReNeu study [see Clinical Studies (14)]. Eligible patients were 2 years of age and older with neurofibromatosis type 1 (NF1) who had symptomatic plexiform neurofibromas (PN).
Ádult Patients
- The median age of adult patients (age ≥18) who received GOMEKLI was 35 years (range: 18-69); 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 GOMEKLI, the median duration of treatment was 22 months (range: 0.4 to 46 months).
- erious 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.
- 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.
- 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.
Pediatric Patients
- For pediatric patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 1.6 to 40 months).
- 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.
- Adverse reactions that required permanent discontinuation of GOMEKLI in ≥1% of patients were urticaria, rash, abdominal pain, constipation, and diarrhea.
- Adverse reactions which required dosage interruption in ≥5% of patients included COVID-19.
- Adverse reactions which required dosage reduction in ≥3% of pediatric patients were rash and decreased neutrophil count.
- The most common adverse reactions (>25%) were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.
Postmarketing Experience
There is limited information regarding Mirdametinib Postmarketing Experience in the drug label.
Drug Interactions
- No clinical DDI 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 currently unknown.
- 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.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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/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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mirdametinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Mirdametinib during labor and delivery.
Nursing Mothers
- 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.
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 safety and effectiveness of GOMEKLI have not been established in pediatric patients younger than 2 years old.
Geriatic 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.
Gender
There is no FDA guidance on the use of Mirdametinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Mirdametinib with respect to specific racial populations.
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
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.
Females of Reproductive Potential and Males
GOMEKLI can cause fetal harm when administered to a pregnant woman.
- 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
Immunocompromised Patients
There is no FDA guidance one the use of Mirdametinib in patients who are immunocompromised.
Administration and Monitoring
Administration
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. 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.
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.
Monitoring
There is limited information regarding Mirdametinib Monitoring in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Mirdametinib in pediatric patients.
Overdosage
There is limited information regarding drug overdose of Mirdametinib in pediatric patients.
Pharmacology
There is limited information regarding Mirdametinib Pharmacology in the drug label.
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 NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.
Structure
There is limited information regarding Mirdametinib Structure in the drug label.
Pharmacodynamics
- Mirdametinib exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.
Pharmacokinetics
There is limited information regarding Mirdametinib Pharmacokinetics in the drug label.
Nonclinical Toxicology
- 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.
Clinical Studies
Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
- The efficacy of GOMEKLI was evaluated in the ReNeu study (NCT03962543), a multicenter, single-arm study in 114 patients ≥2 years of age with symptomatic, inoperable neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) causing significant morbidity.
- An inoperable PN was defined as a PN 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 PN.
- Patients received GOMEKLI 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 PN) or partial response (≥20% reduction in PN volume).
- Responses were assessed by blinded independent central review (BICR) 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 GOMEKLI. 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 other races; and 1.7% were Hispanic or Latino. Approximately half of the patients (53%) had a progressing PN at study entry, 7% had prior treatment with a MEK inhibitor and 69% had prior surgery. Morbidities reported in >25% of patients were pain (90%), disfigurement or major deformity (52%), and motor dysfunction (40%).
Pediatric Patients
A total of 56 pediatric patients received GOMEKLI. 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 PN at study entry, 11% had prior treatment with a MEK inhibitor and 36% had prior surgery. Morbidities reported in >25% of patients were pain (70%), disfigurement or major deformity (50%), and motor dysfunction (27%).
How Supplied
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 to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Protect from light.
Storage
There is limited information regarding Mirdametinib Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Ocular Toxicity Advise patients and caregivers that GOMEKLI 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 GOMEKLI 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 GOMEKLI can cause severe dermatologic adverse reactions and to contact their healthcare provider if they experience any skin reactions.Advise patients and caregivers that GOMEKLI 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 GOMEKLI and for 6 weeks after the last dose.
Males Advise males with female partners of reproductive potential to use effective contraception during treatment with GOMEKLI and for 3 months after the last dose.
Lactation Advise women not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.
Infertility Advise females of reproductive potential that GOMEKLI may impair fertility.
Administration
- Advise patients to swallow GOMEKLI capsules whole (do not open, break or chew capsules)
- Advise patients to either swallow GOMEKLI tablets whole or to disperse GOMEKLI tablets in water and administer orally as a liquid
Precautions with Alcohol
Alcohol-Mirdametinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
GOMEKLI
Look-Alike Drug Names
There is limited information regarding Mirdametinib Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.