Leaflet EZMEKLY 1mg capsules

Ezmekly 1 mg hard capsules

Ezmekly 2 mg hard capsules

Ezmekly 1 mg hard capsules

Each hard capsule contains 1 mg of mirdametinib.

Ezmekly 2 mg hard capsules

Each hard capsule contains 2 mg of mirdametinib.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Ezmekly 1 mg hard capsules

Size 3 (approximately 16 mm × 6 mm) capsule comprised of a light green opaque body and cap with‘MIR 1 mg’ printed in white ink on the cap.

Ezmekly 2 mg hard capsules

Size 1 (approximately 19 mm × 7 mm) capsule comprised of a white opaque body and a blue‑greenopaque cap with ‘MIR 2 mg’ printed in white ink on the cap.

Ezmekly as monotherapy is indicated for the treatment of symptomatic, inoperable plexiformneurofibromas (PN) in paediatric and adult patients with neurofibromatosis type 1 (NF1) aged 2 yearsand above.

Treatment with Ezmekly should be initiated by a physician experienced in the diagnosis and thetreatment of patients with NF1 related tumours.

The recommended dose of Ezmekly is 2 mg/m2 of body surface area (BSA), twice daily(approximately every 12 hours) for the first 21 days of each 28‑day cycle. The maximum dose is 4 mgtwice daily (see Table 1).

For paediatric patients 2 to <6 years of age and for patients who are unable to swallow capsules whole,

Ezmekly is also available as a 1 mg dispersible tablet formulation that can be dispersed in water. Therecommended dose for patients with a BSA less than 0.40 m2 has not been established.

Table 1: Recommended dose based on body surface area

Body surface area (BSA) Recommended dose0.40 to 0.69 m2 1 mg twice daily0.70 to 1.04 m2 2 mg twice daily1.05 to 1.49 m2 3 mg twice daily≥ 1.50 m2 4 mg twice daily

Treatment with Ezmekly should continue until PN progression or the development of unacceptabletoxicity.

If a dose of Ezmekly is missed, an additional dose is not to be taken. The patient should continue withthe next scheduled dose.

If vomiting occurs after Ezmekly is administered, an additional dose is not to be taken. The patientshould continue with the next scheduled dose. Manage events of vomiting as clinically indicated,including use of anti‑emetics.

Interruption and/or dose reduction or permanent discontinuation of Ezmekly may be required based onindividual safety and tolerability (see sections 4.4 and 4.8). Recommended dose reductions are givenin Table 2. Permanently discontinue treatment in patients unable to tolerate Ezmekly after one dosereduction.

Table 2: Recommended dose reductions

Body surface area (BSA) Reduced dose

Morning Evening0.40 to 0.69 m2 1 mg once daily0.70 to 1.04 m2 2 mg 1 mg1.05 to 1.49 m2 2 mg 2 mg≥ 1.50 m2 3 mg 3 mg

Management of patients according to the adverse reactions associated with this medicinal product arepresented in Table 3.

Table 3: Recommended dose modifications for adverse reactions

Severity of adverse reactiona Recommended dose modification for Ezmekly

Ocular toxicity (see sections 4.4 and section 4.8)

Grade ≤ 2 Continue treatment. Consider ophthalmologicexaminations every 2 to 4 weeks untilimprovement.

Grade ≥ 3 Interrupt treatment until improvement. If recoveryoccurs ≤14 days, resume at reduced dose (see

Table 2). If recovery occurs in >14 days, considerdiscontinuation.

Asymptomatic retinal pigment epithelium Continue treatment. Ophthalmic assessmentdetachment (RPED) should be conducted every 3 weeks untilresolution.

Symptomatic RPED Interrupt treatment until resolution. Resume atreduced dose (see Table 2).

Retinal vein occlusion (RVO) Discontinue treatment permanently.

Decreased left ventricular ejection fraction (LVEF) (see sections 4.4 and section 4.8)

Asymptomatic, absolute decrease in LVEF Continue treatment.less than 20% from baseline and is greaterthan the lower limit of normal

Asymptomatic, absolute decrease in LVEF Interrupt treatment until improvement. Resume atof 10 % or greater from baseline and is less reduced dose (see Table 2).than the lower limit of normal.

For any absolute decrease in LVEF 20 % or Discontinue treatment permanently.greater from baseline.

Skin toxicity (see sections 4.4 and section 4.8)

Grade 1 or 2 dermatitis acneiform or Continue treatment.non‑acneiform rash

Intolerable Grade 2 or Grade 3 dermatitis Interrupt treatment until improvement. Resume atacneiform or non‑acneiform rash reduced dose (see Table 2).

Grade 3 or Grade 4 dermatitis acneiform or Interrupt treatment until improvement. Resume atnon‑acneiform rash reduced dose (see Table 2).

Other adverse reactions (see section 4.8)

Intolerable Grade 2 or Grade 3 Interrupt treatment until improvement. Resume atreduced dose (see Table 2).

Grade 4 Interrupt treatment until improvement. Resume atreduced dose (see Table 2). Considerdiscontinuation.

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)version 5.0

No dose adjustment is recommended for patients who are aged 65 or over. Clinical data in patientsaged 65 or over is limited (see section 5.1).

No dose adjustment is recommended in patients with mild or moderate renal impairment based on apopulation pharmacokinetic analysis. Ezmekly has not been studied in patients with severe renalimpairment (CrCL ≥ 15 to < 30 mL/min) or patients with end stage renal disease (ESRD), andtherefore, no dose recommendations can be made (see section 5.2).

No dose adjustment is recommended in patients with mild hepatic impairment (totalbilirubin > ULN to 1.5 x ULN or total bilirubin ≤ ULN and AST > ULN), based on a populationpharmacokinetic analysis. Ezmekly has not been studied in patients with moderate or severe hepaticimpairment, and therefore, no dose recommendation can be made (see section 5.2).

The safety and efficacy of Ezmekly in children below 2 years of age have not been established.

No data are available.

Ezmekly is for oral use.

The capsules can be taken with or without food (see section 5.2).

Ezmekly capsules should be swallowed whole with drinking water. The capsules should not bechewed, broken or opened to ensure the full dose is administered.

For paediatric patients 2 to <6 years of age and for patients who are unable to swallow whole capsules,

Ezmekly is also available as a 1 mg dispersible tablet formulation that can be dispersed in water. Referto the SmPC for Ezmekly dispersible tablets for method of administration.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Ocular toxicity

Patients should be advised to report any new visual disturbances. RVO (retinal vein occlusion) and

RPED (retinal pigment epithelial detachment) were commonly reported in adult patients receiving

Ezmekly in clinical studies (see section 4.8).

A comprehensive ophthalmological evaluation prior to treatment initiation, at regular intervals duringtreatment, and at any time a patient reports new or worsening visual changes such as blurred vision isnecessary in children, adolescents and adults. For ocular adverse reactions, mirdametinib therapyshould be interrupted and then dose reduced or treatment permanently discontinued based on severityof the adverse reaction. If RVO is diagnosed, treatment with mirdametinib should be permanentlydiscontinued. If symptomatic RPED is diagnosed, treatment with mirdametinib should be interrupteduntil resolution and the dose reduced when treatment is resumed. In patients diagnosed with RPEDwithout reduced visual acuity, treatment can be continued but ophthalmic assessment should beconducted every 3 weeks until resolution (see section 4.2).

Decreased left ventricular ejection fraction (LVEF)

Asymptomatic decrease in LVEF ≥ 10% from baseline occurred in 16% of adult patients and 27% ofpaediatric patients in the ReNeu study. All cases of decreased LVEF in adult or paediatric patients inthe clinical studies were asymptomatic (see section 4.8).

Patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutionallower limit of normal (LLN) have not been studied. LVEF should be evaluated by echocardiogrambefore initiation of treatment to establish baseline values, every 3 months during the first year, then asclinically indicated thereafter. Prior to starting treatment, patients should have an ejection fractionabove the institutional LLN.

Decreased LVEF can be managed using treatment interruption, dose reduction or treatmentdiscontinuation (see section 4.2).

Skin toxicity

Skin adverse reactions, including rash (dermatitis acneiform and non‑acneiform rashes), dry skin,pruritus, eczema, and hair changes have been reported in the ReNeu study (see section 4.8).

Patients should contact their doctor or nurse if they experience any skin reactions. Supportive care,e.g. the use of emollient creams, should be initiated at first signs of skin toxicity. Mirdametinibtherapy should be interrupted, the dose reduced or permanently discontinued based on severity of theadverse reaction (see section 4.2).

Carcinogenicity risk

A potential carcinogenicity risk in humans could not be excluded at the clinical exposure range (seesection 5.3).

Women of childbearing potential/Contraception in females and males

Mirdametinib is not recommended in women of childbearing potential who are not usingcontraception (see sections 4.5 and 4.6). Both male and female patients (of reproductive potential)should be advised to use effective contraception.

Each capsule contains less than 1 mmol sodium (23 mg) per dose, which means it is essentially‘sodium‑free’.

No clinical interaction studies have been performed (see section 5.2).

Effects of other medicinal products on mirdametinib pharmacokinetics

In vitro studies showed that mirdametinib is metabolised by multiple uridine diphosphateglucuronosyltransferase (UGT) and carboxyl esterase (CES) enzymes. No clinical studies assessing theeffect of a strong inducer and inhibitor of these enzymes have been performed. Therefore, caution shouldbe made when mirdametinib is concomitantly used with medicinal products known to either induce orinhibit these enzymes: probenecid, diclofenac (UGTs inhibitors), rifampicin (UGT inducer) (seesection 5.2).

Effects of mirdametinib on the pharmacokinetics of other medicinal products

The effect of mirdametinib on the exposure of systemically acting hormonal contraceptives has not beenevaluated. Therefore, use of an additional barrier method should be recommended to women usingsystemically acting hormonal contraceptives (see section 4.6).

Effects of gastric acid reducing agents on mirdametinib

The combination of mirdametinib with proton‑pump inhibitors, antacids, or H2‑receptor antagonists isnot expected to be clinically meaningful as mirdametinib does not exhibit pH dependent dissolution.

Ezmekly can be used concomitantly with gastric pH modifying agents (i.e., H2‑receptor antagonists andproton pump inhibitors) without restrictions.

Women of childbearing potential/Contraception in females and males

Women of childbearing potential should be advised that Ezmekly may cause foetal harm and to avoidbecoming pregnant while receiving Ezmekly. It is recommended that a pregnancy test should beperformed on women of childbearing potential prior to initiating treatment. Both female and malepatients (of reproductive potential) should be advised to use effective contraception during treatmentand for 6 months and 3 months, respectively, after the last dose. The effect of mirdametinib on theexposure of systemically acting hormonal contraceptives has not been evaluated, therefore womenusing systemically acting hormonal contraceptives should be recommended to add a barrier method.

There are limited data on the use of mirdametinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Ezmekly should not be used during pregnancy and in women ofchildbearing potential not using contraception. If a female patient or a female partner of a male patientreceiving Ezmekly becomes pregnant, she should be apprised of the potential risk to the foetus.

Breast‑feeding

It is not known whether mirdametinib or its metabolites are excreted in human milk. A risk to thebreast‑fed child cannot be excluded, therefore breast‑feeding should be discontinued during treatmentwith Ezmekly and should not be resumed for 1 week after the last dose.

Based on findings in animals, Ezmekly may impair fertility in males and females of reproductivepotential. The reversibility of the effects on male and female reproductive organs in animals isunknown (see section 5.3). There are no data on the effect of mirdametinib on human fertility. Thepotential risk for humans is unknown.

Ezmekly may have a moderate influence on the ability to drive and use machines. Fatigue and blurredvision have been reported during treatment with mirdametinib (see section 4.8). Patients whoexperience these symptoms should observe caution when driving or using machines.

In the adult pool of NF1 patients, the most common adverse reactions of any grade were dermatitisacneiform (83%), diarrhoea (55%), nausea (55%), blood creatine phosphokinase increased (47%),musculoskeletal pain (41%), vomiting (37%), and fatigue (36%). Adverse reactions leading todiscontinuation in >1 adult patient were dermatitis acneiform, diarrhoea, nausea, rash, and vomiting.

The following serious adverse reactions were reported: abdominal pain (3%), musculoskeletalpain (1.3%) and retinal vein occlusion (1.3%).

In the paediatric pool of NF1 patients, the most common adverse reaction of any grade were bloodcreatine phosphokinase increased (59%), diarrhoea (53%), dermatitis acneiform (43%),musculoskeletal pain (41%), abdominal pain (40%), vomiting (40%), and headache (36%). Thefollowing serious adverse reaction was reported: musculoskeletal pain (1.7%).

The safety profile of mirdametinib has been determined following evaluation of a combined safetypopulation of 75 adult and 58 paediatric patients dosed at 2 mg/m2 twice daily for the first 21 days ofeach 28‑day cycle. This pool of patients comprised 114 patients (58 adult, 56 paediatric) in ReNeu (thepivotal dataset), and 19 patients (17 adult, 2 paediatric) in NF‑106.

In the adult pool (N = 75), the median total duration of mirdametinib treatment was 18.7 months(range: 0.4 to 45.6 months).

In the paediatric pool (N = 58, including 32 patients aged ≥ 2 to 11 years), the median total duration ofmirdametinib treatment was 21.9 months (range: 1.6 to 40.1 months).

Table 4 presents the adverse reactions identified in the safety population.

Adverse reactions are classified by MedDRA system organ class (SOC). Within each SOC, preferredterms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies ofoccurrence of adverse reactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 4. Adverse reactions reported in the safety population

MedDRA SOC MedDRA term Adult pool (N=75) Paediatric pool (N=58)

Overall Frequency Overall Frequencyfrequency of CTCAE frequency of CTCAE(All grade 3 (All grade 3 and

CTCAE and above CTCAE abovegrades) grades)

Infections and Paronychia Common ‑ Very ‑

Infestations (3%) Common(33%)

Nervous system Headache Very Common ( Very Common (2disorders common (16 1%) common (36 %)%) %)

Eye disorders Blurred vision Common (9 ‑ Common (7 ‑%) %)

Retinal vein Common (3 Common ( ‑ ‑occlusion %) 1%)

RPED (retinal Common (1 ‑ ‑ ‑pigment epithelial %)detachment)

Gastrointestinal Diarrhoea Very ‑ Very Common (5disorders common (55 common (53 %)%) %)

Nausea Very ‑ Very ‑common (55 common (29%) %)

MedDRA SOC MedDRA term Adult pool (N=75) Paediatric pool (N=58)

Overall Frequency Overall Frequencyfrequency of CTCAE frequency of CTCAE(All grade 3 (All grade 3 and

CTCAE and above CTCAE abovegrades) grades)

Vomiting Very ‑ Very ‑common (37 common (40%) %)

Abdominal paina Very Common ( Very Common (3common (20 4%) common (40 %)%) %)

Constipation Very ‑ Very ‑common (19 common (10%) %)

Dry mouth Common (7 ‑ ‑ ‑%)

Stomatitisb Common (5 ‑ Very ‑%) Common (19%)

Skin and Dermatitis Very Common ( Very Common (2subcutaneous acneiform common (83 7%) common (43 %)tissue disorders %) %)

Rashc Very Common ( Very Common (2common (17 1%) common (33 %)%) %)

Dry skin Very ‑ Very ‑common (13 common (17%) %)

Alopecia Very ‑ Very ‑common (12 common (14%) %)

Pruritus Very ‑ Very ‑common (13 common (12%) %)

Eczema Common (3 ‑ Very ‑%) common (14%)

Hair colour Common (1 ‑ Very ‑changes %) common (12%)

Hair texture Common (1 ‑ Common (5 ‑abnormal %) %)

Musculoskeletal Musculoskeletal Very Common ( Very Common (2and connective pain d common (41 7%) common (41 %)tissue disorders %) %)

MedDRA SOC MedDRA term Adult pool (N=75) Paediatric pool (N=58)

Overall Frequency Overall Frequencyfrequency of CTCAE frequency of CTCAE(All grade 3 (All grade 3 and

CTCAE and above CTCAE abovegrades) grades)

General Fatigue Very Common ( Very ‑disorders and common (36 1%) common (12administation %) %)site conditions Oedema Very ‑ Common (5 ‑peripherale common (12 %)%)

Investigations Blood creatine Very Common ( Very Common (5phosphokinase common (47 3%) common (59 %)increased %) %)

AST increased Very ‑ Common (9 ‑common (16 %)%)

Blood alkaline Very ‑ Very ‑phosphatase common (14 common (24increased %) %)

Ejection fraction Very ‑ Very Common (2decreased common (12 common (26 %)%) %)

Neutrophil count Common (8 Common ( Very Verydecreased %) 1%) common (30 common (11%) %)

Leukocyte count Common (7 ‑ Very ‑decreased %) common (39%)

ALT increased Common (7 ‑ Very ‑%) common (21%)a Abdominal pain includes abdominal pain and abdominal pain upper.b Stomatitis includes stomatitis, mouth ulceration, aphthous ulcer.c Rash includes rash, rash maculo‑papular, rash pustular, rash erythematous, rash papular, exfoliative rash,papule, rash macular, rash pruritic.d Musculoskeletal pain includes musculoskeletal pain, myalgia, pain in extremity, back pain, musculoskeletalchest pain, neck pain, non‑cardiac chest pain, arthralgia, bone pain.e Oedema peripheral includes oedema peripheral, peripheral swelling.

Ocular toxicity

In the ReNeu study, retinal vein occlustion (RVO) was observed in 3% of adult patients, including

Grade 3 RVO in 1.7% of patients which resulted in permanent discontinuation. Asymptomatic Grade 1retinal pigment epithelium detachment (RPED) occurred in 1.7% of patients and was managed withoutdose modification. Vision blurred was reported by 12% of adult patients. The median time to firstonset of ocular toxicity in adults was 147 days. The median time to resolution was 267 days. In theseadults, 38% of patients reported resolution of their ocular toxicity, while 25% reported resolution ofevents with sequelae.

Vision blurred was reported by 7% of paediatric patients. The median time to first onset of visionblurred was 161 days in paediatric patients. The median time to resolution was 29 days. All paediatricpatients reported resolution of events of vision blurred (see sections 4.2 and 4.4).

Decreased left ventricular ejection fraction (LVEF)

In the ReNeu study, asymptomatic decreased LVEF was reported in 16% of adults. Of these patients,only one reported an LVEF to < 50%, which led to discontinuation followed by return to normalvalues. Of the remaining adult patients with decreased LVEF, five had a dose interruption, and onepatient had a dose reduction. The median time to first onset of decreased LVEF in adults was 70 days.

Decreased LVEF resolved in 89% of adult patients.

In the ReNeu study, asymptomatic decreased LVEF was reported in 27% of paediatric patients. Ofthese patients, one reported an LVEF to < 50%, which returned to normal values without dosemodification. One patient had a Grade 3 decreased LVEF that resolved without dose modification andanother patient with Grade 2 decreased LVEF had a dose interruption. The remaining 12 patients’events of decreased LVEF were Grade 2 and no action was taken with study treatment in response toany of these events. The median time to first onset of decreased LVEF in paediatric patients was132 days. Decreased LVEF resolved in 67% of paediatric patients (see sections 4.2 and 4.4).

Skin toxicity

In the ReNeu study, dermatitis acneiform and non‑acneiform rashes occurred in 90% of adult patients.

Grade 3 dermatitis acneiform and other rashes occurred in 9% and 1.7% of adult patients, respectively.

Rashes resulted in discontinuations in 10% of adults and dose reductions in 10% of adults. The mediantime to first onset of rashes was 9 days in adult patients. The median time to resolution was 115 days.

In these adult patients, 33 (64%) reported resolution of their rashes, 3 (6%) reported resolution withsequelae, and 8 (15%) reported that their rashes were resolving.

In the ReNeu study, dermatitis acneiform and non‑acneiform rashes occurred in 70% of paediatricpatients. Grade 3 dermatitis acneiform and non‑acneiform rashes occurred in 1.8% and 1.8%,respectively. Rashes resulted in discontinuations in 4% of paediatric patients, and dose reductions in4% of paediatric patients. Dermatitis acneiform occurred with a higher frequency in patients aged 12to 17 years, while other rashes occurred with a higher frequency in patients aged 2 to 11 years. Themedian time to first onset of rashes in paediatric patients was 15 days. The median time to resolutionwas 155 days. In these paediatric patients, 27 (69%) reported resolution of their rashes and 3 (8%)reported that their rashes were resolving (see sections 4.2 and 4.4).

Musculoskeletal pain

In the ReNeu study, musculoskeletal pain (including musculoskeletal pain, myalgia, pain in extremity,back pain, musculoskeletal chest pain, neck pain, non‑cardiac chest pain, arthralgia, and bone pain)were reported by 41% of adult and 41% of paediatric patients. Concomitant medications used to treatmusculoskeletal pain included non‑steroidal anti‑inflammatory medicinal products, non‑opioidanalgesics and glucocorticoids. Treat musculoskeletal pain as clinically indicated.

AST and ALT increased

In the ReNeu study, laboratory shifts of ALT increased were observed in 9% of adult and 21% ofpaediatric patients. Laboratory shifts of AST increased were observed in 18% of adult and 9% ofpaediatric patients. All events were mild to moderate severity with no Grade 3 events reported. ALTand AST increased did not result in any discontinuations, dose reductions or interruptions. Monitorand manage increases in ALT and AST as clinically indicated.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for overdose. If overdose occurs, patients should be closely monitoredfor signs and symptoms of adverse reactions and treated supportively with appropriate monitoring asnecessary. Dialysis is ineffective in the treatment of overdose.

Pharmacotherapeutic group: Antineoplastic agents; Mitogen‑activated protein kinase (MEK)inhibitors, ATC Code: L01EE05

Mirdametinib is a selective, non‑competitive inhibitor of mitogen‑activated protein kinase kinases1 and 2 (MEK1/2). Mirdametinib blocks MEK activity and the rat sarcoma (RAS)‑rapidly acceleratedfibrosarcoma (RAF)‑MEK pathway. Therefore, MEK inhibition blocks proliferation and survival oftumour cells in which the RAF‑MEK‑extracellular related kinase (ERK) pathway is activated.

The efficacy of mirdametinib was evaluated in 114 patients in ReNeu, a multi‑centre, open‑label,single‑arm, Phase 2 study in patients ≥ 2 years of age with symptomatic inoperable NF1‑PN causingsignificant morbidity. An inoperable PN was defined as a PN that cannot be completely surgicallyremoved without risk for substantial morbidity due to: encasement of or close proximity to vitalstructures, invasiveness, or high vascularity of the PN. Patients received Ezmekly 2 mg/m2 orallytwice daily for the first 21 days of each 28‑day cycle until disease progression or unacceptabletoxicity.

A total of 58 adult patients received Ezmekly. The median age was 34.5 years (range 18 to 69 years);85% were Caucasian, 64% were female and 3.4% were greater than 65 years of age. Approximatelyhalf of the patients (53%) had a progressing PN at study entry, 48% had their tumour in the head andneck, and 69% had prior surgery. All patients had significant morbidities. The most commonlyreported morbidities were pain (90%) disfigurement or major deformity (52%), and motor dysfunction(40%).

A total of 56 paediatric patients received Ezmekly; 57% were aged 2 to 11 years and 43% were aged12 to 17 years. The median age was 10.0 years (range 2 to 17 years); 66% were Caucasian and 54%were female. Half of participants (50%) had their tumour in head and neck, most participants had aprogressing PN at study entry (63%) and 36% had prior surgery. The majority of patients (96%) hadsignificant morbidities. The most commonly reported morbidities were pain (70%), disfigurement ormajor deformity (50%) and motor dysfunction (27%).

The primary efficacy endpoint measure was confirmed objective response rate (ORR), defined as thepercentage of patients with complete response (disappearance of the target PN) or confirmed partialresponse (≥ 20% reduction in PN volume confirmed at consecutive tumour assessments approximatelyevery four cycles within 2‑6 months during the 24‑cycle treatment phase). Tumour response status wasassessed by blinded independent central review (BICR) approximately every four cycles usingvolumetric magnetic resonance imaging (MRI) analysis. Objective response rate was evaluated per

Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria withtwo consecutive assessments of partial response or complete response by a BICR within 2‑6 monthsduring the 24‑cycle treatment phase.

A secondary efficacy objective was to determine the duration of response for patients who achieved aconfirmed objective response.

Efficacy results are provided in Table 5. The median time to onset of response was 7.8 months (range:4.0 months to 19.0 months) for the adult cohort and 7.9 months (range: 4.1 months to 18.8 months) forthe paediatric cohort. The median duration of response was not reached for either cohort.

Table 5. Efficacy results in ReNeu

Adult Paediatric(N=58) (N=56)

Confirmed objective response rate per 24 (41%) 29 (52%)

REiNS by BICRa, b n (%)95% CIc (29, 55) (38, 65)

Confirmed complete response, n (%) 0 0

Confirmed partial response, n (%) 24 (41%) 29 (52%)

Duration of response

DoR≥12 monthsd 21 (88%) 26 (90%)

DoR≥24 monthsd 12 (50%) 14 (48%)

Abbreviations: CI = confidence interval; BICR = blinded independent central review; REiNS = Response

Evaluation in Neurofibromatosis and Schwannomatosis; DoR = duration of responsea Confirmed objective response was defined as two consecutive assessments of partial response or completeresponse assessed by a BICR within 2‑6 months during the 24‑cycle treatment phase.b Patients who had no post‑baseline MRI assessment or no confirmed objective response were treated asnon‑responders.c Obtained using the Clopper‑Pearson approach.

d Duration of response (data cut‑off, June 2024) was assessed using the Kaplan‑Meier approach.

The European Medicines Agency has deferred the obligation to submit the results of studies withinone or more subsets of the paediatric population. See section 4.2 for information on paediatric use.

This medicinal product has been authorised under a so‑called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agency(EMEA) will review new information on this medicinal product at least every year and this SmPC willbe updated as necessary.

The pharmacokinetics of mirdametinib was studied in healthy subjects, NF1‑PN patients and advancedcancer patients.

Following multiple oral doses at 2 mg/m2 twice daily, the geomean [geometric % coefficient ofvariation (CV)] Cmax and AUClast in adult participants with NF1‑PN were 188 (52%) ng/mL and431 (43%) ng × h/mL, respectively. Following oral dosing, mirdametinib produced peak steady stateplasma concentrations (Tmax) approximately one hour post‑dose.

In healthy adult subjects at a single dose of 20 mg, co‑administration of mirdametinib with a high‑fat,high‑calorie meal resulted in 43% lower Cmax, while the area under the concentration‑time curve(AUC) was not significantly changed (AUCinf decreased by 7%). The time to reach maximumconcentration (Tmax) was delayed by approximately 3 hours. The effect on Cmax is not consideredclinically relevant due to the absence of effect on overall exposure.

Following a single oral dose of 4 mg [14C]mirdametinib in healthy subjects, the mean apparent volumeof distribution of mirdametinib was 255 L. Human plasma protein binding is >99%. Mirdametinib ismainly bound to human serum albumin (>99%). Binding to α1‑acid glycoprotein (AAG) ranged from17.2% to 54.3%. The blood/plasma ratio for mirdametinib is 0.61.

Mirdametinib is highly metabolised via glucuronidation, hydrolysis, and oxidation via uridinediphosphate glucuronosyltransferase (UGT) and carboxyl esterase (CES) enzymes, resulting in M22 (asecondary O‑glucuronide metabolite) and M15 (a carboxylic acid metabolite), respectively. Less than10% is excreted unchanged.

Effect of mirdametinib on CYP450 enzymes

In vitro, mirdametinib, M15, and M22 are not inhibitors of CYP1A2, CYP2B6, CYP2C19, CYP2D6,or CYP3A4. Mirdametinib and M22 do not inhibit CYP2C8 or CYP2C9. M15 is an inhibitor of

CYP2C8 and CYP2C9 in vitro, however there is a low potential for inhibition at clinically relevantconcentrations. In vitro, mirdametinib is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9 or

CYP2C19. Mirdametinib is an inducer of CYP3A4 in vitro, however there is a low potential for

CYP3A4 induction at clinically relevant concentrations.

Effect of mirdametinib on UDP glucuronosyltransferase (UGT)

In vitro, mirdametinib is not an inhibitor of the isoforms UGT1A1, UGT1A3, UGT1A4, UGT1A6,

UGT1A9, UGT2B7, or UGT2B15 at clinically relevant concentrations. In vitro, M15 was not aninhibitor of the isoforms UGT1A3, UGT1A4, UGT1A6, UGT2B15, or UGT2B17. M15 is an inhibitorof UGT1A1, UGT1A9, UGT2B7 in vitro, however there is a low potential for inhibition at clinicallyrelevant concentrations.

Effect of mirdametinib on drug transporters

In vitro, mirdametinib and M15 do not inhibit the breast cancer resistance protein (BCRP),

P‑glycoprotein (P‑gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 or MATE2Ktransporters.

In vitro, M22 does not inhibit P-gp, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2Ktransporters. Based on in vitro studies, M22 inhibits BCRP, OATP1B1, and OATP2B1, however theclinical relevance of these effects cannot be established due to uncertainties regarding M22 maximalplasma concentrations and its protein binding.

Based on in vitro studies, mirdametinib is a substrate for BCRP and P‑gp transporters and M15 is asubstrate for BCRP, but they are unlikely to be clinically relevant.

In healthy adult subjects, following a single dose of 4 mg of radiolabelled mirdametinib, 68% of thedose was recovered in urine (0.7% unchanged) while 27% was recovered in faeces (8.7% unchangedin urine and faeces). The mean terminal half life is 28 hours. The apparent systemic clearance (CL/F)is 6.34 L/h.

Mirdametinib exposures, as measured by Cmax and AUCtau, generally increased dose proportionallyfrom 1 mg QD/BID to 30 mg BID. A linear relationship between dose and exposure was verified bypopulation pharmacokinetic analyses over the dose range of 1 mg to 20 mg mirdametinib BID. Themean accumulation ratio ranged from 1.1 to 1.9 across dose levels from 1 to 30 mg.

Steady‑state concentrations in patients with NF1‑PN are achieved on average approximately 6 daysfollowing repeat administration.

Based on population pharmacokinetic analysis, age (2 to 86 years), sex and race (72% white, 11%black or African American, and 12% Asian) do not significantly influence the pharmacokinetics ofmirdametinib.

No formal pharmacokinetic studies have been conducted in patients with renal impairment. No dataare available in patients with severe renal impairment or end stage renal disease (ESRD).

Patients with creatinine clearance indicative of mild or moderate renal impairment participated inmirdametinib clinical studies. Population pharmacokinetic analysis suggest that mild or moderate renalimpairment (as estimated by creatinine clearance) do not impact mirdametinib exposure.

No formal pharmacokinetic studies have been conducted in patients with hepatic impairment.

Population pharmacokinetic analyses in patients with mild hepatic impairment indicate no meaningfuleffects on exposure.

The pharmacokinetic profile in children is similar to that of adults.

Non‑clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology.

Mirdametinib was not genotoxic in a bacterial reverse mutation (Ames) assay or in an in vitro humanlymphocyte chromosomal aberration assay but was equivocal in the in vivo micronucleus study and invivo chromosomal aberrations study in rats. A genotoxicity risk in human could not be excluded at theclinical exposure range.

Mirdametinib was not carcinogenic in transgenic mice at a dose of 5 mg/kg/day (3 times the humanexposure). Since a genotoxicity risk in humans could not be excluded at clinical exposure and the2‑year rat carcinogenicity study is performed at exposures below the clinical exposure, acarcinogenicity risk could not be excluded.

Repeat‑dose toxicity

In oral, repeat dose toxicity studies conducted for up to 3 months in rats and dogs, the primarytoxicities due to MEK inhibition were in the skin and GI tract at doses below human exposure. In the3‑month rat study with mirdametinib, at doses approximately equivalent to the human exposure, ratsshowed dysplasia in femoral epiphyseal growth plate, metaphyseal hypocellularity of the bone marrowof long bones, and metaphyseal thickening of bone trabeculae of long bones. Male rats were moresensitive to these effects. These bone effects were not seen in other species (dogs, monkeys or mice).

Reversibility of dysplasia in epiphyseal growth plate was not evaluated. In rats, systemicmineralization and ocular findings (corneal opacities and atrophy or thinning of the cornealepithelium) were observed in repeat dose toxicity studies at doses below human exposure. Increases inliver enzymes (rats) and hepatocellular necrosis (rats, mice, and dogs) were observed at exposuressimilar to clinical exposure. In a 2‑week study in cynomolgus monkeys, gallbladder toxicity wasobserved at exposures >2.5‑fold the human exposure.

CNS effects were observed in dogs in the 3‑month study at exposures approximately 1.5 times thehuman exposure; these effects in dogs, including impaired balance and tremors, were reversible andthere was no microscopic correlate.

In a male and female rat fertility study, mirdametinib at a dose up to 1.0 mg/kg/day(approximately equivalent to the human exposure at the recommended dose based on AUC) did notaffect mating performance or fertility in both sexes. In a 3‑month repeat‑dose toxicology study in rats,mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated withdecreases in the number of corpora lutea at doses ≥ 0.3 mg/kg/day (0.5 times the human exposure), aswell as testicular hypocellularity and decreased weight of epididymides at 1 mg/kg/day (2.1 times thehuman exposure).

In preliminary embryo‑foetal developmental toxicity studies in pregnant rats and rabbits, oral dosingof mirdametinib induced postimplantation loss (early and late resorptions) and decreased foetal bodyweights at exposures below the human exposures at the recommended dose. In the preliminary ratstudy, a single foetus had extremity malformations at doses 3.6‑fold higher than the recommendedhuman dose. Definitive embryo‑foetal development and pre‑ and post‑natal development studies werenot conducted with mirdametinib.

Mirdametinib was equivocal in an in vitro mouse fibroblast phototoxicity assay at significantly higherconcentrations than clinical exposures and was not retained in the skin or eyes of rats, indicating thatthere is low risk for phototoxicity in patients taking mirdametinib.

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Magnesium stearate (E572)

Gelatin (E441)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Brilliant blue (E133)

Potassium hydroxide (E525)

Propylene glycol (E1520)

Purified water

Shellac (E904)

Titanium dioxide (E171)

Not applicable.

42 months.

Store below 30°C.

Store in the original package to protect from light.

High‑density polyethylene (HDPE) bottle, secured with child‑resistant closure and aluminium foilinduction seal.

1 mg hard capsules are provided in a carton containing one bottle of 42 capsules.2 mg hard capsules are provided in a carton containing one bottle of 42 or 84 capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/25/1950/003

EU/1/25/1950/004

EU/1/25/1950/005

Date of first authorisation: 17 July 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS