EZMEKLY Hard capsule Ref.[115576] Active ingredients: Mirdametinib

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 during treatment, and at any time a patient reports new or worsening visual changes such as blurred vision is necessary in children, adolescents and adults. For ocular adverse reactions, mirdametinib therapy should be interrupted and then dose reduced or treatment permanently discontinued based on severity of the adverse reaction. If RVO is diagnosed, treatment with mirdametinib should be permanently discontinued. If symptomatic RPED is diagnosed, treatment with mirdametinib should be interrupted until resolution and the dose reduced when treatment is resumed. In patients diagnosed with RPED without reduced visual acuity, treatment can be continued but ophthalmic assessment should be conducted every 3 weeks until resolution (see section 4.2).

Decreased left ventricular ejection fraction (LVEF)

Asymptomatic decrease in LVEF ≥10% from baseline occurred in 17% of adult patients and 27% of paediatric patients in the ReNeu study. All cases of decreased LVEF in adult or paediatric patients in the clinical studies were asymptomatic (see section 4.8).

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

Decreased LVEF can be managed using treatment interruption, dose reduction or treatment discontinuation (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. Mirdametinib therapy should be interrupted, the dose reduced or permanently discontinued based on severity of the adverse reaction (see section 4.2).

Carcinogenicity risk

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

Women of childbearing potential/Contraception in females and males

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

Excipients with known effect

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 diphosphate glucuronosyltransferase (UGT) and carboxyl esterase (CES) enzymes. No clinical studies assessing the effect of a strong inducer and inhibitor of these enzymes have been performed. Therefore, caution should be made when mirdametinib is concomitantly used with medicinal products known to either induce or inhibit these enzymes: probenecid, diclofenac (UGTs inhibitors), rifampicin (UGT inducer) (see section 5.2).

Effects of mirdametinib on the pharmacokinetics of other medicinal products

Hormonal contraceptives

The effect of mirdametinib on the exposure of systemically acting hormonal contraceptives has not been evaluated. Therefore, use of an additional barrier method should be recommended to women using systemically 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 is not 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 and proton 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 avoid becoming pregnant while receiving Ezmekly. It is recommended that a pregnancy test should be performed on women of childbearing potential prior to initiating treatment. Both female and male patients (of reproductive potential) should be advised to use effective contraception during treatment and for 6 months and 3 months, respectively, after the last dose. The effect of mirdametinib on the exposure of systemically acting hormonal contraceptives has not been evaluated, therefore women using systemically acting hormonal contraceptives should be recommended to add a barrier method.

Pregnancy

There are limited data on the use of mirdametinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Ezmekly should not be used during pregnancy and in women of childbearing potential not using contraception. If a female patient or a female partner of a male patient receiving 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 the breast‑fed child cannot be excluded, therefore breast‑feeding should be discontinued during treatment with Ezmekly and should not be resumed for 1 week after the last dose.

Fertility

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

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

Summary of the safety profile

In the adult pool of NF1 patients, the most common adverse reactions of any grade were dermatitis acneiform (83%), diarrhoea (55%), nausea (55%), blood creatine phosphokinase increased (47%), musculoskeletal pain (41%), vomiting (37%), and fatigue (36%). Adverse reactions leading to discontinuation in >1 adult patient were dermatitis acneiform, diarrhoea, nausea, rash, and vomiting. The following serious adverse reactions were reported: abdominal pain (3%), musculoskeletal pain (1.3%) and retinal vein occlusion (1.3%).

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

Tabulated list of adverse reactions

The safety profile of mirdametinib has been determined following evaluation of a combined safety population of 75 adult and 58 paediatric patients dosed at 2 mg/m² twice daily for the first 21 days of each 28‑day cycle. This pool of patients comprised 114 patients (58 adult, 56 paediatric) in ReNeu (the pivotal 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 of mirdametinib 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, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence 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:

^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, musculoskeletal chest pain, neck pain, non‑cardiac chest pain, arthralgia, bone pain.
^e Oedema peripheral includes oedema peripheral, peripheral swelling.

Description of selected adverse reactions

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 1 retinal pigment epithelium detachment (RPED) occurred in 1.7% of patients and was managed without dose modification. Vision blurred was reported by 12% of adult patients. The median time to first onset of ocular toxicity in adults was 147 days. The median time to resolution was 267 days. In these adults, 38% of patients reported resolution of their ocular toxicity, while 25% reported resolution of events with sequelae.

Vision blurred was reported by 7% of paediatric patients. The median time to first onset of vision blurred was 161 days in paediatric patients. The median time to resolution was 29 days. All paediatric patients 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 normal values. Of the remaining adult patients with decreased LVEF, five had a dose interruption, and one patient 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. Of these patients, one reported an LVEF to < 50%, which returned to normal values without dose modification. One patient had a Grade 3 decreased LVEF that resolved without dose modification and another 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 to any of these events. The median time to first onset of decreased LVEF in paediatric patients was 132 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 median time 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 with sequelae, and 8 (15%) reported that their rashes were resolving.

In the ReNeu study, dermatitis acneiform and non‑acneiform rashes occurred in 70% of paediatric patients. 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 in 4% of paediatric patients. Dermatitis acneiform occurred with a higher frequency in patients aged 12 to 17 years, while other rashes occurred with a higher frequency in patients aged 2 to 11 years. The median time to first onset of rashes in paediatric patients was 15 days. The median time to resolution was 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 treat musculoskeletal pain included non‑steroidal anti‑inflammatory medicinal products, non‑opioid analgesics 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% of paediatric patients. Laboratory shifts of AST increased were observed in 18% of adult and 9% of paediatric patients. All events were mild to moderate severity with no Grade 3 events reported. ALT and AST increased did not result in any discontinuations, dose reductions or interruptions. Monitor and manage increases in ALT and AST as clinically indicated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.