KOSELUGO

Treatment with Koselugo should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours. Posology The recommended dose of Koselugo is 25 mg/m2 of body surface area (BSA), taken orally twice daily (approximately every 12 hours).

Dosing is individualised based on BSA (mg/m2) and rounded to the nearest achievable 5 mg or 10 mg dose (up to a maximum single dose of 50 mg). Different strengths of Koselugo capsules can be combined to attain the desired dose (Table 1).

Table 1. 55 m2 has not been established. Treatment with Koselugo should continue as long as clinical benefit is observed, or until PN progression or the development of unacceptable toxicity. There is limited data in patients older than 18, therefore continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician.

However, start of treatment with Koselugo in adults is not appropriate. Missed dose If a dose of Koselugo is missed, it should only be taken if it is more than 6 hours until the next scheduled dose. Vomiting If vomiting occurs after Koselugo is administered, an additional dose is not to be taken.

The patient should continue with the next scheduled dose. 8). Recommended dose reductions are given in Table 2 and may require the daily dose to be divided into two administrations of different strength or for treatment to be given as a once daily dose.

Table 2. 90 m2 50 35 35 25 25 a Based on BSA as shown in Table 1. b Permanently discontinue treatment in patients unable to tolerate Koselugo after two dose reductions. Dose modifications for the management of adverse reactions associated with this medicinal product are presented in Table 3.

Table 3. Recommended dose modifications for adverse reactions CTCAE Grade* Recommended dose modification Grade 1 or 2 (tolerable – can be managed with supportive care) Continue treatment and monitor as clinically indicated Grade 2 (intolerable – cannot be managed with supportive care) or Grade 3 Interrupt treatment until toxicity is grade 0 or 1 and reduce by one dose level when resuming therapy (see Table 2) Grade 4 Interrupt treatment until toxicity is grade 0 or 1, reduce by one dose level when resuming therapy (see Table 2).

Consider discontinuation * Common Terminology Criteria for Adverse Events (CTCAE) Dose modification advice for left ventricular ejection fraction (LVEF) reduction In cases of asymptomatic LVEF reduction of ≥ 10 percentage points from baseline and below the institutional lower level of normal (LLN), selumetinib treatment should be interrupted until resolution.

Once resolved, selumetinib should be reduced by one dose level when resuming therapy (see Table 2). 4). Dose modification advice for ocular toxicities Selumetinib treatment should be interrupted in patients diagnosed with retinal pigment epithelial detachment (RPED) or central serous retinopathy (CSR) with reduced visual acuity until resolution; reduce selumetinib by one dose level when resuming therapy (see Table 2).

In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. 4). Dose adjustments for co-administration with CYP3A4 or CYP2C19 inhibitors Concomitant use of strong or moderate CYP3A4 or CYP2C19 inhibitors is not recommended and alternative agents should be considered.

If a strong or moderate CYP3A4 or CYP2C19 inhibitor must be co-administered, the recommended Koselugo dose reduction is as follows: • If a patient is currently taking 25 mg/m2 twice daily, dose reduce to 20 mg/m2 twice daily. 5). Table 4.

2). Hepatic impairment Based on clinical trials, no dose adjustment is recommended in patients with mild hepatic impairment. The starting dose should be reduced in patients with […]

Summary of the safety profile The safety profile of selumetinib monotherapy in paediatric patients with NF1 who have inoperable PN has been determined following evaluation of a combined safety population of 74 paediatric patients (20-30 mg/m2 twice daily).

This paediatric ‘pool’ of patients comprised 50 patients in SPRINT Phase II Stratum 1, treated with selumetinib 25 mg/m2 twice daily (the pivotal dataset) and 24 patients in SPRINT Phase I treated with 20 to 30 mg/m2 selumetinib twice daily (the dose finding study).

There were no clinically relevant differences in the safety profile between SPRINT Phase I and SPRINT Phase II Stratum 1. This safety profile was also substantiated by a pool of safety data from 7 AstraZeneca sponsored studies in adult patients with multiple tumour types (N = 347) who received 75 to 100 mg twice daily).

In the paediatric pool, the median total duration of selumetinib treatment in paediatric patients with NF1 who have PN was 55 months (range: < 1 to 97 months), 61% of patients were exposed to selumetinib treatment for > 48 months and 16% for >72 months.

Patients aged ≥ 2 to 11 years (N = 45) had a higher incidence of the following adverse drug reactions (ADRs) compared to patients aged 12 to 18 years (N = 29): hypoalbuminaemia, dry skin, pyrexia, hair colour changes, rash maculo-papular and paronychia.

In the paediatric pool (N = 74; comprising 50 patients from the pivotal SPRINT Phase II Stratum 1 dataset and 24 patients from the supportive SPRINT Phase I dataset), the most common adverse reactions of any grade (incidence ≥ 45%) were vomiting (86%), diarrhoea (81%), blood creatine phosphokinase increased (77%), nausea (77%), dry skin (65%), pyrexia (61%), dermatitis acneiform (61%), asthenic events (59%), paronychia (57%), stomatitis (55%), haemoglobin decreased (54%), non-acneiform rashes (53%), hypoalbuminaemia (51%), and aspartate aminotransferase increased (51%).

Dose interruptions and reductions due to adverse events were reported in 82% and 39% of patients, respectively. The most commonly reported ADRs leading to dose modification (dose interrupted or dose reduced) of selumetinib were vomiting (32%), paronychia (23%), nausea (19%), diarrhoea (15%) and pyrexia (11%).

Permanent discontinuation due to adverse events was reported in 12% of the patients. The following serious adverse reactions were reported: diarrhoea (3%), anaemia (3%), pyrexia (3%), blood CPK increased (3%), blood creatinine increased (1%), oedema peripheral (1%) and vomiting (1%).

Tabulated list of adverse reactions Table 5 presents the adverse reactions identified in the paediatric population with NF1 who have inoperable PN and in adult patients (see footnote to Table 5). The frequency is determined from the paediatric pool (N = 74); comprising 50 patients from the pivotal SPRINT Phase II Stratum 1 dataset and 24 patients from the supportive SPRINT Phase I dataset.

Adverse drug reactions (ADRs) are organised 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) and not known (cannot be estimated from available data), including isolated reports.

Table

Left ventricular ejection fraction (LVEF) reduction Asymptomatic decreases in ejection fraction have been reported in 26% of paediatric patients in the pivotal clinical trial. Median time to initial onset of these adverse reactions was 232 days.

8). Paediatric patients with a history of impaired left ventricular function or a baseline LVEF below institutional LLN have not been studied. LVEF should be evaluated by echocardiogram before initiation of treatment to establish baseline values.

Prior to starting selumetinib treatment, patients should have an ejection fraction above the institutional LLN. LVEF should be evaluated at approximately 3-month intervals, or more frequently as clinically indicated, during treatment.

2). Ocular toxicity Patients should be advised to report any new visual disturbances. Adverse reactions of blurred vision have been reported in paediatric patients receiving selumetinib. 8). In line with clinical practice an ophthalmological evaluation prior to treatment initiation and at any time a patient reports new visual disturbances is recommended.

In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. 2). 2). 8). Liver laboratory values should be monitored before initiation of selumetinib and at least monthly during the first 6 months of treatment, and thereafter as clinically indicated.

2). 8). Dry skin, hair colour changes, paronychia and rash maculo- papular were seen more frequently in younger children (age 3-11 years) and acneiform rash was seen more frequently in post-pubertal children (age 12-16 years). Vitamin E supplementation Patients should be advised not to take any supplemental vitamin E.

Koselugo 10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS. , warfarin or acetylsalicylic acid). 5). Risk of choking Selumetinib is available as a capsule which must be swallowed whole.

Some patients, in particular children < 6 years of age, may be at risk of choking on a capsule formulation due to developmental, anatomical or psychological reasons. 2). 6).

1. 2).