Koselugo Adverse Reactions

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 6 presents the adverse reactions identified in the paediatric population with NF1 who have inoperable PN and in adult patients (see footnote to Table 6). 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. (See Table 6.)

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Description of selected adverse reactions: Left ventricular ejection fraction (LVEF) reduction: In SPRINT, Phase II Stratum 1, LVEF reduction (PT: ejection fraction decreased) was reported in 13 (26%) patients; all cases were grade 2, asymptomatic and did not lead to discontinuation; one (2%) case led to dose interruptions then reduction. Of the 13 patients, 11 patients recovered and for 2 patients the outcome was not reported. The median time to first occurrence of LVEF reduction was 232 days (median duration 252 days). The majority of LVEF reduction adverse reactions were reported as reductions from baseline (≥10% reduction) but were considered to remain in the normal range. Patients with LVEF lower than the institutional LLN at baseline were not included in the pivotal study. In addition, a small number of serious cases of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program. For clinical management of LVEF reduction (see Dosage & Administration and Precautions).
Ocular toxicity: In SPRINT, Phase II Stratum 1, grade 1 and 2 adverse reactions of blurred vision were reported in 7 (14%) patients. Two patients required dose interruption. All adverse reactions were managed without dose reduction. For clinical management of new visual disturbances (see Dosage & Administration and Precautions).
In addition, a single event of RPED was reported in a paediatric patient receiving selumetinib monotherapy (25 mg/m² twice daily) for pilocytic astrocytoma involving the optic pathway in an externally sponsored paediatric study (see Dosage & Administration and Precautions).
Paronychia: In SPRINT, Phase II Stratum 1, paronychia was reported in 28 (56%) patients, the median time to first onset of maximum grade paronychia adverse reaction was 423 days and the median duration of adverse reactions was 51 days. The majority of these adverse reactions were grade 1 or 2 and were treated with supportive or symptomatic therapy and/or dose modification. Grade ≥3 events occurred in 4 (8%) patients. Ten patients (3 with a maximum grade 3 adverse reaction and 7 with a maximum grade 2 adverse reaction) had a selumetinib dose interruption for adverse reactions of paronychia, of whom 5 had dose interruption followed by dose reduction (2 patients required a second dose reduction). In one patient (2%) the event led to discontinuation.
Blood creatine phosphokinase (CPK) increase: Adverse reactions of blood CPK elevation occurred in 39 (78%) of patients in SPRINT Phase II Stratum 1. The median time to first onset of the maximum grade CPK increase was 112 days and the median duration of adverse reactions was 153 days. The majority of adverse reactions were grade 1 or 2 and resolved with no change in selumetinib dose. Grade ≥3 adverse reactions occurred in 3 (6%) patients. A grade 4 adverse reaction led to treatment interruption followed by dose reduction.
Gastrointestinal toxicities: In SPRINT, Phase II Stratum 1, vomiting (43 patients, 86%, median duration 3 days), diarrhoea (37 patients, 74%, median duration 6 days), nausea (36 patients, 72%, median duration 15 days), and stomatitis (26 patients, 52%, median duration 27 days) were the most commonly reported gastrointestinal (GI) reactions. The majority of these cases were grade 1 or 2 and did not require any dose interruptions or dose reductions.
Grade 3 adverse reactions were reported for diarrhoea (8 patients, 16%), nausea (2 patients, 4%), and vomiting (4 patients, 8%). For one patient diarrhoea led to dose reduction and subsequent discontinuation. No dose reduction or discontinuation was required for adverse reactions of nausea, vomiting or stomatitis.
Skin toxicities: In SPRINT, Phase II Stratum 1, dermatitis acneiform was observed in 28 (56%) patients (median time to onset 43 days; median duration of 202 days for the maximum CTCAE grade event). The majority of these cases were grade 1 or 2, observed in post-pubertal patients (>12 years) and did not require any dose interruptions or reductions. Grade 3 adverse reactions were reported in 3 (6%) patients.
Other (non-acneiform) rashes were observed in 27 (54%) patients in the pivotal study and were predominantly grade 1 or 2.
Hair changes: In SPRINT, Phase II Stratum 1, 16 (32)% of patients experienced hair changes (reported as hair lightening [PT: hair colour changes] in 12 patients (24%) and hair thinning [PT: alopecia] in 12 patients (24%)); in 8 patients (16%) both alopecia and hair colour changes were reported during treatment. All cases were grade 1 and did not require dose interruption or dose reduction.