Koselugo Adverse Reactions

Overall summary of the safety profile: The safety of KOSELUGO monotherapy has been evaluated in a combined safety population of 74 paediatric patients (20-30 mg/m² twice daily) with NF1 PN and 347 adult patients (75-100 mg twice daily) with multiple tumour types.
The median total duration of KOSELUGO treatment in paediatric patients with NF1 PN was 55 months (range: <1 - 97 months), 61% of patients were exposed to KOSELUGO treatment for >48 months and 16% for >72 months.
In the Phase II Stratum 1 pivotal study (SPRINT), 50 paediatric patients with NF1 PN were treated with KOSELUGO 25 mg/m² twice daily, see Pharmacology: Pharmacodynamics under Actions. The most common adverse reactions of any grade (incidence ≥45%) were vomiting, blood creatine phosphokinase increased, diarrhoea, nausea, dry skin, pyrexia, asthenic events, dermatitis acneiform, paronychia, haemoglobin decreased, rashes (non-acneiform), hypoalbuminaemia, stomatitis, and aspartate aminotransferase increased. Dose interruptions and reductions due to adverse events were reported in 86% and 32% of patients, respectively. The most commonly reported ADRs leading to dose modification of KOSELUGO were vomiting (16 [32.0%]), nausea (10 [20.0%]), paronychia (10 [20.0%]), diarrhoea (6 [12.0%]) and pyrexia (6 [12.0%]). Permanent discontinuation due to adverse events was reported in 12% of the patients.
Tabulated list of adverse reactions: Table 7 presents the adverse reactions identified in the SPRINT Phase II Stratum 1. Adverse reactions 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 7.)

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Table 8 presents the laboratory abnormalities in SPRINT Phase II Stratum 1. (See Table 8.)

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Adverse Reactions Identified in Other Clinical Trials: Table 9 presents the adverse reactions identified from other clinical trial experience in adult patients (N=347), with multiple tumour types, receiving treatment with KOSELUGO (75 mg twice daily): (See Table 9.)

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In addition, a single event of RPED was reported in a paediatric patient receiving KOSELUGO monotherapy (25 mg/m² twice daily) for pilocytic astrocytoma involving the optic pathway in an externally sponsored paediatric study (see Dosage & Administration and Precautions).
Description of selected adverse reactions: LVEF reduction: In SPRINT, 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 interruption 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 events 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.
Decrease in LVEF should be managed using treatment interruption, dose reduction or treatment discontinuation (see Dosage & Administration and Precautions).
Blurred vision: In SPRINT, grade 1 and 2 events of blurred vision were reported in 7 (14%) patients. Two patients required dose interruption. All events were managed without dose reduction. No retinal involvement was observed in the ophthalmic examinations of paediatric patients.
If patients report new visual disturbances a complete ophthalmological assessment is recommended. Retinal toxicities can be managed using treatment interruption, dose reduction or treatment discontinuation (see Dosage & Administration and Precautions).
Paronychia: In SPRINT, paronychia was reported in 28 (56%) patients, the median time to first onset of maximum grade paronychia adverse event was 423 days and the median duration of events was 51 days. The majority of these events were grade 1 or 2 and were treated with supportive/symptomatic therapy and/or dose modification. Grade ≥3 events occurred in 4 (8%) patients. Ten patients had a KOSELUGO dose interruption for adverse events 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 events of blood CPK elevation occurred in 39 (78%) patients in SPRINT. The median time to first onset of the maximum grade CPK increase was 112 days and the median duration of events was 153 days. The majority of events were grade 1 or 2 and resolved with no change in KOSELUGO dose. Grade ≥3 events occurred in 3 (6%) patients. A grade 4 event led to treatment interruption followed by dose reduction.
Gastrointestinal toxicities: Vomiting (43 patients, 86%), abdominal pain (76%), diarrhoea (37 patients, 74%), nausea (36 patients, 72%), stomatitis (26 patients, 52%), and constipation (34%) 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 events were reported for diarrhoea (16%), nausea (4%), and vomiting (8%). For one patient diarrhoea led to dose reduction and subsequent discontinuation. No dose reduction or discontinuation was required for adverse events of nausea, vomiting or stomatitis. No grade ≥4 events were reported.
Skin toxicities: In SPRINT, 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 events 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, 16 (32%) 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.