Selumetinib

In vitro, selumetinib is an inhibitor of OAT3. The potential for a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 (e.g., methotrexate and furosemide) cannot be excluded.

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 selumetinib dose reduction is as follows:

• If a patient is currently taking 25 mg/m² twice daily, dose reduce to 20 mg/m² twice daily.
• If a patient is currently taking 20 mg/m² twice daily, dose reduce to 15 mg/m² twice daily.

Recommended dose to achieve 20 mg/m² or 15 mg/m² twice daily dose level:

Co-administration with a strong CYP3A4 inducer (600 mg rifampicin daily for 8 days) decreased selumetinib C_max by -26% (90% CI -17, -34) and AUC by -51% (90% CI -47, -54).

Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St.John's Wort) or moderate CYP3A4 inducers with selumetinib should be avoided.

The starting dose should be reduced in patients with moderate hepatic impairment to 20 mg/m² BSA, twice daily.

Recommended dose to achieve 20 mg/m² twice daily dose level:

The effect of selumetinib on the exposure of oral contraceptives has not been evaluated. Therefore, use of an additional barrier method should be recommended to women using hormonal contraceptives.

There are no data on the use of selumetinib in pregnant women. Studies in animals have shown reproductive toxicity including embryofoetal death, structural defects and reduced foetal weights. Selumetinib is not recommended during pregnancy and in women of childbearing potential not using contraception.

If a female patient or a female partner of a male patient receiving selumetinib becomes pregnant, she should be apprised of the potential risk to the foetus.

It is not known whether selumetinib, or its metabolites, are excreted in human milk. Selumetinib and its active metabolite are excreted in the milk of lactating mice. A risk to the breast-fed child cannot be excluded, therefore breast-feeding should be discontinued during treatment with selumetinib.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving selumetinib. It is recommended that a pregnancy test should be performed on women of childbearing potential prior to initiating treatment.

Both male and female patients (of reproductive potential) should be advised to use effective contraception during and for at least 1 week after completion of treatment with selumetinib. It cannot be excluded that selumetinib may reduce the effectiveness of oral contraceptives, therefore women using hormonal contraceptives should be recommended to add a barrier method.

Fertility

There are no data on the effect of selumetinib on human fertility. Selumetinib had no impact on fertility and mating performance in male and female mice, although a reduction in embryonic survival was observed in female mice.

Selumetinib may have a minor influence on the ability to drive and use machines. Fatigue, asthenia and visual disturbances have been reported during treatment with selumetinib and patients who experience these symptoms should observe caution when driving or using machines.

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. The safety of selumetinib monotherapy in adult patients has been evaluated in 137 adult patients with NF1 and inoperable PN (25 mg/m² twice daily, capsules) from Phase III KOMET study.

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. The median total duration of selumetinib treatment in NF1-PN adult patients was about 12 months (range: <1 – 32 months). Of these patients 50.4% of patients were exposed to selumetinib treatment for <12 months and remaining 49.6% patients were exposed to selumetinib for >12 months.

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%).

In the NF1-PN adult patients, the most common adverse reactions of any grade (incidence ≥20%) were acneiform rashes (55%), blood creatine phosphokinase increased (37%), diarrhoea (30%), non- acneiform rashes (27%) and vomiting (20%). A total of 25.5% patients had adverse reactions leading to dose modification of selumetinib (either dose interruptions or reductions). The adverse drug reaction (ADR) leading to dose modification (incidence ≥5%) of selumetinib was blood creatine phosphokinase increased (5.8%). The adverse reactions leading to treatment discontinuation were reported in 1.5% patients.

The safety profile was also substantiated by a pool of safety data from 7 clinical studies in adult patients with multiple tumour types (N=347) who received 75 to 100 mg of selumetinib twice daily.

Tabulated list of adverse reactions

Table 5 presents the adverse reactions identified in the paediatric and adult population with NF1 who have inoperable PN and also in adult patients with multiple tumour types (see footnote to table). The frequency is determined from the paediatric pool and adult patients (N=74 and N=137, respectively) as defined above. 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.

Adverse drug reactions reported in the selumetinib NF1-PN studies and in other identified clinical trials in adult patients with multiple tumour types:

^a NF1-PN Paediatric Pool data (N=74) is pooled from SPRINT Phase I (N=24), SPRINT Phase II, Stratum 1 (N=50). Frequency percentage numbers are rounded to the nearest full number.
^b NF1-PN adult patients data is from KOMET study (N=137). Frequency percentage numbers are rounded to the nearest full number.
^c Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), all studies used CTCAE v5.0, except for SPRINT paediatric study which used CTCAE v4.03.
^d All events were CTCAE grade 3, except for one CTCAE grade 4 event of blood CPK increased and one CTCAE grade 4 event of blood creatinine increased. There were no deaths.
^e All events were CTCAE grade 3, except for one CTCAE grade 4 event of pyrexia and four CTCAE grade 4 events of blood CPK increased. There were no deaths.
^f In the SPRINT study, all lab abnormalities were reported as AEs. In other studies included in the NF1-PN paediatric and adult patients, lab abnormalities were only reported as AEs when they met SAE criteria, resulted in discontinuation, or were clinically relevant as judged by the investigator.
CPK = creatine phosphokinase; AST = aspartate aminotransferase; ALT = alanine aminotransferase
^ See Description of selected adverse reactions
^†† Identified ADRs from other clinical trial experience in adult patients (N=347), with multiple tumour types, receiving treatment with selumetinib (75 mg twice daily). These ADRs have not been reported in paediatric or adult population with NF1 who have inoperable PN.
^* ADRs based on grouping of individual Preferred Terms (PT):
Asthenic events: fatigue, asthenia
Blood albumin decreased: hypoalbuminaemia, blood albumin decreased
CSR/RPED: detachment of macular retinal pigment epithelium, chorioretinopathy
Dyspnoea: dyspnoea exertional, dyspnoea, dyspnoea at rest
Facial oedema: periorbital oedema, face oedema ($ grouping for paediatric pool only)
Facial oedema: periorbital oedema, face oedema, lip swelling, eyelid oedema, swelling face (₤ grouping for KOMET study only)
Haemoglobin decreased: anaemia, haemoglobin decreased
Hair changes: alopecia, hair colour change
Increased blood pressure: blood pressure increased, hypertension
Peripheral oedema: oedema peripheral, oedema, localised oedema, peripheral swelling
Rashes (acneiform): dermatitis acneiform, acne, folliculitis
Rashes (non-acneiform): rash pruritic, rash maculo-papular, rash papular, rash, rash erythematous, rash macular
RVO: retinal vascular disorder, retinal vein occlusion, retinal vein thrombosis
Stomatitis: stomatitis, mouth ulceration ($ grouping for paediatric pool only)
Stomatitis: stomatitis, mouth ulceration, aphthous ulcer, gingival swelling (₤ grouping for KOMET study only)

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 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 reactions were reported as reductions from baseline (≥10% reduction) but were considered to remain in the normal range.

In the NF1-PN adult patients (N=137), LVEF reduction (PT: ejection fraction decreased) was reported in 10 (7%) patients; among them, in 1 (0.7%) patient, the reported ADR was CTCAE grade 3. In 2 (1.5%) patients, LVEF decrease led to dose interruption. At the time of analysis, 7 of the 10 patients had recovered. The median time to first occurrence of LVEF reduction was 342 days (approximately 11 months) [median duration 112.5 days (approximately 4 months)].

Patients with LVEF lower than the institutional LLN at baseline were not included in the pivotal studies. 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.

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.

In the NF1-PN adult patients (N=137), CTCAE grade 1 event of blurred vision was reported in 5 (4%) patients. One patient (0.7%) required dose interruption. All events were managed without dose reduction and at the time of analysis, all 5 patients had recovered.

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.

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.

In the NF1-PN adult patients (N=137), paronychia was reported in 23 (17%) patients. The median time to first onset of maximum grade paronychia was 390 days (approximately 13 months) and the median duration of the maximum grade event was 63 days (approximately 2 months). Nineteen (13.9%) patients had a maximum CTCAE grade of 1 or 2. Grade 3 events occurred in 4 (3%) patients. One patient (0.7%) required dose interruption for adverse event of paronychia, and 3 patients (2.2%) had an event of paronychia that led to dose reduction. Paronychia did not lead to dose discontinuation in any of the patients. At the time of analysis, 11 of the 23 patients had recovered.

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.

In the NF1-PN adult patients (N=137), ADRs of blood CPK increase occurred in 51 (37%) patients. The median time to first onset of the maximum CTCAE grade blood CPK increase was 167 days (approximately 6 months), and the median duration of maximum grade event was 122 days (approximately 4 months). Forty-two patients (30.7%) had maximum CTCAE grade of 1 or 2. A maximum CTCAE grade 3 events occurred in 5 (3.6%) patients, and CTCAE grade 4 events occurred in 4 (2.9%) patients. Six patients had an event of blood CPK increase that led to dose interruptions and dose reduction was required in 3 patients. At the time of analysis, 21 of the 51 patients had recovered.

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 interruptionsor 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.

In the NF1-PN adult patients (N=137), diarrhoea (41 patients, 30%), vomiting (27 patients, 20%), nausea (23 patients, 17%), stomatitis (19 patients, 14%), and constipation (13 patients, 10%) were the most reported gastrointestinal (GI) events. Most of these events were CTCAE grade 1 or 2. In 1 patient (0.7%), CTCAE grade 3 event was reported for stomatitis. Dose interruption was required in 2 patients (1.5%) each with nausea and vomiting, and in 1 patient (0.7%) each with diarrhoea and stomatitis. Dose reduction occurred in 1 patient (0.7%) each with an ADR of nausea and stomatitis. One patient reported an event of nausea that led to treatment discontinuation.

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.

In the NF1-PN adult patients (N=137), acneiform rashes were observed in 75 (55%) patients [median time to onset 19 days; median duration of 124 days (approximately 4 months) for the maximum CTCAE grade event]. Seventy-two (53%) patients reported ADRs with maximum CTCAE grade 1 or 2. CTCAE grade 3 events were reported in 3 (2.2%) patients. In 3 patients (2.2%) acneiform rashes led to dose interruption, and in 2 patients (1.5%) each acneiform rashes led to dose reduction and dose discontinuation. Rashes (non-acneiform) were observed in 37 (27%) patients and were predominantly (36 patients, 26.3%) CTCAE 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.

In the NF1-PN adult patients (N=137), 24 (18%) patients experienced hair changes adverse event [reported as (PT: hair colour changes) in 6 (4.4%) patients and hair thinning (PT: alopecia) in 20 (14.6%) patients]. All cases were CTCAE grade 1 or 2. Dose interruption was reported in 1 (0.7%) patient and dose reduction in 2 (1.5%) patients.