4.1. Therapeutic indications

Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1) aged 1 year to less than 7 years and for older patients with swallowing difficulties.

4.2. Posology and method of administration

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 granules is equivalent to 25 mg/m2 of body surface area (BSA), taken twice daily (approximately every 12 hours).

Dosing in adult and paediatric patients is individualised based on BSA (mg/m2) and rounded to the nearest achievable 2.5 mg, 5 mg or 10 mg dose (up to a maximum single dose of 50 mg). Different strengths of Koselugo granules can be combined to attain the desired dose (Table 1).

Table 1. Recommended granules dose based on body surface area

Body surface area (BSA) a

Recommended dose

0.40 – 0.49 b m2

10 mg twice daily

0.50 – 0.59 m2

12.5 mg twice daily

0.60 – 0.69 m2

15 mg twice daily

0.70 – 0.89 c m2

20 mg twice daily

0.90 – 1.09 m2

25 mg twice daily

1.10 – 1.29 d m2

30 mg twice daily

1.30 – 1.49 m2

35 mg twice daily

1.50 – 1.69 m2

40 mg twice daily

1.70 – 1.89 m2

45 mg twice daily

≥ 1.90 m2

50 mg twice daily

a The recommended granules dose for patients with a BSA less than 0.40 m2 has not been established.

b A gradual increase from an initial dose of 10 mg to 12.5 mg twice daily may be implemented for patients who tolerate the 10 mg twice-daily dose, with consideration given to safety.

c For patients with a BSA 0.70 m2 and above, dosing recommendations for granules are in line with dosing recommendations for capsules.

d If a patient is unable to transition to capsules when they attain a BSA ≥ 1.29 m2 patients can continue to receive the granules.

Treatment with Koselugo should continue as long as clinical benefit is observed, or until PN progression or the development of unacceptable toxicity.

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.

Dose adjustments

Interruption and/or dose reduction or permanent discontinuation of selumetinib may be required based on individual safety and tolerability (see sections 4.4 and 4.8). Recommended dose reductions for the granules are given in Table 2.

Table 2. Recommended granules dose reductions for adverse reactions

Body surface area (BSA)

Initial dose a

(mg/twice daily)

First dose reduction

(mg/dose)

Second dose reduction

(mg/dose) b

Morning

Evening

Morning

Evening

0.40 – 0.49 m2

10

7.5

7.5

5

5

0.50 – 0.59 m2

12.5

10

10

7.5

7.5

0.60 – 0.69 m2

15.0

12.5

12.5

10

10

0.70 – 0.89 m2

20

15

15

12.5

12.5

0.90 – 1.09 m2

25

20

20

15

15

1.10 – 1.29 c m2

30

22.5

22.5

15

15

1.30 – 1.49 m2

35

25

25

25

10

1.50 – 1.69 m2

40

30

30

25

20

1.70 – 1.89 m2

45

35

30

25

20

≥ 1.90 m2

50

35

35

25

25

a Based on BSA as shown in Table 1.

b Permanently discontinue Koselugo in patients unable to tolerate Koselugo after two dose reductions.

c If a patient is unable to transition to capsules when they attain a BSA ≥1.29 m2 patients can continue to receive the granules.

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, and 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).

In patients who develop symptomatic LVEF reduction or a grade 3 or 4 LVEF reduction, selumetinib should be discontinued and a prompt cardiology referral should be carried out (see section 4.4).

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. In patients who are diagnosed with retinal vein occlusion (RVO), treatment with selumetinib should be permanently discontinued (see section 4.4).

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 dose equivalent to 25 mg/m2 twice daily, dose reduce to 20 mg/m2 twice daily.

• If a patient is currently taking dose equivalent to 20 mg/m2 twice daily, dose reduce to 15 mg/m2 twice daily (see Table 4 and section 4.5).

Table 4. Recommended granules dose to achieve 20 mg/m2 or 15 mg/m2 twice daily dose level

Body surface area

20 mg/m2 twice daily (mg/dose)

15 mg/m2 twice daily (mg/dose)

Morning

Evening

Morning

Evening

0.40 – 0.49 m2

7.5

7.5

7.5

5

0.50 – 0.59 m2

10

10

7.5

7.5

0.60 – 0.69 m2

12.5

12.5

10

7.5

0.70 – 0.89 m2

15

15

10

10

0.90 – 1.09 m2

20

20

15

15

1.10 – 1.29 m2

25

25

25

10

1.30 – 1.49 m2

30

25

25

20

1.50 – 1.69 m2

35

30

25

25

1.70 – 1.89 m2

35

35

30

25

≥ 1.90 m2

40

40

30

30

Special populations

Renal impairment

Based on clinical studies no dose adjustment is recommended in patients with mild, moderate, severe renal impairment or those with end stage renal disease (ESRD) (see section 5.2).

Hepatic impairment

Based on clinical studies, no dose adjustment is recommended in patients with mild hepatic impairment. The starting dose should be reduced in patients with moderate hepatic impairment to 20 mg/m2 BSA, twice daily (see Table 4). Koselugo is contraindicated for use in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Ethnicity

Increased systemic exposure has been seen in adult Asian subjects, although there is considerable overlap with Western subjects when corrected for body weight. No specific adjustment to the starting dose is recommended for Asian patients, however these patients should be closely monitored for adverse events (see section 5.2).

Paediatric population

The safety of Koselugo granules in children less than 1 year of age has not been established. No data are available.

Method of administration

Koselugo granules in capsule for opening is for oral use.

Koselugo granules must be administered by carefully opening the capsules and sprinkling the entire contents on a small amount (approximately 1 to 3 teaspoons) of soft food (e.g. smooth yogurt, fruit sauce, fruit puree or fruit jam). The granules must not be mixed in water, milk, vegetable puree, grapefruit or any juice, fruit puree or jam containing Seville orange (bitter orange).

This medicinal product dispensed on or mixed with food must be swallowed within 30 minutes and must not be stored for future use.

The empty capsule shells of Koselugo must be discarded after use. They should not be swallowed, chewed, or dissolved.

Detailed pictograms on how to administer the granules are provided in the package leaflet.

Koselugo is also available as capsules. Paediatric patients from 3 years of age who are able to swallow capsules may be prescribed appropriate doses of Koselugo capsules (see SmPC for Koselugo Capsules).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe hepatic impairment (see sections 4.2 and 5.2).

4.4. Special warnings and precautions for use

Left ventricular ejection fraction (LVEF) reduction

In the SPRINT clinical study, 26% of paediatric patients experienced asymptomatic decreases in ejection fraction, with a median onset time of 232 days. LVEF reduction have been reported in both paediatric and adult patients. A small number of serious reports of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program (see section 4.8).

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. Reduction in LVEF can be managed using treatment interruption, dose reduction or treatment discontinuation (see section 4.2).

Ocular toxicity

Patients should be advised to report any new visual disturbances. Adverse reactions of blurred vision have been reported in patients receiving selumetinib. Isolated cases of RPED, CSR and RVO in adult patients with multiple tumour types, receiving treatment with selumetinib monotherapy and in combination with other anti-cancer agents, and in a single paediatric patient with pilocytic astrocytoma on selumetinib monotherapy, have been observed (see section 4.8).

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. If RPED or CSR is diagnosed and visual acuity is affected, selumetinib therapy should be interrupted and the dose reduced when treatment is resumed (see section 4.2). If RVO is diagnosed, treatment with selumetinib should be permanently discontinued (see section 4.2).

Liver laboratory abnormalities

Liver laboratory abnormalities, specifically AST and ALT elevations, can occur with selumetinib (see section 4.8). 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. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see Table 2 in section 4.2).

Skin and subcutaneous disorders

Skin rash (including maculopapular rash and acneiform rash), paronychia and hair changes have been reported very commonly in the pivotal clinical studies (see section 4.8). 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) in the SPRINT clinical study.

Women of child bearing potential

Koselugo is not recommended in women of child bearing potential who are not using contraception (see section 4.6).

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in healthy adults (aged ≥ 18 years).

Active substances that may increase selumetinib plasma concentrations

Co-administration with a strong CYP3A4 inhibitor (200 mg itraconazole twice daily for 4 days) increased selumetinib Cmax by 19% (90% CI 4, 35) and AUC by 49% (90% CI 40, 59) in healthy adult subjects.

Co-administration with a strong CYP2C19/moderate CYP3A4 inhibitor (200 mg fluconazole once daily for 4 days) increased selumetinib Cmax by 26% (90% CI 10, 43) and AUC by 53% (90% CI 44, 63) in healthy adult subjects, respectively.

Concomitant use of erythromycin (moderate CYP3A4 inhibitor) or fluoxetine (strong CYP2C19/CYP2D6 inhibitor) is predicted to increase selumetinib AUC by ~30-40% and Cmax by ~20%.

Co-administration with strong inhibitors of CYP3A4 (e.g., clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (e.g., ticlopidine) should be avoided. Co‑administration with moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) and CYP2C19 (e.g., omeprazole) should be avoided.

If co‑administration is unavoidable, patients should be carefully monitored for adverse events and the selumetinib dose should be reduced (see section 4.2 and Table 4).

Active substances that may decrease selumetinib plasma concentrations

Co-administration with a strong CYP3A4 inducer (600 mg rifampicin daily for 8 days) decreased selumetinib Cmax 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 Koselugo should be avoided.

Active substances whose plasma concentrations may be altered by 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 (see section 5.2).

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 (see section 4.6).

Effect of gastric acid reducing agents on selumetinib

Selumetinib granules do not exhibit pH dependent dissolution. Koselugo can be used concomitantly with gastric pH modifying agents (i.e., H2‑receptor antagonists and proton pump inhibitors) without restrictions, except for omeprazole which is a CYP2C19 inhibitor.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Koselugo. 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 Koselugo. 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 (see section 4.5).

Pregnancy

There are no data on the use of selumetinib in pregnant women. Studies in animals have shown reproductive toxicity including embryo-foetal death, structural defects and reduced foetal weights (see section 5.3). Koselugo is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 4.4).

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

Breast-feeding

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 (see section 5.3). A risk to the breast-fed child cannot be excluded, therefore breast-feeding should be discontinued during treatment with Koselugo.

Fertility

There are no data on the effect of Koselugo 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 (see section 5.3).

4.7. Effects on ability to drive and use machines

Koselugo 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.

4.8. Undesirable effects

Summary of the safety profile

The safety of selumetinib monotherapy has been evaluated in a pooled safety population of 126 paediatric patients (20-30 mg/m2 twice daily, capsules) from 4 studies with NF1 and inoperable PN [(NF1-PN Paediatric Pool, which includes safety data from SPRINT Phase I (N=24), SPRINT Phase II, Stratum 1 (N=50), China Phase I study; paediatric cohort (N=16), Japan Phase I study (N=12), and Phase I Food effect study (Study 15, N=24)].

In addition, the safety of selumetinib for the granule formulation was evaluated in 36 paediatric patients (dose equivalent to 25 mg/m2 twice daily, granules) with NF1 and symptomatic inoperable PN from the Phase I/II SPRINKLE study.

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.

The median total duration of selumetinib treatment in NF1-PN Paediatric Pool was 27 months (range: < 1– 97 months), 57% of patients were exposed to selumetinib treatment for > 24 months and 40% for > 36 months. 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 NF1-PN Paediatric pool, the most common adverse reactions of any grade (incidence ≥ 40%) were vomiting (62%), acneiform rashes (60%), diarrhoea (56%), blood creatine phosphokinase increased (54%), nausea (52%), paronychia (50%), and dry skin and pyrexia (44% each). Adverse events leading to dose interruptions and reductions were reported in 61.9% and 27.8% of patients, respectively. A total of 47.6% patients had ADRs leading to dose modification of selumetinib (either dose interruptions or reductions). The ADRs leading to dose modification (incidence ≥ 5%) of selumetinib were vomiting (19.8%), paronychia (15.9%), nausea (11.1%), diarrhea (8.7%), pyrexia (6.3%), and rashes (acneiform and non-acneiform; 5.6% each). Any ADRs leading to treatment discontinuation were reported in 4.8% patients.

In the SPRINKLE study, at the time of first data cut-off (DCO1), the median total duration of selumetinib treatment was 11 months (range: < 3 – < 26 months). Thirty-six paediatric patients were treated with selumetinib granules equivalent to 25 mg/m2 twice daily. The most common adverse reactions of any grade (incidence ≥ 40%) were pyrexia and dry skin (47% patients each); and paronychia (44%). Adverse events leading to dose interruptions were reported in 30.6% of patients, while no patients had AEs leading to dose reductions. A total 22.2% patients had ADRs leading to dose modification (either dose interruptions or reductions). The ADRs leading to dose modification (incidence ≥ 5%) were vomiting and pyrexia (11.1% patients each), and diarrhea (5.6%). No patient had ADRs that led to treatment discontinuation.

The observed safety profile of selumetinib granules in the SPRINKLE study was comparable with pooled safety data in paediatric patients treated with selumetinib capsules (NF1-PN Paediatric Pool).

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 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 5). The frequency is determined from the paediatric pool (N = 126) and adult patients (N = 137) 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.

Table 5. Adverse drug reactions reported in the selumetinib NF1-PN studies and in other identified clinical trials in adult patients with multiple tumour types

MedDRA SOC and MedDRA term

Paediatric Pool a

(N = 126)

KOMET Study b

(N = 137)

Overall Frequency

(All CTCAE Grades) c

Frequency of CTCAE Grade 3 and above d

Overall Frequency

(All CTCAE Grades) c

Frequency of CTCAE Grade 3 and above e

Eye disorders

Vision blurred ^

Common (9%)

-

Common (4%)

-

Retinal pigment epithelial detachment (RPED)/ Central serous retinopathy (CSR) * ††

-

-

Uncommon (0.6%)

-

Retinal vein occlusion (RVO) * ††

-

-

Uncommon (0.3%)

-

Respiratory, thoracic and mediastinal disorders

Dyspnoea *

Common (6%)

-

Common (3%)

Common (1%)

Gastrointestinal disorders

Vomiting ^

Very common (62%)

Common (7%)

Very common (20%)

-

Diarrhoea ^

Very common (56%)

Very common (10%)

Very common (30%)

-

Nausea ^

Very common (52%)

Common (2%)

Very common (17%)

-

Stomatitis ^*

Very common (40%)

Common (1%)

Very common (14%)

Common (1%)

Constipation

-

-

Very common (10%)

-

Dry mouth

Common (4%)

-

Common (6%)

-

Skin and subcutaneous tissue disorders

Rashes (acneiform) ^*

Very common (60%)

Common (2%)

Very common (55%)

Common (2%)

Paronychia ^

Very common (50%)

Very common (10%)

Very common (17%)

Common (3%)

Dry skin

Very common (44%)

Common (1%)

Very common (13%)

-

Rashes (non-acneiform) ^*

Very common (39%)

Common (2%)

Very common (27%)

Common (1%)

Hair changes ^*

Very common (29%)

-

Very common (18%)

-

General disorders

Pyrexia

Very common (44%)

Common (5%)

Common (5%)

Common (1%)

Asthenic events *

Very common (37%)

-

Very common (15%)

-

Peripheral oedema *

Very common (18%)

-

Very common (16%)

-

Facial oedema *

Common (8%)

-

Common (4%)

-

Investigations f

Blood CPK increased ^

Very common (54%)

Common (6%)

Very common (37%)

Common (7%)

AST increased

Very common (37%)

Common (2%)

Very common (12%)

Common (1%)

Haemoglobin decreased *

Very common (35%)

Common (2%)

Very common (11%)

Common (2%)

Blood albumin decreased *

Very common (35%)

-

Common (2%)

-

ALT increased

Very common (29%)

Common (2%)

Very common (11%)

Common (1%)

Ejection fraction decreased ^

Very common (21%)

Common (1%)

Common (7%)

Common (1%)

Blood creatinine increased

Very common (19%)

Common (1%)

Common (2%)

-

Increased blood pressure *

Very common (11%)

-

Common (4%)

Common (2%)

a NF1-PN Paediatric Pool data (N = 126) is pooled from SPRINT Phase I (N = 24), SPRINT Phase II, Stratum 1 (N = 50), China Phase I study; paediatric cohort (N=16), Japan Phase I Study (N=12), and Phase I Food effect (N=24) studies. 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 two 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, lip swelling, eyelid oedema, swelling face

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, aphthous ulcer, gingival swelling

Description of selected adverse reactions

Left ventricular ejection fraction (LVEF) reduction

In the NF1-PN Paediatric Pool (N=126), LVEF reduction (PT: ejection fraction decreased) was reported in 26 (21%) patients; among them, in 25 (19.8%) patients, the reported ADRs were CTCAE grade 2, and in 1 (0.8%) patient, the ADR reported was CTCAE grade 3. In 4 (3.2%) patients, LVEF decrease led to dose reduction and in 2 (1.6%) patients, LVEF decrease led to dose interruption. At the time of analysis, of the 26 patients, 20 patients were recovered. The median time to first occurrence of LVEF reduction was 283 days (median duration 110.5 days).

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 (see sections 4.2 and 4.4).

Ocular toxicity

In the NF1-PN Paediatric Pool (N=126), CTCAE grade 1 and 2 events of blurred vision were reported in 11 (9%) patients. Two patients (1.6%) required dose interruption. At the time of analysis, of the 11 patients, 10 patients were recovered.

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.

For clinical management of new visual disturbances (see sections 4.2 and 4.4).

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 sections 4.2 and 4.4).

Paronychia

In the NF1-PN Paediatric Pool (N=126), paronychia was reported in 63 (50%) patients. The median time to first onset of maximum grade paronychia adverse event was 375 days (approximately 12 months) and the median duration of events was 55 days (approximately 2 months). The majority (51 patients, 40.5% the NF1-PN Paediatric Pool) had a maximum CTCAE grade of 1 or 2. Grade ≥ 3 events occurred in 12 (10%) patients. Eighteen patients (14.3%) required dose interruption for adverse event of paronychia, and 9 patients (7.1%) had an AE of paronychia that led to dose reduction. In one patient (0.8%) the event led to treatment 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

ADRs of blood CPK elevation occurred in 68 (54%) patients in the NF1-PN Paediatric Pool (N=126). The median time to first onset of the maximum CTCAE grade CPK increase was 112 days (approximately 4 months) and the median duration of the maximum CTCAE grade event was 126 days (approximately 4 months). The majority (61 cases, 48.4% of the NF1-PN Paediatric Pool) had maximum CTCAE grade event that was grade 1 or 2. A maximum CTCAE grade 3 events occurred in 5 (4%) patients, and CTCAE grade 4 event occurred in 2 (1.6%) patients. Five patients had an AE of blood CPK increase that led to treatment interruptions and required 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 the NF1-PN Paediatric Pool (N=126), vomiting (78 patients, 62%), diarrhoea (71 patients, 56%), nausea (66 patients, 52%), and stomatitis (50 patients, 40%) were the most commonly reported gastrointestinal (GI) events. The majority of these cases were CTCAE grade 1 or 2. CTCAE grade ≥ 3 events were reported for diarrhoea (10%), vomiting (7%), nausea (2%) and stomatitis (1%). Dose modification was required in 25 (19.8%) patients with vomiting, 14 (11.1%) with nausea, 11 (8.7%) with diarrhoea, and 6 (4.8%) with stomatitis. One patient each reported an event of diarrhoea, nausea and stomatitis led to treatment discontinuation. Dose reduction had occurred in one patient with AE of diarrhoea and in 2 patients with AE of stomatitis. No CTCAE grade ≥ 4 events were reported.

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 the NF1-PN Paediatric Pool (N=126), acneiform rashes were observed in 76 (60%) patients [median time to onset 29 days; median duration of 176 days (approximately 6 months) for the maximum CTCAE grade event]. The majority (73 patients, 58% of the NF1-PN Paediatric Pool) of these reported ADRs with maximum CTCAE were grade 1 or 2. In 4 patients (3.2%), acneiform rashes led to dose interruption and 3 patients (2.4%) acneiform rashes led to dose reduction. CTCAE grade 3 events were reported in 3 (2.4%) patients. Other (non-acneiform) rashes were observed in 49 (39%) patients in the NF1-PN Paediatric Pool and were predominantly (46 patients, 36.5% of the NF1-PN Paediatric Pool) CTCAE 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 the NF1-PN Paediatric Pool (N=126), 37 (29%) patients experienced hair changes adverse event (reported as [PT: hair colour changes] in 21 patients (16.7%) and hair thinning [PT: alopecia] in 30 patients (23.8%)). All cases were CTCAE grade 1 (33 patients, 26.2%) or 2 (4 patients, 3.2%) and dose interruption was reported in 1 (0.8%) patient.

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.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific treatment for overdose. If overdose occurs, patients should be closely monitored for signs and symptoms of adverse reactions and treated supportively with appropriate monitoring as necessary. Dialysis is ineffective in the treatment of overdose.