KOSELUGO 25mg capsules medication leaflet

Koselugo 10 mg hard capsules

Koselugo 25 mg hard capsules

Koselugo 10 mg hard capsules

Each hard capsule contains 10 mg of selumetinib (as hydrogen sulfate).

Koselugo 25 mg hard capsules

Each hard capsule contains 25 mg of selumetinib (as hydrogen sulfate).

For the full list of excipients, see section 6.1.

Hard capsule.

Koselugo 10 mg hard capsules

White to off-white, opaque, size 4 (approximately 14 mm x 5 mm), hard capsule, which has a centreband and is marked with “SEL 10” in black ink.

Koselugo 25 mg hard capsules

Blue, opaque, size 4 (approximately 14 mm x 5 mm), hard capsule, which has a centre band and ismarked with “SEL 25” in black ink.

Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiformneurofibromas (PN) in paediatric patients with neurofibromatosis type 1 (NF1) aged 3 years andabove.

Treatment with Koselugo should be initiated by a physician experienced in the diagnosis and thetreatment of patients with NF1 related tumours.

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 mgdose (up to a maximum single dose of 50 mg). Different strengths of Koselugo capsules can becombined to attain the desired dose (Table 1).

Table 1. Recommended dose based on body surface area

Body surface area (BSA) a Recommended dose0.55 - 0.69 m2 20 mg in the morning and 10 mg in the evening0.70 - 0.89 m2 20 mg twice daily0.90 - 1.09 m2 25 mg twice daily1.10 - 1.29 m2 30 mg twice daily1.30 - 1.49 m2 35 mg twice daily1.50 - 1.69 m2 40 mg twice daily1.70 - 1.89 m2 45 mg twice daily≥ 1.90 m2 50 mg twice dailya The recommended dose for patients with a BSA less than 0.55 m2 has not been established.

Treatment with Koselugo should continue as long as clinical benefit is observed, or until PNprogression or the development of unacceptable toxicity. There is limited data in patients olderthan 18, therefore continued treatment into adulthood should be based on benefits and risks to theindividual patient as assessed by the physician. However, start of treatment with Koselugo in adults isnot appropriate.

If a dose of Koselugo is missed, it should only be taken if it is more than 6 hours until the nextscheduled dose.

If vomiting occurs after Koselugo is administered, an additional dose is not to be taken. The patientshould continue with the next scheduled dose.

Interruption and/or dose reduction or permanent discontinuation of selumetinib may be required basedon individual safety and tolerability (see sections 4.4 and 4.8). Recommended dose reductions aregiven in Table 2 and may require the daily dose to be divided into two administrations of differentstrength or for treatment to be given as a once daily dose.

Table 2. Recommended dose reductions for adverse reactions

Body surface area Initial Koselugo First dose reduction Second dose reduction(BSA) dosea (mg/dose) (mg/dose)b(mg/twice daily) Morning Evening Morning Evening20 mg in the0.55 - 0.69 m2 morning and 10 mg 10 10 10 mg once dailyin the evening0.70 - 0.89 m2 20 20 10 10 100.90 - 1.09 m2 25 25 10 10 101.10 - 1.29 m2 30 25 20 20 101.30 - 1.49 m2 35 25 25 25 101.50 - 1.69 m2 40 30 30 25 201.70 - 1.89 m2 45 35 30 25 20≥ 1.90 m2 50 35 35 25 25a 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 productare presented in Table 3.

Table 3. Recommended dose modifications for adverse reactions

CTCAE Grade* Recommended dose modification

Grade 1 or 2 (tolerable Continue treatment and monitor as clinically indicated- can be managed withsupportive care)

Grade 2 (intolerable - Interrupt treatment until toxicity is grade 0 or 1 and reduce by one dosecannot be managed with level when resuming therapy (see Table 2)supportive care) or

Grade 3

Grade 4 Interrupt treatment until toxicity is grade 0 or 1, reduce by one dose levelwhen 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 theinstitutional 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, selumetinibshould 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 epithelialdetachment (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 every3 weeks until resolution. In patients who are diagnosed with retinal vein occlusion (RVO), treatmentwith 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 andalternative agents should be considered. If a strong or moderate CYP3A4 or CYP2C19 inhibitor mustbe 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.

- If a patient is currently taking 20 mg/m2 twice daily, dose reduce to 15 mg/m2 twice daily (see

Table 4 and section 4.5).

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

Body surface 20 mg/m twice daily (mg/dose) 15 mg/m2 twice daily (mg/dose)area Morning Evening Morning Evening0.55 - 0.69 m2 10 10 10 mg once daily0.70 - 0.89 m2 20 10 10 100.90 - 1.09 m2 20 20 20 101.10 - 1.29 m2 25 25 25 101.30 - 1.49 m2 30 25 25 201.50 - 1.69 m2 35 30 25 251.70 - 1.89 m2 35 35 30 25≥ 1.90 m2 40 40 30 30

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

Based on clinical trials, 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 hepaticimpairment (see sections 4.3 and 5.2).

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

The safety and efficacy of Koselugo in children less than 3 years of age has not been established. Nodata are available.

Koselugo is for oral use. It can be taken with or without food (see section 5.2).

The capsules should be swallowed whole with water. The capsules should not be chewed, dissolved,or opened, because this could impair drug release and affect the absorption of selumetinib.

Koselugo should not be administered to patients who are unable or unwilling to swallow the capsulewhole. Patients should be assessed for their ability to swallow a capsule before starting treatment.

Standard medicine swallowing techniques are expected to be sufficient to swallow selumetinibcapsules. For patients who have difficulties swallowing the capsule, referral to an appropriate healthcare professional such as a speech and language therapist could be considered to identify suitablemethods that can be tailored to the particular patient.

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).

Left ventricular ejection fraction (LVEF) reduction

Asymptomatic decreases in ejection fraction have been reported in 26% of paediatric patients in thepivotal clinical trial. Median time to initial onset of these adverse reactions was 232 days. A smallnumber of serious reports of LVEF reduction associated with selumetinib have been reported inpaediatric patients who participated in an expanded access program (see section 4.8).

Paediatric patients with a history of impaired left ventricular function or a baseline LVEF belowinstitutional LLN have not been studied. LVEF should be evaluated by echocardiogram beforeinitiation of treatment to establish baseline values. Prior to starting selumetinib treatment, patientsshould have an ejection fraction above the institutional LLN.

LVEF should be evaluated at approximately 3-month intervals, or more frequently as clinicallyindicated, during treatment. Reduction in LVEF can be managed using treatment interruption, dosereduction or treatment discontinuation (see section 4.2).

Ocular toxicity

Patients should be advised to report any new visual disturbances. Adverse reactions of blurred visionhave been reported in paediatric patients receiving selumetinib. Isolated cases of RPED, CSR and

RVO in adult patients with multiple tumour types, receiving treatment with selumetinib monotherapyand in combination with other anti-cancer agents, and in a single paediatric patient with pilocyticastrocytoma on selumetinib monotherapy, have been observed (see section 4.8).

In line with clinical practice an ophthalmological evaluation prior to treatment initiation and at anytime 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 untilresolution. If RPED or CSR is diagnosed and visual acuity is affected, selumetinib therapy should beinterrupted 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, specifically AST and ALT elevations, can occur with selumetinib (seesection 4.8). Liver laboratory values should be monitored before initiation of selumetinib and at leastmonthly during the first 6 months of treatment, and thereafter as clinically indicated. Liver laboratoryabnormalities 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 beenreported very commonly in the pivotal clinical study (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).

Vitamin E supplementation

Patients should be advised not to take any supplemental vitamin E. Koselugo 10 mg capsules contain32 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. High doses of vitamin E may increasethe risk of bleeding in patients taking concomitant anticoagulant or antiplatelet medicinal products(e.g., warfarin or acetylsalicylic acid). Anticoagulant assessments, including international normalisedratio or prothrombin time, should be conducted more frequently to detect when dose adjustments ofthe anticoagulant or antiplatelet medicinal products are warranted (see section 4.5).

Risk of choking

Selumetinib is available as a capsule which must be swallowed whole. Some patients, in particularchildren < 6 years of age, may be at risk of choking on a capsule formulation due to developmental,anatomical or psychological reasons. Therefore, selumetinib should not be administered to patientswho are unable or unwilling to swallow the capsule whole (see section 4.2).

Women of child bearing potential

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

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 adultsubjects.

Co-administration with a strong CYP2C19/moderate CYP3A4 inhibitor (200 mg fluconazole oncedaily 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, oralketoconazole) or CYP2C19 (e.g., ticlopidine) should be avoided. Co-administration with moderateinhibitors of CYP3A4 (e.g., erythromycin and fluconazole) and CYP2C19 (e.g., omeprazole) shouldbe avoided.

If co-administration is unavoidable, patients should be carefully monitored for adverse events and theselumetinib 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) decreasedselumetinib 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 thepharmacokinetics of concomitantly administered substrates of OAT3 (e.g., methotrexate andfurosemide) cannot be excluded (see section 5.2).

TPGS is a P-gp inhibitor in vitro and it cannot be excluded that it may cause clinically relevant druginteractions with substrates of P-gp (e.g., digoxin or fexofenadine).

The effect of selumetinib on the exposure of oral contraceptives has not been evaluated. Therefore, useof an additional barrier method should be recommended to women using hormonal contraceptives (seesection 4.6).

Effect of gastric acid reducing agents on selumetinib

Selumetinib capsules do not exhibit pH dependent dissolution. Koselugo can be used concomitantlywith gastric pH modifying agents (i.e., H2-receptor antagonists and proton pump inhibitors) withoutrestrictions, except for omeprazole which is a CYP2C19 inhibitor.

Vitamin E

Koselugo capsules contain vitamin E as the excipient TPGS. Therefore, patients should avoid takingsupplemental vitamin E and anticoagulant assessments should be performed more frequently inpatients taking concomitant anticoagulant or antiplatelet medicinal products (see section 4.4).

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 childbearingpotential prior to initiating treatment.

Both male and female patients (of reproductive potential) should be advised to use effectivecontraception during and for at least 1 week after completion of treatment with Koselugo. It cannot beexcluded that selumetinib may reduce the effectiveness of oral contraceptives, therefore women usinghormonal contraceptives should be recommended to add a barrier method (see section 4.5).

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

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

It is not known whether selumetinib, or its metabolites, are excreted in human milk. Selumetinib andits active metabolite are excreted in the milk of lactating mice (see section 5.3). A risk to the breast-fedchild cannot be excluded, therefore breast-feeding should be discontinued during treatment with

Koselugo.

There are no data on the effect of Koselugo on human fertility. Selumetinib had no impact on fertilityand mating performance in male and female mice, although a reduction in embryonic survival wasobserved in female mice (see section 5.3).

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

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 paediatricpatients (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) and24 patients in SPRINT Phase I treated with 20 to 30 mg/m2 selumetinib twice daily (the dose findingstudy). 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 from7 AstraZeneca sponsored studies in adult patients with multiple tumour types (N = 347) who received75 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 toselumetinib 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 patientsaged 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 commonadverse reactions of any grade (incidence ≥ 45%) were vomiting (86%), diarrhoea (81%), bloodcreatine phosphokinase increased (77%), nausea (77%), dry skin (65%), pyrexia (61%), dermatitisacneiform (61%), asthenic events (59%), paronychia (57%), stomatitis (55%), haemoglobin decreased(54%), non-acneiform rashes (53%), hypoalbuminaemia (51%), and aspartate aminotransferaseincreased (51%). Dose interruptions and reductions due to adverse events were reported in 82% and39% of patients, respectively. The most commonly reported ADRs leading to dose modification (doseinterrupted 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 in12% of the patients. The following serious adverse reactions were reported: diarrhoea (3%),anaemia (3%), pyrexia (3%), blood CPK increased (3%), blood creatinine increased (1%), oedemaperipheral (1%) and vomiting (1%).

Table 5 presents the adverse reactions identified in the paediatric population with NF1 who haveinoperable PN and in adult patients (see footnote to Table 5). The frequency is determined from thepaediatric pool (N = 74); comprising 50 patients from the pivotal SPRINT Phase II Stratum 1 datasetand 24 patients from the supportive SPRINT Phase I dataset. Adverse drug reactions (ADRs) areorganised by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged bydecreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adversereactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimatedfrom available data), including isolated reports.

Table 5. Adverse drug reactions reported in the paediatric pool (pivotal SPRINT Phase II

Stratum 1 [N = 50] and supportive SPRINT Phase I [N = 24]) and in other identified clinicaltrials in adult patients (N = 347)††

MedDRA SOC MedDRA Term Overall Frequency Frequency of CTCAE(All CTCAE grades) grade 3 and Above†

NF1 paediatric pool‡ NF1 paediatric pool‡(N = 74) (N = 74)

Eye disorders Vision blurred^ Very common (15%) -

Retinal pigment Uncommon (0.6%) -epithelial detachment(RPED)/ Centralserous retinopathy(CSR)* ††

Retinal vein Uncommon (0.3%) -occlusion (RVO)* ††

Respiratory, Dyspnoea* Common (8%) -thoracic &mediastinaldisorders

Gastrointestinal Vomiting^ Very common (86%) Common (9%)disorders Diarrhoea^ Very common (81%) Very common (15%)

Nausea^ Very common (77%) Common (3%)

MedDRA SOC MedDRA Term Overall Frequency Frequency of CTCAE(All CTCAE grades) grade 3 and Above†

NF1 paediatric pool‡ NF1 paediatric pool‡(N = 74) (N = 74)

Stomatitis^ Very common (55%) Common (1%)

Dry mouth Common (5%) -

Skin and Dry skin Very common (65%) Common (1%)subcutaneous tissuedisorders

Dermatitis Very common (61%) Common (4%)acneiform^

Paronychia^ Very common (57%) Very common (14%)

Rashes (non- Very common (53%) Common (3%)acneiform) ^ *

Hair changes^ * Very common (39%) -

General disorders Pyrexia Very common (61%) Common (8%)

Asthenic events* Very common (59%) -

Peripheral oedema* Very common (31%) -

Facial oedema* Common (8%) -

Investigations Blood CPK Very common (77%) Common (9%)increased^

Haemoglobin Very common (54%) Common (3%)decreased*

Hypoalbuminaemia Very common (51%) -

AST increased Very common (51%) Common (1%)

ALT increased Very common (39%) Common (3%)

Blood creatinine Very common (32%) Common (1%)increased

Ejection fraction Very common (28%) Common (1%)decreased^

Increased blood Very common (18%) -pressure*

Per National Cancer Institute CTCAE version 4.03

CPK = creatine phosphokinase; AST = aspartate aminotransferase; ALT = alanine aminotransferase^ See Description of selected adverse reactions† All reactions 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.†† 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 paediatricpopulation with NF1 who have inoperable PN.‡ Paediatric pool (N = 74) percentage rounded to the nearest decimal.

*ADRs based on grouping of individual preferred terms (PT):

Asthenic events: asthenia, fatigue

CSR/RPED: Detachment of macular retinal pigment epithelium, chorioretinopathy

Dyspnoea: dyspnoea exertional, dyspnoea, dyspnoea at rest

Facial oedema: face odema, periorbital oedema

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 (non-acneiform): rash pruritic, rash maculo-papular, rash papular, rash, rash erythematous, rashmacular

RVO: retinal vascular disorder, retinal vein occlusion, retinal vein thrombosis

Left ventricular ejection fraction (LVEF) reduction

In SPRINT, Phase II Stratum 1, LVEF reduction (PT: ejection fraction decreased) was reported in13 (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 for2 patients the outcome was not reported. The median time to first occurrence of LVEF reduction was232 days (median duration 252 days). The majority of LVEF reduction adverse reactions werereported as reductions from baseline (≥ 10% reduction) but were considered to remain in the normalrange. Patients with LVEF lower than the institutional LLN at baseline were not included in thepivotal study. In addition, a small number of serious cases of LVEF reduction associated withselumetinib 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 SPRINT, Phase II Stratum 1, grade 1 and 2 adverse reactions of blurred vision were reported in7 (14%) patients. Two patients required dose interruption. All adverse reactions were managedwithout dose reduction. 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 selumetinibmonotherapy (25 mg/m2 twice daily) for pilocytic astrocytoma involving the optic pathway in anexternally sponsored paediatric study (see sections 4.2 and 4.4).

Paronychia

In SPRINT, Phase II Stratum 1, paronychia was reported in 28 (56%) patients, the median time to firstonset of maximum grade paronychia adverse reaction was 423 days and the median duration ofadverse reactions was 51 days. The majority of these adverse reactions were grade 1 or 2 and weretreated with supportive or symptomatic therapy and/or dose modification. Grade ≥ 3 events occurredin 4 (8%) patients. Ten patients (3 with a maximum grade 3 adverse reaction and 7 with a maximumgrade 2 adverse reaction) had a selumetinib dose interruption for adverse reactions of paronychia, ofwhom 5 had dose interruption followed by dose reduction (2 patients required a second dosereduction). 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 themedian duration of adverse reactions was 153 days. The majority of adverse reactions were grade 1 or2 and resolved with no change in selumetinib dose. Grade ≥ 3 adverse reactions occurred in3 (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), andstomatitis (26 patients, 52%, median duration 27 days) were the most commonly reportedgastrointestinal (GI) reactions. The majority of these cases were grade 1 or 2 and did not require anydose interruptionsor dose reductions.

Grade 3 adverse reactions were reported for diarrhoea (8 patients, 16%), nausea (2 patients, 4%), andvomiting (4 patients, 8%). For one patient diarrhoea led to dose reduction and subsequentdiscontinuation. 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 timeto onset 43 days; median duration of 202 days for the maximum CTCAE grade event). The majority ofthese cases were grade 1 or 2, observed in post-pubertal patients (> 12 years) and did not require anydose 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 werepredominantly grade 1 or 2.

Hair changes

In SPRINT, Phase II Stratum 1, 16 (32%) of patients experienced hair changes (reported as hairlightening [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 duringtreatment. All cases were grade 1 and did not require dose interruption or dose reduction.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01EE04

Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK 1/2).

Selumetinib blocks MEK activity and the RAF-MEK-ERK pathway. Therefore, MEK inhibition canblock the proliferation and survival of tumour cells in which the RAF-MEK-ERK pathway isactivated.

The efficacy of Koselugo was evaluated in an open-label, multi-centre, single-arm study (SPRINT)

Phase II Stratum 1 of 50 paediatric patients with NF1 inoperable PN that caused significant morbidity.

Inoperable PN was defined as a PN that could not be surgically completely removed without risk forsubstantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, orhigh vascularity of the PN. Patients were excluded for the following ocular toxicities: any current orpast history of CSR, current or past history of RVO, known intraocular pressure > 21 mmHg (or upperlimit of normal adjusted by age) or uncontrolled glaucoma. Patients received 25 mg/m2 (BSA) twicedaily, for 28 days (1 treatment cycle), on a continuous dosing schedule. Treatment was discontinued ifa patient was no longer deriving clinical benefit, experienced unacceptable toxicity or PN progression,or at the discretion of the investigator.

The target PN, the PN that caused relevant clinical symptoms or complications (PN-relatedmorbidities), was evaluated for response rate using centrally read volumetric magnetic resonanceimaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis(REiNS) criteria. Tumour response was evaluated at baseline and while on treatment after every4 cycles for 2 years, and then every 6 cycles.

Patients had target PN MRI volumetric evaluations and clinical outcome assessments, which includedfunctional assessments and patient reported outcomes.

At enrolment, the median age of the patients was 10.2 years (range: 3.5 to 17.4 years), 60% were maleand 84% were Caucasian.

The median target PN volume at baseline was 487.5 mL (range: 5.6 - 3820 mL). PN-relatedmorbidities that were present in ≥ 20% of patients included disfigurement, motor dysfunction, pain,airway dysfunction, visual impairment, and bladder/bowel dysfunction.

The primary efficacy endpoint was objective response rate (ORR), defined as the percentage ofpatients with complete response (defined as disappearance of the target PN) or confirmed partialresponse (defined as ≥ 20% reduction in PN volume, confirmed at a subsequent tumour assessmentwithin 3-6 months), based on National Cancer Institute (NCI) centralised review. Duration of response(DoR) was also evaluated.

Efficacy results are provided based on a data cut-off of March 2021, unless stated otherwise.

Table 6. Efficacy results from SPRINT Phase II Stratum 1

Efficacy parameter SPRINT(N = 50)

Objective response rate a, b

Objective response rate, % (95% CI) 34 (68%) (53.3 - 80.5)

Complete response 0

Confirmed partial response, n (%)b 34(68%)

Duration of response

DoR ≥ 12 months, n (%) 31 (91.2%)

DoR ≥ 24 months, n (%) 26 (76.5%)

DoR ≥ 36 months, n (%) 21 (61.8%)

CI - confidence interval, DoR - duration of response.a Responses required confirmation at least 3 months after the criteria for first partial response were met.b Complete response: disappearance of the target lesion; partial response: decrease in target PN volume by≥ 20% compared to baseline.

An independent centralized review of tumour response per REiNS criteria (data cut-off June 2018)resulted in an ORR of 44% (95% CI: 30.0, 58.7).

The median time to onset of response was 7.2 months (range: 3.3 months to 3.2 years). The median(min-max) time to the maximal PN shrinkage from baseline was 15.1 months (range: 3.3 months to5.2 years). The median DoR from onset of response was not reached; at the time of data cut-off themedian follow-up time was 41.3 months. The median time from treatment initiation to diseaseprogression while on treatment was not reached.

At the time of data cut-off or last scan on treatment for patients who had discontinued treatment,25 (50%) patients remained in confirmed partial response, 1 (2%) had unconfirmed partial responses,12 (24%) had stable disease and 10 (20%) had progressive disease.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Koselugo in one or more subsets of the paediatric population in NF1 PN (see section 4.2 forinformation on paediatric use).

This medicinal product has been authorised under a so-called “conditional approval” scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

At the recommended dose of 25 mg/m2 twice daily in paediatric patients (3 to ≤ 18 years old), thegeometric mean (coefficient of variation [CV%]) maximum plasma concentration (Cmax) was731 (62%) ng/mL and that of the area under the plasma drug concentration curve (AUC0-12) followingthe first dose was 2009 (35%) ng·h/mL. Minimal accumulation of ~1.1-fold was observed at steadystate upon twice daily dosing.

In paediatric patients, at a dose level of 25 mg/m2, selumetinib has an apparent oral clearance of8.8 L/h, mean apparent volume of distribution at steady state of 78 L and mean elimination half-life of~6.2 hours.

In healthy adult subjects, the mean absolute oral bioavailability of selumetinib was 62%.

Following oral dosing, selumetinib is rapidly absorbed, producing peak steady state plasmaconcentrations (tmax) between 1-1.5 hours post-dose.

In separate clinical studies, in healthy adult subjects and in adult patients with advanced solidmalignancies at a dose of 75 mg, co-administration of selumetinib with a high-fat meal resulted in amean decrease in Cmax of 50% and 62%, respectively, compared to fasting administration. Selumetinibmean AUC was reduced by 16% and 19%, respectively, and the time to reach maximum concentration(tmax) was delayed by approximately 1.5 to 3 hours (see section 4.2).

In healthy adult subjects at a dose of 50 mg, co-administration of selumetinib with a low-fat mealresulted in 60% lower Cmax when compared to fasting administration. Selumetinib AUC was reducedby 38%, and the time to reach maximum concentration (tmax) was delayed by approximately 0.9 hours(see section 4.2).

In adolescent patients with NF1 and inoperable PN treated with multiple doses of 25 mg/m2 bid,co-administration of selumetinib with a low-fat meal resulted in 24% lower Cmax when compared tofasting administration. Selumetinib AUC was reduced by 8%, and tmax was delayed by approximately0.57 hours (see section 4.2).

A population PK analysis including children and adolescent patients with NF1 and inoperable PN,adult patients with advanced solid malignancies and healthy adult subjects taken from 15 studiesshowed that concomitant administration of a low or high fat meal resulted in a mean decrease in theexposure (AUC) of selumetinib when compared to fasted administration (23.1% and 20.7%,respectively) which was not considered clinically relevant.

The mean apparent volume of distribution at steady state of selumetinib across 20 to 30 mg/m2 rangedfrom 78 to 171 L in paediatric patients, indicating moderate distribution into tissue.

In vitro plasma protein binding is 98.4% in humans. Selumetinib mostly binds to serum albumin(96.1%) than α-1 acid glycoprotein (< 35%).

In vitro, selumetinib undergoes phase 1 metabolic reactions including oxidation of the side chain,

N-demethylation, and loss of the side chain to form amide and acid metabolites. CYP3A4 is thepredominant isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP2C9,

CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib alsoundergoes direct phase 2 metabolic reactions to form glucuronide conjugates principally involving theenzymes UGT1A1 and UGT1A3. Glucuronidation is a significant route of elimination for selumetinibphase 1 metabolites involving several UGT isoforms.

Following oral dosing of 14C-selumetinib to healthy male subjects, unchanged selumetinib (~40% ofthe radioactivity) with other metabolites including glucuronide of imidazoindazole metabolite (M2;22%), selumetinib glucuronide (M4; 7%), N-desmethyl selumetinib (M8; 3%), and N-desmethylcarboxylic acid (M11; 4%) accounted for the majority of the circulating radioactivity in humanplasma. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma butis approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to35% of the overall pharmacologic activity.

In vitro, selumetinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6, CYP3A4 and CYP2E1. In vitro, selumetinib is not an inducer of CYP1A2 and

CYP2B6. Selumetinib is an inducer of CYP3A4 in vitro, this is however not expected to be clinicallyrelevant.

In vitro, selumetinib inhibits UGT1A3, UGT1A4, UGT1A6 and UGT1A9 however these effects arenot expected to be clinically relevant.

Interactions with transport proteins

Based on in vitro studies, selumetinib is a substrate for BCRP and P-gp transporters but is unlikely tobe subjected to clinically relevant drug interactions. In vitro studies suggest that selumetinib does notinhibit the breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3,

OCT2, OAT1, MATE1 and MATE2K at the recommended paediatric dose. A clinically relevant effecton the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.

In healthy adult subjects, following a single oral 75 mg dose of radiolabelled selumetinib, 59% of thedose was recovered in faeces (19% unchanged) while 33% of the administered dose (< 1% as parent)was found in urine by 9 days of sample collection.

The exposure of 50 mg oral selumetinib was investigated in adult subjects with normal renal function(n = 11) and subjects with ESRD (n = 12). The ESRD group showed 16% and 28% lower Cmax and

AUC, respectively, with the fraction of unbound selumetinib being 35% higher in ESRD subjects. Asa result, the unbound Cmax and AUC ratios were 0.97 and 1.13 in the ESRD group when compared tothe group with normal renal function. A small increase, approximately 20% AUC, in the N-desmethylmetabolite to parent ratio was detected in the ESRD group when compared to the normal group. Asexposure in ESRD subjects was similar to those with normal renal function, investigations in mild,moderate and severe renally impaired subjects were not performed. Renal impairment is expected tohave no meaningful influence on the exposure of selumetinib (see section 4.2).

Adult subjects with normal hepatic function (n = 8) and mild hepatic impairment (Child-Pugh A,n = 8) were dosed with 50 mg selumetinib, subjects with moderate hepatic impairment (Child-Pugh B,n = 8) were administered a 50 or 25 mg dose, and subjects with severe hepatic impairment(Child-Pugh C, n = 8) were administered a 20 mg dose. Selumetinib total dose normalised AUC andunbound AUC were 86% and 69% respectively, in mild hepatic impairment patients, compared to the

AUC values for subjects with normal hepatic function. Selumetinib exposure (AUC) was higher inpatients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment; the total AUCand unbound AUC values were 159% and 141% (Child-Pugh B) and 157% and 317% (Child-Pugh C),respectively, of subjects with normal hepatic function (see section 4.2). There was a trend of lowerprotein binding in subjects with severe hepatic impairment although the protein binding remained> 99% (see section 4.3).

Following a single-dose, selumetinib exposure appears to be higher in Japanese, non-Japanese-Asianand Indian healthy adult subjects compared to Western adult subjects, however, there is considerableoverlap with Western subjects when corrected for body weight or BSA (see section 4.2).

Adult patients (> 18 years old)

The PK parameters in adult healthy subjects and adult patients with advanced solid malignancies, aresimilar to those in paediatric patients (3 to ≤ 18 years old) with NF1.

In adult patients, Cmax and AUC increased dose proportionally over a 25 mg to 100 mg dose range.

Selumetinib was positive in the mouse micronucleus study via an aneugenic mode of action. The freemean exposure (Cmax) at the no observed effect level (NOEL) was approximately 27-times greater thanclinical free exposure at the maximum recommended human dose (MRHD) of 25 mg/m2.

Selumetinib was not carcinogenic in rats or transgenic mice.

In repeat-dose toxicity studies in mice, rats and monkeys, the main effects seen after selumetinibexposure were in the skin, GI tract and bones. Scabs associated with microscopic erosions andulceration at a free exposure similar to the clinical exposure (free AUC) at the MRHD were seen inrats. Inflammatory and ulcerative GI tract findings associated with secondary changes in the liver andlymphoreticular system at free exposures approximately 28 times the clinical free exposure at the

MRHD were observed in mice. Growth plate (physeal) dysplasia was seen in male rats dosed for up to3 months with selumetinib at a free exposure 11 times the clinical free exposure at the MRHD.

GI findings showed evidence of reversibility following a recovery period. Reversibility for skintoxicities and physeal dysplasia was not evaluated. Vascular engorgement of the corpus cavernosum ofthe bulbocavernosus muscle were observed in male mice in a 26-week study at a dose of 40 mg/kg/day(28 times the free AUC in humans at the MRHD) leading to significant urinary tract obstruction aswell as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.

Developmental and reproduction toxicity studies were conducted in mice. Fertility was not affected inmale mice at up to 40 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD). Infemales, mating performance and fertility were not affected at up to 75 mg/kg/day, but a reversibledecrease in the number of live foetuses was observed at this dose level; the NOAEL for effects onreproductive performance was 5 mg/kg/day (approximately 3.5-fold the free AUC in humans at the

MRHD). A treatment-related increase in the incidence of external malformations (open eye, cleftpalate) was reported in absence of maternal toxicity in embryofoetal development studies at> 5 mg/kg/day, and in the pre- and post-natal development study at ≥ 1 mg/kg/day (corresponding to0.4-fold the free Cmax in humans at the MRHD). The other treatment related effects observed atnon-maternotoxic dose levels in these studies consisted of embryo-lethality and decreased foetalweight at ≥ 25 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD),reductions in post-natal pup growth and at weaning a lower number of pups met the pupil constrictioncriterion at 15 mg/kg/day (corresponding to 3.6-fold the free Cmax in humans at the MRHD).

Selumetinib and its active metabolite were excreted in the milk of lactating mice at concentrationsapproximately the same as those in plasma.

Tocofersolan (Vitamin E polyethylene glycol succinate /D α-tocopheryl polyethylene glycolsuccinate).

Koselugo 10 mg hard capsules

Hypromellose (E464)

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Carnauba wax (E903)

Koselugo 25 mg hard capsules

Hypromellose (E464)

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Indigo carmine aluminium lake (E132)

Iron oxide yellow (E172)

Carnauba wax (E903)

Maize starch

Koselugo 10 mg hard capsules

Shellac glaze, standard (E904)

Iron oxide black (E172)

Propylene glycol (E1520)

Ammonium hydroxide (E527)

Koselugo 25 mg hard capsules

Iron oxide red (E172)

Iron oxide yellow (E172)

Indigo carmine aluminium lake (E132)

Carnauba wax (E903)

Shellac, standard (E904)

Glyceryl mono-oleate

Not applicable.

3 years.

Do not store above 30 °C.

Store in the original bottle in order to protect from moisture and light.

Keep the bottle tightly closed.

Koselugo 10 mg hard capsules

High-density polyethylene (HDPE) plastic bottle with white child-resistant polypropylene closure.

Koselugo 25 mg hard capsules

High-density polyethylene (HDPE) plastic bottle with blue child-resistant polypropylene closure.

Each bottle contains 60 hard capsules and a silica gel desiccant. Each carton contains one bottle.

Patients should be instructed not to remove the desiccant from the bottle.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/21/1552/001 10 mg hard capsules

EU/1/21/1552/002 25 mg hard capsules

Date of first authorisation: 17 June 2021

Date of latest renewal: 31 May 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu