KOSELUGO Hard capsule Ref.[27820] Active ingredients: Selumetinib

Left ventricular ejection fraction (LVEF) reduction

Asymptomatic decreases in ejection fraction have been reported in 22% of paediatric patients in the pivotal clinical trial. Median time to initial onset of these adverse reactions was 226 days. 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).

Paediatric 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 paediatric 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 6 first 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 study (see section 4.8). Pustular rash, hair colour changes and dry skin 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 contain 32 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 increase the risk of bleeding in patients taking concomitant anticoagulant or antiplatelet medicinal products (e.g., warfarin or acetylsalicylic acid). Anticoagulant assessments, including international normalised ratio or prothrombin time, should be conducted more frequently to detect when dose adjustments of the 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 particular children <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 patients who 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 C_max 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 C_max 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 C_max by ~20%.

Co-administration with medicinal products that are strong inhibitors of CYP3A4 (e.g., clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (e.g., ticlopidine) should be avoided. Co-administration with medicinal products that are 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 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 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).

TPGS is a P-gp inhibitor in vitro and it cannot be excluded that it may cause clinically relevant drug interactions 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, 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 capsules 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.

Vitamin E

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

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 embryofoetal 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).

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.

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

In the paediatric pool, the median total duration of selumetinib treatment in paediatric patients with NF1 who have PN was 28 months (range: <1 to 71 months), 23% of patients were exposed to selumetinib treatment for >48 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.

In the paediatric pool (N=74; comprises 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 (82%), rash (80%), blood creatine phosphokinase increased (76%), diarrhoea (77%), nausea (73%), asthenic events (59%), dry skin (58%), pyrexia (57%), acneiform rash (54%), hypoalbuminaemia (50%), aspartate aminotransferase increased (50%) and paronychia (45%). Dose interruptions and reductions due to adverse events were reported in 78% and 32% of patients, respectively. The most commonly reported ADRs leading to dose modification (dose interrupted or dose reduced) of selumetinib were vomiting (26%), paronychia (16%), diarrhoea (15%) and nausea (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%).

Tabulated list of adverse reactions

Table 5 presents the adverse reactions identified in the paediatric population with NF1 who have inoperable PN and in adult patients (see footnote to Table 5). The frequency is determined from the paediatric pool (N=74); comprises 50 patients from the pivotal SPRINT phase II stratum 1 dataset and 24 patients from supportive SPRINT phase I dataset. Adverse drug reactions(ADRs) are organised by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); 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 paediatric pool (pivotal SPRINT phase II stratum 1 [N=50] and supportive SPRINT phase I [N=24]) and in other identified clinical trials in adult patients (N=347)^††:

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 paediatric population 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
Rash (acneiform): dermatitis acneiform
Rash: dermatitis acneiform, rash maculo-papular, rash papular, rash, rash erythematous, rash macular
RVO: retinal vascular disorder, retinal vein occlusion, retinal vein thrombosis

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 11 (22%) patients; all cases were grade 2, asymptomatic and did not lead to dose interruptions, reductions or discontinuation. Of the 11 patients, 6 patients recovered and for 5 patients the outcome was not reported. The median time to first occurrence of LVEF reduction was 226 days (median duration 78 days). The majority of LVEF reduction adverse reactions were reported as reductions from baseline (≥10% reduction) but were considered to remain in the normal range. Patients with LVEF lower than the institutional LLN at baseline were not included in the pivotal study. In addition, 2 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 SPRINT, phase II stratum 1, grade 1 and 2 adverse reactions of blurred vision were reported in 4 (8%) patients. Two patients required dose interruption. All adverse reactions were managed without 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 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 SPRINT, phase II stratum 1, paronychia was reported in 23 (46%) patients, the median time to first onset of maximum grade paronychia adverse reaction was 306 days and the median duration of adverse reactions was 96 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 three (6%) patients. Seven patients (3 with a maximum grade 3 adverse reaction and 4 with a maximum grade 2 adverse reaction) had a selumetinib dose interruption for adverse reactions of paronychia, of whom 3 had dose interruption followed by dose reduction (2 patients required a second dose reduction). In one patient (2%) the event led to discontinuation.

Blood creatine phosphokinase (CPK) increase

Adverse reactions of blood CPK elevation occurred in 76% of patients in SPRINT phase II stratum 1. The median time to first onset of the maximum grade CPK increase was 106 days and the median duration of adverse reactions was 126 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 three (6%) patients. A grade 4 adverse reaction led to treatment interruption followed by dose reduction.

Gastrointestinal toxicities

In SPRINT, phase II stratum 1, vomiting (41 patients, 82%, median duration 3 days), diarrhoea (35 patients, 70%, median duration 5 days), nausea (33 patients, 66%, median duration 16 days), and stomatitis (25 patients, 50%, median duration 12 days) were the most commonly reported gastrointestinal (GI) reactions. The majority of these cases were grade 1 or 2 and did not require any dose interruptions or dose reductions.

Grade 3 adverse reactions were reported for diarrhoea (8 patients, 16%), nausea (1 patient, 2%), and vomiting (3 patients, 6%). For one patient diarrhoea led to dose reduction and subsequent discontinuation. No dose reduction or discontinuation was required for adverse reactions of nausea, vomiting or stomatitis.

Skin toxicities

In SPRINT, phase II stratum 1, acneiform rash was observed in 25 (50%) patients (median time to onset 13 days; median duration of 60 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 for 4%.

Other (non-acneiform) rashes were observed in 35 (70%) patients in the pivotal study and were predominantly grade 1 or 2.

Hair changes

In SPRINT, phase II stratum 1, 32% of patients experienced hair changes (reported as hair lightening [PT: hair colour changes] in 11 patients (22%) and hair thinning [PT: alopecia]) in 12 patients (24%)); in 7 patients (14%) both alopecia and hair colour changes were reported during treatment. All cases were grade 1 and did not require dose interruption or dose reduction.

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 national reporting system listed in Appendix V.

Not applicable.