Koselugo · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-099365 · has-adverse-reaction-information · PDF-Seite 29

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 29 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 t

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HOS-099359 · has-adverse-reaction-information · PDF-Seite 8

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. 8 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 t

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HOS-099355 · has-contraindication-information · PDF-Seite 5

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).

HOS-099361 · has-contraindication-information · PDF-Seite 27

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).

HOS-099354 · has-indication-information · PDF-Seite 2

Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in adult and paediatric patients with neurofibromatosis type 1 (NF1) aged 3 years and older.

HOS-099360 · has-indication-information · PDF-Seite 23

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.

HOS-099363 · has-interaction-information · PDF-Seite 28

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 28 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 restriction

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HOS-099357 · has-interaction-information · PDF-Seite 7

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). 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 concomita

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HOS-099358 · has-pregnancy-information · PDF-Seite 8

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).

HOS-099364 · has-pregnancy-information · PDF-Seite 29

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).

HOS-099362 · has-warning-information · PDF-Seite 27

Left ventricular ejection fraction (LVEF) reduction In the SPRINT clinical study, 26% of paediatric patients experienced asymptomatic decreases in ejection fraction, with a median time to maximum CTCAE grade onset 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. In the NF1-PN paediatric population, cases of asymptomatic subretinal fluid were identified and a single retinopathy case was reported (see section 4.8). In postmarketing experience, cases of RPED/CSR have been reported (see section 4.8). 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 27 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 abnormal

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HOS-099356 · has-warning-information · PDF-Seite 5

Left ventricular ejection fraction (LVEF) reduction In the SPRINT clinical study, 26% of paediatric patients experienced asymptomatic decreases in ejection fraction, with a median time to maximum CTCAE grade onset 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 5 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. In the NF1-PN paediatric population, cases of asymptomatic subretinal fluid were identified and a single retinopathy case was reported (see section 4.8). In postmarketing experience, cases of RPED/CSR have been reported (see section 4.8). 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 abnormalit

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