Selumetinib

Selumetinib is a selective inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). It blocks MEK activity and with it the RAF–MEK–ERK pathway, so MEK inhibition can block the proliferation and survival of tumour cells in which that pathway is activated.

Mechanism of Action

• MEK1/2 inhibition: RAF activates MEK, which in turn activates ERK; selumetinib is described as a non-ATP-competitive inhibitor of MEK1 and MEK2 and so reduces signalling down the pathway, with less cell proliferation and a pro-apoptotic effect.
• Active metabolite: N-desmethyl selumetinib makes up less than 10% of the parent drug level in plasma but is about 3 to 5 times more potent, contributing roughly 21–35% of the overall pharmacological activity.
• Efficacy studies: the effect on plexiform neurofibromas in NF1 was assessed in the single-arm phase II SPRINT study (50 children with inoperable PN causing significant morbidity), using response of the target neurofibroma on centrally read volumetric MRI.

Pharmacokinetics

• Absorption: rapid, with peak steady-state plasma concentrations about 2 hours after a dose; absolute oral bioavailability 62% in healthy adults. A high-fat meal lowered Cmax by 50–62% and AUC by 16–19% and delayed tmax; a low-fat meal had a similar effect on Cmax. These changes in AUC are not expected to be clinically relevant, so the capsules can be taken with or without food.
• Exposure: at 25 mg/m² twice daily, children aged 3 to 18 years had a geometric mean Cmax of 731 ng/mL and AUC0–12 of 2,009 ng·h/mL after the first dose; adults had a steady-state Cmax of 789 ng/mL and AUC0–12 of 2,986 ng·h/mL. Accumulation is minimal (about 1.1-fold in children). The granules give a comparable AUC with about 30% lower Cmax than the capsules.
• Distribution: apparent volume of distribution at steady state 78–171 L in children, indicating moderate tissue distribution; 98.4% bound to plasma proteins in vitro, mostly to albumin (96.1%).
• Metabolism: mainly oxidation by CYP3A4, with minor roles for CYP2C19, CYP2C9, CYP2E1 and CYP3A5, and glucuronidation by UGT1A1 and UGT1A3.
• Elimination: after a single radiolabelled 75 mg dose in healthy adults, 59% was recovered in faeces (19% unchanged) and 33% in urine (less than 1% as parent drug) over 9 days. Half-life is about 6.2 hours in children and 9.0 hours in adults; apparent oral clearance 8.8 L/h in children and 14.1 L/h in adults.
• Special populations: exposure in end-stage renal disease was similar to normal renal function. Total AUC was 86% of normal in mild hepatic impairment but 159% in moderate and 157% in severe impairment. Exposure is higher in Japanese, other Asian and Indian healthy adults than in Western subjects, with considerable overlap once corrected for body weight or body surface area.

Koselugo is used as monotherapy for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1):

• Granules in capsule for opening (5 mg and 7.5 mg): patients aged 1 year to less than 7 years, and older patients with swallowing difficulties.
• Hard capsules (10 mg and 25 mg): adult and paediatric patients aged 3 years and older.

• Hypersensitivity to selumetinib or to any of the excipients.
• Severe hepatic impairment.

The safety of selumetinib was evaluated in 126 paediatric patients from four studies (capsules, 20–30 mg/m² twice daily), in 36 paediatric patients given the granules (SPRINKLE study) and in 137 adults with NF1 and inoperable PN (KOMET study). In the paediatric pool the most common reactions (≥40%) were vomiting (62%), acneiform rash (60%), diarrhoea (56%), raised blood creatine phosphokinase (54%), nausea (52%), paronychia (50%), and dry skin and pyrexia (44% each); 61.9% of patients had dose interruptions, 27.8% had dose reductions and 4.8% stopped treatment because of reactions. With the granules the most common reactions were pyrexia and dry skin (47% each) and paronychia (44%), and the profile was comparable to the capsules. In adults the most common reactions (≥20%) were acneiform rash (55%), raised creatine phosphokinase (37%), diarrhoea (30%), non-acneiform rash (27%) and vomiting (20%); 1.5% stopped treatment because of reactions.

Very common (≥1/10): vomiting, diarrhoea, nausea, stomatitis, acneiform rash, paronychia, dry skin, non-acneiform rash, hair changes (hair colour change or thinning), asthenic events (fatigue, asthenia), peripheral oedema, raised blood creatine phosphokinase, raised aspartate and alanine aminotransferases, decreased haemoglobin. In paediatric patients also pyrexia, decreased blood albumin, decreased ejection fraction, raised blood creatinine and increased blood pressure; in adults also constipation.

Common (≥1/100 to <1/10): blurred vision, dyspnoea, dry mouth, facial oedema. In adults also pyrexia, decreased blood albumin, decreased ejection fraction, raised blood creatinine and increased blood pressure.

Uncommon (≥1/1,000 to <1/100): retinal pigment epithelial detachment or central serous retinopathy, and retinal vein occlusion (identified in adults with other tumour types, not in patients with NF1 plexiform neurofibromas).

Reduced ejection fraction was reported in 21% of paediatric and 7% of adult patients (mostly grade 2 in children), paronychia reached grade 3 or higher in 10% of children, and raised creatine phosphokinase reached grade 4 in a few patients. Dose changes in children were most often needed for vomiting, paronychia, nausea and diarrhoea.

Interaction studies have only been performed in healthy adults.

• Strong or moderate CYP3A4 inhibitors and CYP2C19 inhibitors: itraconazole (strong CYP3A4 inhibitor) raised selumetinib Cmax by 19% and AUC by 49%; fluconazole (strong CYP2C19 and moderate CYP3A4 inhibitor) raised Cmax by 26% and AUC by 53%. Erythromycin and fluoxetine are predicted to raise AUC by about 30–40%. Avoid strong inhibitors of CYP3A4 (such as clarithromycin, grapefruit juice and oral ketoconazole) or CYP2C19 (such as ticlopidine), and moderate inhibitors of CYP3A4 (erythromycin, fluconazole) or CYP2C19 (omeprazole). If co-administration cannot be avoided, monitor for adverse events and reduce the dose.
• Strong or moderate CYP3A4 inducers: rifampicin lowered Cmax by 26% and AUC by 51%. Avoid strong inducers (such as phenytoin, rifampicin, carbamazepine and St John’s wort) and moderate CYP3A4 inducers.
• OAT3 substrates: selumetinib inhibits OAT3 in vitro, so a clinically relevant effect on substrates such as methotrexate and furosemide cannot be excluded.
• Oral contraceptives: it cannot be excluded that selumetinib reduces their effectiveness, so women using hormonal contraceptives should add a barrier method.
• Food: grapefruit and Seville (bitter) orange must not be mixed with the granules.

Treatment should be started by a physician experienced in the diagnosis and treatment of patients with NF1-related tumours. The dose is 25 mg/m² of body surface area (BSA) twice daily, about every 12 hours, individualised by BSA and rounded to the nearest achievable dose (up to a maximum single dose of 50 mg). Different strengths can be combined to reach the dose. Treatment continues as long as clinical benefit is observed, or until PN progression or unacceptable toxicity.

• Granules in capsule for opening: open the capsule and sprinkle the entire contents on a small amount (about 1 to 3 teaspoons) of soft food such as 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 (bitter) orange. The dose on food must be swallowed within 30 minutes and not kept for later. The empty shells are discarded, not swallowed, chewed or dissolved. The package leaflet shows how to give the granules.
• Hard capsules: swallowed whole with water, with or without food; not chewed, dissolved or opened, because that could impair drug release and absorption. They are not for patients unable or unwilling to swallow a capsule whole, so swallowing is assessed before starting.

Recommended Doses by Body Surface Area

• Granules (BSA in m², dose twice daily): 0.40–0.49, 10 mg; 0.50–0.59, 12.5 mg; 0.60–0.69, 15 mg; 0.70–0.89, 20 mg; 0.90–1.09, 25 mg; 1.10–1.29, 30 mg; 1.30–1.49, 35 mg; 1.50–1.69, 40 mg; 1.70–1.89, 45 mg; 1.90 or more, 50 mg. The dose has not been established below 0.40 m². In patients who tolerate 10 mg at 0.40–0.49 m², a gradual increase to 12.5 mg twice daily may be considered. From 0.70 m² the granule doses match the capsule doses, and a patient who cannot switch to capsules at 1.29 m² or more can stay on the granules.
• Hard capsules: 0.55–0.69, 20 mg in the morning and 10 mg in the evening; 0.70–0.89, 20 mg twice daily; 0.90–1.09, 25 mg; 1.10–1.29, 30 mg; 1.30–1.49, 35 mg; 1.50–1.69, 40 mg; 1.70–1.89, 45 mg; 1.90 or more, 50 mg twice daily. The dose has not been established below 0.55 m².

Dose Adjustments for Side Effects

• Dose reductions: up to two reductions by dose level, using the BSA tables in the SmPC; treatment is stopped permanently if Koselugo is not tolerated after two reductions. For example, capsules at 1.90 m² or more go from 50 mg to 35 mg and then 25 mg twice daily; granules at 0.90–1.09 m² go from 25 mg to 20 mg and then 15 mg twice daily.
• By grade: grade 1 or 2 reactions that can be managed with supportive care need no change. For intolerable grade 2 or grade 3 reactions, interrupt until grade 0 or 1, then resume one dose level lower. For grade 4, interrupt until grade 0 or 1, resume one level lower and consider stopping.
• Ejection fraction: for an asymptomatic fall of 10 percentage points or more from baseline to below the institutional lower limit of normal, interrupt until resolved and resume one level lower. For a symptomatic or grade 3 or 4 fall, stop and refer promptly to cardiology.
• Eyes: for retinal pigment epithelial detachment (RPED) or central serous retinopathy (CSR) with reduced visual acuity, interrupt until resolved and resume one level lower; without reduced acuity, ophthalmic assessment every 3 weeks until resolution. For retinal vein occlusion, stop permanently.
• CYP3A4 or CYP2C19 inhibitors: use is not recommended. If a strong or moderate inhibitor is unavoidable, reduce from 25 mg/m² to 20 mg/m² twice daily, or from 20 mg/m² to 15 mg/m² twice daily.

Special Populations

• Renal impairment: no adjustment in mild, moderate or severe impairment or end-stage renal disease.
• Hepatic impairment: no adjustment in mild impairment; in moderate impairment the starting dose is reduced to 20 mg/m² twice daily. Koselugo is contraindicated in severe impairment.
• Ethnicity: no specific adjustment for Asian patients, who should be monitored closely for adverse events.
• Children: the safety of the granules below 1 year, and of the capsules below 3 years, has not been established.
• Elderly: safety and efficacy in adults over 65 years with NF1-related PN have not been established; no data.

Missed or Vomited Dose

A missed dose is taken only if more than 6 hours remain until the next scheduled dose. If vomiting follows a dose, no extra dose is taken; the next scheduled dose is taken as usual.

Left Ventricular Ejection Fraction

In the SPRINT study about a quarter of paediatric patients had asymptomatic decreases in ejection fraction, and a few serious reports in children came from an expanded access programme. Patients with a history of impaired left ventricular function or a baseline ejection fraction below the institutional lower limit of normal have not been studied. An echocardiogram is done before starting (the ejection fraction must be above the lower limit of normal) and about every 3 months, or more often as indicated.

Eye Problems

Patients should report any new visual disturbance. Blurred vision has occurred; in children, asymptomatic subretinal fluid and a single case of retinopathy were seen, and RPED and CSR have been reported after marketing. An eye examination is recommended before treatment and whenever new visual disturbances are reported.

Liver Laboratory Values

AST and ALT elevations can occur. Liver values are checked before starting and at least monthly for the first 6 months, then as clinically indicated.

Skin, Nail and Hair Reactions

Skin rash (including maculopapular and acneiform rash), paronychia and hair changes were very common. In the SPRINT study, dry skin, hair colour changes, paronychia and maculopapular rash were more frequent in younger children (3–11 years) and acneiform rash in post-pubertal children (12–16 years).

Hard Capsule Excipient

The hard capsules contain tocofersolan (vitamin E polyethylene glycol succinate); read the SmPC for the hard capsules for any related precautions.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant, and a pregnancy test is recommended before starting. Male and female patients of reproductive potential should use effective contraception during treatment and for at least 1 week after it ends; women using hormonal contraceptives should add a barrier method.
• Pregnancy: no human data; animal studies showed embryo-foetal death, structural defects and reduced foetal weights. Koselugo is not recommended during pregnancy or in women of childbearing potential not using contraception. If a female patient, or the female partner of a male patient, becomes pregnant she should be told of the potential risk to the foetus.
• Breastfeeding: it is not known whether selumetinib passes into human milk; it and its active metabolite pass into the milk of mice. A risk to the breast-fed child cannot be excluded, so breastfeeding should be stopped during treatment.
• Fertility: no human data; in mice there was no effect on fertility or mating, although embryonic survival was reduced in females.

Effect on Driving

Koselugo may have a minor influence on the ability to drive and use machines. Fatigue, asthenia and visual disturbances have been reported, and patients with these symptoms should be careful when driving or using machines.

Granules in capsule for opening: do not store above 25 °C. Hard capsules: do not store above 30 °C. For both, keep the medicine in the original bottle to protect it from moisture and light, with the bottle tightly closed. The granule bottle holds 60 capsules and a silica gel desiccant, and has a child-resistant closure.

Granules in capsule for opening: 2 years. Hard capsules: 3 years.

Prescription only (Rx), subject to restricted medical prescription. Treatment is started by a physician experienced in the diagnosis and treatment of patients with NF1-related tumours. Koselugo is taken by mouth at home, so it is supplied to the patient (or the patient’s carer) or to the treating clinic on prescription.