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Koselugo is a brand name for Selumetinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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 .
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with Koselugo should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours. Posology The recommended dose of Koselugo is 25 mg/m2 of body surface area (BSA), taken orally twice daily (approximately every 12 hours).
Dosing in adult and paediatric patients is individualised based on BSA (mg/m2) and rounded to the nearest achievable 5 mg or 10 mg dose (up to a maximum single dose of 50 mg). Different strengths of Koselugo capsules can be combined to attain the desired dose (Table 1).
3 Table 1. 55 m2 has not been established. Treatment with Koselugo should continue as long as clinical benefit is observed, or until PN progression or the development of unacceptable toxicity. Missed dose If a dose of Koselugo is missed, it should only be taken if it is more than 6 hours until the next scheduled dose.
Vomiting If vomiting occurs after Koselugo is administered, an additional dose is not to be taken. The patient should continue with the next scheduled dose. 8). Recommended dose reductions are given in Table 2 and may require the daily dose to be divided into two administrations of different strength or for treatment to be given as a once daily dose.
Table 2. 90 m2 50 35 35 25 25 a 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 product are presented in Table 3.
4 Table 3. Recommended dose modifications for adverse reactions CTCAE Grade* Recommended dose modification Grade 1 or 2 (tolerable – can be managed with supportive care) Continue treatment and monitor as clinically indicated Grade 2 (intolerable – cannot be managed with supportive care) or Grade 3 Interrupt treatment until toxicity is grade 0 or 1 and reduce by one dose level when resuming therapy (see Table 2) Grade 4 Interrupt treatment until toxicity is grade 0 or 1, and reduce by one dose level when resuming therapy (see Table 2).
Consider discontinuation * Common Terminology Criteria for Adverse Events (CTCAE) Dose modification advice for left ventricular ejection fraction (LVEF) reduction In cases of asymptomatic LVEF reduction of ≥ 10 percentage points from baseline and below the institutional lower level of normal (LLN), selumetinib treatment should be interrupted until resolution.
Summary of the safety profile The safety of selumetinib monotherapy has been evaluated in a pooled safety population of 126 paediatric patients (20-30 mg/m2 twice daily, capsules) from 4 studies with NF1 and inoperable PN [(NF1-PN Paediatric Pool, which includes safety data from SPRINT Phase I (N=24), SPRINT Phase II, Stratum 1 (N=50), China Phase I study; paediatric cohort (N=16), Japan Phase I study (N=12), and Phase I Food effect study (Study 15, N=24)].
In addition, the safety of selumetinib for the granule formulation was evaluated in 36 paediatric patients (dose equivalent to 25 mg/m2 twice daily, granules) with NF1 and symptomatic inoperable PN from the Phase I/II SPRINKLE study.
The safety of selumetinib monotherapy in adult patients has been evaluated in 137 adult patients with NF1 and inoperable PN (25 mg/m2 twice daily, capsules) from Phase III KOMET study. The median total duration of selumetinib treatment in NF1-PN Paediatric Pool was 27 months (range: < 1– 97 months), 57% of patients were exposed to selumetinib treatment for > 24 months and 40% for 9 > 36 months.
The median total duration of selumetinib treatment in NF1-PN adult patients was about 12 months (range: < 1 – 32 months). 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).
8% of patients, respectively. 6% patients had ADRs leading to dose modification of selumetinib (either dose interruptions or reductions). 6% each). 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).
Left ventricular ejection fraction (LVEF) reduction In the SPRINT clinical study, 26% of paediatric patients experienced asymptomatic decreases in ejection fraction, with a median onset time of 232 days. LVEF reduction have been reported in both paediatric and adult patients.
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 6 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.
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. 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. 2). 2). 8). Liver laboratory values should be monitored before initiation of selumetinib and at least monthly during the first 6 months of treatment, and thereafter as clinically indicated.
2). 8). Dry skin, hair colour changes, paronychia and rash maculo-papular were seen more frequently in younger children (age 3-11 years) and acneiform rash was seen more frequently in post-pubertal children (age 12-16 years) in the SPRINT clinical study.
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.
1. 2).
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Once resolved, selumetinib should be reduced by one dose level when resuming therapy (see Table 2). 4). Dose modification advice for ocular toxicities Selumetinib treatment should be interrupted in patients diagnosed with retinal pigment epithelial detachment (RPED) or central serous retinopathy (CSR) with reduced visual acuity until resolution; reduce selumetinib by one dose level when resuming therapy (see Table 2).
In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. 4). Dose adjustments for co-administration with CYP3A4 or CYP2C19 inhibitors Concomitant use of strong or moderate CYP3A4 or CYP2C19 inhibitors is not recommended and alternative agents should be considered.
If a strong or moderate CYP3A4 or CYP2C19 inhibitor must be co-administered, the recommended Koselugo dose reduction is as follows: • If a patient is currently taking 25 mg/m2 twice daily, dose reduce to 20 mg/m2 twice daily. 5). Table 4.
2). Hepatic impairment Based on clinical studies, no dose adjustment is recommended in patients with mild hepatic impairment. The starting dose should be reduced in patients with moderate hepatic impairment to 20 mg/m2 BSA, twice daily (see Table 4).
2). […]
Thirty-six paediatric patients were treated with selumetinib granules equivalent to 25 mg/m2 twice daily. The most common adverse reactions of any grade (incidence ≥ 40%) were pyrexia and dry skin (47% patients each); and paronychia (44%).
6% of patients, while no patients had AEs leading to dose reductions. 2% patients had ADRs leading to dose modification (either dose interruptions or reductions). 6%). No patient had ADRs that led to treatment discontinuation. The observed safety profile of selumetinib granules in the SPRINKLE study was comparable with pooled safety data in paediatric patients treated with selumetinib capsules (NF1-PN Paediatric Pool).
In the NF1-PN adult patients, the most common adverse reactions of any grade (incidence ≥ 20%) were acneiform rashes (55%), blood creatine phosphokinase increased (37%), diarrhoea (30%), non- acneiform rashes (27%) and vomiting (20%).
5% patients had adverse reactions leading to dose modification of selumetinib (either dose interruptions or reductions). 8%). 5% patients. The safety profile was also substantiated by a pool of safety data from 7 clinical studies in adult patients with multiple tumour types (N=347) who received 75 to 100 mg of selumetinib twice daily.
Tabulated list of adverse reactions Table 5 presents the adverse reactions identified in the paediatric and adult population with NF1 who have inoperable PN and also in adult patients with multiple tumour types (see footnote to Table 5).
The frequency is determined from the paediatric pool (N = 126) and adult patients (N = 137) as defined above. Adverse drug reactions (ADRs) are organised by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness.
Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from available data), including isolated reports.
10 Table
, warfarin or acetylsalicylic acid). 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.
2). Koselugo is also available as granules. Patients from 1 year to less than 7 years of age, and older patients with swallowing difficulties may be prescribed appropriate doses of Koselugo granules (see SmPC for Koselugo Granules). 6).
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