Koselugo

Selumetinib.

Each 10 mg hard capsule contains 10 mg of selumetinib (as hydrogen sulfate).
Each 25 mg hard capsule contains 25 mg of selumetinib (as hydrogen sulfate).
Excipients/Inactive Ingredients: 10 mg hard capsule: Capsule content: Vitamin E polyethylene glycol succinate (D α-tocopheryl polyethylene glycol 1000 succinate).
Capsule shell: Hypromellose (E 464), Carrageenan, Potassium chloride, Titanium dioxide (E 171), Carnauba wax and Purified water.
Printing ink: Shellac glaze, Iron oxide black, Propylene glycol, Ammonium hydroxide 28%.
25 mg hard capsule: Capsule content: Vitamin E polyethylene glycol succinate (D α-tocopheryl polyethylene glycol 1000 succinate).
Capsule shell: Hypromellose (E 464), Carrageenan, Potassium chloride, Titanium dioxide (E 171), FD&C Blue 2 (E 132), Ferric oxide yellow (E 172), Purified water, Carnauba wax and/or Corn starch.
Printing ink: Ferric oxide red, Ferric oxide yellow, FD&C blue 2 aluminium lake, Carnauba wax, White shellac, Glyceryl monooleate.

Pharmacology: Pharmacodynamics: Mechanism of action: Selumetinib is an orally available, potent and selective inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) that is not competitive with respect to ATP. MEK1/2 proteins are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. Selumetinib blocks MEK activity and inhibits growth of RAF-MEK-ERK pathway activated cell lines. Therefore, MEK inhibition can block the proliferation and survival of tumour cells in which the RAF-MEK-ERK pathway is activated.
Pharmacodynamic effects: In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human type 1 neurofibromas, oral dosing of selumetinib inhibits ERK phosphorylation, reduces neurofibroma volume, proliferation, number and growth.
Cardiac electrophysiology: The effect of selumetinib on the QTc interval following a single 75 mg oral dose, in a placebo- and positive-controlled (moxifloxacin) study, in 48 healthy adults showed no clinically relevant effect on the QTc interval (<10 msec change). A pharmacokinetic-pharmacodynamic analysis predicted a <10 msec change at 150 mg dose (3-times higher than the recommended maximum dose of 50 mg in paediatric patients with NF1).
Clinical efficacy: SPRINT: The efficacy of KOSELUGO was evaluated in an open-label, multi-centre, single-arm study [SPRINT Phase II Stratum 1 (NCT01362803)] of 50 paediatric patients with NF1 inoperable PN that caused significant morbidity. Morbidities that were present in ≥20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Inoperable PN was defined as a PN that could not be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients received 25 mg/m² (BSA) twice daily, for 28 days (1 treatment cycle), on a continuous dosing schedule. Treatment was discontinued if a 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-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumour response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles.
Patients had target PN MRI volumetric evaluations and clinical outcome assessments, which included functional assessments and patient reported outcomes.
The median age of the patients was 10.2 years (range: 3.5 - 17.4 years), 60% were male, 84% were Caucasian.
Disease characteristics at baseline are provided in Table 1. (See Table 1.)

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The primary efficacy endpoint was Objective Response Rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥20% reduction in PN volume, confirmed at a subsequent tumour assessment within 3-6 months), based on NCI centralised review. Duration of Response (DoR) was also evaluated.
The primary endpoint, ORR was 66% (95% CI 51.2 - 78.8). An independent centralized review of tumour response per REiNS criteria resulted in an ORR of 44% (95% CI 30, 59). Time to onset of response for the majority of patients (24/33 [72.7%]) was within 8 cycles (range 4 - 20 cycles).
The median DoR from onset of response was not reached; at the time of data cut-off the median follow-up time was 24 cycles. Of the 33 patients who had confirmed partial responses, 29 (87.9%) remained in response after 12 cycles; 4 patients were censored not due to progression. The probability to remain in response after 12 and 16 cycles, estimated using the Kaplan-Meier method, was 100% (95% CI not estimated) and 96.2% (95% CI 75.7 - 99.4), respectively. The median time from treatment initiation to disease progression while on treatment was not reached. (See Table 2.)

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At the time of data cut-off, 28 (56%) patients remained in confirmed partial response, 2 (4%) had unconfirmed partial responses, 15 (30%) had stable disease and 3 (6%) had progressive disease.
The median best percentage change in PN volume from baseline was -27.85% (range: 2.2% to -54.5%). Figure shows the best percentage change in target PN volume for each patient. (See figure.)

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Clinical Outcome Assessments: Pain intensity of the target PN was self-reported by patients ≥8 years of age using an 11-point Numeric Rating Scale (NRS-11). A clinically meaningful reduction in pain (defined as, ≥2-point decrease from baseline) was reported for 50% of patients (n=12) at pre-Cycle 13; 12 patients (50%) reported no change (10 of which had a baseline score of ≤1) and no patients showed deterioration.
Parent-reported (all patients) and patient-reported (≥8 years of age) health-related quality of life (HRQoL) was assessed using the Peds-QL questionnaire. Based on MMRM analysis, improvement in HRQoL was reported by patients and parents at pre-Cycle 13 with a mean change from baseline of 6.68 (95% CI 1.34 - 12.02) and 12.7 (95% CI 8.91 - 16.55) respectively. These results should be interpreted in the context of the open-label, single-arm study design and therefore taken cautiously.
Pharmacokinetics: At the recommended dosage of 25 mg/m² twice daily in paediatric patients (3 to ≤18 years old), the geometric mean (coefficient of variation [CV%]) C_max following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC_0-12h) following the first dose was 2009 (35%) ng·h/mL and the AUC_0-6h at steady state was 1958 (41%) ng·h/mL. Selumetinib AUC and C_max increases proportionally over a dose range from 20 mg/m2 to 30 mg/m² (0.8- to 1.2-times the recommended dose). Minimal accumulation of ~1.1-fold was observed at steady state upon twice daily dosing.
In paediatric patients, at a dose level of 25 mg/m², selumetinib has an apparent oral clearance of 8.8 L/h, mean apparent volume of distribution at steady state of 78 L and mean elimination half-life of ~6.2 hours.
Absorption: In healthy adult subjects, the mean absolute oral bioavailability of selumetinib was 62%. Following oral dosing, selumetinib is rapidly absorbed, producing peak steady state plasma concentrations (T_max) between 1-1.5 hours post-dose.
Effect of food: In separate clinical studies, in healthy adult subjects and in adult patients with advanced solid malignancies at a dose of 75 mg, co-administration of selumetinib with a high-fat meal resulted in a mean decrease in C_max of 50% and 62%, respectively, compared to fasting administration. Selumetinib mean AUC was reduced by 16% and 19%, respectively, and the time to reach maximum concentration (T_max) was delayed by approximately 1.5 to 3 hours (see Dosage & Administration).
In healthy adult subjects at a dose of 50 mg, co-administration of selumetinib with a low-fat meal resulted in 60% lower C_max when compared to fasting administration. Selumetinib AUC was reduced by 38%, and T_max was delayed by approximately 0.9 hours (see Dosage & Administration).
Effect of gastric acid reducing agents on KOSELUGO: KOSELUGO 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.
Distribution: The mean apparent volume of distribution at steady state of selumetinib across 20 to 30 mg/m² ranged from 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%).
Biotransformation/ Metabolism: 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 the predominant isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP1A2, CYP2C9, CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib also undergoes direct Phase 2 metabolic reactions to form glucuronide conjugates principally involving the enzymes UGT1A1 and UGT1A3. Glucuronidation is a significant route of elimination for selumetinib Phase 1 metabolites involving several UGT isoforms.
Following oral dosing of ¹⁴C-selumetinib to healthy male subjects, unchanged selumetinib (~40% of the radioactivity) with other metabolites including glucuronide of imidazoindazole metabolite (M2; 22%), selumetinib glucuronide (M4; 7%), N-desmethyl selumetinib (M8; 3%), and N-desmethyl carboxylic acid (M11; 4%) accounted for the majority of the circulating radioactivity in human plasma. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma but is approximately 3- to 5-times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.
Elimination: In healthy adult volunteers, following a single oral 75 mg dose of radiolabelled selumetinib, 59% of the dose 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.
Interactions: 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 CYP3A4, CYP1A2 and CYP2B6. In vitro, selumetinib inhibits UGT1A3, UGT1A4, UGT1A6 and UGT1A9, however these effects are not 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 to be subjected to clinically relevant drug interactions at the recommended paediatric dose. In vitro studies suggest that selumetinib does not inhibit 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 effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.
Special populations: Renal impairment: 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 C_max and AUC, respectively, with the fraction of unbound selumetinib being 35% higher in ESRD subjects. As a result, the unbound C_max and AUC ratios were 0.97 and 1.13 in the ESRD group when compared to the group with normal renal function. A small increase, approximately 20% AUC, in the N-desmethyl metabolite to parent ratio was detected in the ESRD group when compared to the normal group. As exposure 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 to have no meaningful influence on the exposure of selumetinib (see Dosage & Administration).
Hepatic impairment: 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 and unbound 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 in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment; the total AUC and 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 Dosage & Administration).
Ethnicity: Following a single-dose, selumetinib exposure appears to be higher in Japanese, non-Japanese-Asian and Indian healthy adult volunteers compared to Western adult volunteers. However, there is considerable overlap with Western subjects when corrected for body weight or BSA (see Dosage & Administration).
Adult patients (>18 years old): The PK parameters in adult healthy volunteers and adult patients with advanced solid malignancies, are similar to those in paediatric patients (3 to ≤18 years old) with NF1.
In adult patients with solid malignancies, at a dose of 75 mg twice daily, C_max and geometric mean (%CV) AUC were 1307 (76%) ng/mL and 4736 (37%) ng·h/mL, respectively. Peak plasma concentrations of selumetinib were achieved 1.5-hour post-dose with a mean elimination half-life of 7.8 hours. C_max and AUC increased dose proportionally over a 25 mg to 100 mg dose range, and administration of 75 mg selumetinib twice daily resulted in minimal accumulation of ~1.2-fold.
Toxicology: Preclinical safety data: Mutagenicity: Selumetinib showed no mutagenic or clastogenic potential in vitro but produced an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action. The free mean exposure (C_max) at the No Observed Effect Level (NOEL) was approximately 27-times greater than clinical-free exposure at the maximum recommended human dose (MRHD) of 25 mg/m².
Carcinogenicity: Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice at free exposures 24-times (females) and 16-times (males) the free clinical AUC at MRHD and in a 2-year carcinogenicity study in rats at free exposures 2.9-times (females) and 3.7-times (males) the clinical-free AUC at MRHD.
Repeat-dose toxicity: In repeat-dose toxicity studies in mice and rats, the main effects seen after selumetinib exposure were in the skin, scabs associated with microscopic erosions and ulceration in rats at a free exposure similar to the clinical exposure (free AUC) at the MRHD; inflammatory and ulcerative GI tract findings in mice associated with secondary changes in the liver and lymphoreticular system at free exposures approximately 28-times the clinical-free exposure at the MRHD; and growth plate (physeal) dysplasia in male rats 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 skin toxicities and physeal dysplasia were not evaluated.
Reproductive toxicology: Fertility: In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily corresponding to approximately 22-times the human clinical exposure based on free AUC at the MRHD. In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected, but the number of live foetuses was slightly reduced. Following a three-week treatment withdrawal period, no effects were apparent on any parameter. The No Observed Adverse Effect Level (NOAEL) for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately, 3.5-fold human free exposure at the MRHD).
Embryofoetal toxicity: In embryofoetal development studies in mice, selumetinib caused a reduction in the number of live foetuses due to an increase in post-implantation loss, a reduction in mean foetal and litter weights, increased occurrence of open eye and cleft palate at dose levels that did not induce significant maternal toxicity. These effects were seen at an exposure >3.5-fold the clinical exposure at MRHD based on free AUC and indicate that selumetinib may have potential to cause defects in the foetus.
Pre- and postnatal development: Administration of selumetinib to pregnant mice from gestation Day 6 through to lactation Day 20 resulted in reduced pup body weights, and fewer pups met the pupil constriction criterion on Day 21 post-partum. The incidence of malformations (prematurely open eye(s) and cleft palate) was increased at all dose levels. Malformations occurred at maternal concentration (C_max) 0.4-fold below the mean free clinical concentration at MRHD.
Selumetinib and its active metabolite were excreted in the milk of lactating mice at concentrations approximately the same as those in plasma.

KOSELUGO is indicated for the treatment of paediatric patients aged 3 years and above with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

Therapy 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 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 3). (See Table 3.)

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Treatment with KOSELUGO should continue as long as clinical benefit is observed, or until PN progression or the development of unacceptable toxicity.
Method of administration: KOSELUGO should be taken on an empty stomach with no food or drink other than water. Do not consume food 2 hours prior to dosing and 1 hour after dosing (see Interactions and Pharmacology: Pharmacokinetics under Actions).
KOSELUGO capsules should be swallowed whole with water, and should not be chewed, dissolved, or opened.
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: Do not take an additional dose if vomiting occurs after KOSELUGO administration but continue with the next scheduled dose.
Dose adjustments: For adverse events: Interruption and/or dose reduction or permanent discontinuation of KOSELUGO may be required based on individual safety and tolerability (see Precautions and Adverse Reactions).
Recommended dose reductions are given in Table 4 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. (See Tables 4 and 5.)

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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), KOSELUGO treatment should be interrupted until resolution. Once resolved, reduce KOSELUGO by one dose level when resuming therapy (see Table 4).
In patients who develop symptomatic LVEF reduction or a grade 3 or 4 LVEF reduction, KOSELUGO should be discontinued and a prompt cardiology referral should be carried out (see Precautions).
Dose modification advice for ocular toxicities: KOSELUGO 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 KOSELUGO by one dose level when resuming therapy (see Table 4). In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. In patients who are diagnosed with retinal vein occlusion (RVO), treatment with KOSELUGO should be permanently discontinued (see Precautions).
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. If a patient is currently taking 20 mg/m² twice daily, dose reduce to 15 mg/m² twice daily (see Table 6 and Interactions). (See Table 6.)

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Special patient populations: Renal impairment: Based on clinical studies no dose adjustment is recommended in patients with mild, moderate, severe renal impairment or those with End Stage Renal Disease (ESRD) (see Pharmacology: Pharmacokinetics under Actions).
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 6). KOSELUGO is not recommended for use in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Ethnicity: Increased systemic exposure has been seen in adult Asian subjects, although there is considerable overlap with Western subjects when corrected for body weight. No specific adjustment to the starting dose is recommended for paediatric Asian patients, however, these patients should be closely monitored for adverse events (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of KOSELUGO in children less than 3 years of age has not been established. No data are currently available.

There is no specific treatment for overdose. If overdose occurs, patients should be treated supportively with appropriate monitoring as necessary. Dialysis is ineffective in the treatment of overdose.

None.

Cardiomyopathy: Cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline, occurred in 23% of 74 paediatric patients who received KOSELUGO in SPRINT (see Adverse Reactions). Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients.
Left ventricular dysfunction or decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in an unapproved population of adult patients with multiple tumour types who received KOSELUGO. Decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in a paediatric population with NF1 in an expanded access program.
The safety of KOSELUGO has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.
Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction (see Dosage & Administration). In patients who interrupt KOSELUGO for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF to greater than or equal to the institutional LLN, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiologist.
Ocular Toxicity: Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of 74 paediatric patients receiving KOSELUGO in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients.
Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED), occurred in an unapproved population of adult patients with multiple tumour types who received KOSELUGO as a single agent or in combination with other anti-cancer agents. RPED occurred in the paediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation.
Conduct comprehensive ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue KOSELUGO in patients with RVO. Withhold KOSELUGO in patients with RPED, follow up with optical coherence tomography assessments every 3 weeks until resolution, and resume KOSELUGO at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of the adverse reaction (see Dosage & Administration).
Gastrointestinal Toxicity: Diarrhoea occurred in 77% of 74 paediatric patients who received KOSELUGO in SPRINT, including Grade 3 in 15% of patients. Diarrhoea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhoea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhoea was 17 days and the median duration was 2 days.
Serious gastrointestinal toxicities, including perforation, colitis, ileus, and intestinal obstruction, occurred in an unapproved population of adult patients with multiple tumour types who received KOSELUGO as a single agent or in combination with other anti-cancer agents. Colitis occurred in an unapproved population of paediatric patients with multiple tumour types who received KOSELUGO as a single agent.
Advise patients to start an anti-diarrhoeal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhoea episodes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction (see Dosage & Administration).
Skin Toxicity: Rash occurred in 91% of 74 paediatric patients who received KOSELUGO in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients.
Other skin toxicities, including severe palmar-plantar erythrodysesthesia syndrome, occurred in an unapproved population of adult patients with multiple tumour types who received KOSELUGO as a single agent or in combination with other anti-cancer agents.
Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction (see Dosage & Administration).
Increased Creatine Phosphokinase: Increased creatine phosphokinase (CPK) occurred in 76% of 74 paediatric patients who received KOSELUGO in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued KOSELUGO for myalgia.
Rhabdomyolysis occurred in an unapproved adult population who received KOSELUGO as a single agent.
Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction (see Dosage & Administration).
Increased Levels of Vitamin E and Risk of Bleeding: KOSELUGO capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); while KOSELUGO 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K- dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO and supplement) will exceed the recommended or safe limits.
An increased risk of bleeding in patients may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with KOSELUGO. Monitor for bleeding in these patients. Increase international normalized ratio (INR) monitoring, as appropriate, in patients taking a vitamin-K antagonist. Perform anticoagulant assessments, including INR or prothrombin time, more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate (see Interactions).
Embryo-Foetal Toxicity: Based on findings from animal studies and its mechanism of action, KOSELUGO can cause foetal harm when administered to a pregnant woman. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced foetal weight, adverse structural defects, and effects on embryo-foetal survival at approximate exposures >5-times the human exposure at the clinical dose of 25 mg/m² twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose (see Use in Pregnancy & Lactation).
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. 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 KOSELUGO and patients who experience these symptoms should observe caution when driving or using machines.

Contraception in males and females: Women of childbearing potential should be advised to avoid becoming pregnant while receiving KOSELUGO. 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.
KOSELUGO is not recommended in women of childbearing potential not using contraception.
Pregnancy: There are no data on the use of KOSELUGO in pregnant women. Studies in animals have shown reproductive toxicity including embryofoetal death, structural defects and reduced foetal weights (see Pharmacology: Toxicology: Preclinical safety data under Actions). KOSELUGO is not recommended during pregnancy.
It is recommended that a pregnancy test should be performed on women of childbearing potential prior to initiating treatment.
Advise women of childbearing potential to avoid becoming pregnant while receiving KOSELUGO. If a female patient or a female partner of a male patient receiving KOSELUGO becomes pregnant, she should be apprised of the potential hazard to the foetus.
Lactation/Breast Feeding: KOSELUGO and its active metabolite are excreted in the milk of lactating mice (see Pharmacology: Toxicology: Preclinical safety data under Actions). It is not known whether KOSELUGO, or its metabolites, are excreted in human milk. A risk to the breast-fed infant cannot be excluded, therefore breast-feeding mothers are advised not to breast-feed during treatment with KOSELUGO.
Fertility: There are no data on the effect of KOSELUGO on human fertility.
KOSELUGO 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 Pharmacology: Toxicology: Preclinical safety data under Actions).

Overall summary of the safety profile: The safety of KOSELUGO monotherapy has been evaluated in a combined safety population of 74 paediatric patients (20-30 mg/m² twice daily) with NF1 PN and 347 adult patients (75-100 mg twice daily) with multiple tumour types.
The median total duration of KOSELUGO treatment in paediatric patients with NF1 PN was 28 months (range: <1 - 71 months), 23% of patients were exposed to KOSELUGO treatment for >48 months.
In the Phase II Stratum 1 pivotal study (SPRINT), 50 paediatric patients with NF1 PN were treated with KOSELUGO 25 mg/m² twice daily, see Pharmacology: Pharmacodynamics under Actions. The most common adverse reactions of any grade (incidence ≥45%) were vomiting, rash, blood creatine phosphokinase increased, diarrhoea, nausea, dry skin, asthenic events, pyrexia, acneiform rash, hypoalbuminaemia, stomatitis, aspartate aminotransferase increased and paronychia. Dose interruptions and reductions due to adverse events were reported in 80% and 24% of patients, respectively. The most commonly reported ADRs leading to dose modification of KOSELUGO were vomiting (12 [24.0%]), paronychia (7 [14.0%]), diarrhoea (6 [12.0%]) and nausea (5 [10.0%]). Permanent discontinuation due to adverse events was reported in 12% of the patients.
Tabulated list of adverse reactions: Table 7 presents the adverse reactions identified in the SPRINT Phase II Stratum 1. Adverse reactions 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. (See Table 7.)

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Table 8 presents the laboratory abnormalities in SPRINT Phase II Stratum 1. (See Table 8.)

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Adverse Reactions Identified in Other Clinical Trials: Table 9 presents the adverse reactions identified from other clinical trial experience in adult patients (N=347), with multiple tumour types, receiving treatment with KOSELUGO (75 mg twice daily): (See Table 9.)

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In addition, a single event of RPED was reported in a paediatric patient receiving KOSELUGO monotherapy (25 mg/m² twice daily) for pilocytic astrocytoma involving the optic pathway in an externally sponsored paediatric study, see Dosage & Administration and Precautions.
Description of selected adverse reactions: LVEF reduction: In SPRINT, 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 events 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.
Decrease in LVEF should be managed using treatment interruption, dose reduction or treatment discontinuation (see Dosage & Administration and Precautions).
Blurred vision: In SPRINT, grade 1 and 2 events of blurred vision were reported in 4 (8%) patients. Two patients required dose interruption. All events were managed without dose reduction. No retinal involvement was observed in the ophthalmic examinations of paediatric patients.
If patients report new visual disturbances a complete ophthalmological assessment is recommended. Retinal toxicities can be managed using treatment interruption, dose reduction or treatment discontinuation (see Dosage & Administration and Precautions).
Paronychia: In SPRINT, paronychia was reported in 23 (46%) patients, the median time to first onset of maximum grade paronychia adverse event was 306 days and the median duration of events was 96 days. The majority of these events were grade 1 or 2 and were treated with supportive or symptomatic therapy and dose modification. Grade ≥3 events occurred in three (6%) patients. Seven patients had a KOSELUGO dose interruption for adverse events 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 events of blood CPK elevation occurred in 76% of patients in SPRINT. The median time to first onset of the maximum grade CPK increase was 106 days and the median duration of events was 126 days. The majority of events were grade 1 or 2 and resolved with no change in KOSELUGO dose. Grade ≥3 events occurred in three (6%) patients. A grade 4 event led to treatment interruption followed by dose reduction.
Gastrointestinal toxicities: Vomiting (82%), abdominal pain (76%), diarrhoea (70%), nausea (66%), stomatitis (50%), and constipation (34%) 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 events were reported for diarrhoea (16%), nausea (2%), and vomiting (6%). For one patient diarrhoea led to dose reduction and subsequent discontinuation. No dose reduction or discontinuation was required for adverse events of nausea, vomiting or stomatitis. No grade ≥4 events were reported.
Skin toxicities: In SPRINT, 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 events 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, 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.

Pharmacokinetic interactions: 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 volunteers. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and C_max by 23%.
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 volunteers, 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) or 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 Dosage & Administration and Table 6).
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 efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by -38% and C_max by -22%. Avoid concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) or moderate CYP3A4 inducers with KOSELUGO.
Active substances whose plasma concentrations may be altered by selumetinib: In vitro, selumetinib is an inhibitor of OAT3 and the potential for a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded (see Pharmacology: Pharmacodynamics under Actions).
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 medications (see Precautions).

Incompatibilities: None.
Instructions for use, handling and disposal: No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C.
Store in the original bottle to protect from moisture and light. Keep the bottle tightly closed.
Do not remove desiccant.

Other Therapeutic Products

L01EE04 - selumetinib ; Belongs to the class of mitogen-activated protein kinase (MEK) inhibitors. Used in the treatment of cancer.

POM