Koselugo

Paed patients ≥3 yr w/ neurofibromatosis type 1 who have symptomatic inoperable plexiform neurofibromas (PN).

Individualized dosing based on BSA. Recommended dose: 25 mg/m² bd (approx every 12 hr). Max single dose: 50 mg. BSA ≥1.90 m² 50 mg bd, 1.70-1.89 m² 45 mg bd, 1.50-1.69 m² 40 mg bd, 1.30-1.49 m² 35 mg bd, 1.10-1.29 m² 30 mg bd, 0.90-1.09 m² 25 mg bd, 0.70-0.89 m² 20 mg bd, 0.55-0.69 m² 20 mg in the morning & 10 mg in the evening. Continue treatment as long as clinical benefit is observed or until PN progression or unacceptable toxicity develops. Dose adjustments for adverse events: BSA ≥1.90 m² 1st dose reduction: 35 mg in the morning & evening. 2nd dose reduction: 25 mg in the morning & evening, 1.70-1.89 m² 1st dose reduction: 35 mg in the morning & 30 mg in the evening. 2nd dose reduction: 25 mg in the morning & 20 mg in the evening, 1.50-1.69 m² 1st dose reduction: 30 mg in the morning & evening. 2nd dose reduction: 25 mg in the morning & 20 mg in the evening, 1.30-1.49 m² 1st dose reduction: 25 mg in the morning & evening. 2nd dose reduction: 25 mg in the morning & 10 mg in the evening, 1.10-1.29 m² 1st dose reduction: 25 mg in the morning & 20 mg in the evening. 2nd dose reduction: 20 mg in the morning & 10 mg in the evening, 0.90-1.09 m² 1st dose reduction: 25 mg in the morning & 10 mg in the evening. 2nd dose reduction: 10 mg in the morning & evening, 0.70-0.89 m² 1st dose reduction: 20 mg in the morning & 10 mg in the evening. 2nd dose reduction: 10 mg in the morning & evening, 0.55-0.69 m² 1st dose reduction: 10 mg in the morning & evening. 2nd dose reduction: 10 mg once daily. Co-administration w/ CYP3A4 or CYP2C19 inhibitors Reduce dose to 20 mg/m² bd if patient is currently taking 25 mg/m² bd. Reduce dose to 15 mg/m² bd if patient is currently taking 20 mg/m² bd. Moderate hepatic impairment Starting dose: 20 mg/m² bd.

May be taken with or without food: Swallow whole w/ water. Do not chew/dissolve/open.

Patients w/ history of impaired left ventricular ejection fraction or baseline ejection fraction below institutional LLN. Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 mth during 1st yr of treatment, every 6 mth thereafter & as clinically indicated. Possible cardiomyopathy; blurred vision, photophobia, cataracts, ocular HTN, serious ocular toxicities including retinal vein occlusion (RVO) & retinal pigment epithelial detachment (RPED); diarrhoea, serious GI toxicities including perforation, colitis, ileus & intestinal obstruction; rash, skin toxicities including severe palmar-plantar erythrodysesthesia syndrome; increased creatine phosphokinase (CPK) (concurrent w/ myalgia) & rhabdomyolysis; increased risk of bleeding in patients co-administered w/ vit K or anti-platelet antagonists. Conduct comprehensive ophth assessments prior to initiating Koselugo at regular intervals during treatment & for new or worsening visual changes. Permanently discontinue use in patient w/ RVO. W/hold therapy in patients w/ RPED; follow-up w/ optical coherence tomography assessments every 3 wk until resolution & resume treatment at reduced dose. Advise patient to start anti-diarrhoeal (eg, loperamide) immediately after 1st episode of unformed, loose stool & to increase fluid intake during diarrhoea episodes. Monitor for severe skin rashes. Obtain serum CPK prior to initiating Koselugo, periodically during treatment & as clinically indicated. W/hold, reduce dose or permanently discontinue use based on severity of AR. Possible increased vit E levels. Monitor for bleeding; frequently perform anticoagulant assessments including INR or prothrombin time & appropriately adjust vit K antagonist or anti-platelet dose. Not recommended to use concomitantly w/ strong or moderate CYP3A4 or CYP2C19 inhibitors. Patients w/ BSA <0.55 m². Closely monitor Asian patients for adverse events. Possible fatigue, asthenia & visual disturbances; observe caution when driving or using machines. Not recommended in patients w/ severe hepatic impairment. Not recommended in women of childbearing potential not using contraception; advise both male & female patients of reproductive potential to use effective contraception during & for at least 1 wk after completion of treatment. May cause foetal harm. Not recommended during pregnancy. Advise not to breast-feed during treatment. Childn <3.

Blurred vision; epistaxis; vomiting, abdominal pain, diarrhoea, nausea, stomatitis, constipation; dry skin, dermatitis acneiform, paronychia, pruritus, dermatitis, non-acneiform rashes, hair changes; musculoskeletal pain; headache; haematuria, proteinuria; decreased appetite; decreased ejection fraction, sinus tachycardia; skin infection; pyrexia, asthenic events, peripheral oedema; increased BP. Dyspnoea; dry mouth; facial oedema.

Increased C_max & AUC w/ strong CYP3A4 inhibitor; erythromycin; strong CYP2C19/moderate CYP3A4 inhibitor; fluoxetine. Avoid co-administration w/ strong CYP3A4 (eg, clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (eg, ticlopidine) inhibitors; moderate CYP3A4 (eg, erythromycin & fluconazole) or CYP2C19 (eg, omeprazole) inhibitors. Decreased C_max & AUC w/ strong CYP3A4 inducer; efavirenz. Avoid concomitant use w/ strong CYP3A4 (eg, phenytoin, rifampicin, carbamazepine, St. John's wort) or moderate CYP3A4 inducers. Active substances whose plasma conc may be altered by OAT3 inhibitor. Avoid taking vit E supplements.

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POM