Koselugo Special Precautions

Left ventricular ejection fraction (LVEF) reduction: Asymptomatic decreases in ejection fraction have been reported in 22% of paediatric patients in the pivotal clinical trial. Median time to initial onset of these adverse reactions was 226 days. 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 Adverse Reactions).
Paediatric 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 Dosage & Administration).
Ocular toxicity: Patients should be advised to report any new visual disturbances. Adverse reactions of blurred vision have been reported in paediatric patients receiving selumetinib. 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 Adverse Reactions).
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 Dosage & Administration). If RVO is diagnosed, treatment with selumetinib should be permanently discontinued (see Dosage & Administration).
Liver laboratory abnormalities: Liver laboratory abnormalities, specifically AST and ALT elevations, can occur with selumetinib (see Adverse Reactions). Liver laboratory values should be monitored before initiation of selumetinib and at least monthly during the 6 first months of treatment, and thereafter as clinically indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see Table 3 under Dosage & Administration).
Skin and subcutaneous disorders: Skin rash (including maculopapular rash and acneiform rash), paronychia and hair changes have been reported very commonly in the pivotal clinical study (see Adverse Reactions). Pustular rash, hair colour changes and dry skin 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).
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. High doses of vitamin E may increase the risk of bleeding in patients taking concomitant anticoagulant or antiplatelet medicinal products (e.g., warfarin or acetylsalicylic acid). Anticoagulant assessments, including international normalised ratio or prothrombin time, should be conducted more frequently to detect when dose adjustments of the anticoagulant or antiplatelet medicinal products are warranted (see Interactions).
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. Therefore, selumetinib should not be administered to patients who are unable or unwilling to swallow the capsule whole (see Dosage & Administration).
Effects on ability to drive and use machines: 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 selumetinib and patients who experience these symptoms should observe caution when driving or using machines.
Use in Pregnancy: Women of childbearing potential: Koselugo is not recommended in women of childbearing potential who are not using contraception (see Use in Pregnancy & Lactation).