Ojemda

Treatment with tovorafenib should be initiated and supervised by a qualified physician experienced in the use of anti-cancer medicinal products. Patient selection Before taking tovorafenib, patients must have confirmation of BRAF fusion or rearrangement, or BRAF V600 mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose.

If the CE-marked IVD is not available, confirmation of BRAF fusion or rearrangement, or BRAF V600 mutation should be assessed by an alternative validated test. Posology The recommended dose of tovorafenib based on body surface area (BSA) is 380 mg/m2 once weekly.

The maximum recommended dose is 600 mg once weekly (see Table 1). Ojemda may be administered as an immediate release tablet (see Table 1) or as an oral suspension (see tovorafenib 25 mg/ml powder for oral suspension SmPC). 3 m2 has not been established.

40 m2 600 mg Duration of treatment Treatment with tovorafenib should be continued once weekly until disease progression, loss of clinical benefit, or unacceptable toxicity. Missed or delayed doses If a dose is missed by 3 days or less, the missed dose should be taken as soon as possible, and the next dose should be taken on its regularly scheduled day.

If a dose is missed by more than 3 days, the missed dose should be skipped, and the next dose should be taken on its regularly scheduled day. A minimum of 4 days should occur between doses. Vomiting If vomiting occurs immediately after taking a dose, the dose should be repeated.

Dose modifications The management of adverse reactions may require dose reduction, treatment interruption or treatment discontinuation. The recommended dose reductions for adverse reactions for tovorafenib tablets are provided in Table 2.

40 m2 500 mg once weekly 400 mg once weekly The recommended dose modifications for adverse reactions for tovorafenib are in Table 3. 4 Table 3: Recommended dose modifications for adverse reactions Severity of ADRa Dose modificationb Haemorrhage and intratumoural haemorrhage • Intolerable Grade 2 • Grade 3 Withhold administration.

- If improved to Grade 0-1, resume at reduced dose. - If not improved, consider permanent discontinuation. • First occurrence of any Grade 4 Withhold administration. - If improved to Grade 0-1, resume at reduced dose. - If not improved, consider permanent discontinuation.

Summary of the safety profile The safety profile of tovorafenib is based on pooled data from 137 patients 6 months of age and older with relapsed or refractory paediatric LGG harbouring a BRAF alteration in one clinical study (FIREFLY- 1, Arm 1 and 2).

1 months). The safety population characteristics were comprised of patients with a median age of 9 years (range 1 to 24 years); 3 (2%) patients were 6 months to < 2 years of age, 93 (68%) patients were 2 years to < 12 years of age, and 41 (30%) patients were > 12 years of age.

9%). 1%). 1%). 1%). 9%). Tabulated list of adverse reactions Adverse reactions reported in patients treated with tovorafenib monotherapy in FIREFLY-1 (n=137) are listed in Table 4. Adverse reactions are listed below by MedDRA body system organ class and the following frequency convention: very common (≥ 1/10) and common (≥ 1/100 to < 1/10).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4:

Adverse drug reactions reported in paediatric LGG patients in FIREFLY-1 (n=137) Infections and infestations Very common Upper respiratory tract infection, paronychia, viral infection Blood and lymphatic system disorders Very common Anaemiaa Metabolism and nutrition disorders Very common Decreased appetite, hypokalaemia, hypoalbuminemia, hyponatraemia Nervous system disorders Very common Headache Eye disorders Common Blepharitis, dry eye Vascular disorders Very common Haemorrhageb, intratumoural haemorrhagec, flushing Gastrointestinal disorders Very common Vomiting, nausea, constipation, abdominal paind, stomatitise, diarrhoeaf Skin and subcutaneous tissue disorders Very common Rashg, hair colour changes, dry skinh, dermatitis acneiformi, pruritus, skin discolourationj, alopecia, photosensitivity reaction Musculoskeletal and connective tissue disorders Very common Growth retardationk, pain in extremity, myalgia, arthralgia General disorders Very common Fatigue, pyrexia, oedemal Investigations Very common Blood phosphorus decreasedm, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, aspartate aminotransferase increased, weight decreased, alanine aminotransferase increased, lymphocyte count decreased, blood bilirubin increased, white blood cell count decreased.

8). Patients and caregivers should be advised of the risk of intratumoural haemorrhage during treatment with tovorafenib. The risk of tumour haemorrhage may be increased with concomitant use of anticoagulants and antiplatelet therapy.

Monitoring for signs and symptoms of haemorrhage and evaluation as clinically indicated should be done routinely. 2). Other haemorrhage events Haemorrhagic events have been reported very commonly in patients taking tovorafenib. 8). Patients and caregivers should be advised of the risk of haemorrhage during treatment with tovorafenib.

The risk of haemorrhage may be increased with concomitant use of anticoagulants and antiplatelet therapy. 6 Monitoring for signs and symptoms of haemorrhage, and evaluation as clinically indicated should be done routinely. 2). 8). Patients and caregivers should be advised of the risk of effect on growth during treatment with tovorafenib.

Monitoring for growth and development should be done prior to initiation, routinely during and following discontinuation of treatment with tovorafenib. 8). Monitoring of liver function tests including AST, ALT, bilirubin levels should be done prior to initiation, 1 month after initiation and routinely during treatment with tovorafenib.

2). 8). Patients should be monitored for new or worsening skin reactions. Dermatologic consultation and initiation of supportive care should be considered as clinically indicated. Patients and caregivers should be advised of the risk of rash and photosensitivity during treatment with tovorafenib.

The use of precautionary measures against ultraviolet exposure such as use of sunscreen (SPF ≥ 50), sunglasses, and/or protective clothing during treatment with tovorafenib is recommended. 8). Women of childbearing potential/ Contraception in females and males Before initiating treatment in women of childbearing potential, appropriate advice on effective methods of contraception should be provided.

1.