Finlee · 4.4 Special warnings and precautions for use · 1

HOS-288707 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile In clinical studies of paediatric patients treated with dabrafenib in combination with trametinib, the most common adverse reactions (reported at a frequency ≥20%) were: pyrexia (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), dermatitis acneiform (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and transaminases increased (22%). The most frequently reported severe (Grade 3/4) adverse reactions were: neutropenia (15%), pyrexia (11%), transaminases increased (6%) and weight increased (5%). Long-term data on growth and skeletal maturation in paediatric patients are currently limited (see section 5.3). The safety profile in paediatric patients was largely consistent with the safety profile previously established in adult patients. The following additional adverse reactions have so far only been reported in adult patients treated with dabrafenib capsules and trametinib tablets: cutaneous squamous cell carcinoma, seborrhoeic keratosis, peripheral neuropathy (including sensory and motor neuropathy), lymphoedema, dry mouth, actinic keratosis, renal failure, potentiation of radiation toxicity (common), melanoma, acrochordon, sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, left ventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinal perforation, haemophagocytic lymphohistiocytosis (rare), tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, tattoo-associated skin reactions (frequency not known). In addition, cases of biocular panuveitis or biocular iridocyclitis suggestive of Vogt-Koyanagi-Harada syndrome have been reported in adult patients. Tabulated list of adverse reactions The safety of dabrafenib in combination with trametinib has been evaluated in a pooled safety set of 171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advanced solid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 years of age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years of age at enrolment. The mean treatment duration was 2.3 years. Adverse reactions (Table 4) are listed below by MedDRA system organ class ranked by frequency using the following convention: very common (≥1/10), common (≥1/100

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HOS-288703 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-288702 · has-indication-information · PDF-Seite 2

Low-grade glioma Finlee in combination with trametinib is indicated for the treatment of paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. High-grade glioma Finlee in combination with trametinib is indicated for the treatment of paediatric patients aged 1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment.

HOS-288705 · has-interaction-information · PDF-Seite 11

Interaction studies have only been performed in adults. Effect of other medicinal products on dabrafenib Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the active metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during administration with dabrafenib when possible. Dabrafenib should be used with caution if strong inhibitors (e.g. ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) are co-administered with dabrafenib. Co-administration of dabrafenib with potent inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum)) of CYP2C8 or CYP3A4 should be avoided. Administration of ketoconazole (a CYP3A4 inhibitor) 400 mg once daily, with dabrafenib 75 mg twice daily, resulted in a 71% increase in dabrafenib AUC and a 33% increase in dabrafenib Cmax relative to administration of dabrafenib alone. Co-administration resulted in increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 82% and 68%, respectively). A decrease of 16% in AUC was noted for carboxy-dabrafenib. Administration of gemfibrozil (a CYP2C8 inhibitor) 600 mg twice daily, with dabrafenib 75 mg twice daily, resulted in a 47% increase in dabrafenib AUC but did not alter dabrafenib Cmax relative to administration of dabrafenib alone. Gemfibrozil had no clinically relevant effect on the systemic exposure to dabrafenib metabolites (≤13%). Administration of rifampin (a CYP3A4/CYP2C8 inducer) 600 mg once daily, with dabrafenib 150 mg twice daily, resulted in a decrease in repeat-dose dabrafenib Cmax (27%) and AUC (34%). No relevant change in AUC was noted for hydroxy-dabrafenib. There was an increase in AUC of 73% for carboxy-dabrafenib and a decrease in AUC of 30% for desmethyl-dabrafenib. Co-administration of repeat doses of dabrafenib 150 mg twice daily and the pH-elevating agent rabeprazole 40 mg once daily resulted in a 3% increase in AUC and a 12% decrease in dabrafenib Cmax. These changes in dabrafenib AUC and Cmax are considered not clinically meaningful. Medicinal products that alter the pH of the upper gastrointestinal (GI) tract (e.g. proton pump inhibitors, H2- receptor antag

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HOS-288706 · has-pregnancy-information · PDF-Seite 13

Women of childbearing potential/Contraception in females Women of childbearing potential must use effective methods of contraception during therapy and for 2 weeks following discontinuation of dabrafenib and for 16 weeks following discontinuation of trametinib. Dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception, such as a barrier method, should be used (see section 4.5). Pregnancy There are no data from the use of dabrafenib in pregnant women. Animal studies have shown reproductive toxicity and embryo-foetal developmental toxicities, including teratogenic effects (see section 5.3). Dabrafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If the patient becomes pregnant while taking dabrafenib, the patient should be informed of the potential hazard to the foetus. Please see also the trametinib powder for oral solution SmPC (section 4.6) for additional information on trametinib. Breast-feeding It is not known whether dabrafenib is excreted in human milk. A risk to the breast-feeding child cannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue dabrafenib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data in humans for dabrafenib in combination with trametinib. Dabrafenib may impair male and female fertility as effects on male and female reproductive organs have been seen in animals (see section 5.3). Male patients taking dabrafenib in combination with trametinib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Please see the trametinib powder for oral solution SmPC for additional information.

HOS-288704 · has-warning-information · PDF-Seite 6

Finlee is intended for use in combination with trametinib powder for oral solution as there are limited efficacy data for dabrafenib monotherapy and for trametinib monotherapy in BRAF V600 mutation- positive glioma. The trametinib powder for oral solution SmPC must be consulted prior to intiation of treatment. For additional information on warnings and precautions associated with trametinib treatment, please refer to the trametinib powder for oral solution SmPC. BRAF V600E testing The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF glioma. Dabrafenib should not be used in patients with wild-type BRAF glioma (see section 5.1). New malignancies New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used in combination with trametinib. Cutaneous malignancies Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma and new primary melanoma have been observed in adult patients treated with dabrafenib in combination with trametinib (see section 4.8). It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy. Suspicious skin lesions should be managed with dermatological excision and do not require treatment modifications. Patients should be instructed to inform their physicians immediately if new skin lesions develop. 6 Non-cutaneous malignancies In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAP kinase) signalling in BRAF wild-type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure (see section 4.8) when RAS mutations are present. RAS-associated malignancies have been reported in adult clinical studies, both with another BRAF inhibitor (chronic myelomonocytic leukaemia and non-cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreatic adenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with trametinib (colorectal cancer, pancreatic cancer). The benefits and risks should be considered before administering dabrafenib in patients with a prior or concurre

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