Tafinlar · 4.4 Special warnings and precautions for use · 1

HOS-216252 · has-adverse-reaction-information · PDF-Seite 15

Summary of the safety profile The safety of dabrafenib monotherapy is based on the integrated safety population from five clinical studies, BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK-2), BRF113220, and BRF112680, which included 578 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with dabrafenib 150 mg twice daily. The most common adverse reactions (incidence ≥15%) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash, and vomiting. The safety of dabrafenib in combination with trametinib has been evaluated in the integrated safety population of 1 188 adult patients with BRAF V600 mutant unresectable or metastatic melanoma, Stage III BRAF V600 mutant melanoma following complete resection (adjuvant treatment), advanced NSCLC and advanced DTC treated with dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The mean treatment duration was 16 months (see section 5.1). The most common adverse reactions (incidence ≥20%) for dabrafenib in combination with trametinib were: pyrexia, fatigue, nausea, rash, chills, diarrhoea, headache, arthralgia, vomiting, cough, haemorrhage and peripheral oedema. Tabulated list of adverse reactions Adverse reactions associated with dabrafenib obtained from clinical studies and post-marketing surveillance are tabulated below for dabrafenib monotherapy (Table 3) and dabrafenib in combination with trametinib (Table 4). Adverse reactions are listed below by MedDRA system organ class and ranked by frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3 Adverse reactions with dabrafenib monotherapy System organ class Frequency (all grades) Adverse reactions Very common Papilloma Cutaneous squamous cell carcinoma Neoplasms benign, malignant Seborrhoeic keratosis and unspecified (incl cysts and Common polyps) Acrochordon (skin tags) Basal cell

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HOS-216248 · has-contraindication-information · PDF-Seite 6

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

HOS-216247 · has-indication-information · PDF-Seite 2

Melanoma Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adults and adolescents aged 12 years and older with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1). Adjuvant treatment of melanoma Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage III melanoma with a BRAF V600 mutation, following complete resection. Non-small cell lung cancer (NSCLC) Dabrafenib in combination with trametinib is indicated for the treatment of adults with advanced non- small cell lung cancer with a BRAF V600 mutation. 2 Differentiated thyroid cancer (DTC) Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with locally advanced or metastatic differentiated thyroid cancer with a BRAF V600E mutation, refractory to or not eligible for radioactive iodine (RAI) who have progressed during or after prior systemic therapy (for biomarker-based patient selection, see section 4.2).

HOS-216250 · has-interaction-information · PDF-Seite 12

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 75 mg twice daily 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 75 mg twice daily 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 antagonists, antacids) are

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HOS-216251 · has-pregnancy-information · PDF-Seite 14

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 16 weeks following the last dose of trametinib when given in combination with dabrafenib. Dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception 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 trametinib SmPC (see section 4.6) when used in combination with trametinib. Breast-feeding It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are 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 as monotherapy or in combination with trametinib. Dabrafenib may impair male and female fertility as adverse effects on male and female reproductive organs have been seen in animals (see section 5.3). Male patients taking dabrafenib as monotherapy or in combination with trametinib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Please see trametinib SmPC (see section 4.6) when used in combination with trametinib.

HOS-216249 · has-warning-information · PDF-Seite 6

When dabrafenib is given in combination with trametinib, the SmPC of trametinib must be consulted prior to intiation of combination treatment. For additional information on warnings and precautions associated with trametinib treatment, please refer to the trametinib SmPC. BRAF V600 testing The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF melanoma, wild-type BRAF NSCLC or wild-type BRAF DTC therefore dabrafenib should not be used in patients with wild-type BRAF melanoma, wild-type BRAF NSCLC or wild-type BRAF DTC (see sections 4.2 and 5.1). Dabrafenib in combination with trametinib in patients with melanoma who have progressed on a BRAF inhibitor 6 There are limited data in patients taking the combination of dabrafenib with trametinib who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see section 5.1). Therefore, other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established. New malignancies New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used as monotherapy or in combination with trametinib. Cutaneous malignancies Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with dabrafenib alone and in combination with trametinib (see section 4.8). In the Phase III clinical studies MEK115306 and MEK116513 in patients with unresectable or metastatic melanoma, cuSCC occurred in 10% (22/211) of patients receiving dabrafenib as a monotherapy and in 18% (63/349) of patients receiving vemurafenib as a monotherapy, respectively. Across the pivotal combination therapy studies in melanoma and advanced NSCLC, cuSCC occurred in 2% of patients receiving dabrafenib in combination with trametinib. The median time to diagnosis of the first occurrence of cuSCC in study MEK115306 was 223 days (range 56 to 510 days) in the combination therapy arm and 60 days (range 9 to 653 days) in the dabrafenib monotherapy arm. In the Phase III study BRF115532 (COMBI-AD) in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving dabrafenib in combination with trametinib as compared to 1% (5/432) of patients receiving placebo h

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