Mekinist · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-096508 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The safety of trametinib monotherapy has been evaluated in the integrated safety population of 329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with trametinib 2 mg once daily in studies MEK114267, MEK113583, and MEK111054. Of these patients, 211 were treated with trametinib for BRAF V600 mutant melanoma in the randomised open-label Phase III study MEK114267 (METRIC) (see section 5.1). The most common adverse reactions (incidence ≥20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform. 12 The safety of trametinib in combination with dabrafenib 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 trametinib 2 mg once daily and dabrafenib 150 mg twice daily. The mean treatment duration was 16 months (see section 5.1). The most common adverse reactions (incidence ≥20%) for trametinib in combination with dabrafenib were: pyrexia, fatigue, nausea, rash, chills, diarrhoea, headache, arthralgia, vomiting, cough, haemorrhage and peripheral oedema. Tabulated list of adverse reactions Adverse reactions associated with trametinib obtained from clinical studies and post-marketing surveillance are tabulated below for trametinib monotherapy (Table 4) and trametinib in combination with dabrafenib (Table 5). Adverse reactions are listed below by MedDRA system organ class. The following convention has been utilised for the classification of frequency: 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 Not known (cannot be estimated from the available data) Categories have been assigned based on absolute frequencies in the clinical study data. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4 Adverse reactions with trametinib monotherapy System organ class Frequency (all Adverse reactions grades) Folliculitis Paronychia Infection

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HOS-096504 · has-contraindication-information · PDF-Seite 6

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

HOS-096503 · has-indication-information · PDF-Seite 2

Melanoma Trametinib as monotherapy or in combination with dabrafenib 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). Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy (see section 5.1). Adjuvant treatment of melanoma Trametinib in combination with dabrafenib 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) Trametinib in combination with dabrafenib is indicated for the treatment of adults with advanced non- small cell lung cancer with a BRAF V600 mutation. 2 Differentiated thyroid cancer (DTC) Trametinib in combination with dabrafenib 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-096506 · has-interaction-information · PDF-Seite 11

Effect of other medicinal products on trametinib As trametinib is metabolised predominantly via deacetylation mediated by hydrolytic enzymes (e.g. carboxyl-esterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions (see section 5.2). Drug-drug interactions via these hydrolytic enzymes cannot be ruled out and could influence the exposure to trametinib. Trametinib is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that strong inhibition of hepatic P-gp may result in increased levels of trametinib, caution is advised when co- administering trametinib with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole). Effect of trametinib on other medicinal products Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics of other medicinal products via interaction with CYP enzymes or transporters (see section 5.2). Trametinib may result in transient inhibition of BCRP substrates (e.g. pitavastatin) in the gut, which may be minimised with staggered dosing (2 hours apart) of these agents and trametinib. Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co- administered with trametinib monotherapy (see section 5.2). Combination with dabrafenib When trametinib is used in combination with dabrafenib see sections 4.4 and 4.5 of the dabrafenib SmPC for interactions. Radiation treatment Potentiation of radiation treatment toxicity has been reported in patients receiving trametinib in combination with dabrafenib (see sections 4.4 and 4.8). Effect of food on trametinib Patients should take trametinib as monotherapy or in combination with dabrafenib at least one hour prior to or two hours after a meal due to the effect of food on trametinib absorption (see section 4.2 and 5.2). 11

HOS-096507 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/Contraception in females Female patients of reproductive potential must be advised to use effective methods of contraception during treatment with trametinib and for 16 weeks after stopping treatment. Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternative method of contraception, such as a barrier method, should be used when trametinib is used in combination with dabrafenib. Refer to the dabrafenib SmPC for further information. Pregnancy There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Trametinib should not be administered to pregnant women. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, the patient should be informed of the potential hazard to the foetus. Breast-feeding It is not known whether trametinib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding infant cannot be excluded. Trametinib should not be administered to breast-feeding mothers. A decision should be made whether to discontinue breast- feeding or discontinue trametinib, 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 trametinib as monotherapy or in combination with dabrafenib. In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs (see section 5.3). Trametinib may impair fertility in humans. Men taking trametinib in combination with dabrafenib Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Refer to the dabrafenib SmPC for further information.

HOS-096505 · has-warning-information · PDF-Seite 6

When trametinib is given in combination with dabrafenib, the SmPC of dabrafenib must be consulted prior to initiation of treatment. For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib SmPC. 6 BRAF V600 testing The efficacy and safety of trametinib have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation. Trametinib monotherapy compared to BRAF inhibitors Trametinib monotherapy has not been compared with a BRAF inhibitor in a clinical study in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. Based on cross-study comparisons, overall survival and progression-free survival data appear to show similar effectiveness between trametinib and BRAF inhibitors; however, overall response rates were lower in patients treated with trametinib than those reported in patients treated with BRAF inhibitors. Trametinib in combination with dabrafenib in patients with melanoma who have progressed on a BRAF inhibitor There are limited data in patients taking the combination of trametinib with dabrafenib 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 trametinib is used in combination with dabrafenib. Cutaneous malignancies Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with trametinib in combination with dabrafenib. Cases of cuSCC can be managed with excision and do not require treatment modification. Please refer to the dabrafenib SmPC (section 4.4). New primary melanoma New primary melanoma was reported in patients receiving trametinib in combination with dabrafenib. Cases of new primary melanoma can be managed with excision and do not require treatment modification. Please refer to the dabrafenib SmPC (section 4.4). Non-cutaneous malignancies Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present. When tr

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