Braftovi · 4.3 Contraindications · 1

HOS-098451 · has-adverse-reaction-information · PDF-Seite 12

Summary of safety profile The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) has been evaluated in the integrated safety population (ISP) of 372 patients including patients with BRAF V600 mutant unresectable or metastatic melanoma and BRAF V600E mutant advanced NSCLC (hereafter referred to as the Combo 450 ISP). In Combo 450 ISP, 274 patients received the combination for the treatment of BRAF V600 mutant unresectable or metastatic melanoma (in two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1)), and 98 patients received the combination for the treatment of BRAF V600E mutant advanced NSCLC (in one Phase II study (ARRAY-818-202)) (see section 5.1). The most common adverse reactions (>25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy/muscular disorders, and arthralgia. The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic 12 melanoma (hereafter referred to as the Combo 300 population), based on the Phase III study (CMEK162B2301, Part 2). The most common adverse reactions (>25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea. The encorafenib single agent (300 mg orally once daily) safety profile is based on data from 217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to as the pooled encorafenib 300 population). The most common adverse drug reactions (ADRs) (>25%) reported with encorafenib 300 were hyperkeratosis, alopecia, PPES, fatigue, rash, arthralgia, dry skin, nausea, myalgia, headache, vomiting and pruritus. The safety of encorafenib (300 mg orally once daily) in combination with cetuximab (dosed as per its SmPC) was evaluated in 216 patients with BRAF V600E-mutant metastatic colorectal cancer, based on the phase III study ARRAY-818-302. The most common ADRs (>25%) reported in this population were: fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting. The rate of all study drug discontinuation due to any adverse reaction was 1.9 % in patients treated with encorafen

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HOS-098447 · has-contraindication-information · PDF-Seite 8

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

HOS-098446 · has-indication-information · PDF-Seite 2

Melanoma Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Colorectal cancer (CRC) • Encorafenib in combination with cetuximab is indicated for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation, who have received prior systemic therapy. • Encorafenib in combination with cetuximab and FOLFOX is indicated for the first line treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation. Non-small cell lung cancer (NSCLC) Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600E mutation. For biomarker-based patient selection, see section 4.2 2

HOS-098449 · has-interaction-information · PDF-Seite 11

Effects of other medicinal products on encorafenib Encorafenib is primarily metabolised by CYP3A4. CYP3A4 inhibitors Co-administration of moderate (diltiazem) and strong (posaconazole) CYP3A4 inhibitors with single doses of encorafenib in healthy volunteers resulted in a 2 and 3-fold increase in the area under the concentration-time curve (AUC), respectively and in 44.6% and 68.3% increase in maximum encorafenib concentration (Cmax) respectively. Model based predictions indicate that the effect of posaconazole after repeated administrations could be similar for AUC (3-fold increase) and slightly greater for Cmax (2.7-fold increase). Model-based predictions for ketoconazole suggest an increase of approx. 5-fold for encorafenib AUC and 3 to 4- fold for encorafenib Cmax after administration of encorafenib 450 and 300 mg QD, respectively. Therefore, concomitant administration of encorafenib with strong CYP3A4 inhibitors should be avoided (due to increased encorafenib exposure and potential increase in toxicity, see section 5.2). Examples of strong CYP3A4 inhibitors include, but are not limited to, ritonavir, itraconazole, clarithromycin, telithromycin, posaconazole and grapefruit juice. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. Moderate CYP3A4 inhibitors should be co-administered with caution. Examples of moderate CYP3A4 inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, diltiazem, amprenavir and imatinib. When encorafenib is co-administered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety. CYP3A4 inducers Co-administration of encorafenib with a strong CYP3A4 inducer was not assessed in a clinical study; however, a reduction in encorafenib exposure is likely and may result in compromised efficacy of encorafenib. Examples of strong CYP3A4 inducers include, but are not limited to carbamazepine, rifampicin, phenytoin and St. John’s Wort. Alternative agents with no to moderate CYP3A induction potential should be considered. Effects of encorafenib on other medicinal products CYP substrates Encorafenib is a strong inducer of CYP3A4. Concomitant use with agents that are substrates of CYP3A4 (e.g., hormonal contraceptives) may result in loss of efficacy of these agents. If the coadministration of narrow therapeutic index CYP3A4 substrates cannot be avoided, adjust the dose of these substrates in accordance with their approved S

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HOS-098450 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential / Contraception in females Women of childbearing potential must use effective contraception during treatment with encorafenib and for at least 1 month following the last dose. Encorafenib may decrease the efficacy of hormonal contraceptives (see section 4.5). Therefore, female patients using hormonal contraception are advised to use an additional or alternative method such as a barrier method (e.g. condom) during treatment with encorafenib and for at least 1 month following the last dose. Pregnancy There are no data from the use of encorafenib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Encorafenib is not recommended during pregnancy and in women of childbearing potential not using contraception. If encorafenib is used during pregnancy or if the patient becomes pregnant while taking encorafenib, the patient should be informed of the potential hazard to the foetus. Breast-feeding It is unknown whether encorafenib or its metabolites are excreted in human milk. A risk to the breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue encorafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother. Fertility There are no data on the effects of encorafenib on fertility in humans. Based on findings in animals, the use of encorafenib may impact fertility in males of reproductive potential (see section 5.3). As the clinical relevance of this is unknown, male patients should be informed of the potential risk for impaired spermatogenesis.

HOS-098448 · has-warning-information · PDF-Seite 8

Encorafenib is to be given in combination with binimetinib (for patients with BRAF V600 mutant unresectable or metastatic melanoma, and for patients with BRAF V600E mutant advanced NSCLC), or in combination with cetuximab (for patients with BRAF V600E mutant metastatic colorectal cancer who have received prior systemic therapy), or in combination with cetuximab and FOLFOX (for first line treatment of patients with BRAF V600E mutant metastatic colorectal cancer). For additional information on warnings and precautions associated with binimetinib, cetuximab, 5-fluorouracil, folinic acid or oxaliplatin treatment, see section 4.4 of respective medicines SmPC. Encorafenib in combination with binimetinib in patients who have progressed on a BRAF inhibitor There are limited data for the use of the combination of encorafenib with binimetinib in patients who have progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastatic melanoma with BRAF V600 mutation. These data show that the efficacy of the combination would be lower in these patients. Encorafenib in combination with binimetinib in patients with brain metastases There are limited efficacy data with the combination of encorafenib and binimetinib in patients with a BRAF V600 mutant melanoma or BRAF V600E mutant NSCLC which have metastasised to the brain (see section 5.1). Left ventricular dysfunction (LVD) LVD defined as symptomatic or asymptomatic decreases in ejection fraction has been reported when encorafenib is used in combination with binimetinib. It is recommended that left ventricular ejection fraction (LVEF) is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of encorafenib and binimetinib, one month after initiation, and then at approximately 3- month intervals or more frequently as clinically indicated, while on treatment. If during treatment LVD occurs, see section 4.2 of binimetinib SmPC. The safety of encorafenib in combination with binimetinib has not been established in patients with a baseline LVEF that is either below 50% or below the institutional lower limits of normal. Therefore, in these patients, binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, Grade 3-4 LVEF decrease or for absolute decrease of LVEF from baseline of ≥ 10%, binimetinib and encorafenib should be discontinued and LVEF should be evaluated every 2 weeks until recovery.

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