Zelboraf · 4.3 Contraindications · 1

HOS-155471 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most common adverse drug reactions (ADR) of any grade (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥ 5%) Grade 3 ADRs were cuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCC was most commonly treated by local excision. Tabulated summary of adverse reactions ADRs which were reported in melanoma patients are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used 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 In this section, ADRs are based on results in 468 patients from a phase III randomised open label study in adult patients with BRAF V600 mutation-positive unresectable or stage IV melanoma, as well as a phase II single-arm study in patients with BRAF V600 mutation-positive stage IV melanoma who had previously failed at least one prior systemic therapy (see section 5.1). In addition ADRs originating from safety reports across all clinical trials and post-marketing sources are reported. All terms included are based on the highest percentage observed among phase II and phase III clinical trials. Within each frequency grouping, ADRs are presented in order of decreasing severity and were reported using NCI-CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity. 10  Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III studyand events originating from safety reports across all trials(1) and post-marketing sources(2). System organ class Very Common Common Uncommon Rare Infections and Folliculitis infestations Neoplasms benign, SCC of the skin(d), Basal cell Non-cuSCC(1)(3) Chronic malignant and keratoacanthoma, carcinoma, new myelomonocytic unspecified seborrhoeic primary leukaemia(2)(4), (including cysts and keratosis, skin melanoma(3) pancreatic polyps) papilloma

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HOS-155467 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4

HOS-155466 · has-indication-information · PDF-Seite 2

Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation- positive unresectable or metastatic melanoma (see section 5.1).

HOS-155469 · has-interaction-information · PDF-Seite 8

Effects of vemurafenib on Drug Metabolizing Enzymes Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated that vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer. Concomitant use of vemurafenib with agents metabolized by CYP1A2 with narrow therapeutic windows (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, theophylline) is not recommended. If co-administration cannot be avoided, exercise caution, as vemurafenib may increase plasma exposure of CYP1A2 substrate drugs. Dose reduction of the concomitant CYP1A2 substrate drug may be considered, if clinically indicated. Co-administration of vemurafenib increased the plasma exposure (AUC) of caffeine (CYP1A2 substrate) 2.6-fold. In another clinical trial, vemurafenib increased Cmax and AUC of a single 2 mg dose of tizanidine (CYP1A2 substrate) approximately 2.2-fold and 4.7-fold, respectively. Concomitant use of vemurafenib with agents metabolized by CYP3A4 with narrow therapeutic windows is not recommended. If co-administration cannot be avoided, it needs to be considered that vemurafenib may decrease plasma concentrations of CYP3A4 substrates and thereby their efficacy may be impaired. On this basis, the efficacy of contraceptive pills metabolized by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window may be considered, if clinically indicated (see sections 4.4 and 4.6). In a clinical trial, co-administration of vemurafenib decreased the AUC of midazolam (CYP3A4 substrate) by an average 39% (maximum decrease up to 80%). Mild induction of CYP2B6 by vemurafenib was noted in vitro at a vemurafenib concentration of 10 µM. It is currently unknown whether vemurafenib at a plasma level of 100 µM observed in patients at steady state (approximately 50 µg/ml) may decrease plasma concentrations of concomitantly administered CYP2B6 substrates, such as bupropion. Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate). Exercise caution and consider additional INR (international normalized ratio) monitoring when vemurafenib is used concomitantly with warfarin (see section 4.4). Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be excluded. Concomitant adminis

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HOS-155470 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential / Contraception in females Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after treatment. Vemurafenib might decrease the efficacy of hormonal contraceptives (see section 4.5). Pregnancy There are no data regarding the use of vemurafenib in pregnant women. Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses (see section 5.3). In animal studies, vemurafenib was found to cross the placenta. Based on its mechanism of action, vemurafenib could cause fetal harm when administered to a pregnant woman. Vemurafenib should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus. 9 Breast-feeding It is not known whether vemurafenib is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue vemurafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility. However, in repeat-dose toxicity studies in rats and dogs, no histopathological findings were noted in reproductive organs in males and females (see section 5.3).

HOS-155468 · has-warning-information · PDF-Seite 5

Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. The efficacy and safety of vemurafenib in patients with tumours expressing rare BRAF V600 mutations other than V600E and V600K have not been convincingly established (see section 5.1). Vemurafenib should not be used in patients with wild type BRAF malignant melanoma. Hypersensitivity reaction Serious hypersensitivity reactions, including anaphylaxis have been reported in association with vemurafenib (see sections 4.3 and 4.8). Severe hypersensitivity reactions may include Stevens-Johnson syndrome, generalised rash, erythema or hypotension. In patients who experience severe hypersensitivity reactions, vemurafenib treatment should be permanently discontinued. Dermatologic reactions Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with vemurafenib in the post-marketing setting (see section 4.8). In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued. Potentiation of radiation toxicity Cases of radiation recall and radiation sensitization have been reported in patients treated with radiation either prior, during, or subsequent to vemurafenib treatment. Most cases were cutaneous in nature but some cases involving visceral organs had fatal outcomes (see sections 4.5 and 4.8). Vemurafenib should be used with caution when given concomitantly or sequentially with radiation treatment. QT prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in previously treated patients with metastatic melanoma (see section 4.8). QT prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment with vemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval. Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients before treatment with vemurafenib, after one month of treatment and after dose modification. Further monitoring is recommended in particular in patients with moderate to severe he

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