Cotellic · 4.3 Contraindications · 1

HOS-097395 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The safety of Cotellic in combination with vemurafenib has been evaluated in 247 patients with advanced BRAF V600 mutated melanoma in Study GO28141.The median time to onset for the first Grade ≥3 adverse events was 0.6 months in the Cotellic plus vemurafenib arm vs 0.8 months in the placebo plus vemurafenib arm. The safety of Cotellic in combination with vemurafenib has also been evaluated in 129 patients with advanced BRAF V600 mutated melanoma in Study NO25395. The safety profile of Study NO25395 was consistent with that observed in Study GO28141. In Study GO28141, the most common adverse reactions (>20%) observed with a higher frequency in the Cotellic plus vemurafenib arm were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood creatine phosphokinase, and vomiting. The most common adverse reactions (>20%) observed with a higher frequency in the placebo plus vemurafenib arm were arthralgia, alopecia, and hyperkeratosis. Fatigue was observed at similar frequencies in both arms. Please refer to the vemurafenib SmPC for complete descriptions of all undesirable effects associated with vemurafenib treatment. Tabulated list of adverse reactions Adverse drug reactions (ADRs) are based on results from a multi-centre, randomised, double-blind, placebo-controlled, Phase III Study (GO28141) that evaluated the safety and efficacy of Cotellic in combination with vemurafenib as compared to vemurafenib alone in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV). ADR frequencies are based upon the safety analysis of patients treated with cobimetinib plus vemurafenib with a median follow up of 11.2 months (data cut-off date of 19 September 2014). 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 Table 3 lists adverse reactions considered associated with the use of Cotellic. Within each frequency grouping, ADRs are presented in order of decreasing severity and were reported according to NCI- CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity in Study GO28141

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HOS-097391 · has-contraindication-information · PDF-Seite 6

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

HOS-097390 · has-indication-information · PDF-Seite 2

Cotellic is indicated for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1).

HOS-097393 · has-interaction-information · PDF-Seite 8

Effects of other medicinal products on cobimetinib CYP3A inhibitors Cobimetinib is metabolized by CYP3A and cobimetinib AUC increased approximately 7 fold in the presence of a strong CYP3A inhibitor (itraconazole) in healthy subjects. The magnitude of interaction could potentially be lower in patients. 8 Strong CYP3A inhibitors (see section 4.4.) Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. Strong CYP3A inhibitors include, but are not limited to ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. For strong CYP3A inhibitors used short-term (7 days or less), consider interrupting cobimetinib therapy during the duration of inhibitor use. Moderate CYP3A inhibitors (see section 4.4.) Caution should be exercised if cobimetinib is co-administered with moderate CYP3A inhibitors. Moderate CYP3A inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib. When cobimetinib is co-administered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety. Mild CYP3A inhibitors Cobimetinib can be co-administered with mild inhibitors of CYP3A without dose adjustment. CYP3A inducers Co-administration of cobimetinib with a strong CYP3A inducer was not assessed in a clinical study, however, a reduction in cobimetinib exposure is likely. Therefore, concomitant use of moderate and strong CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin, and St. John’s Wort) should be avoided. Alternative agents with no or minimal CYP3A induction should be considered. Given that cobimetinib concentrations are likely to be significantly reduced when co-administered with moderate to strong CYP3A inducers, patient’s efficacy may be compromised. P-glycoprotein inhibitors Cobimetinib is a substrate of P-glycoprotein (P-gp). Concomitant administration of P-gp inhibitors such as ciclosporin and verapamil may have the potential to increase plasma concentrations of cobimetinib. Effects of cobimetinib on other medicinal products CYP3A and CYP2D6 substrates A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of

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HOS-097394 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential / Contraception Women of childbearing potential should be advised to use two effective contraceptive methods, such as a condom or other barrier method (with spermicide, if available) during treatment with Cotellic and for at least three months following treatment discontinuation. Pregnancy There are no data from the use of Cotellic in pregnant women. Studies in animals have shown embryolethality and foetal malformations of the great vessels and skull (see section 5.3). Cotellic should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus. Breast-feeding It is not known whether cobimetinib is excreted in human breast milk. A risk to the newborns/infants cannot be excluded. A decision should be made whether to discontinue breast-feeding or discontinue Cotellic therapy, 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 cobimetinib. In animals, no fertility studies have been performed, but adverse effects were seen on reproductive organs (see section 5.3). The clinical relevance of this is unknown.

HOS-097392 · has-warning-information · PDF-Seite 6

Before taking Cotellic in combination with vemurafenib, patients must have BRAF V600 mutation- positive tumour status confirmed by a validated test. Cotellic in combination with vemurafenib in patients who have progressed on a BRAF inhibitor There are limited data in patients taking the combination of Cotellic with vemurafenib 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. Cotellic in combination with vemurafenib in patients with brain metastases Limited data show that the safety of the combination of Cotellic and vemurafenib in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain is consistent with the known safety profile of Cotellic in combination with vemurafenib. The efficacy of the Cotellic and vemurafenib combination in these patients has not been evaluated. The intracranial activity of Cotellic is unknown (see sections 5.1 and 5.2). 6 Haemorrhage Haemorrhagic events, including major haemorrhagic events can occur (see section 4.8). Caution should be used in patients with additional risk factors for bleeding, such as brain metastases, and/or in patients that use concomitant medicinal products that increase the risk of bleeding (including antiplatelet or anticoagulant therapy). For management of haemorrhage please see section 4.2. Serous retinopathy Serous retinopathy (fluid accumulation within the layers of the retina) has been observed in patients treated with MEK-inhibitors, including Cotellic (see section 4.8). The majority of events were reported as chorioretinopathy or retinal detachment. Median time to initial onset of serous retinopathy events was 1 month (range 0-9 months). Most events observed in clinical studies were resolved, or improved to asymptomatic Grade 1, following dose interruption or reduction. Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. If symptoms of new or worsening visual disturbances are identified, an ophthalmologic examination is recommended. If serous retinopathy is diagnosed, Cotellic treatment should be withheld until visual

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