英文药名：Zelboraf(vemurafenib Filmcoated Tablets) 中文药名：威罗菲尼薄膜片 生产厂家：英国罗氏（Roche） 药品介绍 欧盟委员会批准罗氏公司生产的药物Zelboraf（vemurafenib，威罗菲尼），用于治疗BRAF V600突变阳性的转移性黑色素瘤，该病是一种致命的，具有危险性的皮肤癌。Zelboraf通过阻断突变型BRAF蛋白的功能起到治疗作用。 全球产品开发主任，罗氏首席医疗官，医学博士Hal Barron说：“这次的批准对BRAF突变阳性的转移性黑色素瘤患者来说是一个重大的新闻，Zelboraf能起到显著的治疗作用。此外，罗氏也能更好地为患者、医生和社会做贡献。” 罗氏生产的试剂cobas 4800 BRAF V600 Mutation Test 检测治疗患者合适的药物，结果发现Zelboraf是唯一一个能改善BRAF V600突变阳性的转移性黑色素瘤患者生存率的药物。 经测试表明，与化疗相比，Zelboraf有许多优越之处。使用Zelboraf后，患者死亡率的风险降低了63%。与以往治疗方法的生存率相比，Zelboraf显著地延长了患者的生存期（13.2个月）。通常化疗治疗后，患者只有9.6个月生存期的期望。 Zelboraf成为唯一的，且首个在2011年获FDA批准用于改善BRAF V600突变阳性的转移性黑色素瘤患者的生存率的药物。与此同时，用于检测BRAF V600基因突变的试剂，称为cobas 4800 BRAF V600 Mutation Test 也获得批准。现在，它们同时在美国获得批准使用，获得CE认证，并在欧洲上市销售。 其它已批准Zelboraf使用的国家包括：以色列、巴西、瑞士和新西兰。澳大利亚、印度和世界其它国家正在审查Zelboraf使用的可能性。罗氏在世界各地招募超过2000名曾接受治疗或没有治疗的BRAF V600突变阳性的转移性黑色素瘤患者，进行药物安全性的试验。所有关于Zelboraf安全性的研究都得出相同的结果。 Zelboraf用于治疗成人BRAF V600突变阳性、经手术不能切除或转移性黑色素瘤，是一种口服的小分子激酶抑制剂。不建议野生型BRAF黑色素瘤患者使用该药。 当黑色素瘤在首次诊断后扩散到身体其它部位时，它就会成为致命性的疾病。但是，如果早期能发现，这种类型的癌症还是可以被治疗的。黑色素瘤患者通常不会有很长的生存期，有些仅仅只有几个月的时间。通常情况下，少部分1/4的患者在诊断后有1年的生存期。 关于使用BRAF V600检测突变 这是一种聚合酶链反应诊断测试；由RocheM开发；FDA批准其在指定的国家里使用，并可以在BRIM2 和 BRIM3测试中检测BRAF 4600E突变的肿瘤；此方法最近已被证明优于Sanger测序的方法。在检测突变和快速显示结果上，它比Sanger法更敏感，更可靠。 第二阶段的测试BRIM2招募了132名曾受过治疗的V600E突变阳性的转移性黑色素瘤患者，第三阶段的测试BRIM3治疗对象为曾没有接受过治疗的V600E突变阳性的转移性黑色素瘤患者，并将Zelboraf与达卡巴嗪（dacarbazine）化疗相比较。 罗氏和Plexxikon在2006年获得许可证，签订合作合同，共同开发Zelboraf。 作用机制： 是一种低分子量，口服可利用，BRAF丝氨酸-苏氨酸激酶，包括BRAFV600E的某些突变形式的抑制剂。在体外在相似浓度Vemurafenib还抑制其它激酶例如CRAF，ARAF，野生型RAF，SRMS，ACK1，MAP4K5和FGR。在BRA基因中某些突变包括V600E导致组成性激活的BRAF蛋白，可能在缺乏生长因子中引起细胞增殖，正常需要生长因子。在有突变的BRAFV600E黑色素瘤的细胞和动物模型中Vemurafenib有抗肿瘤效应。 适应证和用途 ZELBORAF™是一种激酶抑制剂适用于有不可切除或转移黑色素瘤有用FDA-批准的检验检测BRAFV600E突变患者的治疗。 使用限制：有野生型BRAF黑色素瘤患者中建议不使用ZELBORAF。 剂量和给药方法 （1）推荐剂量：960mg口服bid。 （2）接近12小时间隔给予ZELBORAF有或无进餐。 （3）应用一杯水完整吞服ZELBORAF。不应咀嚼或压碎ZELBORAF。 （4）症状性不良药物反应的处理可能需要减低剂量，中断治疗，或终止ZELBORAF治疗。不建议减低剂量导致剂量低于480mg。 剂型和规格 膜衣片：240mg 禁忌证 无 警告和注意事项 （1）24%患者中发生皮肤鳞状细胞癌(cuSCC)。治疗开始前和当用治疗时每2个月进行皮肤学评价。切除处理和继续治疗不调整剂量。 （2）治疗期间和再次开始治疗时曾报道严重超敏反应，包括过敏反应。经受严重超敏反应患者中终止ZELBORAF。 （3）曾报道严重皮肤学反应，包括Stevens-Johnson综合征和中毒性表皮坏死溶解。经受严重皮肤学反应患者中终止治疗。 （4）曾报道QT延长。治疗前和调整剂量后监视ECG和电解质。在第15天，治疗头3个月期间每3个月，其后每3个月，或更常如临床指示时监视ECGs。如QTc超过500 ms，短暂中断ZELBORAF，校正电解质异常，和控制对QT延长风险因子。 （5）可能发生肝实验室异常。治疗开始前和治疗期间每月，或当临床指示时监视肝酶和胆红素。 （6）曾报道光敏性。服用ZELBORAF时建议患者避免暴露阳光。 （7）曾报道严重眼科反应，包括葡萄膜炎，虹膜炎和视网膜静脉阻塞。对眼科反应常规监视患者。 （8）曾报道新原发性恶性黑色素瘤。切除处理，和继续治疗无剂量调整。如上所述，进行皮肤学监视。 （9）妊娠：可能致胎儿危害. 忠告妇女对胎儿潜在风险. （10）为了选择适于ZELBORAF治疗患者，用一种FDA-批准的检验BRAF突变。尚未在有野生型BRAF黑色素瘤患者中研究ZELBORAF的疗效和安全性。 不良反应 最常见不良反应(≥ 30%)是关节痛，皮疹，脱发，疲乏，光敏反应，恶心，瘙痒和皮肤乳头状瘤。 药物相互作用 （1）CYP底物：建议不要的同时使用ZELBORAF与被CYP3A4，CYP1A2或CYP2D6代谢治疗窗狭窄药物。如不能避免共同给药，谨慎对待和考虑减低同时CYP1A2或CYP2D6底物药物的剂量。 （2）ZELBORAF可能增加同时给药华法林[warfarin]暴露。当ZELBORAF与华法林同时使用时谨慎对待和考虑另外INR监视。 特殊人群中使用 （1）哺乳母亲：当接受ZELBORAF时终止哺乳。 Zelboraf 240mg Film-coated Tablets 1. Name of the medicinal product Zelboraf 240 mg film-coated tablets. 2. Qualitative and quantitative composition Each tablet contains 240 mg of vemurafenib (as a co-precipitate of vemurafenib and hypromellose acetate succinate). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet (tablet). Pinkish white to orange white, oval, biconvex film-coated tablets of approximately 19 mm, with 'VEM' engraved on one side. 4. Clinical particulars 4.1 Therapeutic indications Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma (see section 5.1). 4.2 Posology and method of administration Treatment with vemurafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products. Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test (see sections 4.4 and 5.1). Posology The recommended dose of vemurafenib is 960 mg (4 tablets of 240 mg) twice daily (equivalent to a total daily dose of 1,920 mg). Vemurafenib may be taken with or without food, but consistent intake of both daily doses on an empty stomach should be avoided (see section 5.2). Duration of treatment Treatment with vemurafenib should continue until disease progression or the development of unacceptable toxicity (see tables 1 and 2 below). Missed doses If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time. Vomiting In case of vomiting after vemurafenib administration the patient should not take an additional dose of the medicinal product but the treatment should be continued as usual. Posology adjustments Management of adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation (see tables 1 and 2). Posology adjustments resulting in a dose below 480 mg twice daily are not recommended. In the event the patient develops Cutaneous Squamous Cell Carcinoma (cuSCC), it is recommended to continue the treatment without modifying the dose of vemurafenib (see sections 4.4 and 4.8). Table 1: Dose modification schedule based on the grade of any AEs (a) The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE). Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in previously treated patients with metastatic melanoma. Management of QTc prolongation may require specific monitoring measures (see section 4.4). Table 2: Dose modification schedule based on prolongation of the QT interval Special population Older people No special dose adjustment is required in patients aged > 65 years old. Renal impairment Limited data are available in patients with renal impairment. A risk for increased exposure in patients with severe renal impairment cannot be excluded. Patients with severe renal impairment should be closely monitored (see sections 4.4 and 5.2). Hepatic impairment Limited data are available in patients with hepatic impairment. As vemurafenib is cleared by the liver, patients with moderate to severe hepatic impairment may have increased exposure and should be closely monitored (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of vemurafenib has not been yet established in children and adolescents (<18 years). No data are available. Non-Caucasian patients The safety and efficacy of vemurafenib has not been established in non-Caucasian patients. No data are available. Method of administration Vemurafenib tablets are to be swallowed whole with water. Vemurafenib tablets should not be chewed or crushed. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use 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. 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 hepatic impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with vemurafenib is not recommended in patients with QTc>500 milliseconds (ms). If during treatment the QTc exceeds 500 ms, vemurafenib treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur once the QTc decreases below 500 ms and at a lower dose as described in table 2. Permanent discontinuation of vemurafenib treatment is recommended if the QTc increase meets values of both >500 ms and >60 ms change from pre-treatment values. Ophthalmologic reactions Serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have been reported. Monitor patients routinely for ophthalmologic reactions. Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with vemurafenib (see section 4.8). It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per local standard of care. The prescriber should examine the patient monthly during and up to six months after treatment for cuSCC. In patients who develop cuSCC, it is recommended to continue the treatment without dose adjustment. Monitoring should continue for 6 months following discontinuation of vemurafenib or until initiation of another anti-neoplastic therapy. Patients should be instructed to inform their physicians upon the occurrence of any skin changes. Non-Cutaneous Squamous Cell Carcinoma (non-cuSCC) Cases of non-cuSCC have been reported in clinical trials where patients received vemurafenib. Patients should undergo a head and neck examination, consisting of at least a visual inspection of oral mucosa and lymph node palpation prior to initiation of treatment and every 3 months during treatment. In addition, patients should undergo a chest Computerised Tomography (CT) scan, prior to treatment and every 6 months during treatment. Anal examinations and pelvic examinations (for women) are recommended before and at the end of treatment or when considered clinically indicated. Following discontinuation of vemurafenib, monitoring for non-cuSCC should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices. New primary melanoma New primary melanomas have been reported in clinical trials. Cases were managed with excision and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above for cutaneous squamous cell carcinoma. Other Malignancies Based on mechanism of action, vemurafenib may cause progression of cancers associated with RAS mutations (see section 4.8). Carefully consider benefits and risks before administering vemurafenib to patients with a prior or concurrent cancer associated with RAS mutation. Liver injury Liver laboratory abnormalities may occur with vemurafenib (see section 4.8). Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption or with treatment discontinuation (see sections 4.2 and 4.4). Hepatic impairment No adjustment to the starting dose is needed for patients with hepatic impairment. Patients with mild hepatic impairment due to liver metastases without hyperbilirubinaemia may be monitored according to the general recommendations. There are only very limited data available in patients with moderate to severe hepatic impairment. Patients with moderate to severe hepatic impairment may have increased exposure (see section 5.2). Thus close monitoring is warranted especially after the first few weeks of treatment as accumulation may occur over an extended period of time (several weeks). In addition ECG monitoring every month during the first three months is recommended. Renal impairment No adjustment to the starting dose is needed for patients with mild or moderate renal impairment. There are only limited data available in patients with severe renal impairment (see section 5.2). Vemurafenib should be used with caution in patients with severe renal impairment and patients should be closely monitored. Photosensitivity Mild to severe photosensitivity was reported in patients who received vemurafenib in clinical studies (see section 4.8). All patients should be advised to avoid sun exposure while taking vemurafenib. While taking the medicinal product, patients should be advised to wear protective clothing and use a broad spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (Sun Protection Factor ≥ 30) when outdoors to help protect against sunburn. For photosensitivity grade 2 (intolerable) or greater, dose modifications are recommended (see section 4.2). Effects of vemurafenib on other medicinal products Vemurafenib may increase the plasma exposure of medicinal products predominantly metabolised by CYP1A2 and decrease the plasma exposure of medicines predominantly metabolised by CYP3A4, including oral contraceptives. Dose adjustments for medicinal products predominantly metabolised via CYP1A2 or CYP3A4 should be considered based on their therapeutic windows before concomitantly treating with vemurafenib (see sections 4.5 and 4.6). Exercise caution and consider additional INR (International Normalised Ratio) monitoring when vemurafenib is used concomitantly with warfarin. Effect of other medicinal products on vemurafenib Vemurafenib pharmacokinetics could be affected by medicines that inhibit or influence P-gp (e.g. verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) (see section 4.5). Concomitant administration of potent inducers of P-gp, glucuronidation, CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John's Wort [hypericin]) should be avoided when possible (see section 4.5). Alternative treatment with less inducing potential should be considered to maintain the efficacy of vemurafenib. Concurrent administration with ipilimumab In a Phase I trial, asymptomatic grade 3 increases in transaminases (ALT/AST >5 x ULN) and bilirubin (total bilirubin >3x ULN) were reported with concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the concurrent administration of ipilimumab and vemurafenib is not recommended. 4.5 Interaction with other medicinal products and other forms of interaction Effects of vemurafenib on CYP substrates CYP1A2 inhibition was observed when a single dose of caffeine was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 2.5-fold increase (maximum up to 10-fold) in caffeine plasma exposure after vemurafenib treatment. Vemurafenib may increase the plasma exposure of substances predominantly metabolised by CYP1A2 and dose adjustments should be considered. CYP3A4 induction was observed when a single dose of midazolam was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 32% decrease (maximum up to 80%) in midazolam plasma exposure after vemurafenib treatment. Vemurafenib may decrease the plasma exposure of substances predominantly metabolised by CYP3A4. On this basis, the efficacy of contraceptive pills metabolised by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window should be considered (see sections 4.4 and 4.6). 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. When a single dose of warfarin was co-administered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (mean 20%) (see section 4.4). Caution should be exercised when vemurafenib is co-administered with warfarin (CYP2C9) in patients with melanoma. Vemurafenib 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. Due to the long half-life of vemurafenib, the full inhibitory effect of vemurafenib on a concomitant medicinal product might not be observed before 8 days of vemurafenib treatment. After cessation of vemurafenib treatment, a washout of 8 days might be necessary to avoid an interaction with a subsequent treatment. Effects of vemurafenib on substance transport systems In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters P-gp and BCRP. The clinical relevance of this finding is unknown. It cannot be excluded that vemurafenib may increase the exposure of other medicines transported by P-gp (e.g. aliskiren, colchicine, digoxin, everolimus, fexofenadine) or BCRP (e.g. methotrexate, mitoxantrone, rosuvastatin). Many anticancer drugs are substrates of P-gp and/or BCRP and therefore there is a theoretical risk for an interaction with vemurafenib. The possible effect of vemurafenib on other transporters is currently unknown. Effects of concomitant medicines on vemurafenib In vitro studies suggest that CYP3A4 metabolism and glucuronidation are responsible for the metabolism of vemurafenib. Biliary excretion appears to be another important elimination pathway. There are no clinical data available showing the effect of strong inducers or inhibitors of CYP3A4 and/or transport protein activity on vemurafenib exposure. Vemurafenib should be used with caution in combination with potent inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir). Concomitant administration of potent inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John's Wort [Hypericum perforatum]) may lead to suboptimal exposure to vemurafenib and should be avoided. In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and BCRP. The effects of P-gp and BCRP inducers and inhibitors on vemurafenib exposure are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by medicines that influence P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole) or BCRP (e.g. cyclosporine, gefitinib). It is currently unknown whether vemurafenib is a substrate also to other transport proteins. 4.6 Fertility, pregnancy and lactation 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. Vemurafenib should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus. 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 on reproductive organs (see section 5.3). 4.7 Effects on ability to drive and use machines The effects of vemurafenib on the ability to drive and use machines have not been studied. Patients should be made aware of the potential fatigue or eye problems that could be a reason for not driving. 4.8 Undesirable effects Summary of the safety profile The most common adverse drug reactions (ADR) (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. CuSCC was very commonly reported and 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. Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials* and post-marketing sources#. * Events originating from safety reports across all trials # Events originating from post-marketing sources. § Pre-existing chronic myelomonocytic leukaemia with NRAS mutation. + A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility. Description of selected adverse reactions Hepatic enzyme increase (b) Liver enzyme abnormalities reported in the phase III clinical study are expressed below as the proportion of patients who experienced a shift from baseline to a grade 3 or 4 liver enzyme abnormalities: • Very common: GGT • Common: ALT, alkaline phosphatase, bilirubin • Uncommon: AST There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin. Cutaneous squamous cell carcinoma (c) (cuSCC) Cases of cuSCC have been reported in patients treated with vemurafenib. The incidence of cuSCC in vemurafenib-treated patients across studies was approximately 20%. The majority of the excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Most lesions classified as “other” (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, cyst/benign cyst). CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Cases of cuSCC were typically managed with simple excision, and patients generally continued on treatment without dose modification (see sections 4.2 and 4.4). Non-cutaneous squamous cell carcinoma (non-cuSCC) Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinical trials. Surveillance for non-cuSCC should occur as outlined in section 4.4. New primary melanoma New primary melanomas have been reported in clinical trials. These cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined in section 4.4. Hypersensitivity reactions (d) Serious hypersensitivity reactions, including anaphylaxis have been reported in association with vemurafenib. 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 (see section 4.4). Dermatologic Reactions (e) 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. In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued. QT prolongation Analysis of centralised ECG data from an open-label uncontrolled phase II QT sub-study in 132 patients dosed with vemurafenib 960 mg twice daily (NP22657) showed an exposure-dependent QTc prolongation. The mean QTc effect remained stable between 12-15 ms beyond the first month of treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed within the first 6 months (n=90 patients). Two patients (1.5%) developed treatment-emergent absolute QTc values >500 ms (CTC Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of >60 ms (see section 4.4). Special populations Older people In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with vemurafenib were ≥ 65 years. Older patients (≥ 65 years) may be more likely to experience adverse reactions, including cuSCC, decreased appetite, and cardiac disorders. Gender During clinical trials with vemurafenib, grade 3 adverse reactions reported more frequently in females than males were rash, arthralgia and photosensitivity. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below). Ireland IMB Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Malta ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose There is no specific antidote for overdose of vemurafenib. Patients who develop adverse reactions should receive appropriate symptomatic treatment. No cases of overdose have been observed with vemurafenib in clinical trials. In case of suspected overdose, vemurafenib should be withheld and supportive care initiated. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15 Mechanism of action and pharmacodynamic effects Vemurafenib is a low molecular weight, orally available, inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Preclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit BRAF kinases with activating codon 600 mutations (table 4). Table 4: Kinase inhibitory activity of vemurafenib against different BRAF kinases (f) Estimated from 2099 melanomas with annotated BRAF codon 600 mutations in the public COSMIC database, release 54 (July 2011). This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays in available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays the IC50 against V600 mutated cell lines (V600E, V600R, V600D and V600K mutated cell lines) ranged from 0.016 to 1.131 μM whereas the inhibitory concentration 50 against BRAF wild type cell lines were 12.06 and 14.32 μM, respectively. Determination of BRAF mutation status Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. In the phase II and phase III clinical trials, eligible patients were identified using a real-time polymerase chain reaction assay (the cobas 4800 BRAF V600 Mutation Test). This test has CE marking and is used to assess the BRAF mutation status of DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumour tissue. It was designed to detect the predominant BRAF V600E mutation with high sensitivity (down to 5% V600E sequence in a background of wild type sequence from FFPE-derived DNA). Non-clinical and clinical studies with retrospective sequencing analyses have shown that the test also detects the less common BRAF V600D mutations and V600K mutations with lower sensitivity. Of the specimens available from the non-clinical and clinical studies (n=920), that were mutation-positive by the cobas test and additionally analyzed by sequencing, no specimen was identified as being wild type by both Sanger and 454 sequencing. Clinical efficacy and safety The efficacy of vemurafenib has been evaluated in 336 patients from a phase III clinical trial (NO25026) and 132 patients from a phase II clinical trial (NP 22657). All patients were required to have advanced melanoma with BRAF V600 mutations according to the cobas 4800 BRAF V600 Mutation Test. Results from the Phase III study (NO25026) in previously untreated patients An open-label, multicentre, international, randomised phase III study supports the use of vemurafenib in previously untreated patients with BRAF V600E mutation-positive unresectable or metastatic melanoma. Patients were randomised to treatment with vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 on day 1 every 3 weeks). A total of 675 patients were randomised to vemurafenib (n=337) or dacarbazine (n=338). Most patients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had stage M1c disease (65%). The co-primary efficacy endpoints of the study were overall survival (OS) and progression-free survival (PFS). At the pre-specified interim analysis with a December 30, 2010 data cut-off, significant improvements in the co-primary endpoints of OS (p<0.0001) and PFS (p<0.0001) (unstratified log-rank test) were observed. Upon Data Safety Monitoring Board (DSMB) recommendation, those results were released in January 2011 and the study was modified to permit dacarbazine patients to cross over to receive vemurafenib. Post-hoc survival analyses were undertaken thereafter as described in table 5. Table 5: Overall survival in previously untreated patients with BRAF V600 mutation-positive melanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib) (g) Censored results at time of cross-over Non-censored results at time of cross-over: March 31 2011: HR (95% CI) = 0.47 (0.35, 0.62); October 3 2011: HR (95% CI) = 0.67 (0.54, 0.84); February 1 2012: HR (95% CI) = 0.76 (0.63, 0.93); December 20 2012: HR (95% CI) = 0.79 (0.66, 0.95) Figure 1: Kaplan-Meier curves of overall survival – previously untreated patients (December 20, 2012 cut-off) Table 6 shows the treatment effect for all pre-specified stratification variables which are established as prognostic factors. Table 6: Overall survival in previously untreated patients with BRAF V600 mutation-positive melanoma by LDH, tumour stage and ECOG status (post hoc analysis, December 20, 2012 cut-off, censored results at time of cross over) LDH: Lactate Dehydrogenase, ECOG PS: Eastern Cooperative Oncology Group Performance Status Table 7 shows the overall response rate and progression-free survival in previously untreated patients with BRAF V600 mutation-positive melanoma. Table 7: Overall response rate and progression-free survival in previously untreated patients with BRAF V600 mutation-positive melanoma (h) Unstratified log-rank test for PFS and Chi-squared test for Overall Response Rate. (i) As of December 30, 2010, a total of 549 patients were evaluable for PFS and 439 patients were evaluable for overall response rate. (j) As of February 01, 2012, a total of 675 patients were evaluable for the post-hoc analysis update of PFS. A total of 57 patients out of 673 whose tumours were analysed retrospectively by sequencing were reported to have BRAF V600K mutation-positive melanoma in NO25026. Although limited by the low number of patients, efficacy analyses among these patients with V600K-positive tumours suggested similar treatment benefit of vemurafenib in terms of OS, PFS and confirmed best overall response. No data are available in patients with melanoma harbouring rare BRAF V600 mutations other than V600E and V600K. Results from the phase II study (NP22657) in patients who failed at least one prior therapy A phase II single-arm, multi-centre, multinational study was conducted in 132 patients who had BRAF V600E mutation-positive metastatic melanoma according to the cobas 4800 BRAF V600 Mutation Test and had received at least one prior therapy. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients was male (61%), Caucasian (99%), and had stage M1c disease (61%). Forty-nine percent of patients failed ≥ 2 prior therapies. With a median follow-up of 12.9 months (range, 0.6 to 20.1), the primary endpoint of confirmed best overall response rate (CR + PR) as assessed by an independent review committee (IRC) was 53% (95% CI: 44%, 62%). Median overall survival was 15.9 months (95% CI: 11.6, 18.3). The overall survival rate at 6 months was 77% (95% CI: 70%, 85%) and at 12 months was 58% (95% CI: 49%, 67%). Nine of the 132 patients enrolled into NP22657 had V600K mutation-positive tumours according to retrospective Sanger sequencing. Amongst these patients, 3 had a PR, 3 had SD, 2 had PD and one was not evaluable. 5.2 Pharmacokinetic properties Vemurafenib is a Class IV substance (low solubility and permeability), using the criteria described in the Biopharmaceutics Classification System. The pharmacokinetic parameters for vemurafenib were determined using non-compartmental analysis in a phase I and phase III studies (20 patients after 15 days of dosing at 960 mg twice daily, and 204 patients in steady state day 22) as well as by population PK analysis using pooled data from 458 patients. Among these patients, 457 were Caucasians. Absorption The absolute bioavailability of the vemurafenib 240 mg tablet is unknown. Vemurafenib at 960 mg twice daily is absorbed with a median Tmax of approximately 4 hours. Vemurafenib exhibits high inter-patient variability. In the phase II study, AUC0-8h and Cmax at day 1 were 22.1 ± 12.7 µg·h/mL and 4.1 ± 2.3 µg/mL. Accumulation occurs upon multiple twice daily dosing of vemurafenib. In the non-compartmental analysis, after dosing with 960 mg vemurafenib twice daily the Day 15 / Day 1 ratio ranged from 15- to 17-fold for AUC, and 13- to 14-fold for Cmax, yielding AUC0-8h and Cmax of 380.2 ± 143.6 µg·h/mL and 56.7 ± 21.8 µg/mL, respectively, under steady-state conditions. Food (high fat meal) increases the relative bioavailability of a single 960 mg dose of vemurafenib. The geometric mean ratios between the fed and fasted states for Cmax and AUC were 2.6 and 4.7 fold, respectively. The median Tmax was increased from 4 to 8 hours when a single vemurafenib dose was taken with food. The effect of food on steady state vemurafenib exposure is currently unknown. Consistent intake of vemurafenib on an empty stomach may lead to significantly lower steady state exposure than consistent intake of vemurafenib with or a short time after a meal. Occasional intake of vemurafenib on an empty stomach is expected to have limited influence on steady state exposure due to the high accumulation of vemurafenib at steady state. Safety and efficacy data from pivotal studies were collected from patients taking vemurafenib with or without food. Variability in exposure may also occur due to differences in gastro-intestinal fluid content, volumes, pH, motility and transition time and bile composition. At steady state, the mean vemurafenib exposure in plasma is stable during the 24-hour interval as indicated by the mean ratio of 1.13 between the plasma concentrations before and 2-4 hours after the morning dose. Following oral dosing, the absorption rate constant for the population of metastatic melanoma patients is estimated to be 0.19 hr-1 (with 101% between patient variability). Distribution The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 91 L (with 64.8% between patient variability). It is highly bound to human plasma proteins in vitro (>99%). Biotransformation The relative proportions of vemurafenib and its metabolites were characterised in a human mass balance study with a single dose of 14C-labeled vemurafenib administered orally. CYP3A4 is the primary enzyme responsible for the metabolism of vemurafenib in vitro. Conjugation metabolites (glucuronidation and glycosylation) were also identified in humans. However, the parent compound was the predominant component (95%) in plasma. Although metabolism does not appear to result in a relevant amount of metabolites in plasma, the importance of metabolism for excretion cannot be excluded. Elimination The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 29.3 L/day (with 31.9% between patient variability). The population elimination half-life estimated by the population PK analysis for vemurafenib is 51.6 hours (the 5th and 95th percentile range of the individual half-life estimates is 29.8 - 119.5 hours). In the human mass balance study with vemurafenib administered orally, on average 95% of the dose was recovered within 18 days. The majority of vemurafenib-related material (94%) was recovered in faeces, and <1% in urine. Biliary excretion of unchanged compound may be an important route of elimination. However, due to the unknown absolute bioavailability, the importance of hepatic and renal excretion for the clearance of parent vemurafenib is uncertain. Vemurafenib is a substrate and inhibitor of P-gp in vitro. Special populations Older people Based on the population PK analysis, age has no statistically significant effect on vemurafenib pharmacokinetics. Gender The population pharmacokinetic analysis indicated a 17% greater apparent clearance (CL/F) and a 48% greater apparent volume of distribution (V/F) in males than in females. It is unclear whether this is a gender or a body size effect. However, the differences in exposure are not large enough to warrant dose adjustment based on body size or gender. Renal impairment In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, mild and moderate renal impairment did not influence the apparent clearance of vemurafenib (creatinine clearance >40 ml/min). There are no data in patients with severe renal impairment (see sections 4.2 and 4.4). Hepatic impairment Based on preclinical data and the human mass balance study, major part of vemurafenib is eliminated via the liver. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, increases in AST and ALT up to three times the upper limit of normal did not influence the apparent clearance of vemurafenib. Data are insufficient to determine the effect of metabolic or excretory hepatic impairment on vemurafenib pharmacokinetics (see sections 4.2 and 4.4). Paediatric population No studies have been conducted to investigate the pharmacokinetics of vemurafenib in paediatric patients. 5.3 Preclinical safety data The preclinical safety profile of vemurafenib was assessed in rats, dogs, and rabbits. Repeat-dose toxicology studies identified the liver and bone marrow as target organs in the dog. Reversible toxic effects (hepatocellular necrosis and degeneration) in the liver at exposures below the anticipated clinical exposure (based on AUC comparisons) were noted in the 13-week dog study. Focal bone marrow necrosis was noted in one dog in a prematurely terminated 39-week BID dog study at exposures similar to the anticipated clinical exposure (based on AUC comparisons). In an in vitro bone marrow cytotoxicity study, slight cytotoxicity was observed in some lympho-haematopoietic cell populations of rat, dog and human at clinically relevant concentrations. Vemurafenib was shown to be phototoxic, in vitro, on cultured murine fibroblasts after UVA irradiation, but not in vivo in a rat study at doses up to 450 mg/kg/day (at exposures below the anticipated clinical exposure (based on AUC comparison). No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility. However, in repeat-dose toxicity studies, no histopathological findings were noted on reproductive organs in males and females in rats and dogs at doses up to 450 mg/kg/day (at exposures below the anticipated clinical exposure based on AUC comparison). No teratogenicity was observed in embryofoetal development studies in rats and rabbits at doses up to respectively 250 mg/kg/day and 450 mg/kg/day leading to exposures below the anticipated clinical exposure (based on AUC comparison). However, exposures in the embryofoetal development studies were below the clinical exposure based on AUC comparison, it is therefore difficult to define to what extent these results can be extrapolated to humans. Therefore an effect of vemurafenib on the foetus cannot be excluded. No studies were performed regarding pre- and postnatal development. No signs of genotoxicity were identified in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) nor in the in vivo rat bone marrow micronucleus test conducted with vemurafenib. Carcinogenicity studies have not been conducted with vemurafenib. 6. Pharmaceutical particulars 6.1 List of excipients Core Croscarmellose sodium Colloidal anhydrous silica Magnesium stearate Hydroxypropylcellulose Film-coating Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc Iron oxide red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Aluminium / Aluminium perforated unit dose blisters Pack-size: 56 x 1 film-coated tablets (7 blisters of 8 x 1 tablet) 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Roche Registration Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom 8. Marketing authorisation number(s) EU/1/12/751/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 17 February 2012 Go to top of the page 10. Date of revision of the text 20 February 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Vemurafenib （Zelboraf锭剂, Hoffmann-LaRoche, Inc.）：一种BRAF抑制剂，可用于治疗无法切除或转移性黑色素瘤，且BRAFV600E突变的病人，侦测方式是透过同时通过核准的搭配诊断试验－cobas 4800 BRAF V600 Mutation Test（RocheMolecular Systems）。是第二项经证实可延长黑色素瘤病人存活时间的治疗。 2011年8月17日，FDA批准Zelboraf(vemurafenib)用以治疗晚期或不可切除的黑色素瘤，黑色素瘤是最危险的一类皮肤癌。 Zelboraf特别适用于治疗有基因BRAF V600E突变的黑色素瘤患者。 Zelboraf获准的同时，FDA还批准了首个用于检测cobas 4800 BRAF V600突变的检测方法，这一检测方法将有助于确定病人的黑色素瘤细胞是否存在BRAF V600E突变。 BRAF蛋白通常与调节细胞生长相关，但它在约半数晚期黑色素瘤病人中发生突变。Zelboraf是一种BRAF抑制剂，能阻断V600E发生突变BRAF蛋白的功能。　　 “Zelboraf是FDA批准的第二个治疗黑色素瘤的新药，该药能改善病人的总生存数。” FDA药物评价与研究中心肿瘤药物产品办公室主任Richard Pazdur说：“FDA在3月批准的Yervoy (ipilimumab)，是另一种治疗晚期黑色素瘤的新药，接受该药物治疗也可以延长病人的生存期。” Zelboraf通过了FDA的优先评审项目审查。Zelboraf和BRAF V600E检验的检测方法都提前通过审批，药物的目标日期是2011年10月28日，而诊断方法的目标日期是2011年11月12日。 Zelboraf的安全性和有效性通过一项国际化的研究得到证实，该研究纳入675例晚期黑色素瘤伴BRAF V600E突变的患者，这些病人以前未经治疗。病人分别接受Zelboraf或达卡巴嗪治疗，试验设计的测定指标是总生存期（即从治疗开始到死亡的时间）。 接受Zelboraf治疗的患者未曾达到生存中值 (77%的患者仍生存)而接受达卡巴嗪治疗的患者生存中值为8个月(64%仍生存)。 “Zelboraf和cobas检测方法的获批是一个代表性的案例，即配套的诊断方法如何发展，以用于保证更有效地诊断患者，以一种安全的方法提供高度个性化的治疗方案”，FDA体外诊断设备评价和安全性办公室主任Alberto Gutierrez称。 cobas 4800 BRAF V600突变检验方法的获批是基于临床研究的数据，这些数据同时也评估了Zelboraf的安全性和有效性。黑色素瘤病人的组织标本被采集来检测该突变。 Zelboraf组病人最常报告的副作用包括关节痛、皮疹、脱发、疲乏、恶心以及皮肤对日光敏感。大约26%的病人发生了可手术治疗的皮肤鳞状细胞癌。所以，接受Zelboraf治疗的病人应避免日晒。 Zelboraf的用药指引告知医务人员和病人有关Zelboraf的潜在风险。 2011年7月，FDA发布了新的指导草案推进配套诊断方法的开发和审评。指导方案目前处于征集意见阶段。 Zelboraf由罗氏集团旗下的Genentech公司销售，cobas 4800 BRAF V600突变检测由加利福尼亚州普莱森顿罗氏分子系统公司生产。