2013年1月6日，欧盟委员会(EC)已批准Votubia(everolimus，依维莫司，在美国商品名为Afinitor )用于伴有结节性硬化症(TSC)及其并发症风险、但不需要立即开展手术的肾血管平滑肌脂肪瘤(RAML)成人患者的治疗，该药是首个获欧盟批准可用于这 一患者群体的药物，在此之前，手术介入是唯一的选择。 EC的药物批准，适用于所有27个欧盟成员国，包括冰岛和挪威。 Afinitor是一种mTOR抑制剂，已被批准用于治疗乳腺癌、肾细胞癌和胰腺神经内分泌肿瘤等5种类型癌症。在欧洲，依维莫司治疗TSC已被授予孤儿药地位。孤儿药是指治疗那些发病率≤5/10000的疾病药物。 产品处方描述 【商品名】AFINITOR 【通用名】依维莫司 【英文名】AFINITOR 【成份】依维莫司 【适应症】 适用于用舒尼替尼[sunitinib]或索拉非尼[sorafenib]治疗失败后晚期肾细胞癌患者的治疗。 【剂量和给药方法】 1、10mg每天1次有或无食物。 2、治疗中断和/或剂量减低至5mg每天1次可能需要处理不良药物反应。 3、对有Child-Pugh类别B肝损伤患者，减低剂量至5mg每天1次。 4、如需要中度CYP3A4或P-糖蛋白(PgP)抑制剂，减低AFINITOR剂量至2.5mg每天1次;如耐受考虑增加至5mg每天1次。 5、如需要CYP3A4的强诱导剂，增加AFINITOR剂量5mg增量至最大20mg每天1次。 【禁忌】 对活性物质，对其它雷帕霉素衍生物，或对任何辅料超敏性。超敏性反应比阿姆纤维症状包括，单不限于，过敏，呼吸困难，脸红，胸痛，或胸血管水肿(如，气道或舌肿胀，有或无呼吸损伤)用依维莫司和其它雷帕霉素衍生物曾观察到。 【注意事项】 1、非-感染性肺炎：监查临床症状或放射学变化;曾发生致命性病例.用剂量减低或停药处理直至症状解决,和考虑皮质甾体。 2、感染：增加的风险感染,某些致命性。监视征象和症状,和及时治疗。 3、口腔溃疡：口溃疡,口炎,和口粘膜炎是常见处理包括口腔洗涤(无酒精或过氧化物)和局部治疗。 4、实验室检验改变：可能发生血清肌酐，血糖，和脂质的升高。还可能发生血红蛋白，嗜中性，和血小板减低。治疗前和以后定期监测肾功能，血糖，脂质，和血液学参数。 5、免疫接种：避免活疫苗和密切接触曾接受活疫苗者。 6、妊娠中使用：当给予妊娠妇女时可能发生胎儿危害。告知妇女对胎儿潜在危害。 【不良反应】 最常见不良反应(发生率 ≥30%)是口炎，感染，虚弱，疲乏，咳嗽，和腹泻。 【药物相互作用】 1、强CYP3A4或PgP抑制剂：避免同时使用。 2、中度CYP3A4或PgP抑制剂：如需要联用，谨慎使用和减低AFINITOR剂量。 3、强CYP3A4诱导剂：避免同时使用。如不能避免联用，增加AFINITOR剂量。 【在特殊人群中的使用】 1、哺乳母亲：停止药物或哺乳，考虑药物对母亲的重要性。 2、肝损伤：有Child-Pugh类别C肝损伤患者中不应使用AFINITOR。对有Child-Pugh类别B肝损伤患者减低剂量至5mg每天。 Afinitor Tablets 1. Name of the medicinal product  Afinitor 2.5mg tablets Afinitor 5mg tablets Afinitor 10mg tablets 2. Qualitative and quantitative composition Afinitor 2.5mg tablets: Each tablet contains 2.5 mg everolimus. Excipient with known effect: Each tablet contains 74 mg lactose. Afinitor 5mg tablets Each tablet contains 5 mg everolimus. Excipients with known effect: Each tablet contains 149 mg lactose. Afinitor 10mg tablets: Each tablet contains 10 mg everolimus. Excipients with known effect: Each tablet contains 297 mg lactose. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Tablet. Afinitor 2.5mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other. Afinitor 5mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other. Afinitor 10mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other. 4. Clinical particulars 4.1 Therapeutic indications Hormone receptor-positive advanced breast cancer Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. Neuroendocrine tumours of pancreatic origin Afinitor is indicated for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease. Renal cell carcinoma Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy. 4.2 Posology and method of administration Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of anticancer therapies. Posology For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets. The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. If a dose is missed, the patient should not take an additional dose, but take the next prescribed dose as usual. Dose adjustment due to adverse reactions Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily. Table 1 summarises the dose adjustment recommendations for specific adverse reactions (see also section 4.4). Table 1 Afinitor dose adjustment recommendations Adverse reaction Severity1 Afinitor dose adjustment Non-infectious pneumonitis Grade 2 Consider interruption of therapy until symptoms improve to Grade ≤1. Re-initiate treatment at 5 mg daily. Discontinue treatment if failure to recover within 4 weeks. Grade 3 Interrupt treatment until symptoms resolve to Grade ≤1. Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation. Grade 4 Discontinue treatment. Stomatitis Grade 2 Temporary dose interruption until recovery to Grade ≤1. Re-initiate treatment at same dose. If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate treatment at 5 mg daily. Grade 3 Temporary dose interruption until recovery to Grade ≤1. Re-initiate treatment at 5 mg daily. Grade 4 Discontinue treatment. Other non-haematological toxicities (excluding metabolic events) Grade 2 If toxicity is tolerable, no dose adjustment required. If toxicity becomes intolerable, temporary dose interruption until recovery to Grade ≤1. Re-initiate treatment at same dose. If toxicity recurs at Grade 2, interrupt treatment until recovery to Grade ≤1. Re-initiate treatment at 5 mg daily. Grade 3 Temporary dose interruption until recovery to Grade ≤1. Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation. Grade 4 Discontinue treatment. Metabolic events (e.g. hyperglycaemia, dyslipidaemia) Grade 2 No dose adjustment required. Grade 3 Temporary dose interruption. Re-initiate treatment at 5 mg daily. Grade 4 Discontinue treatment. Thrombocytopenia Grade 2 (<75, ≥50x109/l) Temporary dose interruption until recovery to Grade ≤1 (≥75x109/l). Re-initiate treatment at same dose. Grade 3 & 4 (<50x109/l) Temporary dose interruption until recovery to Grade ≤1 (≥75x109/l). Re-initiate treatment at 5 mg daily. Neutropenia Grade 2 (≥1x109/l) No dose adjustment required. Grade 3 (<1, ≥0.5x109/l) Temporary dose interruption until recovery to Grade ≤2 (≥1x109/l). Re-initiate treatment at same dose. Grade 4 (<0.5x109/l) Temporary dose interruption until recovery to Grade ≤2 (≥1x109/l). Re-initiate treatment at 5 mg daily. Febrile neutropenia Grade 3 Temporary dose interruption until recovery to Grade ≤2 (≥1.25x109/l) and no fever. Re-initiate treatment at 5 mg daily. Grade 4 Discontinue treatment. 1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Special populations Elderly patients (≥65 years) No dose adjustment is required (see section 5.2). Renal impairment No dose adjustment is required (see section 5.2). Hepatic impairment − Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. − Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily. − Severe hepatic impairment (Child-Pugh C) – Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded. Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment (see also sections 4.4 and 5.2). Paediatric population The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data are available. Method of administration Afinitor should be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed. 4.3 Contraindications  Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use  Non-infectious pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) has been described in patients taking Afinitor (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Patients should be advised to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose adjustments. If symptoms are moderate (Grade 2) or severe (Grade 3) the use of corticosteroids may be indicated until clinical symptoms resolve. Infections Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus, have been described in patients taking Afinitor. Some of these infections have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally fatal. Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy. Hypersensitivity reactions Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3). Concomitant use of angiotensin-converting enzyme (ACE) inhibitors Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Oral ulceration Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Afinitor (see section 4.8). In such cases topical treatments are recommended, but mouthwashes containing alcohol, peroxide, iodine and thyme derivatives should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5). Renal failure events Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor (see section 4.8). Renal function should be monitored particularly where patients have additional risk factors that may further impair renal function. Laboratory tests and monitoring Renal function Elevations of serum creatinine, usually mild, and proteinuria have been reported (see section 4.8). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter. Blood glucose Hyperglycaemia has been reported (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More frequent monitoring is recommended when Afinitor is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor. Blood lipids Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter, as well as management with appropriate medical therapy, is recommended. Haematological parameters Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and periodically thereafter. Carcinoid tumours In a randomised, double-blind, multi-centre trial in patients with carcinoid tumours, Afinitor plus depot octreotide was compared to placebo plus depot octreotide. The study did not meet the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and efficacy of Afinitor in patients with carcinoid tumours have not been established. Interactions Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, dose adjustments of Afinitor can be taken into consideration based on predicted AUC (see section 4.5). Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased plasma concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is not recommended. Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5). Hepatic impairment Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment (see section 5.2). Afinitor is only recommended for use in patients with severe hepatic impairment (Child-Pugh C) if the potential benefit outweighs the risk (see sections 4.2 and 5.2). No clinical safety or efficacy data are currently available to support dose adjustment recommendations for the management of adverse reactions in patients with hepatic impairment. Vaccinations The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5). Lactose Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Wound healing complications Impaired wound healing is a class effect of rapamycin derivatives, including everolimus. Caution should therefore be exercised with the use of Afinitor in the peri-surgical period. 4.5 Interaction with other medicinal products and other forms of interaction  Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 2 below. CYP3A4 and PgP inhibitors increasing everolimus concentrations Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells. CYP3A4 and PgP inducers decreasing everolimus concentrations Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells. Table 2 Effects of other active substances on everolimus Active substance by interaction Interaction – Change in Everolimus AUC/Cmax Geometric mean ratio (observed range) Recommendations concerning co-administration Potent CYP3A4/PgP inhibitors Ketoconazole AUC ↑15.3-fold (range 11.2-22.5) Cmax ↑4.1-fold (range 2.6-7.0) Concomitant treatment of Afinitor and potent inhibitors is not recommended. Itraconazole, posaconazole, voriconazole Not studied. Large increase in everolimus concentration is expected. Telithromycin, clarithromycin Nefazodone Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir Moderate CYP3A4/PgP inhibitors Erythromycin AUC ↑4.4-fold (range 2.0-12.6) Cmax ↑2.0-fold (range 0.9-3.5) Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot be avoided. If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg daily or 2.5 mg daily may be considered. However, there are no clinical data with this dose adjustment. Due to between subject variability the recommended dose adjustments may not be optimal in all individuals, therefore close monitoring of side effects is recommended. If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average elimination time for most commonly used moderate inhibitors) before the Afinitor dose is returned to the dose used prior to initiation of the co-administration. Imatinib AUC ↑ 3.7-fold Cmax ↑ 2.2-fold Verapamil AUC ↑3.5-fold (range 2.2-6.3) Cmax ↑2.3-fold (range1.3-3.8) Ciclosporin oral AUC ↑2.7-fold (range 1.5-4.7) Cmax ↑1.8-fold (range 1.3-2.6) Fluconazole Not studied. Increased exposure expected. Diltiazem Dronedarone Not studied. Increased exposure expected. Amprenavir, fosamprenavir Not studied. Increased exposure expected. Grapefruit juice or other food affecting CYP3A4/PgP Not studied. Increased exposure expected (the effect varies widely). Combination should be avoided. Potent and moderate CYP3A4 inducers Rifampicin AUC ↓63% (range 0-80%) Cmax ↓58% (range 10-70%) Avoid the use of concomitant potent CYP3A4 inducers. If patients require co-administration of a potent CYP3A4 inducer, an Afinitor dose increase from 10 mg daily up to 20 mg daily should be considered using 5 mg increments or less applied on Day 4 and 8 following start of the inducer. This dose of Afinitor is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment. If treatment with the inducer is discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction), before the Afinitor dose is returned to the dose used prior to initiation of the co-administration. Dexamethasone Not studied. Decreased exposure expected. Carbamazepine, phenobarbital, phenytoin Not studied. Decreased exposure expected. Efavirenz, nevirapine Not studied. Decreased exposure expected. St John's Wort (Hypericum perforatum) Not studied. Large decrease in exposure expected. Preparations containing St John's Wort should not be used during treatment with everolimus Agents whose plasma concentration may be altered by everolimus Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). The effect is likely to be due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected (see section 4.4). Co-administration of everolimus and depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumours could not be established. Co-administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety. Concomitant use of angiotensin-converting enzyme (ACE) inhibitors Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4). Vaccinations The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Afinitor. The use of live vaccines should be avoided during treatment with Afinitor (see section 4.4). Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines. 4.6 Fertility, pregnancy and lactation  Women of childbearing potential/Contraception in males and females Women of childbearing potential must use a highly effective method of contraception (e.g. oral, injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending treatment. Male patients should not be prohibited from attempting to father children. Pregnancy There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). The potential risk for humans is unknown. Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimus should not breast-feed. Fertility The potential for everolimus to cause infertility in male and female patients is unknown, however amenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus (see section 5.3). 4.7 Effects on ability to drive and use machines  Afinitor may have a minor or moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Afinitor. 4.8 Undesirable effects  Summary of the safety profile The safety profile is based on pooled data from 2,406 patients treated with Afinitor in eight clinical studies, consisting of four randomised, double-blind, placebo controlled phase III studies and four phase II studies, related to the approved indications. The most common adverse reactions (incidence ≥1/10) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, weight decreased, peripheral oedema, asthenia, pruritus, epistaxis, hyperglycaemia, hypercholesterolaemia, headache, and vomiting. The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, fatigue, infections, pneumonitis, diarrhoea, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, hypophosphataemia, rash, and hypertension. The grades follow CTCAE Version 3.0. Tabulated list of adverse reactions Table 3 presents the frequency category of adverse reactions reported in the pooled analysis considered for the safety pooling. Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3 Adverse reactions reported in clinical studies Infections and infestations Very common Infections a, * Blood and lymphatic system disorders Very common Anaemia Common Thrombocytopenia, neutropenia, leukopenia, lymphopenia Uncommon Pancytopenia Rare Pure red cell aplasia Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Very common Decreased appetite, hyperglycaemia, hypercholesterolaemia Common Hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidaemia, hypokalaemia, dehydration, hypocalcaemia Psychiatric disorders Common Insomnia Nervous system disorders Very common Dysgeusia, headache Uncommon Ageusia Eye disorders Common Eyelid oedema Uncommon Conjunctivitis Cardiac disorders Uncommon Congestive cardiac failure Vascular disorders Common Hypertension, haemorrhage b Uncommon Flushing, deep vein thrombosis Respiratory, thoracic and mediastinal disorders Very common Pneumonitis c, epistaxis Common Cough, dyspnoea Uncommon Haemoptysis, pulmonary embolism Rare Acute respiratory distress syndrome Gastrointestinal disorders Very common Stomatitis d, diarrhoea, nausea, vomiting Common Dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia, dysphagia Hepatobiliary disorders Common Alanine aminotransferase increased, aspartate aminotransferase increased Skin and subcutaneous tissue disorders Very common Rash, pruritus Common Dry skin, nail disorders, mild alopecia, acne, erythema, onychoclasis, palmar-plantar erythrodysaesthesia syndrome, skin exfoliation, skin lesion Rare Angioedema Musculoskeletal and connective tissue disorders Common Arthralgia Renal and urinary disorders Common Proteinuria*, blood creatinine increased, renal failure* Uncommon Increased daytime urination, acute renal failure* Reproductive system and breast disorders Uncommon Menstruation irregular Rare Amenorrhoea General disorders and administration site conditions Very common Fatigue, peripheral oedema, asthenia Common Pyrexia Uncommon Non-cardiac chest pain Rare Impaired wound healing Investigations Very common Weight decreased * See also subsection “Description of selected adverse reactions” a Includes all reactions within the 'infections and infestations' system organ class including (common) pneumonia and (uncommon) herpes zoster, sepsis, and isolated cases of opportunistic infections [e.g. aspergillosis, candidiasis and hepatitis B (see also section 4.4)] b Includes different bleeding events not listed individually c Includes (common) pneumonitis, interstitial lung disease, lung infiltration and (rare) pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitis d Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulceration and (uncommon) glossodynia, glossitis Description of selected adverse reactions In clinical studies and post-marketing spontaneous reports, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected event during periods of immunosuppression. In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome) and proteinuria. Monitoring of renal function is recommended (see section 4.4). In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of amenorrhoea (secondary amenorrhoea and other menstrual irregularities). Elderly patients In the safety pooling, 36% of the Afinitor-treated patients were ≥65 years of age. The number of patients with an adverse reaction leading to discontinuation of the medicinal product was higher in patients ≥65 years of age (19% vs. 12%). The most common adverse reactions leading to discontinuation were pneumonitis, stomatitis, fatigue and dyspnoea. 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability. General supportive measures should be initiated in all cases of overdose. 5. Pharmacological properties 5.1 Pharmacodynamic properties  Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE10 Mechanism of action Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo. Clinical efficacy and safety Hormone receptor-positive advanced breast cancer BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomisation was stratified by documented sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥24 weeks) from at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. The primary endpoint for the study was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigator's assessment (local radiology). Supportive PFS analyses were based on an independent central radiology review. Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate, safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group performance status) deterioration. A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) + exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). The median duration of treatment was 29.5 weeks (range 1.0-123.3 weeks) for patients receiving everolimus + exemestane and 14.1 weeks (range 1.0-101.0 weeks) for the placebo + exemestane group. The efficacy results were obtained from the final PFS analysis (see Table 4 and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of progression. Table 4 BOLERO-2 efficacy results Analysis Afinitora n=485 Placeboa n=239 Hazard ratio p value Median progression-free survival (months) (95% CI) Investigator radiological review 7.8 (6.9 to 8.5) 3.2 (2.8 to 4.1) 0.45 (0.38 to 0.54) <0.0001 Independent radiological review 11.0 (9.7 to 15.0) 4.1 (2.9 to 5.6) 0.38 (0.31 to 0.48) <0.0001 Best overall response (%) (95% CI) Objective response rateb 12.6% (9.8 to 15.9) 1.7% (0.5 to 4.2) n/ad <0.0001e Clinical benefit ratec 51.3% (46.8 to 55.9) 26.4% (20.9 to 32.4) n/ad <0.0001e a Plus exemestane b Objective response rate = proportion of patients with complete or partial response c Clinical benefit rate = proportion of patients with complete or partial response or stable disease ≥24 weeks d Not applicable e p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the Cochran-Armitage permutation test. OS data are not mature at the time of the interim analysis and no statistically significant treatment-related difference in OS was noted [HR=0.77 (95% CI: 0.57, 1.04)]. Figure 1 BOLERO-2 Kaplan-Meier progression-free survival curves (investigator radiological review) The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy, number of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis, and across major demographic and prognostic subgroups) a positive treatment effect was seen with everolimus + exemestane with an estimated hazard ratio versus placebo + exemestane ranging from 0.25 to 0.60. No differences in the time to ≥5% deterioration in the global and functional domain scores of QLQ-C30 were observed in the two arms. Advanced neuroendocrine tumours of pancreatic origin (pNET) RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET, demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold prolongation of median progression-free-survival (PFS) (11.04 months versus 4.6 months), (HR 0.35; 95% CI: 0.27, 0.45; p<0.0001) (see Table 5 and Figure 2). RADIANT-3 involved patients with well- and moderately-differentiated advanced pNET whose disease had progressed within the prior 12 months. Treatment with somatostatin analogues was allowed as part of BSC. The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Following documented radiological progression, patients could be unblinded by the investigator. Those randomised to placebo were then able to receive open-label Afinitor. Secondary endpoints included safety, objective response rate, response duration and overall survival (OS). In total, 410 patients were randomised 1:1 to receive either Afinitor 10 mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 78.5% Caucasian). Fifty-eight percent of the patients in both arms received prior systemic therapy. The median duration of blinded study treatment was 37.3 weeks (range 1.1-129.9 weeks) for patients receiving everolimus and 16.1 weeks (range 0.4-146.0 weeks) for those receiving placebo. Table 5 RADIANT-3 – Progression-free survival results Population n Afinitor n=207 Placebo n=203 Hazard ratio (95% CI) p-value   410 Median progression-free survival (months) (95% CI)     Investigator radiological review 410 11.04 (8.41, 13.86) 4.60 (3.06, 5.39) 0.35 (0.27, 0.45) <0.0001 Independent radiological review 410 13.67 (11.17, 18.79) 5.68 (5.39, 8.31) 0.38 (0.28, 0.51) Figure 2 RADIANT-3 – KaplanMeier progression-free survival curves (investigator radiological review) Following disease progression 172 of the 203 patients (84.7%) initially randomised to placebo crossed over to open-label Afinitor. The overall survival results show no statistically significant difference in OS (HR=0.89 [95% CI: 0.64, 1.23]). Advanced renal cell carcinoma RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind study comparing everolimus 10 mg/day and placebo, both in conjunction with best supportive care, was conducted in patients with metastatic renal cell carcinoma whose disease had progressed on or after treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted. Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score (favourable- vs. intermediate- vs. poor-risk groups) and prior anticancer therapy (1 vs. 2 prior VEGFR-TKIs). Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid Tumours) and assessed via a blinded, independent central review, was the primary endpoint. Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related symptoms, and quality of life. After documented radiological progression, patients could be unblinded by the investigator: those randomised to placebo were then able to receive open-label everolimus 10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the time of the second interim analysis as the primary endpoint had been met. In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139). Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88% Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days (range 21-295 days) for those receiving placebo. Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a statistically significant 67% reduction in the risk of progression or death (see Table 6 and Figure 3). Table 6 RECORD-1 – Progression-free survival results Population n Afinitor n=277 Placebo n=139 Hazard ratio (95%CI) p-value     Median progression-free survival (months) (95% CI)     Primary analysis All (blinded independent central review) 416 4.9 (4.0-5.5) 1.9 (1.8-1.9) 0.33 (0.25-0.43) <0.0001a Supportive/sensitivity analyses All (local review by investigator) 416 5.5 (4.6-5.8) 1.9 (1.8-2.2) 0.32 (0.25-0.41) <0.0001a MSKCC prognostic score (blinded independent central review) Favourable risk 120 5.8 (4.0-7.4) 1.9 (1.9-2.8) 0.31 (0.19-0.50) <0.0001 Intermediate risk 235 4.5 (3.8-5.5) 1.8 (1.8-1.9) 0.32 (0.22-0.44) <0.0001 Poor risk 61 3.6 (1.9-4.6) 1.8 (1.8-3.6) 0.44 (0.22-0.85) 0.007 Figure 3 RECORD-1 – KaplanMeier progression-free survival curves (independent central review) Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo. Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while none were observed in patients receiving placebo. Therefore, the progression-free survival advantage primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor treatment group). No statistically significant treatment-related difference in overall survival was noted (hazard ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following disease progression for patients allocated to placebo confounded the detection of any treatment-related difference in overall survival. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Afinitor in all subsets of the paediatric population in neuroendocrine tumours of pancreatic origin and in renal cell carcinoma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties  Absorption In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP. Food effect In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 mg (as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile. Distribution The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma in cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment. Biotransformation Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100 times less activity than everolimus itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological activity. Elimination Mean oral clearance (CL/F) of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours. No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces. Steady-state pharmacokinetics After administration of everolimus in patients with advanced solid tumours, steady-state AUC0- was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks. Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0- and pre-dose trough concentration at steady-state. Special populations Hepatic impairment The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dose studies of Afinitor tablets in 8 and 34 subjects with impaired hepatic function relative to subjects with normal hepatic function. In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function. In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively. Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic impairment based on their Child-Pugh status. Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment (see sections 4.2 and 4.4). Renal impairment In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients. Elderly patients In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance of everolimus was detected. Ethnicity Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions. Based on analysis of population pharmacokinetics, CL/F is on average 20% higher in black transplant patients. 5.3 Preclinical safety data The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits. The major target organs were male and female reproductive systems (testicular tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or minipigs. Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at systemic exposure levels within the range of therapeutic exposure or above, with the exception of the findings in rats, which occurred below therapeutic exposure due to a high tissue distribution. In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg which caused a reduction in male fertility. There was evidence of reversibility. In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% of the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increases in pre-implantation loss. Everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus caused embryo/ foetotoxicity at systemic exposure below the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late resorptions. Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic potential in mice and rats up to the highest doses, corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure. 6. Pharmaceutical particulars 6.1 List of excipients  Butylated hydroxytoluene (E321) Magnesium stearate Lactose monohydrate Hypromellose Crospovidone type A Lactose anhydrous 6.2 Incompatibilities  Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 25°C. Store in the original package in order to protect from light and moisture. 6.5 Nature and contents of container Aluminium/polyamide/aluminium/PVC blister containing 10 tablets. Packs containing 10 (5mg and 10mg tablets only), 30 or 90 tablets. Not all pack sizes may be marketed. 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 Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 8. Marketing authorisation number(s) Afinitor 2.5mg tablets: EU/1/09/538/009 EU/1/09/538/010 Afinitor 5mg tablets: EU/1/09/538/001 EU/1/09/538/003 EU/1/09/538/007 Afinitor 10mg tablets: EU/1/09/538/004 EU/1/09/538/006 EU/1/09/538/008 9. Date of first authorisation/renewal of the authorisation Date of authorisation: 03 August 2009 Date of latest renewal: 05 August 2014 10. Date of revision of the text 16 May 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 美国FDA批准诺华AFINITOR(依维莫司，everolimus)用于治疗晚期肾癌 近日，FDA批准Afinitor(everolimus)口服片剂用于治疗那些采用了其他抗癌药之后病情仍持续恶化的晚期肾癌患者。 肾细胞癌是最常见的肾癌类型，病发于肾小管上皮细胞。通常，这类患者体内的癌细胞对放疗和化疗等标准疗法会产生抵抗性，从而使大多数人通过肾脏摘除达到治疗 目的。若患者的癌变部位仅限定在肾脏，60-70%的人生存期可达到5年，但癌细胞一旦发生转移，则患者生存期将会大幅降低。 FDA相关部门负责人表示，Afinitor为那些采用了sunitinib或sorafenib后失败的患者提供了一种全新的治疗选择，像Afinitor这样具有靶向作用的药物可以让患者在病情无恶化的情况下延长存活时间。 Afinitor属激酶抑制剂，它可以妨碍细胞之间的信息传达，阻止肿瘤生长。该药也可用于那些曾采用过其他激酶抑制剂(如Sutent或Nexavar)的晚期肾细胞癌 患者。Sutent和Nexavar属于多靶点型激酶抑制剂，即可以同时作用于多个细胞。而Afinitor则通过阻断一种特定的蛋白质(人雷帕霉素靶蛋 白/mTOR)起作用，干扰癌细胞的生长、分裂和新陈代谢。 依维莫司—是晚期肾癌患者新的治疗选择 美国FDA批准依维莫司用于肾癌。研究结果显示，依维莫司可明显增加癌症病人的无进展生存期，对于经舒尼替尼或索拉非尼治疗无效的晚期肾细胞癌病人，依维莫司提供了一个新的治疗选择。 2009年3月30日，诺华公司原免疫抑制药物依维莫司(everolimus，Afinitor)用于肾癌获得美国FDA批准。2008年11月，FDA要求补充数据而将本品的注册延迟了3月，而现在它给与了放行的绿灯。 诺华制药部总裁JoeJimenez接受采访时表示，“依维莫司确实是一个有潜力治疗多种肿瘤的药物，甚至在开始进行乳癌、胃癌和非小细胞肺癌研究之前，我们就相信它将成为一个重磅炸弹级产品。对于诺华来说，它是一个重要产品。 依维莫司是西罗莫司(sirolimus，又称雷帕霉素，即rapamycin)的衍生物，故依维莫司又称40-O-(2-羟乙基)-雷帕霉素，或40-O-(2-羟乙基)-西罗莫司。 依维莫司是一个特异性抑制mTOR分子(哺乳动物雷帕霉素靶蛋白)的药物。临床上主要用来预防肾移植和心脏移植手术后的排斥反应。其作用机制主要包括免疫抑制作用、抗肿瘤作用、抗病毒作用、血管保护作用。常与环孢素等其他免疫抑制剂联合使用以降低毒性。 FDA药物评审中心肿瘤药物评审处主任RobertJustice医生评论道，“对于经舒尼替尼或索拉非尼治疗无效的晚期肾细胞癌病人，依维莫司提供了一个新的治疗选择。试验结果表明，像依维莫司这样的靶向治疗药物可明显增加癌症病人的无进展生存期。” 肾细胞癌是最常见的肾癌，对化疗和放疗反应往往欠佳，初始治疗方法常为手术切除肿瘤。未发生转移的肾细胞癌病人的五年存活率为60-70%。已发生癌细胞转移的晚期癌症病人的生存率明显降低. Afinitor(everolimus，依维莫司片)被批准用于治疗无效的晚期肾癌患者 RAD001在美国获得优先审查用于满足那些使用其他药物治疗不能获得疗效的晚期肾癌患者 • RAD001提议的商品名为Afinitor®，已在美国、欧洲和瑞士申报。 • 目前The Lancet发表的数据显示RAD001可降低疾病进展风险70%并延长至疾病进展时间达一倍以上。 • RAD001作为每天一次的口服用药，通过持续地对mTOR的靶向抑制作用，对于晚期肾癌患者显示出良好的前景。 日前，诺华对外宣布RAD001(everolimus，依维莫司片)已经获得FDA的快速审批。这个决定是基于该药物的潜在性能即对于使用常规治疗失败的晚期肾癌患者作为首选用药，RAD001显示出卓越的疗效。 诺华也向EMEA (European Medicines Agency) 和Swissmedic (the Swiss Agency for Therapeutic Products) 提出了RAD001市场授权申请。对于RAD001，诺华提议的商品名Afinitor®, 已经获得EMEA的批准同时在美国处于审批阶段。 申报是基于试验RECORD-1 (肾细胞癌患者每天口服RAD001作为治疗)获得的数据。试验的中期研究结果已经发表在2008年7月23日的The Lancet上以及今年早些时候的ASCO大会上。试验数据显示对于那些采用常规治疗方法失败的晚期肾癌患者，RAD001在至肿瘤进展时间和降低疾病进 展风险这两个指标方面均显示出疗效1。 “目前，对于那些采用常规治疗手段失败的晚期肾癌患者没有什么更好的治疗方法，”诺华肿瘤，发展部全球负责人、副总裁，医学博士Alessandro Riva介绍说, “现在RAD001得到的最新数据表明它能进一步为上述患者带来充满前景的新治疗方法。” FDA的优先审查地位是给予那些有可能填补目前未满足医疗需要的药品。 有关肾细胞癌 (RCC) 发生在肾或肾细胞的癌症，在全球新发生癌症中占2%并且有不断增长的趋势2。 对其他靶向治疗无效的mRCC患者，RAD001可改善其PFS Motzer等报道，与安慰剂比较，RAD001(everolimus)在改善其他靶向药物治疗转移性肾癌(mRCC)进展后患者的无进展生存(PFS)上有显着地统计学意义和临床意义，并表现出良好的安全性。 该研究入组接受索拉非尼、舒尼替尼或两药联用少于6个月、或疾病进展的透明细胞型RCC患者362例，按2:1的比例随机分入RAD001(10 mg/d po)组和安慰剂组，并均给予最佳支持治疗。安慰剂治疗患者疾病进展时给予RAD001治疗。主要终点为PFS。 -------------------------------------------------------------- 注：以下产品不同规格和不同价格，购买以咨询为准！ -------------------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: AFINITOR 2.5mg/tab 30tabs/box 原产地英文药品名: EVEROLIMUS 中文参考商品译名: AFINITOR 2.5毫克/片 30片/盒 中文参考药品译名: 依维莫司 生产厂家中文参考译名: Novartis Pharma 生产厂家英文名: 诺华制药 --------------------------------------------------------------- 产地国家: 德国 原产地英文商品名: AFINITOR 5mg/tab 30tablets/box 原产地英文药品名: EVEROLIMUS 中文参考商品译名: AFINITOR 5毫克/片 30片/盒 中文参考药品译名: 依维莫司 生产厂家中文参考译名: Novartis Pharma 生产厂家英文名: 诺华制药 ------------------------------------------------------------------ 产地国家: 德国 原产地英文商品名: AFINITOR 10mg/tab 30tablets/box 原产地英文药品名: EVEROLIMUS 中文参考商品译名: AFINITOR 10毫克/片 30片/盒 中文参考药品译名: 依维莫司 生产厂家中文参考译名: Novartis Pharma 生产厂家英文名: 诺华制药 ------------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: AFINITOR 2.5mg/tab 28tabs/box 原产地英文药品名: EVEROLIMUS 中文参考商品译名: AFINITOR 2.5毫克/片 28片/盒 中文参考药品译名: 依维莫司 生产厂家中文参考译名: Novartis Pharma 生产厂家英文名: 诺华制药 ---------------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: AFINITOR 5mg/tab 28tabs/box 原产地英文药品名: EVEROLIMUS 中文参考商品译名: AFINITOR 5毫克/片 28片/盒 中文参考药品译名: 依维莫司 生产厂家中文参考译名: Novartis Pharma 生产厂家英文名: 诺华制药 ----------------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: AFINITOR 10mg/tab 28tabs/box 原产地英文药品名: EVEROLIMUS 中文参考商品译名: AFINITOR 10毫克/片 28片/盒 中文参考药品译名: 依维莫司 生产厂家中文参考译名: Novartis Pharma 生产厂家英文名: 诺华制药 该药品相关信息网址1: http://www.afinitor.com