英文药名: Afinitor(Everolimus Tablets)

中文药名: 依维莫司片

品牌药生产厂家: Novartis

药品说明

适应证和用途

AFINITOR是一种激酶抑制剂适用于用舒尼替尼[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）10 mg每天1次有或无食物。
（2）治疗中断和/或剂量减低至5 mg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5 mg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2.5 mg每天1次；如耐受考虑增加至5 mg每天1次。

（5）如需要CYP3A4的强诱导剂，增加AFINITOR剂量 in 5 mg增量至最大20 mg每天1次。
剂型和规格
2.5 mg, 5 mg和10 mg片 无记号。
禁忌证
超敏性 to 依维莫司, to other雷帕霉素[rapamycin]衍生物,或to any of the 辅料.
警告和注意事项
（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5 mg每天。

包装规格：
·10mg *30片

·2.5mg *30片

·5mg*30 片

Novartis drug Afinitor® approved by FDA as first medication for children and adults with a benign brain tumor associated with tuberous sclerosis

Subependymal giant cell astrocytoma (SEGA) is a benign brain tumor associated with tuberous sclerosis (TS)1
Prior to the approval of Afinitor, brain surgery was the only treatment option for patients with growing SEGAs1
Approval is based on a 28-patient study showing nearly one-third of patients had a reduction of 50% or greater in the size of their largest SEGA at six months2
Worldwide regulatory submissions underway, including applications filed in the EU and Switzerland
East Hanover, N.J., October 29, 2010 /PRNewswire/ — Novartis Pharmaceuticals Corporation (“Novartis”) announced today that the US Food and Drug Administration (FDA) has approved Afinitor® (everolimus) tablets for patients with subependymal giant cell astrocytoma (SEGA), a benign brain tumor associated with tuberous sclerosis (TS), who require therapeutic intervention but are not candidates for curative surgical resection2.

This accelerated approval of Afinitor is based on an open-label, single-arm, 28-patient study conducted by Cincinnati Children’s Hospital Medical Center2. The effectiveness of Afinitor is based on an analysis of change in SEGA volume. A Phase III study is underway that compares Afinitor to placebo to explore the clinical benefits of Afinitor for the treatment of patients with SEGA associated with TS3.

Prior to this FDA approval, the only treatment option for growing SEGAs, which primarily affect children and adolescents, was brain surgery1,4,5. Tuberous sclerosis is a genetic disorder affecting approximately 25,000 to 40,000 people in the US that may cause benign tumors to form in vital organs6. SEGAs, benign brain tumors, occur in up to 20% of patients with TS1.

“Today’s FDA decision is an important milestone for the children and adults living with SEGA associated with tuberous sclerosis,” said Hervé Hoppenot, President of Novartis Oncology. “We are committed to furthering research for patients with tuberous sclerosis and will continue to work towards addressing their unmet medical needs.”

In this study, nearly one-third of patients (32%) experienced a reduction of 50% or greater in the size of their largest SEGA at six months relative to baseline. None of the patients developed a new SEGA while receiving Afinitor2.

The most common adverse reactions observed (incidence ≥30%) in the open-label, single-arm trial were mouth sores, upper respiratory tract infections, sinusitis, middle ear infections and fever2.

“SEGAs can be challenging for individuals with tuberous sclerosis and for the whole family, which is why we are encouraged to see ongoing research and new treatment options like Afinitor for these individuals,” said Vicky Whittemore, Vice President and Chief Scientific Officer of the patient advocacy group the Tuberous Sclerosis Alliance.

For the treatment of patients with SEGA associated with TS, Afinitor received FDA priority review status, which is granted to drugs that offer major advances in treatment. This indication was approved under the FDA’s accelerated approval program, which provides patients access to a treatment where previously there was an unmet medical need even though clinical benefit has yet to be confirmed7. Novartis is continuing to study the efficacy and clinical benefit of Afinitor for patients with SEGA associated with TS in a Phase III trial3.

Novartis has submitted marketing applications for everolimus to the European Medicines Agency (EMA) and the Swiss Agency for Therapeutic Products (Swissmedic), and additional regulatory submissions are underway worldwide.

About the study
In an open-label, single-arm study, 28 patients aged three years and above (median age=11, range 3-34) with evidence of SEGA growth initially received everolimus orally at a dose of 3 mg/m². As of March 8, 2010, the median duration of treatment was 24.4 months (range 4.7-37.3 months)2.

In the study, 32% of patients experienced a reduction of 50% or greater in the size of their largest SEGA at six months relative to baseline. None of the patients developed a new SEGA while receiving everolimus2.

The reliability of the frequency of adverse reactions and laboratory abnormalities reported in this trial is limited because of the small number of patients. The most common adverse reactions (≥10%, all grades) reported among the 28 patients with evidence of established SEGA growth included: stomatitis or mouth sores (86%), upper respiratory tract infection (82%), sinusitis (39%), middle ear infection (36%), fever (32%), convulsion (29%), acne-like skin inflammation (25%), diarrhea (25%), cellulitis or acute infection of the deep tissues of skin or muscle (21%), vomiting (21%), cough (21%), body tinea or fungal infection (18%), headache (18%), personality change (18%), rash (18%), skin infection (18%), dry skin (18%), gastroenteritis or inflammation of the gastrointestinal tract (18%), contact dermatitis (14%), dizziness (14%), external ear infection (14%), allergic rhinitis or inflammation of nasal passages (14%), gastric infection (14%), nasal congestion (14%), excoriation or skin abrasion (14%), acne (11%), constipation (11%), abdominal pain (11%) and pharyngitis or inflammation of the pharynx (11%)2.

Grade three adverse reactions included convulsion, infections (single cases of sinusitis, pneumonia, tooth infection and viral bronchitis) and single cases of stomatitis, aspiration, cyclic neutropenia, sleep apnea syndrome, vomiting, dizziness, white blood cell count decreased and neutrophil count decreased. A grade four convulsion was reported2.

Key laboratory abnormalities observed in >1 patient (and listed in decreasing order of frequency) included elevations in aspartate transaminase (AST) concentrations (89%), total cholesterol (68%), alanine transaminase (ALT) concentrations (46%), triglycerides (43%) (hypertriglyceridemia reported as adverse reaction in 11% of patients, blood triglycerides increased reported as adverse reaction in 7% of patients), glucose (25%) and creatinine (11%), and reductions in white blood cell counts (54%) (reported as adverse reaction in 11% of patients), hemoglobin (39%), glucose (32%) and platelet counts (21%). Most of these laboratory abnormalities were mild (grade one). Single cases of grade three elevated AST concentrations and low absolute neutrophil count (ANC) were reported. No grade four laboratory abnormalities were noted. Two cases of neutrophil count decreased and blood immunoglobulin G decreased were reported as adverse reactions2.

All data from the study reported in this press release are based on the cut-off date of March 8, 2010.

About the EXIST-1 Phase III trial
EXIST-1, a Phase III randomized, placebo-controlled trial aimed at evaluating the results of the open-label, single-arm trial, is examining everolimus treatment in patients with SEGAs associated with TS. Endpoints include SEGA response, seizure rate and skin lesion response rate. The trial has completed accrual and patients continue to be followed3.

The trial involves patients in 10 countries, including Australia, Belgium, Canada, Germany, Italy, the Netherlands, Poland, Russia, the UK and the US3.

About Afinitor (everolimus)
Afinitor® (everolimus) tablets is now approved in the US to treat patients with SEGA associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of Afinitor is based on an analysis of change in SEGA volume. Improvement in disease-related symptoms or increase in survival has not been shown. Afinitor is available in the US in 2.5 mg, 5 mg and 10 mg tablet strengths.

For more information visit www.AFINITOR.com/SEGA-TS or call 1-888-4-AFINITOR. US patients who may be eligible for financial assistance can learn about the AfiniTRAC™ reimbursement support program by contacting 1-888-9-AfiniTRAC or visiting the Afinitor website.

Afinitor is also approved in the US for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib and in the European Union (EU) for the treatment of patients with advanced RCC whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

In the US, everolimus is available in different dosage strengths under the trade name Zortress® for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. In the EU, everolimus is available in different dosage strengths under the trade name Certican® for the prevention of organ rejection in heart and kidney transplant recipients.

Not all indications are available in every country. As an investigational compound, the safety and efficacy profile of everolimus has not yet been established outside the US in patients with SEGA associated with TS. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for SEGAs anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Patients should not take Afinitor if they are allergic to Afinitor or to any of its ingredients. Patients should tell their healthcare provider before taking Afinitor if they are allergic to sirolimus (Rapamune®) or temsirolimus (Torisel®).

Afinitor can cause serious side effects including infections or lung or breathing problems.

Afinitor may make patients more likely to develop an infection, such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include reactivation of hepatitis B in people who have had hepatitis B in the past. In some people these infections may be severe, and can even lead to death. Patients may need to be treated as soon as possible. Patients should tell their healthcare provider right away if they have a temperature of 100.5°F or above, chills or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stool or dark urine, yellowing of the skin or pain in the patient’s upper right side.

In some patients lung or breathing problems may be severe, and can even lead to death. Patients should tell their healthcare provider right away if they have any of these symptoms: new or worsening cough, shortness of breath, difficulty breathing or wheezing. Patients may need to stop taking Afinitor for a while or use a lower dose.

Afinitor can cause mouth ulcers and sores. Patients should tell their healthcare provider if they have pain, discomfort or open sores in their mouth. Their healthcare provider may tell them to use a special mouthwash or mouth gel that does not contain alcohol or peroxide.

Patients will have regular blood tests before they start and during their treatment with Afinitor. These tests will monitor how their kidneys and liver are working, their blood sugar and cholesterol levels as well as the number of blood cells in their body. Patients who receive Afinitor for the treatment of SEGA will need regular blood tests to measure how much Afinitor is in their blood since this will help their doctor decide how much Afinitor they need to take.

Afinitor may affect the way other medicines work, and other medicines can affect how Afinitor works. Using Afinitor with other medicines can cause serious side effects. Patients should tell their healthcare provider about all of the medicines they take, including prescription and non-prescription medicines, vitamins, herbal supplements such as: St. John’s Wort, and medicine for fungal infections, bacterial infections, tuberculosis, seizures, HIV-AIDS, heart conditions or high blood pressure and medicines that suppress their immune system. Patients should not drink grapefruit juice or eat grapefruit during their treatment.

Patients should not take Afinitor tablets which are broken or crushed. Patients should not chew or crush the tablets.

Patients should tell their healthcare provider about all their medical conditions, including if they have or have had liver problems, diabetes or high blood sugar, high cholesterol levels, infections, hepatitis B or other medical conditions.

Patients should tell their healthcare provider if they are scheduled to receive any vaccinations. Patients should not receive a live vaccine or be around people who have recently received a live vaccine during treatment with Afinitor.

It is not known if Afinitor will harm a patient’s unborn baby. Patients should use effective birth control while using Afinitor and for 8 weeks after stopping treatment.

Common side effects of Afinitor in patients with SEGA include mouth ulcers, infections of the respiratory tract, sinuses and ears and fever. Common side effects of Afinitor in patients with advanced kidney cancer include mouth ulcers, infections, feeling weak or tired, cough and diarrhea.

瑞士诺华公司的Afinitor口服片剂用于治疗采用其他抗癌药之后病情仍持续恶化的晚期肾癌患者。

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。FDA相关部门表示，Afinitor为那些采用sunitinib或sorafenib治疗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。

FDA批准Afinitor(everolimus)(Novartis 诺华生产)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。

*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。
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。

*关于 RAD001
RAD001，一种口服mTOR抑制剂， 是一种处于研究阶段的药物用于多种肿瘤的治疗。在癌细胞内，RAD001干扰作为肿瘤细胞分裂和血管生成的中心调控器的mTOR蛋白。
RECORD-1试验中显示的安全性与先前的II期试验得到的结果一致。患者服用RAD001常见的不良反应包括口腔溃疡 (40%), 疲劳感/虚弱 (37%)以及皮疹 (25%)。很少发生的与药物相关的3或4级不良反应 (>1%): 包括口腔溃疡 (3%), 肺炎 (3%), 感染 (3%),疲劳感/虚弱 (4%), 腹泻 (1%), 粘膜炎 (1%)，呼吸短促 (1%). 由于不耐受导致的患者停用RAD001的发生率很低 (6%)。
作为研究阶段的化合物，RAD001的使用只能是在严格的控制和监测下的临床试验中。RAD001的活性成分为everolimus，它以商品名Certican® 用于预防心脏移植、肾移植时产生的器官排异。Certican在2003年在欧洲获批。

*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）上有显著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。
结果显示，RAD001组272例，安慰剂组138例，191例患者获（占410例的47%）PFS，其中RAD001组101例，安慰剂组90例。RAD001组和安慰剂组常见的不良反应分别为：口腔炎36例 vs. 7例，贫血28例 vs. 15例，无力28例 vs. 20例，因不良事件导致的治疗终止分别为10%和4%，而相应的减量治疗分别为4%和<1%。68例死亡，随访仍在进行以评价次要终点OS。

重要的安全性信息
对依维莫司、其他雷帕霉素衍生物或任何一种赋形剂过敏的患者禁用Afinitor。在采用本产品治疗过程中可能发生严重不良反应，包括非感染性肺炎和感染性疾病，因此应该对患者进行认真监测，及时发现不良反应，必要时应给予治疗。此外，发生非感染性肺炎时可能需要暂时减少给药剂量和/或中断或停止治疗。发生了系统性侵袭性真菌感染的患者禁用Afinitor。采用Afinitor治疗时，口腔溃疡是一种常见的不良作用。在开始采用Afinitor治疗之前应对患者的肾功能、血糖、脂质和血液学参数进行检测，而且以后还要定期检测。应该避免使用强效或中效的CYP3A4或P-糖蛋白抑制剂。与强效CYP3A4诱导剂合用时，建议增加Afinitor的给药剂量。正在服用Afinitor的患者应该避免接种活疫苗或者与接种过活疫苗的人密切接触。严重肝功能不全患者禁用Afinitor。孕妇服用Afinitor可能会对胎儿产生有害影响。
 
不考虑因果关系时，最常见的不良反应（发生率≥30%）有口腔炎、感染、衰弱、疲乏、咳嗽和腹泻。不考虑因果关系时，最常见的3/4级不良反应（发生率≥3%）有感染、呼吸困难、疲乏、口腔炎、脱水、肺炎、腹痛和衰弱。最常见的实验室检查异常（发生率≥50%）有贫血、高胆固醇血症、高甘油三酯血症、高血糖症、淋巴细胞减少症和肌酐水平升高。最常见的3/4级实验室检查异常（发生率≥3%）有淋巴细胞减少症、高血糖症、贫血、低磷酸盐血症和高胆固醇血症。在接受Afinitor治疗的患者中还观察到由于急性呼吸衰竭引起的死亡（0.7%）、感染（0.7%）和急性肾功能衰竭（0.4%）。
 
Afinitor获准用于治疗进行性胰源性神经内分泌肿瘤

2011年5月6日，诺华公司宣布美国食品药品管理局(FDA)已批准Afinitor(依维莫司)片剂用于治疗不可切除的进行性胰源性神经内分泌肿瘤(PNET)局部晚期或转移性患者。Afinitor先前已经获准治疗室管膜下巨细胞星形细胞瘤伴结节性硬化症以及晚期肾细胞癌。

Afinitor以mTOR为靶点，mTOR是肿瘤细胞分裂、血管生长以及细胞代谢的重要调控因子。临床前研究和临床研究的数据已证实，mTOR在多种类型肿瘤的发生和进展中起一定的作用，其中包括晚期PNET。
FDA批准Afinitor这项新适应证是基于RAD001治疗晚期神经内分泌肿瘤试验的数据。该试验是一项前瞻性、双盲、随机、平行、安慰剂对照的多中心研究，受试者为410例晚期低度或中度分化的PNET，旨在探讨对于这类患者，Afinitor+最佳姑息治疗相对于安慰剂的疗效和安全性。其结果显示，Afinitor治疗使无瘤生长时间加倍(中位值为4.6~11.0个月)，并使癌症进展风险相对于安慰剂减少65%。另外，在所有患者亚组中使用Afinitor治疗者的无进展生存均获得一致性改善。

与使用Afinitor有关的最常见的不良药物反应为口腔溃疡、皮疹、腹泻、疲乏、痤疮样皮炎、感染、虚弱无力、恶心、肢端肿胀、食欲减退、头痛、肺炎、味觉异常、鼻衄、黏膜炎症、体重下降以及呕吐。报告最多的3~4级不良药物反应包括口腔溃疡、疲乏、白细胞计数下降、腹泻、感染、肺炎以及糖尿病。接受Afinitor治疗的患者中还有乙型肝炎再激活和肺栓塞的报告。