近日，FDA批准一种新的儿科剂型Afinitor （Everolimus 中文译名：依维莫司）用来治疗患有罕见脑肿瘤的年幼儿童。这种新配方，依维莫司片作为口服混悬液（Afinitor Disperz），是第一种被批准的儿科专用剂型用来治疗儿童肿瘤，这种新剂型可以快速溶解，提供更小的剂量递增，从而允许更大的给药灵活性。该产品的适应症是治疗室管膜下巨细胞星形细胞瘤（SEGA）。室管膜下巨细胞星形细胞瘤
批准日期：2018年4月20日 公司：诺华公司
AFINITOR（依维莫司[everolimus]）片剂，用于口服
AFINITOR DISPERZ（依维莫司[everolimus]）混悬液，用于口服
初始美国批准：2009年
最近的重大变化
适应症和用法：4/2018
剂量和用法：4/2018
警告和注意事项：4/2018
作用机理
依维莫司是雷帕霉素（mTOR的）的哺乳动物靶的抑制剂，丝氨酸-苏氨酸激酶，thePI3K/AKT途径的下游。mTOR途径在几种人癌症和结节性硬化症复合物（TSC）中失调。依维莫司结合在细胞内的蛋白质，FKBP-12，在抑制复合物的形成与mTORcomplex 1（mTORC1的）和mTOR THUS激酶活性的抑制所得。依维莫司降低S6核糖体蛋白质激酶（S6K1）和真核起始因子4E结合蛋白（4E-BP1），mTOR的下游效应，在蛋白质合成中所涉及的活性。S6K1是一个基片的mTORC1的磷酸化并从而导致所述受体的配体非依赖性激活的estrogenreceptor的活化结构域。此外，依维莫司抑制表达ofhypoxia诱导因子（E. G.HIF-1）和降低的血管内皮生长因子（VEGF）的表达。
通过依维莫司mTOR的抑制已显示，以减少在体外和/或体内研究的细胞增殖，血管发生，和葡萄糖摄取。
的PI3K/Akt/mTOR途径的组成型活化可以向内分泌在乳腺癌耐药。在vitrostudies显示出没有雌激素依赖性和HER2+乳腺癌细胞对依维莫司的抑制作用敏感，和依维莫司和Akt，HER2，或芳香酶抑制剂那样的组合治疗增强了以协同方式的抗肿瘤依维莫司酶活的。
mTORC1信号的两个调节器是癌基因抑制剂马铃薯球蛋白-硬化复合物1和2（TSC1，TSC2）。
丢失或TSC1的失活或TSC2要么导致下游信号的激活。在TSC，一种遗传性疾病，无论是在TSC1或TSC2基因引线的失活突变，以错构瘤的形成在整个身体以及asseizures和癫痫。在神经元发育异常，异常axonogenesis和dendriteformation，增加兴奋性突触的电流，降低髓鞘形成和皮质层structurecausing在神经发育和功能的异常中断的mTOR的激活导致。与mTOR抑制剂治疗的动物模型ofmTOR失调在大脑中导致癫痫发作的抑制，预防新发癫痫的发展，并预防过早死亡。
适应症和用法
AFINITOR是一种激酶抑制剂，适用于治疗：
绝经后晚期激素受体阳性，HER2阴性乳腺癌联合失败oftreatment来曲唑或阿那曲唑后依西美坦。
胰腺来源的渐进神经内分泌肿瘤（PNET）和成人渐进，分化良好的，非functionalneuroendocrine胃肠（GI）或肺来源的肿瘤（NET）的成年人thatare不能切除的，局部晚期或转移性。
使用限制：AFINITOR不适用于功能性类癌患者的治疗。
用舒尼替尼或索拉非尼治疗失败后患有晚期肾细胞癌（RCC）的成人。
成人肾血管平滑肌脂肪瘤和结节性硬化症（TSC），需立即手术治疗。
AFINITOR和AFINITOR DISPERCES是激素抑制剂
具有室管膜下巨细胞星形细胞瘤（SEGA）的TSC需要治疗干预但不能进行治愈性切除。
AFINITOR DISPERZ的适应症是成年和老年儿童患者2年adjunctivetreatment及以上与TSCassociatedpartial性发作激酶抑制剂。
剂量和用量
不要将AFINITOR和AFINITOR DISPERSION结合使用以达到每日总剂量。
抑制或诱导P-糖蛋白（P-gp）和CYP3A4。
乳腺癌：
每日口服10毫克。
NET：
每日口服10毫克。
RCC：
每日口服10毫克。
TSC相关肾血管平滑肌脂肪瘤：
每日口服10毫克。
TSC Associated SEGA：
每日口服4.5毫克/平方米;调整剂量达到5-15ng/mL的水平。
TSC相关部分发作癫痫发作：
每日口服5毫克/平方米;调整剂量达到5-15ng/mL的水平。
剂量形式和强度
AFINITOR：2.5毫克，5毫克，7.5毫克和10毫克片剂。
AFINITOR DISPERSION：2毫克，3毫克和5毫克片剂。
禁忌症
临床上显着对依维莫司或其他雷帕霉素的超敏反应。
警告和注意事项
非传染性肺炎：监测临床症状或放射学变化。根据严重程度有或没有中断。
感染：监测感染的体征和症状。根据严重程度扣留或严重停用。
严重的超敏反应：永久停止临床显着的超敏反应。
血管性水肿：同时服用ACE抑制剂的患者可能有血管神经性水肿的风险。永久停止血管神经性水肿。
口腔炎：开始治疗时开始使用地塞米松无酒精漱口水。
肾功能衰竭：在治疗前监测肾功能，之后定期监测。
创伤愈合受损：在围手术期间要谨慎行事。
老年患者：监测和调整不良反应的剂量。
代谢紊乱：在治疗前监测血清葡萄糖和脂质，之后定期监测。扣留或永久停止基于
严重程度。
骨髓抑制：在治疗前监测血液学参数，之后定期监测。基于严重性扣留或永久停止。
接种疫苗的风险或减少免疫反应：避免接种疫苗并与接种活疫苗的人密切接触。
在开始治疗之前完成推荐的儿童接种疫苗。
胚胎胎儿毒性：可导致胎儿伤害。告知患者胎儿的潜在风险并使用有效的感染。
不良反应
乳腺癌，NET，RCC：最常见的不良反应（incidence≥30％）包括口腔炎，感染，皮疹，乏力，腹泻，水肿，腹痛，恶心，发热，乏力，咳嗽，头痛，和decreasedappetite。
TSC相关性肾血管平滑肌脂肪瘤：最常见的不良反应（发生率≥30％）是口腔炎。
TSC相关SEGA：最常见的不良反应（发生率≥30％）是口腔炎和呼吸道感染。
TSC相关部分发作癫痫发作：最常见的不良反应（发生率≥30％）是口腔炎。
要报告疑似不良反应，请联系诺华
Pharmaceuticals Corporation，1-888-669-6682或FDA，1-800-FDA-1088或www.fda.gov/medwatch。
药物相互作用
P-gp和强效CYP3A4抑制剂：避免同时使用。
P-gp和中度CYP3A4抑制剂：按建议减少剂量。
P-gp和强CYP3A4诱导剂：按建议增加剂量。
用于特定人群
对于乳腺癌，NET，RCC或TSC相关的肾血管平滑肌脂肪瘤患者，肝功能受损，减少剂量。
对于患有TSC相关SEGA或TSC相关部分性发作性癫痫发作和严重肝功能损害的患者，降低起始剂量并调整剂量以达到目标。
包装提供/存储和处理
AFINITOR
2.5毫克片剂：白色至微黄色，带有边缘的细长片剂，一面刻有“LCL”，另一面刻有“NVR”;可用于：
28片水泡................................................... NDC 0078-0594-51
每个纸箱包含4个泡罩卡，每个卡片7片
5毫克片剂：白色至微黄色，带有覆盖边缘的细长片剂，一面刻有“5”，另一面刻有“NVR”;可用于：
28片水泡...................................................... NDC 0078-0566-51
每个纸箱包含4个泡罩卡，每个卡片7片
7.5毫克片剂：白色至微黄色，带有封闭边缘的细长片剂，一面刻有“7P5”，另一面刻有“NVR”;可用于：
28片水泡.............................................. ..... NDC 0078-0620-51
每个纸箱包含4个泡罩卡，每个卡片7片
10毫克片剂：白色至微黄色，带有覆盖边缘的细长片剂，一面刻有“UHE”，另一面刻有“NVR”;可用于：
28片水泡............................................................... NDC 0078-0567-51
每个纸箱包含4个泡罩卡，每个卡片7片
AFINITOR DISPERSION
2毫克口服悬浮液片：白色至微黄色圆形平底片，一面刻有“D2”，另一面刻有“NVR”;可用于：
28片水泡.............................................. ........... NDC 0078-0626-51
每个纸箱包含4个泡罩卡，每个卡片7片
用于口服混悬液的3mg片剂：白色至微黄色，圆形，扁平片剂，一侧为“D3”，另一侧为“NVR”;可用于：
28片水泡.............................................. .NDC 0078-0627-51
每个纸箱包含4个泡罩卡，每个卡片7片
口服悬浮液5毫克片剂：白色至微黄色圆形平底片，一面刻有“D5”，另一面刻有“NVR”;可用于：
28片水泡.............................................. ...... NDC 0078-0628-51
每个纸箱包含4个泡罩卡，每个卡片7片
储存在25°C（77°F）; 15°C至59°F（59°F至86°F）。参见USP受控室温。
存放在原装容器中，避光和防潮。
遵循抗癌药物的特殊处理和处理程序。
完整说明资料附件：
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/afinitor.pdf
AFINITOR(everolimus) tablets, for oral use
AFINITOR DISPERZ(everolimus tablets for oral suspension)
Initial U.S. Approval: 2009

Important Safety Information
Patients should not take AFINITOR if they are allergic to AFINITOR or to any of its ingredients. Patients should tell their health care provider before taking AFINITOR if they are allergic to sirolimus (Rapamune®) or temsirolimus (Torisel®).
AFINITOR can cause serious side effects, some of which can be severe and can even lead to death. Your health care team may have ways to help manage side effects that do occur. It’s important to talk with your doctor or nurse about side effects you experience and the best ways to manage them. Serious side effects include:
Lung or Breathing Problems: In some patients, lung or breathing problems may be severe and can even lead to death. Patients should tell their health care provider right away if they have any of these symptoms: new or worsening cough, shortness of breath, chest pain, difficulty breathing, or wheezing.
Infections: 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. Patients may need to be treated as soon as possible. Patients should tell their health care provider right away if they have a temperature of 100.5°F or above, have chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, chills, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stools or dark urine, yellowing of the skin, or pain in the upper right side of the stomach.
Severe Allergic Reactions: Severe allergic reactions can happen in people who take AFINITOR. Call your health care provider or get medical help right away if you get signs and symptoms of a severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness.
Angioedema: Patients who take an angiotensin-converting enzyme (ACE) inhibitor medicine during treatment with AFINITOR are at a possible increased risk for a type of allergic reaction called angioedema. Talk with your health care provider before taking AFINITOR if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with AFINITOR.
Kidney Failure: Patients taking AFINITOR may develop kidney failure. Patients should have tests to check their kidney function before and during their treatment with AFINITOR.
Delayed Wound Healing: AFINITOR can cause incisions to heal slowly or not heal well. Call your health care provider right away if your incision is red, warm, or painful; if you have blood, fluid, or pus in your incision; if your incision opens up; or if your incision swells.
Increased Blood Sugar and Fat (cholesterol and triglycerides) Levels in Blood: Your health care provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in your blood before you start and during treatment with AFINITOR.
Decreased Blood Cell Counts: AFINITOR can cause you to have decreased red blood cells, white blood cells, and platelets. Your health care provider should do blood tests to check your blood cell counts before you start and during treatment with AFINITOR.
Before taking AFINITOR, tell your health care provider about all your medical conditions, including if you:
Have or have had kidney problems
Have or have had liver problems
Have diabetes or high blood sugar
Have high blood cholesterol levels
Have any infections
Previously had hepatitis B
Are scheduled to receive any vaccinations. You should not receive a live vaccine or be around people who have recently received a live vaccine during your treatment with AFINITOR. If you are not sure about the type of vaccine, ask your health care provider
Are pregnant, could become pregnant, or have a partner who could become pregnant AFINITOR can cause harm to your unborn baby. If you are a woman who is able to become pregnant, you should use effective birth control while using AFINITOR and for 8 weeks after your last dose. Talk to your health care provider about birth control options while taking AFINITOR
Are breastfeeding or plan to breastfeed. Do not breastfeed during treatment and for 2 weeks after your last dose.
Are about to have surgery, if you have had a recent surgery, or if you have an unhealed wound.
Tell your health care provider about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Using AFINITOR with certain other medicines can cause serious side effects. Keep a list of medicines you take and show it to your health care provider when you get a new medicine. Especially tell your health care provider if you take St John’s wort (Hypericum perforatum), medicines that weaken your immune system (your body’s ability to fight infections and other problems), or medicines for:
Fungal infections
Bacterial infections
Tuberculosis
Seizures
HIV-AIDS
Heart conditions or high blood pressure
If you are taking any medicines for the conditions listed above, your health care provider might need to prescribe a different medicine or your dose of AFINITOR may need to be changed. Tell your health care provider before you start taking any new medicine.
Common Side Effects
The most common side effect of AFINITOR is mouth ulcers and sores. When you start treatment with AFINITOR, your health care provider may tell you to also start a prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your health care provider's instructions on how to use this prescription mouthwash. Tell your health care provider if you have pain, discomfort, or open sores in your mouth. Your health care provider may tell you to restart this mouthwash or to use a special mouthwash or mouth gel that does not contain alcohol, hydrogen peroxide, iodine, or thyme.