近日，美国FDA批准盐酸罗拉吡坦Varubi(Rolapitant)胶囊片用于延长期的化疗所致的恶心呕吐症状的治疗。Varubi可与其他抗呕吐药物联合使用，用于防治癌症化疗引发的恶心呕吐的初始发作和反复发作。
FDA药品评估研究中心的药物评估三期办公室负责人助理——Amy Egan所述，化疗引起的恶心呕吐仍然是一个主要的亟待解决的问题，这不仅会影响到患者的生活，有时还会打乱他们的治疗节奏。今天，FDA对Vaubi的批准将为接受延长化疗的癌症患者防治恶心呕吐提供了另一个很好的治疗选择。
Varubi属于神经激肽（NK-1）受体拮抗剂，NK-1受体的活化在化疗引起的恶心呕吐的过程中扮演着重要的角色，尤其是在延长期中。经此次FDA的批准，Varubi将会以片剂的形式提供给患者。Varubi能够有效抑制负责代谢某一药物的CYP2D6酶。Varubi不能与经CYP2D6酶代谢的硫利达嗪一起使用，因为Varubi与其合用会引起硫利达嗪血药浓度增加，由此导致严重的心律不齐。
为了验证Varubi的安全性和疗效，有关专家收治了2800名需要接受化疗的癌症患者，其中包括了高致吐性药物（比如顺铂、蒽环类抗生素与环磷酰胺的合用）以及低致吐性的药物，采用随机双盲的方法进行临床对照试验，其中A组给服Varubi、格拉司琼和地塞米松，B组给服安慰剂、格拉司琼和地塞米松。经过相同时间治疗之后，与B组相比，A组的患者的治疗化疗引起的恶心呕吐的效果更加明显。
批准日期：2015年9月1日；公司：Tesaro Inc
VARUBI™(rolapitant)片，供为口服使用
美国初次批准：2015
作用机制
Rolapitant是一个人物质P/NK1受体的选择性和竞争性拮抗剂。Rolapitant对NK2或NK3受体或对一组其它受体，转运蛋白，酶和离子通道没有显著亲和力。Rolapitant在动物化疗诱发呕吐的模型中也有活性。
适应症和用途
VARUBI™是一种物质P/神经激肽1(NK1)受体拮抗剂适用与其它止吐药联用在成年为预防延迟恶心和呕吐伴随致吐癌化疗，包括，但不限于，高致吐化疗开始和重复疗程.
剂量和给药方法
⑴推荐剂量是化疗开始前约1至2小时给予180mg rolapitant。
⑵与地塞米松和一种5-HT3受体拮抗剂联用给药，对给药资料见完整处方资料。
⑶对地塞米松无需剂量调整。
剂型和规格
片：90mg的rolapitant
禁忌证
同时使用与硫利达嗪，一种CYP2D6底物
警告和注意事项
与有狭窄治疗指数CYP2D6底物相互作用：一次单剂量VARUBI对CYP2D6的抑制性影响持续至少7天和可能持续更长。避免使用匹莫齐特[pimozide]；如不嫩避免与有一个狭窄治疗指数其它CYP2D6底物同时使用监视不良反应。
不良反应
最常见不良反应(≥ 5%)是：
⑴基于顺铂高度致吐化疗：中性粒细胞减少和打嗝
⑵中度致吐化疗和蒽环类药物和环磷酰胺联用：减低食欲，中性粒细胞减少和眩晕。
药物相互作用
⑴BCRP和P-gp底物有一个狭窄治疗指数：BCRP和P-gp被VARUBI抑制可导致增加同时药物血浆浓度和对不良反应潜能。对特异性实例见完整处方资料。
⑵强CYP3A4诱导剂(如，利福平[rifampin])：显著减低 rolapitant的血浆浓度可减低VARUBI的疗效；在需要这类药物慢性给药患者中避免使用VARUBI。
供应/贮存和处置
VARUBI是可得到为膜包衣，胶囊形状，蓝片，在一侧凹陷有T0101和其它侧100。每片含90mg rolapitant。VARUBI片被包装在一个Aclar泡壳有铝箔衬纸和供应如下：
NDC 69656-101-02 一个单剂量包装(2片作为一组一对泡卡)
贮存在20º至25ºC(68º至77ºF；外出允许在15°C至30°C间(59°F至86°F) [见USP控制室温]

TESARO Announces U.S. FDA Approval of VARUBI(TM) (rolapitant) for Nausea and Vomiting Associated With Cancer Chemotherapy
 U.S. Food and Drug Administration (FDA) has approved VARUBI™ (rolapitant) in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. 
VARUBI is a selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, with a plasma half-life of approximately seven days. Results from three Phase 3 trials of VARUBI demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25 to 120 hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens. In addition, patients who received VARUBI reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. A 180 milligram dose of VARUBI is to be administered approximately one to two hours prior to chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, when administering VARUBI. 
"The approval of VARUBI, our first product, represents a significant milestone in TESARO's evolution into an integrated biopharmaceutical company with strong development and commercialization capabilities," said Lonnie Moulder, CEO of TESARO. "Results from the Phase 3 trials of VARUBI demonstrated that patients receiving emetogenic chemotherapy agents, including platinum and cyclophosphamide-containing regimens, benefitted from the addition of VARUBI to their antiemetic regimen. Data from multiple well-controlled trials demonstrate that patients who receive only a 5-HT3 receptor antagonist and dexamethasone often continue to suffer from nausea and vomiting for several days following chemotherapy administration. Patient surveys and our primary market research also point to the high rate of CINV and its potentially debilitating effects. We look forward to expanding the awareness of CINV and working with healthcare providers to make this important medicine available to patients during the fourth quarter." 
"While important strides in preventing nausea and vomiting associated with chemotherapy have been made, still up to half of patients receiving emetogenic cancer chemotherapy can experience delayed CINV," said Richard J. Gralla, M.D., Professor of Medicine at Albert Einstein College of Medicine in New York. "Because NK-1 receptors are key drivers of CINV, especially in the delayed Phase, NK-1 receptor antagonists such as VARUBI, when combined with a 5-HT3 receptor antagonist and a corticosteroid, provide enhanced protection from CINV, and do so in the delayed timeframe where the most help is needed."
The full prescribing information for VARUBI will be available at www.VarubiRx.com.
About Chemotherapy-Induced Nausea and Vomiting (CINV)
Chemotherapy-induced nausea and vomiting is a debilitating, yet often preventable, side effect of chemotherapy.
Up to 50% of patients undergoing highly or moderately emetogenic chemotherapy experience delayed CINV (25 to 120 hours post chemotherapy)—even when prescribed a 5-HT3 receptor antagonist and corticosteroid.
Blocking both 5-HT3 and NK-1 receptors has been shown to offer better control of nausea and vomiting than inhibiting 5-HT3 receptors alone. Adding a single dose of VARUBI to an antiemetic regimen, including a 5-HT3 receptor antagonist and corticosteroid, further improves prevention of CINV in the delayed Phase following chemotherapy.
About the VARUBI (Rolapitant) Clinical Program
The superior efficacy of VARUBI was established in multiple randomized, well-controlled, blinded clinical trials that enrolled more than 2,500 patients. VARUBI, when administered in combination with a 5-HT3 receptor antagonist and dexamethasone, was superior to a 5-HT3 receptor antagonist and dexamethasone in preventing CINV in patients receiving either moderately or highly emetogenic chemotherapy.
The clinical profile of VARUBI in cisplatin-based highly emetogenic chemotherapy (HEC) was confirmed in two identical Phase 3 studies: HEC1 and HEC2. Both trials met their primary endpoint of complete response (CR), and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone) in the delayed Phase (25-120 hours) of CINV. In HEC1, 264 patients received rolapitant 180 mg and 262 received control. The proportion of patients achieving a CR was 72.7% vs. 58.4% (p= < 0.001). In HEC2, 271 patients received rolapitant and 273 received control. The proportion of patients achieving a CR was 70.1% vs. 61.9% (p=0.043). The most common adverse reactions (≥3%) among patients receiving cisplatin-based chemotherapy were neutropenia (9% VARUBI vs. 8% control), hiccups (5% vs. 4%), and abdominal pain (3% vs. 2%).
A Phase 3 trial was also conducted to evaluate rolapitant 180 mg compared to active control in 1,332 patients receiving moderately emetogenic chemotherapy regimens, including anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. This trial met its primary endpoint of CR, and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone) in the delayed Phase of CINV. The proportion of patients achieving a CR was 71.3% vs 61.6% (p= < 0.001). The most common adverse reactions (≥3%) among patients receiving these chemotherapies were decreased appetite (9% VARUBI vs. 7% control), neutropenia (7% vs. 6%), dizziness (6% vs. 4%), dyspepsia (4% vs. 2%), urinary tract infection (4% vs. 3%), stomatitis (4% vs. 2%), and anemia (3% vs. 2%).
Primary data from the three Phase 3 studies have recently been published online ahead of print in Lancet Oncology, the analysis of the non-AC MEC population was presented at the 2015 annual meeting for the Multinational Association for Supportive Care in Cancer, and commentary has been provided in Nature Reviews Clinical Oncology.
VARUBI Additional Safety Information
VARUBI is contraindicated in patients receiving thioridazine, a CYP2D6 substrate with a narrow therapeutic index.
Use of VARUBI should be avoided in patients who are receiving pimozide, a CYP2D6 substrate with a narrow therapeutic index. Adverse reactions should be monitored if concomitant use of VARUBI and other CYP2D6 substrates with a narrow therapeutic index cannot be avoided. The inhibitory effect of VARUBI on CYP2D6 lasts for at least 7 days and may last longer after administration of a single dose of VARUBI.
About VARUBI
VARUBI is a substance P/neurokinin-1 (NK-1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. A Positron Emission Tomography (PET) study with rolapitant in normal, healthy volunteers demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK-1 receptors at high levels for up to 120 hours. VARUBI has a half-life of approximately 7 days, which may contribute to the ability of a single dose of VARUBI to cover the entire delayed CINV Phase (25-120 hours).
An intravenous formulation of rolapitant is also being developed. TESARO licensed exclusive rights for the development, manufacture, commercialization and distribution of VARUBI (rolapitant) from OPKO Health, Inc.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed3ef3f8-8cb7-40db-9d75-e728ee607760