美国FDA批准Ninlaro(IXAZOMIB CITRATE)，新口服药物治疗多发性骨髓瘤 FDA的药品评价和研究中心中血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“当学习到更多有关多发性骨髓瘤的生物学，我们受到有新途径治疗该级别的鼓舞，” “今天的批准是今年被批准为多发性骨髓瘤的第三个药物和提供患者用一种新口服治疗，它减慢疾病进展当其他治疗已失败。” FDA在今年2月批准Farydak(panobinostat)和这个月早些时候批准Darzalex(daratumumab)。优先审评和孤儿药物指定。 批准日期：2015年11月20日  公司：武田制药美国公司 NINLARO®(ixazomib)胶囊，为口服使用 美国初次批准：2015 作用机制 Ixazomib是一种可逆性蛋白体抑制剂。Ixazomib优先结合和抑制胰凝乳蛋白酶-样20S蛋白酶体的β 5亚单位的活性。 Ixazomib在体外诱导多发性骨髓瘤细胞系的凋亡。Ixazomib对来自多种以前治疗后，包括硼替佐米[bortezomib]，来那度胺，和地塞米松已复发患者的骨髓瘤细胞显示体外细胞毒性。在多发性骨髓瘤细胞系中Ixazomib和来那度胺的联用显示协同的细胞毒效应。在体内，在一种小鼠多发性骨髓瘤肿瘤异种移植模型ixazomib显示抗肿瘤活性。 适应证和用途 NINLARO是一个蛋白体抑制剂适用与来那度胺和地塞米松联用为有多发性骨髓瘤患者曽接受至少一种以前治疗的治疗。 剂量和给药方法 ⑴  推荐起始剂量4mg口服在28-天疗程的第1，8，和15天。 ⑵  剂量应被服用食物前至少一小时或后至少2小时。 剂型和规格 胶囊：4mg，3mg，2.3mg 禁忌证 无。 警告和注意事项 ⑴  血小板减少：治疗期间监视血小板计数至少每月和调整，当需要时。 ⑵  胃肠道毒性：对严重腹泻，便秘，恶心,和呕吐，当需要时调整给药。 ⑶  外周神经病变：监视患者外周神经病变的症状和调整给药，当需要时. ⑷  外周水肿：监视液体潴留。研究潜在原因，当适当。调整给药，当需要时。 ⑸  皮肤反应：监视患者皮疹和调整给药，当需要时。 ⑹  肝毒性：治疗期间监视肝酶。 ⑺  胚胎胎儿毒性：NINLARO可能致胎儿危害。忠告生殖潜能女性和使用有效避孕。 不良反应 最常见不良反应(≥ 20%)是腹泻，便秘，血小板减少，外周神经病变，恶心，外周水肿，呕吐,和背痛。 药物相互作用 强CYP3A诱导剂：避免与NINLARO同时使用 特殊人群中使用 ⑴  肝受损：在有中度或严重肝受损患者减低NINLARO开始剂量至3mg。 ⑵ 肾受损：有严重肾受损或肾病终末期需要透析患者减低NINLARO开始剂量至3mg。 ⑶ 哺乳：终止哺乳。 供应/贮存和处置 供应 NINLARO被供应如下： 4 mg明胶胶囊：浅橙色，大小3，用黑墨汁在帽上印有“Takeda”和体上“4.0mg”。NINLARO 4mg胶囊含4mg的ixazomib等同于5.7mg的ixazomib柠檬酸盐。 ● 一粒4mg胶囊在一个单吸塑包装(NDC 63020-080-01) ● 三粒4mg单吸塑包装在一个纸盒(NDC 63020-080-02) 3.0 mg明胶胶囊：浅灰色，大小4，用黑墨汁在帽上印有“Takeda” 和仔体上“3.0mg”。NINLARO 3mg胶囊含3mg的ixazomib等同于4.3mg的ixazomib柠檬酸盐。 ● 一粒3mg胶囊在一个单吸塑包装(NDC 63020-079-01) ● 三粒 3mg单包装在纸盒内(NDC 63020-079-02) 2.3 mg明胶胶囊：浅粉红色，大小4，用黑墨汁在帽上印有“Takeda”和在体上“2.3mg”。 NINLARO 2.3mg胶囊含2.3mg ixazomib等同于3.3mg ixazomib柠檬酸盐。 ● 一粒2.3mg胶囊在一个单吸塑包装(NDC 63020-078-01) ● 三粒2.3mg单包装在一纸盒包装(NDC 63020-078-02)胶囊被各个包装在一个PVC-铝/铝泡罩。 贮存 NINLARO可能被贮藏在室温。不要高于30°C(86°F)。不要冻结。贮藏胶囊在原始包装直至直至用前立即。 处置和遗弃 NINLARO是细胞毒性。胶囊不应被打开或压碎。应避免直接接触胶囊内容物。在胶囊破裂情况中，避免胶囊内容物与皮肤或眼直接接触。如发生与皮肤接触，用肥皂和水彻底洗涤。如发生与眼接触，用水彻底地冲洗。 任何未使用药物产品或废料应按照当地要求遗弃。 NINLARO(IXAZOMIB CITRATE)CAPSULE ORAL NINLARO® (ixazomib) is the first and only oral medication of its kind, a proteasome inhibitor, that you can take at home. A study showed that adding NINLARO to REVLIMID® (lenalidomide) and dexamethasone improved median progression-free survival (PFS) by nearly 6 months (20.6 months with the NINLARO regimen and 14.7 months with the placebo regimen).  NINLARO® (ixazomib) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. INDICATION NINLARO® (ixazomib) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. WARNINGS AND PRECAUTIONS •Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and typically recovered to baseline by the start of the next cycle. •Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for severe symptoms. •Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed. •Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms. •Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification. •Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly during treatment and adjust dosing as needed. •Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO. Women using hormonal contraceptives should also use a barrier method of contraception. ADVERSE REACTIONS The most common adverse reactions (≥ 20%) in the NINLARO regimen and greater than the placebo regimen, respectively, were diarrhea (42%, 36%), constipation (34%, 25%), thrombocytopenia (78%, 54%; pooled from adverse events and laboratory data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). SPECIAL POPULATIONS •Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment. •Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable. •Lactation: Advise nursing women not to breastfeed during treatment with NINLARO and for 90 days after the last dose https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fcef9088-ebab-4bd8-933f-c35f9c8bd50b 武田Ninlaro（ixazomib）-为FDA批准第三个治疗多发性骨髓瘤创新药物 2015年11月23日，由日本制药巨头武田（Takeda）开发的一款口服抗癌药Ninlaro（ixazomib）近日喜获FDA批准，联合Revlimid（lenalidomide，来那度胺）及地塞米松（dexamethasone），用于既往已接受过至少一种治疗方案的多发性骨髓瘤（MM）患者。此前FDA已授予ixazomib优先审查资格和孤儿药地位。 Ninlaro是一种蛋白酶体抑制剂，能够阻断多发性骨髓瘤细胞的酶，进而阻碍其生长及生存的能力。Ninlaro是FDA批准的首个口服蛋白酶体抑制剂。Ninlaro的获批，是基于一项随机双盲临床研究，该研究涉及722例复发性多发性骨髓瘤患者，数据显示，与安慰剂+来那度胺+地塞米松联合治疗组相比，Ninlaro+来那度胺+地塞米松联合治疗组无进展生存期（PFS：20.6个月 vs 14.7个月）显著延长。 Ninlaro也标志着FDA在本年度批准的第三个多发性骨髓瘤创新药物： ——诺华Farydak：今年2月，FDA批准诺华抗癌药Farydak（panobinostat）联合Velcade（bortezomib，硼替佐米）和地塞米松（dexamethasone）用于既往接受至少2种治疗方案（包括Velcade和一种免疫调节（IMiD）药物）治疗失败的多发性骨髓瘤（MM）患者。Farydak（panobinostat）是一种新型、广谱组蛋白脱乙酰酶（HDAC）抑制剂，具有一种新的作用机制，通过阻断组蛋白脱乙酰酶（HDAC）发挥作用，该药能够对癌细胞施以严重的应激直至其死亡，而健康细胞则不受影响。Faryda是FDA批准治疗多发性骨髓瘤（MM）的首个组蛋白脱乙酰酶（HDAC）抑制剂，该药的表观遗传学活性，可能有助于恢复多发性骨髓瘤细胞的功能。 —强生Darzalex：11月初，FDA加速批准强生单抗药物Darzalex（daratumumab），用于接受过至少三线治疗的多发性骨髓瘤（MM）患者。 Darzalex是FDA批准治疗多发性骨髓瘤（MM）的首个单克隆抗体药物。daratumumab是一种人源化抗CD38单克隆抗体，具有广谱杀伤活性，靶向结合多发性骨髓瘤细胞表面高度表达的跨膜胞外酶CD38分子，可通过多种机制诱导肿瘤细胞的快速死亡。 关于多发性骨髓瘤： 多发性骨髓瘤（multiple myeloma，MM）是一种浆细胞癌，见于骨髓。多发性骨髓瘤中，一组浆细胞（或骨髓瘤细胞）转化为癌细胞并增生，使浆细胞的数目高于正常水平。由于浆细胞在体内广泛游走，有可能累及体内多数骨骼，可能导致压缩性骨折、骨溶解性病灶和相关疼痛。多发性骨髓瘤可导致若干严重健康问题，累及骨骼、免疫系统、肾脏和个体的红细胞计数，部分较常见症状包括骨骼疼痛和疲乏，疲乏是贫血的症状。多发性骨髓瘤属罕见癌症，每年新发病例在美国约为20000人、全球约为114000人。