Imbruvica(依鲁替尼，ibrutinib)胶囊

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Generic Name and Formulations:
Ibrutinib 140mg; caps.

Company:
Pharmacyclics and Janssen Biotech
Indications for IMBRUVICA:
Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy.

Adult Dose for IMBRUVICA:
Swallow whole with water. MCL: 560mg once daily. CLL: 420mg once daily. Concomitant moderate CYP3A inhibitors: 140mg once daily. Dose modifications for toxicities: see full labeling.

Children's Dose for IMBRUVICA:
Not established.

Pharmacological Class:
Bruton’s tyrosine kinase (BTK) inhibitor.

Warnings/Precautions:
Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Hepatic or renal impairment. Monitor creatinine levels periodically. Maintain adequate hydration. Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.

Interactions:
Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for short-term (≤7days) use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin); consider interrupting ibrutinib therapy. If concomitant moderate CYP3A inhibitors must be used (eg, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, ciprofloxacin): reduce ibrutinib dose (see Adults). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort); consider alternatives. Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants.

Adverse Reactions:
Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia, arthralgia, stomatitis, sinusitis, dizziness.

How Supplied:
Caps—90, 120
2013年11月13日，美国食品药品管理局（FDA)加速批准了Pharmacyclics公司和强生的Imbruvica（通用名：Ibrutinib，依鲁替尼）上市，用于治疗一种罕见的侵袭性血癌——套细胞淋巴瘤（MCL）。
依鲁替尼(Ibrutinib)是一种口服的名为布鲁顿酪氨酸激酶（BTK）抑制剂的首创新药, 该药通过与靶蛋白Btk活性位点半胱氨酸残基（Cys-481）选择性地共价结合, 不可逆性地抑制BTK, 从而有效地阻止肿瘤从B细胞迁移到适应于肿瘤生长环境的淋巴组织。
套细胞淋巴瘤（MCL）常见于中老年，是一种罕见但进展迅速的非霍奇金B细胞淋巴瘤（NHL）。在美国，其患者人数占据所有非霍奇金淋巴瘤病例的6％。依鲁替尼（Imbruvica)是获准用于治疗套细胞淋巴瘤（MCL）的第三种药品。之前2006年获批的Velcade（Bortezomib，硼替佐米。中国注册名：万珂。千禧制药/日本武田制药）和2013年获批Revlimid的（Lenalidomide，来那度胺,中国注册名：瑞复美。塞尔基因公司）已被批准用于治疗这种疾病。依鲁替(Imbruvica,Ibrutinib)治疗费用每年将高达13万美元，这也是美国最贵的抗癌药之一， 而塞尔基因公司（celgene)的来那度胺（Revlimid, Lenalidomide, 瑞复美)治疗费用更高， 每年将耗费15万美元
依鲁替尼(Ibrutinib)于今年2月份被美国FDA授予突破性治疗药物资格。Imbruvica是FDA推出突破性新药新政以来获准的第二个享此待遇的药品。FDA于本月早些时候批准了罗氏（Roche）的Gazyva (obinutuzumab），用于治疗慢性淋巴细胞白血病（CLL），是首个获FDA突破疗法认定并获批的药物。
商品名：Imbruvica
通用名：Ibrutinib
别名:PCI-32765,CRA-032765
中文名：依鲁替尼
CAS 登录号:936563-96-1
中文化学名:1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮
英文化学名：1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
适应症：套细胞淋巴瘤。
作用机理：不可逆布鲁顿酪氨酸激酶(BTK)抑制剂,与Btk活性位点半胱氨酸残基（Cys-481）选择性地共价结合,从而有效灭活BTK活性
药物分类：孤儿药，突破性药物
用法用量：每天口服1次(4粒140mg胶囊)共560mg
药物公司：Pharmacyclics, 强生
IMBRUVICA Rx
Pharmacological Class:
Bruton’s tyrosine kinase (BTK) inhibitor.

Active Ingredient(s):
Ibrutinib 140mg; caps.

Company
Pharmacyclics and Janssen Biotech
Indication(s):
Treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Both indications are based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Pharmacology:
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

Clinical Trials:
The safety and efficacy of Imbruvica in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated patients. Imbruvica was administered orally at 560mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR).

Based on investigator assessment, results showed an ORR of 65.8% (95% CI: 56.2%, 74.5%) with a complete response (CR) in 17.1% and a partial response (PR) in 48.6%. The median duration of response (DOR) was 17.5 months (95% CI: 15.8, not reached). An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%. The median time to response was 1.9 months.

The safety and efficacy of Imbruvica in patients with CLL who have received at least one prior therapy were evaluated in an open-label, multi-center trial of 48 previously treated patients. Imbruvica was administered orally at 420mg once daily until disease progression or unacceptable toxicity.

The ORR and DOR were assessed using a modified version of the International Workshop on CLL criteria by an IRC. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.

Legal Classification:
Rx

Adults:
Swallow whole with water. MCL: 560mg once daily. CLL: 420mg once daily. Concomitant moderate CYP3A inhibitors: 140mg once daily. Dose modifications for toxicities: see full labeling.

Children:
Not established.

Warnings/Precautions:
Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Hepatic or renal impairment. Monitor creatinine levels periodically. Maintain adequate hydration. Pregnancy (Category D); avoid. Nursing mothers: not recommended.

Interaction(s)
Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for short-term (≤7days) use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin); consider interrupting ibrutinib therapy. If concomitant moderate CYP3A inhibitors must be used (eg, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, ciprofloxacin): reduce ibrutinib dose (see Adults). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort); consider alternatives. Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants.

Adverse Reaction(s)
Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia, arthralgia, stomatitis, sinusitis, dizziness.

How Supplied:
Caps—90, 120

LAST UPDATED:
3/3/2014
美国FDA批准Imbruvica为罕见血癌
2013年11月13日美国食品药品监督管理局(FDA)批准Imbruvica(ibrutinib)治疗患者有套细胞淋巴瘤(MCL)，一种罕见和侵袭型血癌。
MCL是非霍奇金淋巴瘤一种罕见型式和在美国所有非霍奇金淋巴瘤病例6%。在MCL被诊断时，通常已播散至淋巴结，骨髓和其他器官。
Imbruvica是意向对已接受至少一种既往治疗有MCL患者。其作用通过抑制癌症繁殖和播散所需的酶。Imbruvica是第三被批准治疗MCL的药物。万珂[Velcade硼替佐米](2006)和雷利米得[Revlimid] (2013)也曾被批准治疗此疾病。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，M.D.说：“Imbruvica的批准证明FDA为罕见疾病患者提供治疗的承诺，”“监管局与公司合作加快药物的发展，审查和批准，反映了对突破性治疗指定程序的承诺。”
Imbruvica是接受FDA批准的第二个突破性治疗指定药物。2012年7月通过的食品和药品管理安全性和创新法，给予FDA能力在承办单位要求下如果初步的临床证据表明药物对严重或危及生命疾病患者超过可得到治疗实质性改进时FDA可能提供指定某个药物为突破性治疗。
在监管局加速批准程序下加速批准Imbruvica，该程序允许FDA根据临床资料显示药物对一个替代性终点合理地预测对患者临床获益影响时批准某个治疗严重疾病药物加速批准当公司进行确证性临床试验时提供患者更早得到有前途新药。FDA还授权Imbruvica优先审评和孤儿产品指定因为药物分别显示在治疗严重情况中安全性或有效性潜能和意向治疗罕见疾病。
Imbruvica对MCL的加速批准是根据一项研究其中111例参加者每天给予Imbruvica直至其疾病进展或副作用成为不能耐受。结果显示接近66%参加者治疗后其癌周数或消失(总体缓解率)。尚未确定对生存或疾病相关症状的改善。
在接受Imbruvica参加者中报道的最常见副作用是血小板减少，腹泻，中性粒细胞减少，贫血，疲乏，肌肉骨骼痛，水肿，上呼吸道感染，恶心，瘀伤，呼吸困难，便秘，皮疹，腹痛，呕吐，和食欲减低。其他临床上有意义副作用包括出血，感染，肾问题和其他类型癌症的发生。
Imbruvica是由总部在加州桑尼维尔，Pharmacyclics和Raritan，总部在新泽西的Janssen Biotech合作上市。