Inrebic（fedratinib）胶囊

公司：Celgene公司

批准日期：2019年8月16日

治疗：骨髓纤维化

Inrebic（fedratinib）是一种高选择性JAK2抑制剂，用于治疗骨髓纤维化患者。

FDA批准Inrebic（fedratinib）治疗骨髓纤维化患者

新泽西州SUMMIT消息 - （美国商业资讯） -  Celgene公司（纳斯达克股票代码：CELG）今天宣布美国食品和药物管理局（FDA）批准Inrebic（fedratinib）用于治疗中度2或高危原发性成人患者或继发性（红细胞增多症后或原发性血小板增多症）骨髓纤维化

“对Inrebic的批准是Celgene的另一个重要里程碑，并强调了我们对患有血癌的人的承诺，”Celgene首席医疗官Jay Backstrom，M.D.，M.P.H。说。 “我们很高兴能够将Inrebic作为一种新的治疗方案，可用于骨髓纤维化患者，包括之前接受过ruxolitinib治疗的患者。”

“骨髓纤维化可导致患者多方面受损，包括出现衰弱症状，”美国康涅狄格州健康安东尼奥癌症中心医学博士安德森梅斯癌症中心主任，医学博士，医学博士Ruben Mesa说。 “近十年来，这种疾病尚未得到批准。有了Inrebic，现在医生和患者可以选择骨髓纤维化。“

Inrebic开发项目包括多项研究（包括JAKARTA和JAKARTA2），其中608名患者接受了超过一剂（30 mg至800 mg），其中1名459名患有骨髓纤维化，1名包括97名曾接受过ruxolitinib治疗的患者。 JAKARTA研究评估了每日一次口服剂量的Inrebic与安慰剂相比，对于中度2或高风险，原发性或继发性（继发于真性红细胞增多症或原发性血小板增多症后）的骨髓纤维化患者的疗效和安全性。 JAK抑制剂脾脏肿大（称为脾肿大），血小板计数≥50×109 / L（基线血小板中位数为214×109 / L; 16％<100×109 / L，84％≥ 100×109 / L）.1,2在JAKARTA研究中，当从基线到第6周期结束（第24周）进行评估时，脾脏体积减少了35％或更多，进行了为期4周的随访扫描，接受INREBIC 400 mg治疗的患者中37％（96名患者中的35名）与1名患者（1名96名患者）接受治疗接受安慰剂治疗的患者（p <0.0001）.1 INREBIC也通过改良的骨髓纤维化症状评估表（MFSAF）v2.0日记2（夜间出汗，瘙痒，腹部不适，早期饱腹感，肋骨下疼痛）测量总症状评分。左侧，骨骼或肌肉疼痛）从基线到第6周期结束时评估为50％或更高，40％（89名患者中的36名）接受400 mg治疗，而接受治疗的患者中有9％（81名患者中有7名）安慰剂（p <0.0001）.1

Inrebic对严重致命的脑病有一个盒装警告，包括Wernicke's。据报道，临床试验中接受Inrebic治疗的患者中有1.3％（608名患者中有8名）患有严重脑病，其中0.16％（608名中有1名）致命。 Wernicke的脑病是由硫胺素（维生素B1）缺乏引起的神经系统急症。所有患者在开始使用Inrebic前，定期在治疗期间和临床指征时应评估硫胺素水平.1不要在硫胺素缺乏患者中开始使用Inrebic;在治疗开始前补充硫胺素。如果怀疑是脑病，立即停用Inrebic并开始使用肠外硫胺素。监测直至症状消退或改善，硫胺素水平正常化。

在JAKARTA研究中，21％接受Inrebic 400 mg治疗的患者出现严重不良反应（n = 96），最常见（≥2％）为心力衰竭（5％）和贫血（2％）。 1 1％的患者发生心源性休克致命的不良反应.1％的患者因不良反应而永久性停药。在接受Inrebic治疗的患者中，≥2％永久停药的最常见原因包括心力衰竭（3％），血小板减少，心肌缺血，腹泻和血肌酐增加（每种2％）.1

在随机治疗期间由于不良反应引起的剂量中断发生在21％接受Inrebic的患者中。接受Inrebic治疗的患者中有3％以上需要中断剂量的不良反应包括腹泻和恶心。在随机治疗期间由于不良反应引起的剂量减少发生在19％接受Inrebic的患者中。接受Inrebic治疗的患者需要减少剂量的不良反应包括贫血（6％），腹泻（3％），呕吐（3％）和血小板减少（2％）。

“Inrebic是一种备受欢迎的新型骨髓纤维化治疗方法，”MPN宣传和教育国际公司首席执行官兼创始人Ann Brazeau说。 “随着我们开始在诊断，理解和治疗这种疾病方面取得更大进展，这项FDA的批准标志着骨髓纤维化患者的一个重要里程碑。”

关于骨髓纤维化

骨髓纤维化是一种严重且罕见的骨髓疾病，会破坏人体正常的血细胞生成。骨髓逐渐被纤维性瘢痕组织取代，这限制了骨髓制造血细胞的能力.3这种疾病可导致贫血，虚弱，疲劳和脾脏和肝脏肿大等症状.3骨髓纤维化分类作为骨髓增生性肿瘤，一组罕见的血液来源于造血干细胞.4在美国，有16,000到18,500人患有骨髓纤维化，每10万人中有5人和1.5人每年会被诊断出患有骨髓纤维化。 6男性和女性都受到影响，虽然这种疾病可以影响所有年龄段的人，但诊断时的中位年龄范围为60至67岁.7,8

关于雅加达

JAKARTA是一项关键的3期，多中心，随机，双盲，安慰剂对照试验，评估每日一次口服剂量的Inrebic与安慰剂相比，对于中度2或高危原发性或继发性（继发性红细胞增多症）患者的疗效原发性血小板增多症，脾脏肿大，血小板计数≥50×109 / L2（中位基线血小板计数为214×109 / L; 16％的患者血小板计数<100×109 / L，84％之前未接受过JAK抑制剂治疗的患者的血小板计数≥100×109 / L。该研究纳入了289名随机接受Inrebic 500 mg（n = 97）或400 mg（n = 96）的患者或安慰剂（n = 96）1在24个国家的94个地点。

主要终点是脾反应率，定义为通过磁共振成像（MRI）或计算机断层扫描（CT）测量的在第6周末脾脏体积达到大于或等于基线减少35％的患者比例4周后进行随访扫描。次要终点包括症状反应率，定义为通过修改的骨髓纤维化症状评估表（MFSAF）v2.0日记2测量从基线到第6周末评估时总症状评分降低50％或更多的患者比例。 （盗汗，瘙痒，腹部不适，早饱，左侧肋骨疼痛，骨骼或肌肉疼痛）.1

关于Inrebic

Inrebic（fedratinib）是一种口服激酶抑制剂，具有抗野生型和突变激活的Janus相关激酶2（JAK2）和FMS样酪氨酸激酶3（FLT3）的活性。 Inrebic是一种JAK2选择性抑制剂，对家族成员JAK1，JAK3和TYK2具有更高的JAK2效力。 JAK2的异常激活与骨髓增生性肿瘤相关，包括骨髓纤维化和真性红细胞增多症。在表达突变活性JAK2或FLT3的细胞模型中，Inrebic减少信号转导和转录激活因子（STAT3 / 5）蛋白的磷酸化，抑制细胞增殖，并诱导凋亡细胞死亡。在JAK2V617F驱动的骨髓增生性疾病的小鼠模型中，Inrebic阻断了STAT3 / 5的磷酸化，提高了存活率并改善了疾病相关症状，包括白细胞减少，血细胞比容，脾肿大和纤维化。

INDICATION

Inrebic（fedratinib）适用于治疗患有中度2或高危原发性或继发性（继发于真性红细胞增多症或原发性血小板增多症后）骨髓纤维化（MF）的成人患者。

重要安全信息

警告：包括WERNICKE在内的脑病

包括Wernicke's在内的严重致命性脑病发生在Inrebic治疗的患者身上。 Wernicke的脑病是一种神经紧急情况。在开始Inrebic之前，在治疗期间定期评估所有患者的硫胺素水平，并且如临床指示。对于硫胺素缺乏症患者，不要开始使用Inrebic;在治疗开始前补充硫胺素。如果怀疑是脑病，立即停用Inrebic并开始使用肠外硫胺素。监测直至症状消退或改善，硫胺素水平正常化。

警告和注意事项

脑病，包括Wernicke's：严重和致命性脑病，包括Wernicke's脑病，已在Inrebic治疗的患者中发生。在临床试验中用Inrebic治疗的患者中有1.3％（8/608）报告了严重病例，0.16％（1/608）的病例是致命的。

Wernicke的脑病是由硫胺素（维生素B1）缺乏引起的神经系统急症。 Wernicke脑病的体征和症状可能包括共济失调，精神状态改变和眼肌麻痹（如眼球震颤，复视）。精神状态，精神错乱或记忆障碍的任何变化都应引起对包括Wernicke在内的潜在脑病的关注，并促使进行全面评估，包括神经系统检查，硫胺素水平评估和成像。在开始Inrebic之前，在治疗期间定期评估所有患者的硫胺素水平，并且如临床指示。对于硫胺素缺乏症患者，不要开始使用Inrebic;在治疗开始前补充硫胺素。如果怀疑是脑病，立即停用Inrebic并开始使用肠外硫胺素。监测直至症状消退或改善，硫胺素水平正常化。

贫血：34％的Inrebic治疗患者出现新的或恶化的3级贫血。第一级3级贫血发病的中位时间约为2个月，75％的病例发生在3个月内。平均血红蛋白水平在12至16周后达到最低点，16周后部分恢复和稳定。 51％的Inrebic治疗患者接受红细胞输血，并且1％的患者因贫血而永久性地停止Inrebic。考虑减少红细胞输血依赖的患者的剂量

血小板减少症：随机治疗期间新发或恶化的≥3级血小板减少症发生在12％的Inrebic治疗患者中。第一级3级血小板减少症发病的中位时间约为1个月; 75％的病例发生在4个月内。 3.1％Inrebic治疗的患者接受血小板输注。由于血小板减少症和需要临床干预的出血而永久停止治疗，均发生在2.1％的Inrebic治疗患者中。在基线时，在治疗期间定期获得全血细胞计数（CBC），并且如临床指示。对于有活动性出血或4级血小板减少症的3级血小板减少症，中断Inrebic直至小于或等于2级或基线。重复剂量，每日100毫克，低于最后给定剂量，并按临床指示监测血小板。

胃肠道毒性：胃肠道毒性是Inrebic治疗患者中最常见的不良反应。在随机治疗期间，66％的患者出现腹泻，62％的患者出现恶心，39％的患者出现呕吐。 3级腹泻5％，呕吐3.1％。任何级别恶心，呕吐和腹泻发作的中位时间为1天，75％的病例在治疗后2周内发生。考虑在Inrebic治疗期间提供适当的预防性止吐治疗（例如，5-HT3受体拮抗剂）。在症状首次出现时立即用止泻药物治疗腹泻。 3级或更高级别的恶心，呕吐或腹泻在48小时内对支持措施无效，中断Inrebic直至达到1级或更低或基线。重复剂量，每日100毫克，低于最后给定剂量。监测硫胺素水平并根据需要补充。

肝脏毒性：随机治疗期间ALT和AST升高（所有等级）分别为43％和40％，3级或4级分别为1％和0％的Inrebic治疗患者。任何转氨酶升高的中位发病时间约为1个月，75％的病例发生在3个月内。在基线时监测肝功能，在治疗期间定期监测肝功能，并按临床指示。对于3级或更高的ALT和/或AST升高（大于5×ULN），中断Inrebic剂量直至达到1级或更低或达到基线。重复剂量，每日100毫克，低于最后给定剂量。如果再次出现3级或更高的ALT / AST升高，停止用Inrebic治疗。

淀粉酶和脂肪酶升高：在Inrebic治疗的患者中发展出3级或更高的淀粉酶2％和/或脂肪酶10％的升高。任何等级淀粉酶或脂肪酶升高的中位发病时间为15天，其中75％的病例发生在开始治疗的1个月内。一名患者在fedratinib临床开发计划中发生胰腺炎（n = 608），并且治疗中断后胰腺炎消退。在基线时监测淀粉酶和脂肪酶，在治疗期间定期监测，并且如临床指示。对于3级或更高级别的淀粉酶和/或脂肪酶升高，中断Inrebic直至分级为1级或更低或达到基线。重复剂量，每日100毫克，低于最后给定剂量。

不良反应：Inrebic治疗与安慰剂的最常见不良反应是腹泻（66％对16％），恶心（62％对15％），贫血（40％对14％）和呕吐（39％）与5％）。在随机治疗期间由于不良反应引起的剂量中断发生在21％接受Inrebic的患者中。接受Inrebic治疗的患者中有3％以上需要中断剂量的不良反应包括腹泻和恶心。在随机治疗期间由于不良反应引起的剂量减少发生在19％接受Inrebic的患者中。接受Inrebic治疗的患者需要减少剂量的不良反应包括贫血（6％），腹泻（3％），呕吐（3％）和血小板减少（2％）。

药物相互作用：Inrebic与强效CYP3A4抑制剂共同给药增加了fedratinib暴露。暴露增加可能会增加不良反应的风险。考虑不强烈抑制CYP3A4活性的替代疗法。或者，当使用强CYP3A4抑制剂时，减少Inrebic的剂量。使用强效和中度CYP3A4诱导剂避免使用Inrebic。使用双重CYP3A4和CYP2C19抑制剂避免使用Inrebic。 Inrebic与CYP3A4底物，CYP2C19底物或CYP2D6底物的药物共同给药会增加这些药物的浓度，这可能会增加这些药物不良反应的风险。监测不良反应，并在与Inrebic共同给药时根据需要调整CYP3A4，CYP2C19或CYP2D6底物的剂量。

怀孕/哺乳期：考虑Inrebic对母亲的益处和风险，以及为孕妇开具Inrebic时胎儿可能面临的风险。由于母乳喂养儿童可能出现严重不良反应，建议患者在使用Inrebic治疗期间不要进行母乳喂养，并在最后一次给药后至少1个月。

肾功能损害：给患有严重肾功能不全的患者时减少Inrebic剂量。对于轻度至中度肾功能不全患者，建议不要修改起始剂量。由于潜在的暴露增加，预先存在中度肾功能损害的患者需要更加强化的安全性监测，并且如果需要，基于不良反应进行剂量修改。

肝功能损害：避免在患有严重肝功能损害的患者中使用Inrebic。

请参阅完整的处方信息，包括盒装警告。

Source: Celgene Corporation

Posted: August 2019

FDA Approves Inrebic

FDA Approves Inrebic (fedratinib) for the Treatment of Patients With Myelofibrosis

SUMMIT, N.J.--(BUSINESS WIRE)-- Celgene Corporation (NASDAQ: CELG) today announced the U.S. Food and Drug Administration (FDA) has approved Inrebic (fedratinib) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.1

“The approval of Inrebic is another important milestone for Celgene and underscores our commitment to people living with blood cancers,” said Jay Backstrom, M.D., M.P.H., Chief Medical Officer for Celgene. “We are excited to provide Inrebic as a new treatment option that may be used in patients with myelofibrosis, including patients previously treated with ruxolitinib.”

“Myelofibrosis can cause patients to suffer in many ways, including experiencing debilitating symptoms,” said Ruben Mesa, M.D., FACP, Director of the Mays Cancer Center at UT Health San Antonio Cancer Center MD Anderson. “There has not been a new treatment approved for this disease in nearly a decade. With Inrebic, physicians and patients now have another option available for myelofibrosis.”

The Inrebic development program consisted of multiple studies (including JAKARTA and JAKARTA2) in 608 patients who received more than one dose (ranging from 30 mg to 800 mg),1 of whom 459 had myelofibrosis,1 including 97 previously treated with ruxolitinib.1 The JAKARTA study evaluated the efficacy and safety of once-daily oral doses of Inrebic compared with placebo in patients with intermediate-2 or high-risk, primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis who were previously untreated with a JAK inhibitor, had enlarged spleens (a condition known as splenomegaly), and had a platelet count of ≥50 x 109/L (median baseline platelet count was 214 x 109/L; 16% <100 x 109/L and 84% ≥100 x 109/L).1,2 In the JAKARTA study, spleen volume was reduced by 35% or greater, when assessed from baseline to the end of cycle 6 (week 24), with a 4-week follow-up scan, in 37% (35 of 96) of patients treated with INREBIC 400 mg versus 1% (1 of 96) of patients who received placebo (p<0.0001).1 INREBIC also improved the Total Symptom Score as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain) by 50% or greater when assessed from baseline to the end of cycle 6 in 40% of (36 of 89) patients treated with 400 mg, versus 9% (7 of 81) of patients who received placebo (p<0.0001).1

Inrebic has a Boxed Warning for serious and fatal encephalopathy, including Wernicke’s. Serious encephalopathy was reported in 1.3% (8 of 608) of patients treated with Inrebic in clinical trials and 0.16% (1 of 608) of the cases were fatal. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Thiamine levels should be assessed in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated.1 Do not start Inrebic in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Inrebic and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

In the JAKARTA study, serious adverse reactions occurred in 21% of patients treated with Inrebic 400 mg once daily (n=96), with the most common (≥2%) being cardiac failure (5%) and anemia (2%).1 Fatal adverse reactions of cardiogenic shock occurred in 1% of patients.1 Permanent discontinuation due to an adverse reaction occurred in 14% of patients. The most frequent reasons for permanent discontinuation in ≥2% of patients receiving Inrebic included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each).1

Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received Inrebic. Adverse reactions requiring dosage interruption in >3% of patients who received Inrebic included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received Inrebic. Adverse reactions requiring dosage reduction in >2% of patients who received Inrebic included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

“Inrebic is a much-welcomed new treatment for the myelofibrosis community,” said Ann Brazeau, Chief Executive Officer and Founder, MPN Advocacy and Education International. “This FDA approval marks an important milestone for people living with myelofibrosis as we embark on making greater strides in the diagnosis, understanding and treatment of this disease.”

About Myelofibrosis

Myelofibrosis is a serious and rare bone marrow disorder that disrupts the body’s normal production of blood cells. Bone marrow is gradually replaced with fibrous scar tissue, which limits the ability of the bone marrow to make blood cells.3 The disorder can lead to anemia, weakness, fatigue and enlargement of the spleen and liver, among other symptoms.3 Myelofibrosis is classified as a myeloproliferative neoplasm, a group of rare blood cancers that are derived from blood-forming stem cells.4 In the U.S., between 16,000 and 18,500 are living with myelofibrosis,5 and 1.5 of every 100,000 people will be diagnosed with myelofibrosis each year.6 Both men and women are affected, and while the disease can affect people of all ages, the median age at diagnosis ranges from 60 to 67 years.7,8

About JAKARTA

JAKARTA was a pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy of once-daily oral doses of Inrebic compared with placebo in patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with splenomegaly and a platelet count of ≥50 x 109/L2 (median baseline platelet count was 214 x 109/L; 16% of patients had a platelet count <100 x 109/L and 84% of patients had a platelet count ≥100 x 109/L) who were previously untreated with a JAK inhibitor.1,2 The study included 289 patients randomized to receive either Inrebic 500 mg (n=97) or 400 mg (n=96) or placebo (n=96)1 across 94 sites in 24 countries.

The primary endpoint was spleen response rate, defined as the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) with a follow-up scan 4 weeks later. Secondary endpoints included symptom response rate, defined as the proportion of patients with a 50% or greater reduction in Total Symptom Score when assessed from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain).1

About Inrebic

Inrebic (fedratinib) is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Inrebic is a JAK2-selective inhibitor with higher potency for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2 or FLT3, Inrebic reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, Inrebic blocked phosphorylation of STAT3/5, increased survival and improved disease-associated symptoms, including reduction of white blood cells, hematocrit, splenomegaly and fibrosis.1

INDICATION

Inrebic (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

IMPORTANT SAFETY INFORMATION

WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S
Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with Inrebic. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated. Do not start Inrebic in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Inrebic and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

WARNINGS AND PRECAUTIONS

Encephalopathy, including Wernicke’s: Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in Inrebic-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with Inrebic in clinical trials and 0.16% (1/608) of cases were fatal.

Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated. Do not start Inrebic in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Inrebic and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Anemia: New or worsening Grade 3 anemia occurred in 34% of Inrebic-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of Inrebic-treated patients and permanent discontinuation of Inrebic occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent

Thrombocytopenia: New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of Inrebic-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% Inrebic-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of Inrebic-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt Inrebic until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated.

Gastrointestinal Toxicity: Gastrointestinal toxicities are the most frequent adverse reactions in Inrebic-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patient and vomiting in 39% of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during Inrebic treatment. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt Inrebic until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose. Monitor thiamine levels and replete as needed.

Hepatic Toxicity: Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of Inrebic-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt Inrebic dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If re-occurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with Inrebic.

Amylase and Lipase Elevation: Grade 3 or higher amylase 2% and/or lipase 10% elevations developed in Inrebic-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt Inrebic until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose.

ADVERSE REACTIONS: The most common adverse reactions for Inrebic treated vs. placebo were diarrhea (66% vs. 16%), nausea (62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received Inrebic. Adverse reactions requiring dosage interruption in >3% of patients who received Inrebic included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received Inrebic. Adverse reactions requiring dosage reduction in >2% of patients who received Inrebic included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

DRUG INTERACTIONS: Coadministration of Inrebic with a strong CYP3A4 inhibitor increases fedratinib exposure. Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of Inrebic when administering with a strong CYP3A4 inhibitor. Avoid Inrebic with strong and moderate CYP3A4 inducers. Avoid Inrebic with dual CYP3A4 and CYP2C19 inhibitor. Coadministration of Inrebic with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with Inrebic.

PREGNANCY/LACTATION: Consider the benefits and risks of Inrebic for the mother and possible risks to the fetus when prescribing Inrebic to a pregnant woman. Due to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Inrebic, and for at least 1 month after the last dose.

RENAL IMPAIRMENT: Reduce Inrebic dose when administered to patients with severe renal impairment. No modification of the starting dose is recommended for patients with mild to moderate renal impairment. Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions.

HEPATIC IMPAIRMENT: Avoid use of Inrebic in patients with severe hepatic impairment.

Please see full Prescribing Information, including Boxed WARNING.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through next-generation solutions in protein homeostasis, immuno-oncology, epigenetics, immunology and neuro-inflammation. For more information, please visit www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn, Facebook and YouTube.

Forward-Looking Statements

1. This press release contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words "expects," "anticipates," "believes," "intends," "estimates," "plans," "will," "outlook" and similar expressions. Forward-looking statements are based on management's current plans, estimates, assumptions and projections, and speak only as of the date they are made. We undertake no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, many of which are discussed in more detail in our Annual Report on Form 10-K and our other reports filed with the U.S. Securities and Exchange Commission, including factors related to the proposed transaction between Bristol-Myers Squibb and Celgene, such as, but not limited to, the risks that: management’s time and attention is diverted on transaction related issues; disruption from the transaction make it more difficult to maintain business, contractual and operational relationships; legal proceedings are instituted against Bristol-Myers Squibb, Celgene or the combined company that could delay or prevent the proposed transaction; and Bristol-Myers Squibb, Celgene or the combined company is unable to retain key personnel.

Source: Celgene Corporation

Posted: August 2019