Colesevelam Hydrochloride

药品简介 氯马昔巴特口服溶液由美国Mirum开发，是一种口服顶端钠依赖性回肠胆汁酸转运体(ASBT)抑制剂，用于治疗1岁及以上阿拉杰里综合征（AlagilleSyndrome,ALGS）患者的胆汁淤积性瘙痒症。 ALGS是一种常染色体显性遗传的胆汁淤积性肝病，可导致终末期肝病和死亡，其发病率为1/30,000至1/50,000之间，已在NRDRS（中国国家罕见病注册系统）中注册，属于罕见疾病。 氯马昔巴特口服溶液是目前全球首个且唯一获批用于阿拉杰里综合征患者胆汁淤积性瘙痒的药物。 美国上市：2021年09月29日，通过FDA的审批，用于治疗1岁及以上阿拉杰里综合征（Alagille Syndrome,ALGS）患者的胆汁淤积性瘙痒。 欧洲上市：2022年12月09日，通过欧洲EMA审查获批上市。 中国上市：2023年05月29日，在国内获批进口上市。 医保报销：暂未纳入中国医保目录。 基本信息 通用名称：氯马昔巴特口服溶液 英文名称：Maralixibat Chloride Oral Solution 汉语拼音：Lümaxibate Koufurongye 成份：本品主要成份为氯马昔巴特。 化学名称：(4R,5R)-1-[[4-[[4-[3,3-二丁基-7-（二甲氨基）-2,3,4,5-四氢-4-羟基-1,1-二氧化-1-苯并硫杂庚英-5-基]苯氧基]甲基]苯基]甲基]-4-氮杂-1-氮杂双环[2.2.2]辛烷氯化物 化学结构式： 分子式：C40H56ClN304S 分子量：710.41 适应症 用于治疗1岁及以上阿拉杰里综合征（Alagille Syndrome，ALGS）患者的胆汁淤积性瘙痒。 用法用量 1、剂量 推荐剂量为380µg/kg每日一次，于每日第一餐前约30分钟服药。起始剂量为190µg/kg口服，每日一次；一周后如果可以耐受，剂量可增加至380µg/kg，每日一次。70kg以上患者的最大日剂量体积为每日3ml或28.5mg。按体重给药的指南参见表1。选择适当的口服给药器，按给药剂量要求给药。 表1：按患者体重计算个体剂量 2、药物漏服 如果漏服一次药物，且处于常规服药时间后的12小时内，则尽快补服，并恢复原来的给药方案。如果漏服时间超过12小时，则可忽略该次给药，并恢复原给药方案。 3、用法 对于服用胆汁酸结合树脂的患者，在给予本品至少4小时之前或4小时之后再给予胆汁酸结合树脂（参见【药物相互作用】）。 4、管理不良事件的剂量调整 在开始使用本品治疗前，应确定肝功能指标变异的基线模式，以便于识别潜在的肝损伤迹象。在本品治疗期间监测肝功能（例如ALT[丙氨酸氨基转移酶]、AST[天门冬氨酸氨基转移酶]、TB[总胆红素]、DB[直接胆红素]和国际标准化比值[INR]）。如果在没有其他原因的情 况下出现新的肝功能检查异常，则应中断本品治疗。一旦肝功能指标异常值恢复到基线值或稳定在新的基线值，可考虑以190µg/kg的剂量重新开始本品治疗，并在可耐受的情况下增加至380µg/kg。如果再次出现肝功能指标异常或观察到与临床肝炎相符的症状，应考虑永久停用本品（参见【注意事项】）。 尚未在肝功能失代偿患者中开展本品临床研究。如果患者发生肝功能失代偿事件（例如静脉曲张破裂出血、腹水、肝性脑病），应永久停用本品。 5、特殊人群用药 肝功能损害患者 本品的临床研究纳入了基线时肝功能受损的ALGS患者。尚未确定在ALGS伴有临床意义的门静脉高压患者和失代偿期肝硬化患者中的疗效和安全性（参见【临床试验】、【用法用量】以及【注意事项】）。 注意事项 1、首次开瓶以后，储存在25℃以下。药瓶开封后，应在60日内使用完毕。首次开封后60日，丢弃所有剩余的药物。 2、请置于儿童触及范围之外。 3、肝功能检查异常 纳入临床试验1的患者在基线时肝功能检查异常。在临床试验1中，相对于基线值，观察到治疗后出现的肝功能指标升高或恶化。大多数异常包括ALT、AST或T/DB升高。在临床试验1中，1名患者（基线时TB升高）在28周后由于TB较基线升高而停用本品。在临床试验1的长期开放扩展期内，4名患者因ALT升高导致对本品剂量调整（n=1）、剂量中断（n=2）或永久停药（n=2）（参见【不良反应】）。 应进行肝功能检查获得基线水平，并在治疗期间进行监测。如果在没有其他原因的情况下发生异常，可以考虑减少剂量或中断治疗。对于持续性或反复肝功能异常，应考虑终止给药。 未在ALGS肝硬化患者中评价本品的使用。在本品治疗期间监测患者的肝功能指标升高以及与肝脏相关的不良反应进程。对于持续性或反复肝功能异常的患者，权衡继续使用本品的潜在风险与治疗获益。如果患者进展为门静脉高压或发生肝功能失代偿事件，应永久停用本品。 4、胃肠道不良反应 据报道，腹泻、腹痛和呕吐为本品治疗的最常见的不良反应（参见【不良反应】）。3名患者（3%）发生呕吐被认为是严重不良事件，并采取了住院或静脉输液治疗措施。 如果发生腹泻、腹痛和/或呕吐，且未发现其他病因，应考虑减少本品剂量或中断给药。对于腹泻或呕吐，应监测脱水情况并及时治疗。如果患者出现持续性腹泻或腹泻伴有便血、呕吐、需要治疗的脱水或发烧等体征和症状，应考虑中断本品给药。 当腹泻、腹痛和/或呕吐消失时，以190µg/kg/天的剂量重新开始本品治疗，并在患者可耐受的情况下增加剂量。如果再次用药后出现这些不良反应，则考虑终止本品治疗。 5、脂溶性维生素（FSV）缺乏 脂溶性维生素（FSV）包括维生素A、D、E和K（使用INR水平测量）。ALGS患者在基线时可能存在FSV缺乏。本品可能会影响脂溶性维生素的吸收。在临床试验1中，有3名（10%）患者在48周的治疗期间报告治疗后出现的FSV缺乏。 在开始本品治疗前获得基线FSV水平，并在治疗期间监测血清FSV以及任何临床表现。如果确诊为FSV缺乏，应及时补充FSV。如果已补充足量的FSV，但FSV缺乏持续存在或加重，应考虑停用本品。 特殊人群 孕妇及哺乳期妇女用药 妊娠 因为口服给药后全身吸收较少，孕妇服用本品推荐的临床剂量，预计不会导致可测量的胎儿暴露（参见【临床药理】）。 本品可能会抑制脂溶性维生素的吸收。监测FSV是否缺乏并根据需要进行补充。妊娠期间可能需要额外补充FSV（参见【注意事项】）。 哺乳 本品口服后吸收较少，在推荐剂量下，预计母乳喂养不会导致婴儿暴露于本品（参见【临床药理】）。目前还没有关于人母乳中本品是否可测得、其对母乳喂养婴儿的影响或其对乳汁生成影响的数据。ALGS患者可能患有FSV缺乏，这是其疾病的一部分。本品可能会减少脂溶性维生素的吸收（参见【注意事项】）。哺乳期间应监测FSV水平，如果观察到FSV缺乏，应补充FSV摄入量。应综合考虑母乳喂养对婴儿发育及健康的获益、母亲对本品的需求，以及本品或母亲基础疾病对母乳喂养婴儿的任何潜在不良影响。 儿童用药 本品治疗儿童ALGS患者胆汁淤积性瘙痒的安全性和有效性已在一项针对1至15岁患者（N=31）的研究中得到证实，该研究包括18周开放性治疗期、4周安慰剂对照随机撤药期和随后的26周开放性治疗期。从4项21岁以下患者（N=55）的研究中获得了其他安全性信息（参见【不良反应】和【临床试验】）。 本品在1岁以下患者中用药的安全性和有效性尚未确定。 老年用药 本品在65岁及以上的成年患者中治疗ALGS相关瘙痒的安全性和有效性尚未确定。 药物相互作用 其他药物对本品的影响 胆汁酸结合树脂 胆汁酸结合树脂可能与肠道中的氯马昔巴特结合。在给予本品至少4小时之前或4小时之后再给予胆汁酸结合树脂（例如考来烯胺、考来维仑或考来替泊）。 本品对其他药物的影响 OATP2B1底物 基于体外研究，氯马昔巴特是一种OATP2B1抑制剂。不能排除胃肠道中OATP2B1抑制剂会引起OATP2B1底物（例如他汀类药物）的口服吸收减少。可考虑根据需要监测OATP2B1底物（例如他汀类药物）的药物作用（参见药代动力学部分）。 药理作用 米氯马昔巴特是回肠胆汁酸转运蛋白（IBAT）的可逆抑制剂，可减少回肠末端对胆汁酸（主要是盐形式）的重吸收。 瘙痒是ALGS患者的常见症状，其病理生理机制尚不完全清楚。尽管氯马昔巴特改善ALGS患者瘙痒的完整机制尚不清楚，但正如所观察到的血清胆汁酸减少一样，它可能涉及对IBAT的抑制作用，从而导致胆盐的再摄取减少。 毒理研究 遗传毒性：Ames试验、染色体畸变试验和小鼠微核试验结果均为阴性。 生殖毒性：大鼠经口给予氯马昔巴特，剂量高至750（雄性）或2000（雌性）mg/kg/天，未见对生育力的影响。 妊娠大鼠于器官发生期经口给予氯马昔巴特至1000mg/kg/天[基于AUC（血浆浓度-时间曲线下面积），约为最大推荐剂量的3300至12000倍]或妊娠兔于器官发生期经口给予氯马昔巴特至250mg/kg/天[基于AUC，约为最大推荐剂量的1200至4700倍]，未见对胚胎-胎仔发育的影响。围产期毒性试验中，雌性大鼠于器官发生期至哺乳期经口给予氯马昔巴特，剂量高至750mg/kg/天，未见对产后发育的影响。基于AUC，最高试验剂量下氯马昔巴特的母体系统暴露量约为最大推荐剂量的2500至9400倍。 致癌性：TgRasH2小鼠连续26周经口给予氯马昔巴特，剂量高至25（雄性）或75（雌性）mg/kg/天，未见药物相关的肿瘤发生。 药代动力学 由于氯马昔巴特的全身吸收较少，因此无法可靠地计算推荐剂量下的药代动力学参数。在大多数血浆样品中，儿童ALGS患者的氯马昔巴特血药浓度低于定量限度（0.25ng/ml）。在临床试验1中，接受本品380µg/kg（每日一次）治疗后儿童ALGS患者中氯马昔巴特最高血药浓度为5.93ng/ml。 在健康成年人中以1mg至500mg的剂量单次口服氯马昔巴特后，剂量小于20mg时，氯马昔巴特的血浆浓度低于定量限度（0.25ng/ml），并且无法可靠地估计PK参数。 空腹状态下单次给药30mg后，中位Tmax为0.75小时，平均（SD）Cmax和AUClast分别为1.65（1.10）ng/ml和3.43（2.13）ng·h/ml。 吸收 在推荐剂量下单次或多次给药后，氯马昔巴特吸收极少，血浆浓度通常低于定量限度（0.25ng/ml）。在空腹状态下，单次口服30、45和100mg氯马昔巴特液体制剂后，当剂量增加3.3倍（从30mg增加到100mg），AUClast和Cmax剂量依赖式地分别增加4.6倍和2.4倍。在健康成年人中以高达100mg的剂量（每日一次）重复口服氯马昔巴特后，未观察到氯马昔巴特的蓄积。 食物效应 在进食高脂餐的同时单次口服氯马昔巴特，会降低吸收的速率和程度。相对于空腹状态下口服30mg，餐后状态下氯马昔巴特的AUC和Cmax数值降低64.8%至85.8%。食物对氯马昔巴特全身暴露变化的影响没有临床意义（参见【用法用量】）。 分布 氯马昔巴特在体外与人血浆蛋白的结合率较高（91%）。 清除 健康成人单次口服30mg氯马昔巴特后，平均半衰期（t1/2）为1.6小时。 代谢 在血浆中未检测到氯马昔巴特代谢物。口服[14C]氯马昔巴特后，发现了3种微量代谢物，占氯马昔巴特相关粪便放射性总量的<3%。 排泄 粪便排泄是主要清除途径。单次口服5mg14C-氯马昔巴特后，粪便中排泄73%，尿中排泄0.066%。94%的粪便排泄为氯马昔巴特原型。 特殊人群 肾功能损害患者：尚未研究肾功能损害患者（包括终末期肾脏疾病[ESRD]或接受血液透析的患者）中氯马昔巴特的药代动力学。 药物相互作用研究 其他药物对氯马昔巴特产生的影响：氯马昔巴特不是药物转运蛋白MDR1（P-gp）、BCRP、OATP1B1、OATP1B3或OATP2B2的底物；因此，预计伴随药物不会影响氯马昔巴特的分布。 氯马昔巴特对其他药物产生的影响：在体外，在临床相关浓度下，氯马昔巴特不会诱导CYP亚型1A2、2B6或3A4，也不会抑制CYP亚型1A2、2B6、2C8、2C9、2C19或2D6。氯马昔巴特在体外抑制CYP3A4，但是不太可能对CYP3A4底物的药代动力学产生临床相关影响。在体外，氯马昔巴特在临床相关浓度下不抑制转运蛋白MDR1（P-gp）、BCRP、OAT1、OAT3、OATP1B1、OATP1B3、PEPT1、OCT1、OCT2、OCT3、OCTN1、OCTN2、MRP2、MATE1或MATE2-K。 氯马昔巴特在体外抑制药物转运蛋白OATP2B1，这可能导致依赖OATP2B1介导的胃肠道摄取的药物吸收减少。在临床研究中，将4.75mg氯马昔巴特（早晨每日一次）与日剂量的辛伐他汀或洛伐他汀在晚上共同给药，对这些他汀类药物及其代谢物的药代动力学没有临床相关影响。同时使用4.75mg氯马昔巴特不会影响阿托伐他汀的药代动力学。但是，尚未在临床研究中评估氯马昔巴特在较高剂量下对OATP2B1底物药代动力学的影响。 药品中标价格 （数据来源：山西/河北/辽宁/宁夏等省份招标挂网、戊戌数据整理） END ★ 点击下方卡片，发现更多精彩

MORRISTOWN, N.J., Nov. 12, 2024 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc., a wholly owned biopharmaceutical subsidiary of Alfasigma S.p.A., today announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) that addresses the supplemental New Drug Application (sNDA) for OCALIVA® (obeticholic acid, OCA) seeking full approval for the treatment of indicated patients with primary biliary cholangitis (PBC) – a rare, progressive disease that disproportionally affects women. The FDA informed Intercept that it is unable to approve the sNDA in its current form, consistent with the outcome of the Gastrointestinal Drugs Advisory Committee (GIDAC) meeting in September 2024. In its letter, the FDA also said it was continuing to consider safety data from Study 747-302, along with other safety information. OCALIVA continues to be available for the treatment of appropriate patients living with PBC in the U.S. under accelerated approval status. Healthcare professionals who have questions about OCALIVA can contact Intercept Medical Information, and patients with questions should contact their healthcare providers. “We believe in the totality of evidence supporting OCALIVA and intend to work closely with the FDA on next steps,” said Vivek Devaraj, U.S. President and Chairman at Intercept. “We remain committed to patients living with PBC who have limited treatment options.” OCALIVA’s safety profile is based on extensive data from long-term clinical-trials, published real-world evidence and external-control studies, as well as 8 years of post-marketing patient experience that collectively spans 42,000 patient years. About Primary Biliary CholangitisPrimary biliary cholangitis (PBC) is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent (approximately 1 in 10,000) in women over the age of 40. PBC causes bile acid to build up in the liver, resulting in inflammation and scarring (fibrosis), which, if left untreated, can lead to cirrhosis, a liver transplant, or death. About InterceptIntercept is a biopharmaceutical company and a wholly owned subsidiary of Alfasigma S.p.A. focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, including primary biliary cholangitis (PBC) and severe alcohol-associated hepatitis (sAH). Intercept owns the commercial rights to OCALIVA in the U.S. market. For more information, please visit www.interceptpharma.com or connect with the Company on LinkedIn, Threads and X (formerly Twitter). About Ocaliva® (obeticholic acid) OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of adult patients with primary biliary cholangitis (PBC) without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. IMPORTANT SAFETY INFORMATION WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis. OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation; have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment. Contraindications OCALIVA is contraindicated in patients with: decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) complete biliary obstruction Warnings and Precautions Hepatic Decompensation and Failure in PBC Patients with Cirrhosis Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among post-marketing cases reporting it, median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis. Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage. Hepatotoxicity was observed in the OCALIVA clinical trials. A dose-response relationship was observed for the occurrence of hepatic adverse reactions including jaundice, worsening ascites, and primary biliary cholangitis flare with dosages of OCALIVA of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC. Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment. Severe Pruritus Severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled clinical trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid binding resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing. Reduction in HDL-C Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment. Adverse Reactions The most common adverse reactions (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema. Drug Interactions Bile Acid Binding Resins Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible. Warfarin The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin. CYP1A2 Substrates with Narrow Therapeutic Index Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended when co-administered with OCALIVA. Inhibitors of Bile Salt Efflux Pump Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin. Please click here for Full Prescribing Information, including Boxed WARNING. To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ContactFor more information about Intercept, please contact:For media:media@interceptpharma.com