Theophylline

OCA significantly reduces ALT and AST, liver biomarkers associated with poor clinical outcomes, as early as Week 2 in both OCA treatment groups, and by Month 6, normalized ALT in >50% and AST in almost 33% of patients with elevated levels at baselineMORRISTOWN, N.J., June 04, 2024 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc., a biopharmaceutical company and wholly owned subsidiary of Alfasigma S.p.A. focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, today announced new sub-analyses from its Phase 3 POISE trial in primary biliary cholangitis (PBC) showing the effect of obeticholic acid (OCA) across a number of key biomarkers of liver health in people living with PBC will be presented at the European Association for the Study of the Liver (EASL) Congress 2024 being held June 5-8, 2024, in Milan, Italy. Additional analyses showing the impact of OCA on enhanced liver fibrosis (ELF) and transient elastography (TE), aminotransferase to platelet ratio index (APRI) score and fibrosis-4 (FIB-4) index, and normalization of inflammatory and immune biomarkers in patients from POISE will also be presented. “These new analyses highlight the potential impact of OCA on multiple serum biochemical and inflammatory markers associated with better clinical outcomes,” said Robert G. Gish, M.D. FAASLD, Professor at Loma Linda University Department of Medicine. “Additionally, by leveraging noninvasive measurements like ELF, TE, FIB-4, and APRI, we see that OCA has the potential to stabilize fibrosis regardless of severity at baseline, suggesting that earlier treatment with OCA may benefit patients by preventing fibrosis progression. As a clinician, it is important that we understand the multifaceted aspects of this disease and tailor treatment for our patients accordingly.” The landmark Phase 3 POISE study evaluated the safety and efficacy of once-daily treatment with OCA in PBC patients with an inadequate therapeutic response to, or who were unable to tolerate, ursodeoxycholic acid. Patients were randomized to one of three groups in the trial: placebo, OCA 5 mg with option to titrate to 10 mg after 6 months, or OCA 10 mg daily. The study included a 12-month double-blind phase, as well as a long-term safety extension phase up to five years. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assessed at all visits. This analysis showed that among the intention-to-treat (ITT) population, OCA significantly reduced ALT and AST in both OCA groups (p<0.001) as early as Week 2, and by Month 6, normalized ALT in > 50% and AST in almost 33% of patients with elevated levels at baseline. Among the 61% of patients with ALT >41 U/L at baseline,16% receiving placebo normalized at Month 6 compared to 55% on OCA titration and 53% on OCA 10 mg (p≤0.001 for both). As early as Week 2, three to four times more patients had normalized ALT in both OCA groups (both p<0.01 vs. placebo).Among the 71% of patients with AST >34 U/L at baseline, normalization rates at Month 6 were 12% in the placebo arm, 30% in the OCA titration arm, and 31% in the OCA 10 mg arm (p<0.05 for both).The proportions of patients normalizing ALT and AST on OCA were maintained through Month 12. Additional post hoc analyses showed the impact of OCA on ELF and TE, APRI score, and FIB-4 index, and normalization of inflammatory and immune biomarkers in patients from POISE. In a post hoc analysis assessing the impact of OCA on ELF and TE, no worsening in noninvasive measures of fibrosis (ELF and TE liver stiffness) was observed throughout the OCA treatment suggesting that OCA stabilized fibrosis over time regardless of severity at baseline. OCA stabilized ELF over 24 months in patients with evidence of moderate or severe fibrosis or cirrhosis at baseline.OCA stabilized TE measures over 24 months in patients with a TE of <10 or ≥ 10 kPa at baseline. In a post hoc analysis evaluating the impact of OCA on APRI score and FIB-4 index, overall APRI and FIB-4 scores decreased with OCA treatment and increased in the placebo group in the 12-month double blind phase. Among patients with higher FIB-4 at baseline, FIB-4 increased to a lesser extent in the OCA group compared with placebo while OCA treatment decreased APRI in both high and low APRI subgroups. A post hoc analysis assessing the impact of OCA on normalization of inflammatory and immune biomarkers showed OCA significantly increased the proportion of patients with PBC who achieved normalization of the inflammatory biomarkers, tumor necrosis factor alpha (TNFα), high-sensitivity C-reactive protein (hsCRP) or immunoglobulin M (IgM), the latter of which is associated with better clinical outcomes. “Building on data presented at Digestive Disease Week, these data suggest that in addition to reductions in ALP, OCA significantly reduces ALT and AST, two important liver biomarkers used to assess clinical outcomes,” said Sangeeta Sawhney, Senior Vice President and Head of U.S. Research & Development at Intercept. “Additional analyses of the Phase 3 POISE trial continue to enhance our understanding of PBC treatment response, which may help minimize the risk of disease progression in people living with PBC. We look forward to sharing these findings with the scientific community at EASL.” About the POISE TrialThe POISE trial studied the safety and efficacy of once-daily treatment with Ocaliva in PBC patients with an inadequate therapeutic response to, or who were unable to tolerate, ursodeoxycholic acid (UDCA). There were 217 patients randomized to one of three groups in the trial: placebo, OCA 10 mg, or OCA 5 mg for six months titrated to 10 mg based on clinical response. Seven subjects did not participate in the open-label extension and were not included in the current study. Patients completing the double-blind phase had the option to continue in an open-label extension (OLE) phase for a maximum of five additional years, during which all patients received treatment with OCA 5-10 mg once daily. Of the 198 patients who completed the double-blind phase, more than 95 percent continued in the long-term safety extension phase of the trial for up to 5 years. Additional information regarding the POISE trial can be found on the NIH clinical study listing website: http://clinicaltrials.gov/ct2/show/NCT01473524. 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 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. 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). ContactFor more information about Intercept, please contact: For media:media@interceptpharma.com

先来看两位同行在论坛上分享的莫西沙星过敏经历：@ 微 **：因扁桃体发炎自己给自己配了莫西沙星（0.4 g/片）等，服药后出现出冷汗、呕吐、呼吸急促、四肢麻针感等不良反应，经过补液、地塞米松静推、吸氧等对症处理后缓解。对于这次过敏反应，站友做了自我总结：1. 想当然的按照以往所谓的经验随便用药（之前用过 2 次莫西沙星，均无过敏反应发生）, 没有请专业人士看过后再用药。2. 对于两种药的配伍禁忌了解不清楚，也不排除同时要药后产生的不良反应。3. 不要以为自己在医院工作很懂，术业有专攻，生命只有一次，用药要谨慎。下面我们来了解一下莫西沙星。1999莫西沙星年首次在德国上市，先后在英国、美国、墨西哥应用。2002年在我国正式上市并广泛应用。随着临床应用的不断扩大，不良反应的报道也逐渐增多，虽然绝大多数为轻中度不良反应，但亦有莫西沙星所致严重不良反应的相关报道。莫西沙星属于第四代喹诺酮类药物，对革兰氏阳性菌、革兰氏阴性菌（铜绿假单胞菌除外）、非典型致病菌和厌氧菌有较强的抗菌作用。此外，其对肺炎衣原体、肺炎支原体和军团菌也有很强的抗菌活性，主要用于治疗呼吸系统感染、泌尿生殖系统感染、腹腔感染、皮肤软组织感染等疾病。一提到莫西沙星，你会首先想到它的哪些不良反应呢？有没有想过这些不良反应严重可致死呢？心脏毒性莫西沙星的心脏毒性表现为 Q-T 间期延长 (特别是低血钾症患者)、心悸、心动过速、血管扩张等，罕见的引起室性快速心率失常、晕厥、高血压、低血压等。因此，基于安全考虑，下列患者应禁用莫西沙星：先天性或证明有获得性 QT 间期延长患者；电解质紊乱，尤其是未纠正的低钾血症患者；有临床意义的心动过缓患者；有临床意义的心力衰竭并伴有左心室射血分数降低患者；既往发生过有症状的心律失常患者。此外，可能引起 Q-T 间期延长的药物有：抗心律失常 ⅠA 类、Ⅲ 类药（奎尼丁、胺碘酮、索他洛尔）、西沙必利、红霉素、三环类抗抑郁药等均可能导致患者 Q-T 间期延长，与莫西沙星联用会使心脏不良事件发生的风险增高。神经毒性有中枢神经系统疾病或癫痫史的患者不宜使用莫西沙星；重症肌无力、肝肾功能不全、G6PD 缺乏的患者应慎用。莫西沙星为 8-甲氧氟喹诺酮类抗菌药，化学结构中含有氟原子，脂溶性高，易透过血脑屏障。中枢神经系统不良反应为该药已知不良反应，主要表现为精神错乱、幻觉、情绪稳定、多梦、睡眠失调、癫痫发作，这可能与喹诺酮类药物可阻断中枢抑制性递质 γ-氨基丁酸（GABA）与受体结合，导致中枢神经系统兴奋性增高有关。莫西沙星作为喹诺酮类药物可能引起严重过敏反应。喹诺酮类药物导致过敏的机制可通过IgE和T细胞介导的过敏反应，前者表现为风疹，后者表现为斑丘疹、急性泛发性疱疹性脓疱病、Stevens-Johnson综合征和表皮毒性坏死症。临床常用的喹诺酮类药物包括左氧氟沙星、环丙沙星和莫西沙星。三种药物的过敏反应发生的几率为：莫西沙星（0.141%）＞左氧氟沙星（0.041%）＞环丙沙星（0.026%）。临床上关于莫西沙星引起的过敏性反应的报道较为常见。因此给予喹诺酮类药物时应该密切关注患者用药后的反应，一旦出现意识模糊、血压下降等应该及时处理。此外，对于院外接受治疗的患者，也应告知患者注意用药后的自我监护，防止意外发生！药物之间相互影响（1）抗酸药、硫糖铝、复合维生素和其他含有多价阳离子的物质喹诺酮类药物会与碱金属和过渡态金属阳离子以螯合物形式结合，当莫西沙星与上述药物合用，可能大大影响其吸收，同时也导致血浆中的莫西沙星的浓度远低于预期。因此，应在使用这些药物至少 4 小时前或 8 小时后再口服盐酸莫西沙星片。（2）华法林莫西沙星有增强华法林或其衍生物对患者的抗凝效果，此外，患者所患的感染性疾病及其伴随炎症过程、年龄和一般状态都是抗凝活性增加的危险因素。因此，如果莫西沙星与华法林或其衍生物合并使用，必须严密监控患者的凝血酶原时间、国际标准化比值或其他合适的抗凝测试。（3）糖尿病治疗药物莫西沙星可能会影响患者的血糖。血糖障碍主要发生于那些同时口服降糖药（如磺酰脲类药物）或使用胰岛素的老年患者中。因此，当对糖尿病人使用莫西沙星时应密切监测血糖，如发生血糖波动，如低血糖反应，需立即停用莫西沙星并开展适当治疗。（4）非甾体抗炎药甾体抗炎药可降低患者兴奋阈值，诱发癫痫，因此应避免与莫西沙星联用。（5）皮质类固醇药物老年患者若在接受皮质类固醇治疗时使用莫西沙星，则其发生肌腱断裂的风险将会增加。因此，在向老年患者，尤其是同时使用皮质类固醇的老年患者开具处方时应谨慎，应告知患者，并嘱咐患者如发生任何症状的肌腱炎或肌腱断裂应停用莫西沙星并及时就医。其他不良反应细菌耐药性的发生：在没有证据证明高度疑似细菌感染或用来预防细菌感染的情况下，使用盐酸莫西沙星并不能使患者受益，反而会增加耐药菌发生的风险。对驾驶或操作机械能力的影响：建议患者在驾驶或操作机械之前考虑自己对盐酸莫西沙星是否有反应。盆腔炎性疾病：针对复杂盆腔感染患者治疗时，需考虑使用盐酸莫西沙星的注射液进行治疗，而不推荐口服莫西沙星治疗。盆腔炎性疾病可能是由对氟喹诺酮类耐药的淋病奈瑟氏菌导致的。在此类患者中，莫西沙星应当与另外一种合适的抗生素（例如头孢菌素）同时使用，除非能够排除对莫西沙星耐药的淋病奈瑟氏菌。如果治疗 3 天后临床上无改善，应当重新考虑治疗。莫西沙星用药注意事项1、为预防不良反应的发生，临床应用时不但须注意询问患者用药过敏史，对于过敏体质或者曾有药物过敏史的患者应避免使用。肝功能受损和转氨酶比正常值上限高于5倍的患者禁用。（喹诺酮类抗生素18岁以下禁用。）2、更重要的是严格按药品说明书要求合理用药，并加强用药监护，定期监测肝脏功能，如出现不良反应应及时停药并对症治疗。鉴于老年患者中不良反应发生率较高，对于这类特殊人群，使用莫西沙星时更应高度关注，密切观察用药过程中患者的不适。3、联合用药时需要考虑到药物相互作用可能导致的不良反应，当莫西沙星与延长QT间期的药物、糖皮质激素类和茶碱类药物合用时，可能会加重不良反应症状。因此联合用药时更需慎重。4、静脉给药时需要注意避免输液过快。增加药物浓度或加快给药速度可能增加QT间期延长的幅度。静脉滴注推荐剂量为一次0.4g，一日1次，滴注时间为90分钟。5、18 岁以下患者禁用。妊娠和哺乳期妇女禁用。参考文献：[1]席宇飞,徐勤芬,李晓宇,刘皋林.莫西沙星片过敏致急性心肌梗死1例[J].中国药物警戒,2015,12(07):444-445.[2]王华,孟华,贾婧超,杜立文.服用过量莫西沙星片致急性心肌梗死1例[J].宁夏医学杂志,2019,41(04):328.[3]石浩强.“沙星”类抗菌物药被加上黑框警告[J].江苏卫生保健,2017(09):32-33.[4]药飞,王东晓.临床药师在莫西沙星致QT间期延长不良事件中的实践[J].中国药物应用与监测,2020,17(02):96-99.[5]周小颖.1例莫西沙星致癫痫样发作病例分析[J].心理月刊,2020,15(08):227.[6]刘慧敏,李聪,李春雷,王聪聪,陈富超.1例疑似莫西沙星片致过敏性休克的肺部感染患者的病例分析[J].中南药学,2020,18(07):1266-1267.[7]李冠英, 李成建, 王茜. 莫西沙星不良反应 [J]. 中国误诊学杂志, 2009(28).[8]莫西沙星用药助手说明书往期回顾咳咳咳…感冒后咳嗽一个月仍不见好转，镇咳药均不见效！PIC的“阿喀琉斯之踵”其实不是这些药物…什么是内致热源和外致热源？激素退烧可行不可行？一文详述……为何静点左氧氟沙星导致患者全身出血！左氧氟沙星的使用，这些细节一定要注意……降钙素原（PCT）升高评估细菌感染？没这么简单……关于降钙素原升高的临床意义，这些感染才适用！PCT多高才能用抗生素，阈值是多少编辑 | 聪明的一休授权转载、投稿等请联络梅斯医学管理员克里@梅斯医学（微信号：medsci-）