Repotrectinib

FDA在2024年11月6-7日，联合了HESI，USP，多家制药外企进行了2天的workshop，主题是：可接受的活性物质相关的亚硝胺杂质（NDSRI）摄入和处方更新后药物的生物等效性评估方法的最新进展。本文由FDA药物评估与研究中心的科学负责人分享，主要内容如下：1. 药物中亚硝胺杂质生成的风险因素：•  含氮化合物（如二级或三级胺）•  亚硝化剂（如辅料中的亚硝酸盐杂质）•  适宜的pH条件•  生产条件（如混合、干燥、制粒等）•  储存条件2. 药物中亚硝胺杂质的主要缓解策略：•  API生产控制：严格控制API的生产过程•  供应商资质：评估辅料供应商和批次中潜在的亚硝酸盐杂质•  抗氧化剂和pH调节剂：如维生素C、维生素E和碳酸钠等•  生产控制：控制混合、干燥等环节•  pH控制：维持中性pH可防止亚硝胺形成•  热和湿度控制：高温和湿度条件下亚硝胺形成更多•  抗氧化剂：如抗坏血酸、咖啡酸和阿魏酸，可有效减少亚硝胺杂质。3. 盐酸二甲双胍案例研究推荐文章：AI智能体发布大家都在用的“智能体小程序”作者精彩原创集锦1、创新药研发中原料药工艺与沟通交流常见难点2、创新药研发中「制剂工」常见难点3、创新药研发中「变更」相关难点4、创新药研发中「质量分析控制」相关难点（1）5、创新药研发中「质量分析控制」相关难点（2）6、创新药研发难点分析与CMC研究策略探讨7、《已上市化学药品药学变更研究技术指导原则（试行）原料药变更的问答》浅析8、FDA：原料药中亚硝胺风险评估的最新观点9、亚硝胺「传奇」：5年来监管和制药界的反思10、【学习笔记】2023年度CDE审评报告11、FDA审评：吡托布鲁替尼的药学变更桥接(完)12、CDE：ICH指南在国内的实施概况13、「解读」FDA审评：repotrectinib胶囊5次CMC会议内容14、FDA：IND阶段CMC关注点15、药品注册检验难点与建议16、最新 FDA 人用药物亚硝胺杂质指南更新的「底层」参考17、不同国家地区注册检验差异对比曾文亮 博士  近20年药物研发经验，擅长新药研发与注册申报，近5年积累了近十个小分子新药中美IND申报成功和两个1类抗肿瘤新药上市申报成功经验。先后任职于某大型CRO医药研发公司、USP大中华区研发中心和港资原料药厂等，主导过MNC质量研究项目、USP各论更新和药厂QC实验室通过国家GMP检查和WHO审计。  受中国医药保健品进出口商会邀请在二十二届世界制药原料药中国展（CPHI）主导策划了“小分子创新药质量研究和注册策略”沙龙并发表主题演讲；同时受专业药学论坛邀请发表了《创新药质量研究要点和案例分析》、《中美新药申报沟通交流常见问题和案例分析》、《亚硝胺杂质的FDA和EMA控制策略》、《分析方法开发，验证和转移的统计学评价》和《FDA483中清洁验证的典型案例分析》等十余次主题演讲。  更多精彩内容可关注：▲ 关注文亮频道，探索未知世界声明：  根据《中华人民共和国广告法》和《互联网药品信息服务管理办法》相关规定，本平台内容不属于药品广告范畴。所涉药品信息仅作客观陈述，不具备商业推广属性。  本平台发布内容仅代表作者基于专业认知的学术观点，仅代表作者个人观点，不代表任何组织及本公众号立场，如有不当之处，敬请指正。如需转载，请注明作者及来源：蒲公英Ouryao

LOUISVILLE, Ky., July 07, 2025 (GLOBE NEWSWIRE) -- Onco360®, the nation’s leading independent specialty pharmacy, has added Augtyro™ (repotrectinib) manufactured by Bristol Myers Squibb to its comprehensive list of limited distribution therapies. Augtyro was initially approved on November 15, 2023, for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). In June 2024, Augtyro obtained an indication for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity and have progressed following treatment or have no satisfactory alternative therapy. The approval was based on results from the TRIDENT-1 clinical trial (NCT03093116), which evaluated Augtyro in adult patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive solid tumors.1 “We remain committed to support the specialized needs of patients battling cancer, as well as those facing rare and complex diseases. We are grateful for the opportunity to work alongside the team at Bristol Myers Squibb in support of patients prescribed Augtyro.” said Benito Fernandez, Chief Commercial Officer. Please see the full Prescribing Information for Augtyro. IMPORTANT SAFETY INFORMATION FOR AUGTYRO Warnings and Precautions Central Nervous System Adverse Reactions Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.Dizziness, including vertigo, occurred in 65%; Grade 3 dizziness occurred in 2.8% of patients.Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%.Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients.Mood disorders occurred in 6% of patients. Mood disorders occurring in >1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients.Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in >1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%).The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Interstitial Lung Disease (ILD)/Pneumonitis ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%.Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed. Hepatotoxicity Increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%.Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity. Myalgia with Creatine Phosphokinase (CPK) Elevation AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Concurrent increased CPK within a 7-day window was observed in 3.7% of patients.Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement. Hyperuricemia 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Skeletal Fractures Fractures occurred in 2.3% of patients and involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy.Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12- year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO is not approved for use in pediatric patients less than 12 years of age.Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures. Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose. Adverse Reactions The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea. Drug Interactions Effects of Other Drugs on AUGTYRO Avoid concomitant use with P-gp inhibitors, strong or moderate CYP3A inducers, and strong or moderate CYP3A inhibitors. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO. Effects of AUGTYRO on other DrugsCertain CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates. Contraceptives Repotrectinib can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females of childbearing potential to use an effective nonhormonal contraceptive. About Onco360 Oncology Pharmacy:Onco360 is the nation’s largest independent Oncology Pharmacy and clinical support services company. Onco360 was founded in 2003 to bring together the stakeholders involved in the cancer treatment process and serve the specialized needs of oncologists, patients, hospitals, cancer centers of excellence, manufacturers, health plans, and payers. It dispenses nationally through its network of URAC-, and ACHC-accredited Oncology Pharmacies. Onco360 is headquartered in Louisville, Kentucky, and is a flagship specialty pharmacy brand of PharMerica Corporation, a leading institutional pharmacy, specialty infusion, and hospital services company servicing healthcare facilities in the United States. For more information about Onco360, please visit Onco360.com. Media Contact: Benito Fernandez, Chief Commercial OfficerBenito.Fernandez@Onco360.com516-640-1332 References: 1Augtyro (Repotrectinib) [Package Insert]. Princeton, NJ. Bristol Myers Squibb Company. 2024. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 2Repotrectinib Expands Treatment Options for Lung Cancers with ROS1 Fusions. National Cancer Institute. Repotrectinib Shrinks ROS1-Positive NSCLC Tumors - NCI. Access June 19, 2025.