Repotrectinib

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.

产品信息NAVOLISIB 片剂NDA序号219249规格3 mg和9 mg使用途径口服申请人GENENTECH, Inc.治疗分类肿瘤RLD新分子实体拟定适应症磷脂酰肌醇-4,5-二磷酸3-激酶（PIK）催化亚基α亚型蛋白（p110α；由PIKCA基因编码）的选择性抑制剂，用于治疗乳腺癌产品外观薄膜衣片：• 3 毫克：红色圆形凸面片剂，一面刻有"INA 3"字样。• 9 毫克：粉色椭圆形片剂，一面刻有"INA 9"字样。ICHQ12制定既定条件：申请人提交一份产品生命周期管理（PLCM）文件，详细说明了有关既定条件（ECs）、非既定条件（non-ECs）以及批准后变更管理协议（PACMP）的拟定计划。申请人通过信息请求回复（2024年6月25日）确认："对PLCM文件中所列既定条件的变更将按照法规和指南执行，如PLCM第2节'既定条件的识别'中所述：'将根据适用法规要求，按照EC变更类型及其对产品质量的影响程度向监管机构报告相关变更'"。根据FDA意见，本申请无需进行PQS评估，因PLCM中列出的所有既定条件都将遵循法规和指南执行。OPQ对EC的评估重点在于申请人是否对拟定的EC具有科学合理性依据，并排除了FDA通常可能视为EC的内容。申请人同意（2024年8月22日）在产品生命周期管理模块3.2的R-5表中更新既定条件。PACMP包括将包装中的片剂数量由每瓶30片改为28片的提案，以与28天给药周期保持一致。瓶包装保持不变。申请人计划提交CBE-0文件用于28片瓶装配置。申请人的提案合理，变更风险较低。用于调整片剂数量、相关标签及支持变更数据包的比对方案是可接受的。解读：申请人在NDA申请时根据Q12递交了一份产品生命周期管理文件，定义了EC，即瓶装片数量，它的修订，可以递交CDE-0。该EC的制定和管理文件得到了FDA的同意。ICH Q12指南用于指导产品生命周期管理及EC条件的设定。申请人可参考该指南，根据产品的研发情况及上市后可能的变更情况，设定EC条件，并提交相应的研究数据和方案，与监管方沟通达成一致，可将上市后变更级别进行相应的降级，提高变更执行的时间。制剂桥接针对Inavolisib片剂3毫克和9毫克所提出的商业化处方已从多个临床处方演变而来，申请人进行了细微调整以适应不同剂量强度（b）（4），如图1所示。引入了薄膜包衣（b）（4），并对拟定商业配方的颜色进行了优化，以获得足够的市场认可。模块3.2.P.2提供了所有临床制剂与主要稳定性研究用制剂的定性和定量对比。表4显示了用于I期临床、III期临床、主要稳定性研究及拟上市制剂的配方对比。采用拟定转速桨法对关键临床批次（配方F08/09和F14/15）进行了溶出度检测。在制剂桥接研究期间，还使用50rpm的拟定质控方法对代表性关键批次进行了检测。申请人通过不同pH条件（pH1.1、pH4.5和pH6.8）的体外溶出试验实现了各临床研发阶段制剂的桥接研究，具体结果见图12A、B和C。自早期处方开发阶段至II期及主要稳定性研究阶段，片剂在pH1.1至pH6.8范围内均显示出相似的溶出行为，符合速释制剂特征。此外，图13A、B、C分别展示了采用商业检测方法（USP装置2（桨法）50转/分钟）在0.1N盐酸介质、pH4.5醋酸盐缓冲液及pH6.8磷酸盐缓冲液中对III期批次与主要稳定性批次进行的溶出曲线比较（注：处方F15未在50转/分钟条件下测试。因F15与F09处方组成相同，预计其溶出曲线一致）。在 0.1 N HCl 中，所有制剂均表现出相似的极快速溶出行为，30 分钟内溶解达（4）（6）在 pH 4.5 醋酸盐缓冲液和 pH 6.8 磷酸盐缓冲液中，所有制剂均呈现相似溶出曲线（f2 > 50）。结论：申请人通过体外溶出度对比试验充分桥接了临床研发阶段的制剂变更，证明各制剂间具有相似性（*（4）分钟内释放（4）%*）。  生物药剂学总体建议：基于提交信息的完整性，从生物药剂学角度评估，建议批准用于 NDA 219249 的Inavolisib片（3 mg 与 9 mg）的溶出方法：采用 USP 溶出装置 2（3 mg 规格使用 500 mL 0.1 N HCl，9 mg 规格使用 900 mL 0.1 N HCl），转速 50 rpm，批放行和稳定性检测的验收标准为 Q=30 分钟内溶出（4）%。解读：制剂处方从临床1期到关键临床，再至注册稳定性研究，共有四代处方的更新迭代。甚至关键临床到注册稳定性研究之间，处方都有变更。使用的溶出方法数据表明，四代处方的溶出是一致的，同时也对比了pH4.5和6.8介质条件下的溶出，也是一致的。此时采用的溶出转速不是50rpm，不同于拟业的商业化溶出转速。同时对比了关键临床批次与注册稳定性研究的批次之间的溶出差异，此时采用了拟商业化的溶出方法和pH4.5，6.8的介质，数据表明两者没有差异，是可比的，因此临床研发期间的制剂变更，体外溶出充分的桥接了它们的一致性。推荐文章：1. 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