Olmesartan Medoxomil

CLOZARIL (clozapine) NDA 019758 Heritage Life Sciences (Barbados) c/o Heritage Life Sciences Therapeutics (USA) Veterans Health Administration (VHA) medical and pharmacy records Descriptive study In FDA’s review of the effectiveness of the clozapine REMS, FDA conducted several analyses of clozapine registry patients, describing adherence to absolute neutrophil count monitoring, as specified by the clozapine REMS, and estimating the cumulative risk of severe neutropenia. The study results were included in the November 19 Joint Meeting of the Drug Safety and Risk Management and Psychopharmacologic Drugs Advisory Committee briefing package, where the committee voted to remove the clozapine REMS. Based on the advice from the Advisory Committee and the Agency’s re-evaluation, the Agency removed the clozapine REMS and issued a DSC. DSC August 27,2025 FDA Drug Safety Communication: FDA removes risk evaluation and mitigation strategy (REMS) program for the antipsychotic drug Clozapine (REMS release, labeling changes) Toprol-XL and Lopressor (Metoprolol), Inderal LA (propranolol), [beta blockers] Multiple NDAs Multiple sponsors Sentinel System Retrospective cohort study The results from a retrospective cohort study in Sentinel indicated an association between beta blocker use and hypoglycemia in pediatric populations. FDA approved safety labeling changes to describe the risk for hypoglycemia in pediatrics or individuals unable to communicate signs of hypoglycemia. This resulted in a labeling change. Beta Blockers Safety Communications & Labeling Changes (Sentinel Initiative), July. 25, 2025. FDA Labeling Change: Additional Language to Mitigate the Risk of Hypoglycemia Associated with Beta Blockers in Children Beta blockers | Sentinel Initiative Entyvio (vedolizumab) BLA 761359 Takeda Pharmaceuticals Sentinel System Descriptive study The results from a descriptive Sentinel study did not indicate an increased risk for Interstitial lung disease (ILD) in patients treated with vedolizumab or natalizumab for inflammatory bowel disease. However, there were other data from case reports from the medical literature and FDA FAERS. This resulted in FDA adding “interstitial lung disease, pneumonitis” to the Postmarketing Experience subsection of labeling. Entyvio Safety Communications & Labeling Changes (Sentinel Initiative), April 18, 2024. FDA Labeling Change: Vedolizumab & Interstitial Lung Disease (ILD) Prolia (Denosumab) BLA 125320 Amgen Medicare claims data Retrospective cohort study In FDA’s review of denosumab, an FDA retrospective cohort study in Medicare found an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking this medication. This resulted in a DSC and addition of a Boxed Warning for an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease. FDA added a boxed warning. DSC, January 19, 2024 (severe hypocalcemia). FDA Drug Safety Communication: FDA adds Boxed Warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab) Prolia label change, November 22, 2022. FDA Drug Safety Communication: FDA investigating risk of severe hypocalcemia in patients on dialysis receiving osteoporosis medicine Prolia Anticoagulant, oral Multiple NDAs Multiple sponsors Sentinel System Retrospective cohort study FDA conducted a retrospective cohort study in the Sentinel System to examine severe uterine bleeding events requiring medical intervention in women treated with oral anticoagulants. The study found a risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions. This finding contributed to a class-wide label change for this risk with oral anticoagulants and that this should be assessed in females of reproductive potential and those with abnormal uterine bleeding. There was also a communication via the Sentinel initiative website. Oral Anticoagulants Safety Communications & Labeling Changes (Sentinel Initiative), January. 28, 2021. FDA Labeling Change: Oral Anticoagulants and Clinically Significant Uterine Bleeding Methotrexate, oral Multiple NDAs Multiple sponsors Sentinel System A chart confirmed analysis was conducted in one Sentinel Data Partner An FDA medical chart review analysis conducted in a Sentinel Data Partner, found the incidence of low-dose oral methotrexate wrong frequency dosing errors to be 0.4%. This resulted in adding the risk of improper dosing to Section 5 (Warnings and Precautions), removing an option for doses given every 12 hours for 3 days each week from Section 2 (Dosage and Administration). Oral Methotrexate (Sentinel Initiative), December. 17, 2021. FDA Labeling Change: Oral Methotrexate and Wrong Frequency Dosing Errors Singulair (montelukast) NDA 021409 Organon Sentinel System Retrospective cohort study Retrospective cohort studies conducted in the Sentinel system informed the re-evaluation of the benefits and risks of montelukast use. Considering the totality of evidence, including the negative Sentinel studies resulted in FDA strengthening existing warnings about serious behavior and mood-related changes with montelukast (Singulair and generics). There was also a communication via the Sentinel initiative website. Singulair Safety Communications & Labeling Changes (Sentinel Initiative), March. 3, 2020. FDA Requires Boxed Warning about Serious Mental Health Side Effects for Asthma and Allergy Drug Montelukast (Singulair); Advises Restricting Use for Allergic Rhinitis Hydrochlorothiazide (HCTZ)-containing products Multiple NDAs Multiple sponsors Sentinel System Retrospective cohort study An FDA conducted retrospective cohort study in the Sentinel System assessed the risk of non-melanoma skin cancer for patients treated with HCTZ-containing products. The study identified an association with an increased risk of non-melanoma skin cancer, predominantly for squamous cell carcinoma and in white patients taking large cumulative doses. These findings informed additions to adverse reactions and patient information sections of the labeling, and a communication via the Sentinel initiative website. HCTZ Safety Communications & Labeling Changes (Sentinel Initiative), August. 20, 2020. FDA Labeling Change: Hydrochlorothiazide and Non-Melanoma Skin Cancer Feraheme, infed, injectafer, monoferric, venofer (Parenteral Iron Products) Multiple NDAs Multiple sponsors Sentinel System Descriptive study An FDA Sentinel analysis characterized the frequency of IV iron utilization relative to live birth and stillbirth deliveries. The finding contributed to a class-wide labeling update for parenteral iron products to add new safety information to Section 8 (Use in Specific Populations, Pregnancy) of the label. This update describes the risk of severe adverse reactions to pregnant women and their fetus. There was also a communication via the Sentinel initiative website. Parenteral Iron Safety Communications & Labeling Changes (Sentinel Initiative) The class-wide labeling update regarding risks to pregnant women and their fetus was approved on September. 11, 2020. FDA Labeling Change: Parenteral Iron Products and Risk of Severe Adverse Reactions to Pregnant Women and their Fetuses Comtan, Stalevo (Entacapone) NDA 021485/ 20796 Orion Corporation VHA claims, medical records, and cancer registry Retrospective cohort study In FDA’s review of entacapone, an FDA conducted retrospective cohort study in the VA found no clear evidence of an increased risk of prostate cancer in patients treated with entacapone versus add-on dopamine agonist or monoamine oxidase inhibitor. This resulted in a DSC. Entacapone DSC, August 13, 2019 (no increase in prostate cancer risk). FDA Drug Safety Communication: FDA review finds no increased risk of prostate cancer with Parkinson's disease medicines containing entacapone (Comtan, Stalevo) Pradaxa (dabigatran) NDA 022512 Boehringer Ingelheim Pharmaceuticals, Inc Medicare claims data Retrospective cohort study In FDA’s review of dabigatran, an FDA conducted retrospective cohort study among Medicare patients, showed lower risks stroke and death but higher risk for gastrointestinal bleeding with PRADAXA compared to warfarin. FDA still considered Pradaxa to have a favorable benefit/risk profile and made no changes to the labeling. This resulted in a DSC. Dabigatran Drug Safety Communication, May 13, 2014 FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin Enbrel (etanercept) BLA 103795 Amgen Inc. Sentinel System Descriptive study FDA conducted a drug utilization analysis of TNF alpha inhibitors in pregnant women in the Sentinel System. The study found that among pregnant women with a chronic inflammatory condition, there was a preference to use etanercept compared to other TNF alpha inhibitors. This assessment was one source of evidence considered for the Pregnancy and Lactation Labeling Rule (PLLR) Conversion Safety Labeling Change. There was also a communication via the Sentinel initiative website. ENBREL Safety Communications & Labeling Changes (Sentinel Initiative), July. 11, 2017. FDA Labeling Change: Etanercept (Enbrel) and Use in Pregnancy Gadolinium-based contrast agents (GBCA) Multiple NDAs Multiple sponsors Sentinel System Descriptive study Analyses on gadolinium retention were done with FDA Sentinel data and other data streams. These analyses, in part, resulted in class-wide updates to Section 5 (Warnings and Precautions) to include the risk of gadolinium retention in tissues, including the brain, for months to years, a medication guide, required manufacturers to conduct additional safety assessments. There was also a communication via the Sentinel initiative website. GBCAs Safety Communications & Labeling Changes (Sentinel Initiative), December. 19, 2017. FDA Warns that Gadolinium-Based Contrast Agents (GBCAs) are Retained in the Body; Requires New Class Warnings Comtan, Stalevo (entacapone) NDA 021485/ 20796 Orion Corporation Medicare claims data Retrospective cohort study FDA conducted a retrospective cohort study in Medicare to assess cardiovascular risk associated with entacapone use. FDA found no clear evidence of increased cardiovascular risk with entacapone. The study resulted in a publication and DSC. Entacapone DSC, October 26, 2015. FDA Drug Safety Communication: FDA review found no increased cardiovascular risks with Parkinson’s disease drug entacapone Movement Disorder Society Publication, 2013 . Benicar (olmesartan) NDA 021286 Daiichi Sankyo Medicare claims data Retrospective cohort study In FDA’s review of Olmesartan, an FDA conducted retrospective cohort study in Medicare found no clear evidence of increased cardiovascular risks associated with high dose use in diabetic patients. As a result, FDA’s recommendations for use of olmesartan (BENICAR, BENICAR HCT, AZOR, TRIBENZOR, and generics) in patients with diabetes remained the same. This resulted in a DSC and the addition of the study information in the labeling. Olmesartan DSC, June 24, 2014 (Medicare study results added to labeling). FDA Drug Safety Communication: FDA review of cardiovascular risks for diabetics taking hypertension drug olmesartan not conclusive; label updates required Benicar, Benicar hct (Olmesartan), Azor, Tribenzor (medoxomil) Multiple NDAs Daiichi Sankyo Inc. Mini-Sentinel and Medicare Retrospective cohort study In FDA’s review of Olmesartan, an FDA evaluation of the FDA Adverse Event Reporting System (FAERS) and the published literature found evidence of an association between olmesartan and sprue-like enteropathy. To evaluate an ARB class association FDA conducted a retrospective cohort study in Mini-Sentinel and Medicare. These study results did not support a class effect. This resulted in an FDA safety communication that Olmesartan-containing products can cause intestinal problems known as sprue-like enteropathy. Olmesartan Safety Communications & Labeling Changes (Sentinel Initiative), July. 3, 2013. FDA Approves Labeling Changes to Include Intestinal Problems (Sprue-Like Enteropathy) Linked to Blood Pressure Medicine Olmesartan Medoxomil Pradaxa (dabigatran) NDA 022512 Boehringer Ingelheim Pharmaceuticals, Inc Mini-Sentinel Retrospective cohort study In 2012, an FDA conducted retrospective cohort study in Mini-Sentinel evaluated new information about the risk of serious bleeding associated with use of dabigatran (PRADAXA) and warfarin (COUMADIN, JANTOVEN, and generics). The results indicated that bleeding rates associated with new use of Pradaxa did not appear to be higher than bleeding rates associated with new use of warfarin, which was consistent with observations from the large clinical trial used to approve Pradaxa. FDA issued a DSC to communicate the findings and a communication via the Sentinel initiative website. DSC November, 02,2012 FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) Sentinel Initiative, October. 31, 2012. Update on the Risk for Serious Bleeding Events with the Anticoagulant Pradaxa (Dabigatran) Epogen, Procrit, Aranesp (Erythropoietin stimulating agents (ESA)) BLA 103234 and BLA 103951 Amgen Medicare claims data Retrospective cohort study In FDA’s review of the effects of a labeling change recommending lower doses of ESAs in dialysis patients, an FDA retrospective cohort study in Medicare which assessed the effects of the changes in reimbursement policy in addition to changes in the ESA’s drug labeling found that the risk of MACE and mortality was unchanged, and risk of stroke was reduced following the labeling change. In Black patients, there was a substantial reduction in MACE and mortality after the labeling change. A bundled comprehensive payment system for dialysis that includes the costs of ESAs, and a revised drug label that recommends more conservative dosing had no adverse effects on older dialysis patients covered by fee-for-service Medicare. This resulted in a publication. The labeling change regarding use in patients with chronic kidney disease (CKD) was approved on June 24,2011 JAMA Publication, 2016. Avandia (rosiglitazone) NDA 021071 GlaxoSmithKline Medicare claims data Retrospective cohort study FDA conducted a retrospective cohort study in Medicare that evaluated the risk of heart attacks in patients taking rosiglitazone. The study resulted in labeling changes and an update to the Risk Evaluation and Mitigation Strategy (REMS) to include a restricted access and distribution program for all three rosiglitazone products. This also resulted in two Drug Safety Communications (DSC). Rosiglitazone DSC, May 18, 2011 (imposition of REMS for rosiglitazone use). FDA Drug Safety Communication: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl Rosiglitazone DSC and labeling change, February 3, 2011 (Medicare results added to label). FDA Drug Safety Communication: Avandia (rosiglitazone) labeling now contains updated information about cardiovascular risks and use in certain patients Imitrex (sumatriptan), Treximet® (sumatriptan and naproxen sodium) NDA 020626/ 020080/ 020132/ 021926/ GSK Pregnancy registry Prospective registry study The Sumatriptan/Naratriptan/Treximet Pregnancy Registry collected data on fetal malformations and birth defects from in-utero exposure to sumatriptan (January 1996 to September 2012). A prospective study conducted by the Sponsor identified too few exposed pregnancy outcomes to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Section 8 of the label was updated to reflect that data from the prospective pregnancy exposure registry and other epidemiological studies of pregnant women did not show an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population. Completed Pregnancy Registry Study (ClinicalTrials.gov ID NCT01059604) Sumatriptan and Naratriptan Pregnancy Registry Study IMITREX labeling update December 14, 2017: See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy TREXIMET labeling update April 28,2021: TREXIMET labeling update April 28, 2021: See Section: 8 USE INSPECIFIC POPULATIONS, 8.1 Pregnancy Amerge (naratriptan) NDA 020763 GSK Pregnancy registry Prospective registry study The Sumatriptan/Naratriptan/Treximet Pregnancy Registry collected data on adverse fetal outcomes from in utero exposure to naratriptan. Section 8 of the AMERGE labeling was updated to reflect that no definitive conclusions could be drawn from the registry and epidemiological studies regarding the risk of birth defects following exposure to naratriptan. AMERGE label update November 29, 2016 See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy Proton pump inhibitors (PPI) Multiple NDAs Multiple sponsors Medicare claims data Case-control study In FDA’s review of drugs repurposed for treating patients with COVID-19 or drugs being taken by patients with COVID-19, there was concern that PPI use might increase the risk of developing severe COVID-19. An FDA conducted case control study in Medicare compared new users of PPIs versus new users of histamine-2 receptor antagonists and found that PPIs were not associated with increased risk uncomplicated or complicated (ICU, mechanical ventilation, death) COVID-19 hospitalizations. This provided reassurance to FDA that regulatory action was not needed. This resulted in a publication. Pharmacotherapy publication, 2024 . Angiotensin-converting enzyme (ACE) Inhibitors (multiple) and angiotensin receptor blockers (ARB) (multiple) Multiple NDAs Multiple sponsors Medicare claims data Case-control study In FDA’s review of ACE inhibitors or ARBs, an FDA conducted case-control study in Medicare evaluated the effect of ACE inhibitors or ARBs on the risk of developing severe COVID-19 and found that use of these drugs was not associated with increased risk of hospitalized COVID-19 or COVID-19-related mortality. No labeling changes were warranted. This resulted in a publication. Journal of General Internal Medicine publication, 2021. EPOGEN, PROCRIT, ARANESP (Erythropoietin stimulating agents (ESA)) BLA 103234 and 103951 Amgen Medicare Retrospective cohort study FDA reviewed the effect of the REMS for ESA use for chemotherapy-induced anemia, during and after the discontinuation of the REMS, and conducted a restrospective cohort study in Medicare that showed that the REMS had minimal impact on ESA use or transfusion rates and that the removal of the REMS did not affect subsequent ESA use or blood transfusions. Study results provided reassurance that FDA's removal of the REMS had not led to increased ESA use or transfusions. This resulted in a publication. Pharmacoepidemiology Drug Safety publication, 2021 . LYBREL (ethinyl estradiol; levonorgestrel) NDA 021864 Pfizer Sentinel System Retrospective cohort study An FDA conducted retrospective cohort study evaluated the risk of venous thromboembolism (VTE) for extended cycle contraceptives to determine whether these posed a greater risk of VTE due to increased hormone exposure, compared to 28-day products. The study provided reassurance that VTE risk was not substantially different between traditional and extended use oral contraceptives. JAMA Publication 2018 Januvia (sitagliptin) NDA 021995 Merck Pregnancy registry Prospective registry study A prospective study conducted by the Sponsor in a pregnancy registry identified too few exposed pregnancy outcomes to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Section 8 of the labeling was updated to reflect that the data available for pregnant women exposed to sitagliptin were not sufficient to inform a drug- associated risk for major birth defects and miscarriage. JANUVIA label update February 9, 2018. See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy - Risk Summary Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.

去年Alnylam和Roche公布的Zilebesiran在KARDIA-2试验结果的时候，笔者就引用“天边的乌云”来形容（参见【药海听涛】晴空乌云：Alnylam公布高血压药物的KARDIA-2试验结果）。当时，对于KARDIA-3的态度也只是认为“既有启示、也难免引入挑战”，没想到一年后揭盖子的时候，KARDIA-3直接读出了未达到显著性的结果。 https://alnylampharmaceuticalsinc.gcs-web.com/static-files/a763e465-b043-4df4-824b-ccbaa8326c73 在这项二期临床中（NCT06272487），入组标准是有CVD病史或高危因素、使用2-4种降压药但仍无法有效控制血压的高血压患者。 将eGFR≥45的3a期肾功能轻中度异常患者270例，纳入cohort A（本次披露范围），按照1:1:1分入Zilebesiran 300/600mg和安慰剂组；将eGFR 30-44的3b期肾功能中重度异常患者105例，纳入cohort B，按照1:1:1:1分入Zilebesiran 150/300/600mg和安慰剂组。这里的剂量设计已经体现出研究者对Zilebesiran联用其他降压药的安全性风险顾虑，特别是对肾功能中重度异常的患者更加谨慎，毕竟KARDIA-2的各个联用方案中Zilebesiran的剂量都是600mg。 上次KARDIA-2在随机分组上就踩了肾功能基线不均匀的雷，这次KARDIA-3的基线更是一步一个坑的隐患：首先是既往CVD病史，300mg组和600mg组之间居然差出了快一倍；然后是接受过降压药数量，300mg组的用药线数也是肉眼可见偏高。这些与血压高度相关的基线出现显著失衡，给临床终点带来噪音应该是可以想见的，比如600mg组是不是因为用了更少的利尿剂或者钙通道阻滞剂而导致与AGT siRNA联用的效果更差了（毕竟A+C+D机制的降压效果更好）？ 主要临床终点是3个月后两个Zilebesiran剂量组与安慰剂对诊室SBP降低的幅度，600mg剂量组降幅-10.6mmHg、相比安慰剂降幅-3.3mmHg（-8.2, 1.6）、p=0.18，300mg剂量组降幅-12.3mmHg、相比安慰剂降幅-5.0mmHg（-9.9, -0.2）、p=0.04。首先直接结论就是总体结果未达到显著性，600mg组是完全崩坏，300mg组也只是勉强p值在0.05以内、置信区间没过0；其次，两个剂量组有效性与剂量倒挂，也挺要命；再次，在2-4种背景降压药基础上add-on Zilebesiran边际产生的降压幅度绝对值仅仅是3-5mmHg，这也显著低于KARDIA-2在1种背景降压药基础上add-on Zilebesiran的边际降压幅度7-19mmHg。 另外，Zilebesiran的结果还完败给同样在ESC上公布的Baxdrostat（醛固酮合成酶CYP11B2抑制剂，AZ曾以$1.3b+0.5b从Cincor购得），后者在同样是针对使用2-3种降压药无法有效控制血压的患者的三期临床中，3个月边际降压幅度高达-8.7~-9.8mmHg、p<0.0001。 https://www.astrazeneca.com/content/dam/az/Investor_Relations/events/ESC2025-Presentation-20250831.pdf 次要终点里，6个月的诊室SBP降幅和3个月的24小时平均动态SBP降幅也都不显著，6个月的24小时平均动态SBP降幅表现稍好了一点，特别是夜间相比安慰剂的SBP降幅更大，有可能是心血管获益的来源。 在有效性一片惨淡的结果中，总要挖地三尺刨出一些积极的亚组结果，于是发现基线使用利尿剂且SBP仍超过140的患者，两个剂量组与安慰剂相比3个月SBP降幅为-9.2mmHg和-7.0mmHg，不过有效性与剂量依然倒挂，只能说获益比总患者群体大一点。与利尿剂的协同效应也并不出乎意料，利尿剂使得患者血容量减少、进而上调RAAS系统，更有利于靶向AGT的Zilebesiran发挥作用。 再来看安全性，Zilebesiran联用多种降压药确实普遍带来了不良反应增加，特别是低血压、高血钾和肾损伤都有明显增加，在600mg组中低血压发生率4.4%、血钾超过5.5mmol/L发生率8.8%、eGFR降低超过30%发生率8.8%，这与KARDIA-2中Zilebesiran 600mg联用奥美沙坦相比（考虑到两个RAAS通路抑制剂联用的肾损伤更受关注），这三个比例都明显更偏高（后者发生率分别为4.7%、6.7%、6.7%）。 说实话，这次KARDIA-3二期临床“翻车”也并不算很意外，毕竟之前KARDIA-2里Zilebesiran与单药联用的边际药效已有隐忧。然而令人略费解的是Alnylam/Roche对这个试验结果的反应，好像就是“没什么反应”，整个电话会也没看到什么洗地的动作，对统计学不显著、基线不均衡、不良反应增加等等都没有做额外的挽尊，仿佛KARDIA-3是从胜利走向胜利的过场。 最终，两家合作方共同“欣然”宣布，三期临床ZENITH试验将于2025年底启动，这将是一个11,000例的超大规模临床试验，临床终点将是心血管CVOT事件（采取该终点必要性的疑问已在前几篇中提过），剂量将采取300mg Q6M、基线要求必须使用利尿剂，这两条大概是KARDIA-3给ZENITH留下的最直接印记。 如此淡然的态度，再加上周一美股的休市，让才疏学浅的笔者一时间不知道是不是自己对KARDIA-3结果的理解南辕北辙，颇让人回想起1789年7月14日某本著名日记里的那行字“今日无事”。 往期Zilebesiran临床结果分析 【药海听涛】狂飙：AGT siRNA二期临床降压效果惊艳【药海听涛】一鼓作气or步步为营：Zilebesiran二期临床再次达阵 【药海听涛】晴空乌云：Alnylam公布高血压药物的KARDIA-2试验结果