アジルサルタン阿齐沙坦说明书
阿齐沙坦及片
阿齐沙坦片阿齐沙坦（又称阿齐沙坦酯，英语：Azilsartan）（INN）是治疗高血压症的血管紧张素II受体拮抗剂药物，多用于治疗高血压症，也是血管紧张素II受体拮抗剂（沙坦类）药物。
作为前体药物的阿齐沙坦酯（azilsartan medoxomil、INN、代码 TAK-491），2010年4月28日，日本武田制药公司（Takeda）所研发的该药物完成了三期临床试验，2011年获得美国FDA批准，该药物为一种血管紧张素II受体拮抗剂，可单独使用或与其它降血压药物一起使用，被视作坎地沙坦酯的下一代产品。
中文名: 阿齐沙坦英文名：Azilsartan商品名： Edarbi (Azilsartan medoxomil) 依达比化学英文名(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl2-ethoxy-1-([2'-(5-oxo-4,5-dihy dro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-1H-benzimidazole-7-car boxylateCAS号863031-21-4分子式化学式 C30H24N4O8分子量 568.5临床实验: 阿齐沙坦酯对于降低血压有着较为显著的疗效，一项1291位病人参与、长达六星期的实验比较40毫克、80毫克的阿齐沙坦酯和40毫克的奥美沙坦酯（Benicar®、由第一制药三共株式会社研发）或320毫克的缬沙坦的效果，结果40毫克的阿齐沙坦酯可降低13.4mmHg的血压、80毫克的阿齐沙坦酯则是14.5mmHg、40毫克的Benicar是12mmHg、320公克的缬沙坦则是10.2mmHg。
另有一项为期六周的实验，将20毫克、40毫克、80毫克的阿齐沙坦酯和40毫克的奥美沙坦酯进行了比较，共有1272位病人参与。
结果显示，20毫克的阿齐沙坦酯能降血压10.8mmHg、40毫克的阿齐沙坦酯则是12.1mmHg、80毫克的阿齐沙坦酯是13.2mmHg、40毫克的奥美沙坦酯则为11.2mmHg。
阿利沙坦酯片Allisartan-详细说明书与重点
阿利沙坦酯片Allisartan【成份】本品主要成份为阿利沙坦酯，其化学名称为2-丁基-4-氯-1-[[2’-（1H-四唑-5-基）[1，1`-联苯基]-4-基]甲基]咪唑-5- 甲酸-[[（异丙基氧基）羰基]氧基]甲基酯。
化学结构式：分子式：C27H29ClN6O5分子量：553.01【性状】本品为白色薄膜衣片，除去包衣后显白色或类白色。
【适应症】用于轻、中度原发性高血压的治疗。
【规格】80mg，240mg。
【用法用量】对大多数病人，通常起始和维持剂量为每天一次240mg，继续增加剂量不能进一步提高疗效。
治疗4周可达到最大降压效果。
食物会降低本品的吸收，建议不与食物同时服用。
【警示语】孕妇注意：当在妊娠中晚期使用时，直接作用于肾素-血管紧张素系统的药物会对发育中的胎儿造成损害，甚至导致死亡。
如发现妊娠，应尽快停用本品。
【不良反应】本品不良反应一般轻微且短暂，多数可自行缓解或对症处理后缓解。
临床随机双盲安慰剂对照试验（本品组137例，安慰剂组138例）发现，应用本品总的不良反应发生率与安慰剂类似，分别为8.8%和10.1%。
无论是否与药物肯定有关，发生率≥1%的不良反应有：除上述不良反应外，在3个随机对照临床研究中，690名患者使用本品后发生的不良事件如下，不能确定这些不良事件是否与本品有因果关系：全身：发热、乏力；心血管系统：心率加快、心悸；消化系统：恶心、胃部不适、胃痛、腹部不适、腹泻；骨骼肌肉系统：左侧腰痛、双膝关节酸痛、腿痛；神经/精神系统：头昏、头胀；呼吸系统：鼻塞、咳嗽、打喷嚏、流涕、上呼吸道感染、气短、胸痛；皮肤：瘙痒、口唇疱疹；特殊感觉：黑朦、牙痛、眼胀、耳鸣；泌尿生殖系统：尿痛、痛经实验室发现：临床随机对照试验中，轻中度原发性高血压患者应用本品后，很少在实验室检查结果方面出现有重要意义的变化。
偶见肝功能或肾功能指标升高，ALT和AST轻度升高分别见于0.87%和0.58%的患者，肌酐轻度升高见于0.29%的患者，没有病人因此而停止服药，其临床意义不详。
日本简要药学资料查询2015-4
日本药学相关资料的查询前言日本医药化工在全球占有很重要的地位，并且资料公开程度高，因此在我们医药开发中经常会引用或 借鉴他们的文献资料。
但是受限于日本网站基本上只接受日文查询，对于没有任何日语基础的朋友来说， 查找资料会存在一定困难。
虽然资料的查找路径比较固定，但日文网站经常会改版，例如 PMDA 和 JPO 在今 年三月份均已改版，方法大致没变，但窗口大多和以前版本不一样。
因此，在以前写过一个相关资料检索 的基础上，并从无日语基础查找资料的方法和要点出发，在此做了一些总结。
主要涉及的资料，包括说明 书、IF 文件、审查报告书、申报资料概要、橙皮书以及专利，但对于某些需要一定日语基础的方法，在此 不做总结。
局限于笔者水平未能详尽， 请见谅并欢迎纠正及补充，任何相关问题可通过页脚中的方式联系。
在我们检索中，最核心的问题是要确保日文关键词的准确性。
常用的谷歌、百度之类网站翻译，实践 证明大多并不可信。
通常来说，简单化合物，如甲醇、乙腈、丙酮等都能通过网站翻译直接中日或者日中 翻译出来，但中药、植物名、复杂的化合物以及较新的化合物用网站翻译工具基本不对，若运用网站翻译 成段的句子就更不可取了。
中日互译的网站或工具书远不及英日互译的发达，因此我的建议是以英语为标 准，即先找出正确的英文通用名，再由英文通用名检索出日文名。
也推荐通过这个网址来查，http://moldb.nihs.go.jp/jan/，只要有 CAS 号就可以查到日文名和英文 名，也可以通过英文或日文名来互查。
另外日文假名间不能有空格，否则会视为两个单词。
由于同一个资料可以通过多个路径来检索，因此在此例举个别品种，选择较为简捷的路径以图文结合 解说。
丛林 2015 年 4 月 QQ 3706734051 / 27目录第一部分 药学资料 ........................................................................................................................................... 3 一 关键词语 ................................................................................................................................................... 3 二 说明书与 IF 文件 ...................................................................................................................................... 3 三 审查报告书及申报资料概要 ................................................................................................................... 6 第二部分 专利 ................................................................................................................................................. 9 第三部分 橙皮书 ............................................................................................................................................. 10 附件一 日本药品注册分类 ......................................................................................................................... 12 附件二 日本药效分类编号（2013 年更新版） ........................................................................................ 142 / 27第一部分 药学资料一 关键词语医療用医薬品：处方药 一般用医薬品：OTC ジェネリック：仿制药 添付文書：说明书 インタビューフォーム：IF 文件或综述资料 審査報告書：审查报告书 申請資料概要：申报资料概要 PMDA 网站：http://www.pmda.go.jp/二 说明书与 IF 文件IF 文件和说明书都会根据上市后收集安全性以及有效性逐步完善，并可能在较短的时间内就更新。
阿齐沙坦片体外溶出方法
阿齐沙坦片体外溶出方法杨锐*李玲玲李婷丛海建姜锋**（扬子江药业集团上海海尼药业有限公司上海 201318）摘要目的：优化阿齐沙坦片体外溶出条件，为该品种的仿制药一致性评价工作提供基础。
方法：采用中国药典2015年版四部0931第二法（桨法），pH 1.0（含0.03% SDS）、pH 4.5（含0.4% SDS）、pH 6.8、水（含0.2% SDS）为溶出介质，转速为50 r/min，HPLC 法测定溶出曲线。
结果：阿齐沙坦在4种溶出介质中专属性良好，平均回收率分别为99.01%（RSD 1.31%）、99.57%（RSD 1.04%）、99.87%（RSD 1.62%）、101.67%（RSD 1.53%）。
结论：建立的溶出曲线测定方法准确、可靠，可为阿齐沙坦片的仿制药体外溶出评价提供参考。
关键词阿齐沙坦片 溶出曲线 体外溶出中图分类号：R972.4; R917 文献标志码：A 文章编号：1006-1533(2020)07-0065-06Study on in vitro dissolution method of azilsartan tabletsYANG Rui*, LI Lingling, LI Ting, CONG Haijian, JIANG Feng**(Shanghai Haini Pharmaceutical Co., Ltd., Yangtze River Pharmaceutical Group, Shanghai 201318, China) ABSTRACT Objective: To optimize the in vitro dissolution conditions of azilsartan tablets and provide experimental basis for generic drugs quality consistency evaluation. Methods: According to the second dissolution method (paddle method) stated in 0931 of Chinese Pharmacopeia (2015 Edition), the dissolution of azilsartan in different media (pH 1.0, containing 0.03% SDS; pH 4.5, containing 0.4% SDS; pH 6.8; water, containing 0.2% SDS) with rotation of 50 rpm was determined by HPLC. Results: Azilsartan tablets had good specificity in the four kinds of dissolution media and their average recoveries were 99.01% (RSD 1.31%), 99.57% (RSD 1.04%), 98.77% (RSD 1.62%) and 101.67% (RSD 1.53%), respectively. Conclusion: The established method for the determination of azilsartan dissolution is accurate and reliable and can provide a reference for in vitro dissolution evaluation of azilsartan tablets.KEy WORDS azilsartan tablet; dissolution profile; in vitro dissolution阿齐沙坦是新一代选择性A T1亚型血管紧张素Ⅱ受体拮抗剂（ARBs）类抗高血压药，与血管紧张素转化酶抑制剂类抗高血压药比，具有不会引起干咳、平稳降压的优点。
美国FDA阿齐沙坦脂注册说明
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese HIGHLIGHTS do not include all the information needed to use EDARBI safely and effectively. See full prescribing information for EDARBI.Edarbi (azilsartan medoxomil) tabletsInitial U.S. Approval: 2011WARNING: FETAL TOXICITYSee full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue Edarbi as soon as possible. (5.1)• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)---------------------------RECENT MAJOR CHANGES------------------------Indications and Usage 04/2011 Boxed Warning 11/2011 Warnings and PrecautionsFetal Toxicity (5.1) 11/2011 ---------------------------INDICATIONS AND USAGE-------------------------- Edarbi is an angiotensin II receptor blocker indicated for the treatment of hypertension,to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Edarbi may be used, either alone or in combination with other antihypertensive agents. (1)-----------------------DOSAGE AND ADMINISTRATION--------------------The recommended dose in adults is 80 mg taken once daily. Consider a starting dose of 40 mg for patients who are treated with high doses of diuretics. (2.1)Edarbi may be administered with or without food. (2.1)Edarbi may be administered with other antihypertensive agents. (2.1) -------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 40 mg and 80 mg. (3)--------------------------CONTRAINDICATIONS---------------------------------- • Do not co-administer aliskiren with Edarbi in patients with diabetes. (4)-----------------------WARNINGS AND PRECAUTIONS-----------------------• Correct volume or salt depletion prior to administration of Edarbi.(5.2)• Monitor for worsening renal function in patients with renal impairment. (5.3)------------------------------ADVERSE REACTIONS------------------------------The most common adverse reaction in adults was diarrhea (2%). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-825-3327 or FDA at 1-800-FDA-1088 or /medwatch.-----------------------------DRUG INTERACTIONS-------------------------------- Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. (7)-----------------------USE IN SPECIFIC POPULATIONS----------------------- • Nursing Mothers: Discontinue nursing or drug. (8.3)• Geriatric Patients: Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. Nooverall difference in efficacy versus younger patients, but greater sensitivity of some older individuals cannot be ruled out. (8.5) • In patients with an activated renin-angiotensin system, as by volume- or salt-depletion, renin-angiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can causeexcessive hypotension. In susceptible patients, e.g., with renalartery stenosis, RAAS blockers can cause renal failure (5.2, 5.3). • Pediatrics: Safety and efficacy in children have not been established.See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labelingRevised: 7/2012FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: Fetal Toxicity1 INDICATIONSANDUSAGE2 DOSAGEANDADMINISTRATION2.1 Recommended Dose2.2 Handling Instructions2.3 Special Populations3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Fetal Toxicity5.2 Hypotension in Volume- or Salt-Depleted Patients5.3 Impaired Renal Function6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Clinical Laboratory Findings7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment 10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 General Information17.2 FDA-Approved Patient Labeling*Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNING: FETAL TOXICITY• When pregnancy is detected, discontinue Edarbi as soon as possible [see Warnings and Precautions (5.1).• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)].1. INDICATIONS AND USAGEEdarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Edarbi. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Edarbi may be used alone or in combination with other antihypertensive agents.2. DOSAGE AND ADMINISTRATION2.1 Recommended DoseThe recommended dose in adults is 80 mg taken orally once daily. Consider a starting dose of 40 mg for patients who are treated with high doses of diuretics.If blood pressure is not controlled with Edarbi alone, additional blood pressure reduction can be achieved by taking Edarbi with other antihypertensive agents.Edarbi may be taken with or without food [see Clinical Pharmacology (12.3)].2.2 Handling InstructionsDo not repackage Edarbi. Dispense and store Edarbi in its original container to protect Edarbi fromlight and moisture.2.3 Special PopulationsNo initial dose adjustment is recommended for elderly patients, patients with mild-to-severe renal impairment, end-stage renal disease, or mild-to-moderate hepatic dysfunction. Edarbi has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].3. DOSAGE FORMS AND STRENGTHSEdarbi is supplied as white to nearly white round tablets in the following dosage strengths:•40 mg tablets - debossed “ASL” on one side and “40” on the other•80 mg tablets - debossed “ASL” on one side and “80” on the other4 CONTRAINDICATIONS•Do not co-administer aliskiren with Edarbi in patients with diabetes. (4)5 WARNINGS AND PRECAUTIONS5.1 Fetal ToxicityUse of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Edarbi as soon as possible [see Use in Specific Populations (8.1)].5.2 Hypotension in Volume- or Salt-Depleted PatientsIn patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi. Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.5.3 Impaired Renal FunctionAs a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors andangiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbi [see Drug Interactions (7), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months; of these, 588 were treated for at least 1 year.Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4 % (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation,hypotension/orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo. Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of >0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below:Gastrointestinal Disorders: nauseaGeneral Disorders and Administration Site Conditions: asthenia, fatigueMusculoskeletal and Connective Tissue Disorders: muscle spasmNervous System Disorders: dizziness, dizziness posturalRespiratory, Thoracic and Mediastinal Disorders: cough6.2 Clinical Laboratory FindingsIn controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively. None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.7 DRUG INTERACTIONSNo clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications.Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors(COX-2 Inhibitors)In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy.The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.Dual Blockade of the Renin-Angiotensin System (RAS)Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Edarbi and other agents that affect the RAS.Do not coadminister aliskiren with Edarbi in patients with diabetes. Avoid use of aliskiren with Edarbi in patients with renal impairment (GFR <60 mL/min).8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category DUse of drugs that affect the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Edarbi as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Edarbi, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observeinfants with histories of in utero exposure to Edarbi for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].8.3 Nursing MothersIt is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric UseNeonates with a history of in utero exposure to Edarbi:If oliguria or hypotension occurs, support blood pressure and renal function. Exchange transfusionsor dialysis may be required.Safety and effectiveness in pediatric patients under 18 years of age have not been established.8.5 Geriatric UseNo dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].8.6 Renal ImpairmentDose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.8.7 Hepatic ImpairmentNo dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGELimited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patient's clinical status. Azilsartan is not dialyzable [see Clinical Pharmacology (12.3)].11 DESCRIPTIONEdarbi (azilsartan medoxomil), a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist.The drug substance used in the drug product formulation is the potassium salt of azilsartan medoxomil, also known by the US accepted name of azilsartan kamedoxomil and is chemically described as (5Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium salt.Its empirical formula is C 30H 23KN 4O 8 and its structural formula is:Azilsartan kamedoxomil is a white to nearly white powder with a molecular weight of 606.62. It is practically insoluble in water and freely soluble in methanol. Edarbi is available for oral use as tablets. The tablets have a characteristic odor. Each Edarbi tabletcontains 42.68 or 85.36 mg of azilsartan kamedoxomil, which is equivalent to containing 40 mg or 80 mg respectively, of azilsartan medoxomil and the following inactive ingredients: mannitol, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionAngiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes(ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, witheffects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiacstimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosteronesecreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore,independent of the pathway for angiotensin II synthesis.An AT2 receptor is also found in many tissues, but this receptor is not known to be associated withcardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis ofangiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors alsoinhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure. 12.2 PharmacodynamicsAzilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to 32 mg azilsartan medoxomil inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasmaangiotensin I and II concentrations and plasma renin activity increased while plasmaaldosterone concentrations decreased after single and repeated administration of Edarbi tohealthy subjects; no clinically significant effects on serum potassium or sodium wereobserved.Effect on Cardiac Repolarization: A thorough QT/QTc study was conducted to assess the potential of azilsartan to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of Edarbi.12.3 PharmacokineticsAbsorption: Azilsartan medoxomil is hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations(C max) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.Distribution: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.Metabolism and Elimination: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and MII do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9.Following an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.Special PopulationsThe effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartanmedoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD.Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations inthe Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrationswere observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. Themajor human metabolite, M-II was also positive in this assay during a 24 hr assay withoutmetabolic activation.Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay. Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day.13.2 Animal Toxicology and/or PharmacologyReproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3000 mg MII/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.14 CLINICAL STUDIESThe antihypertensive effects of Edarbi have been demonstrated in a total of 7 double-blind, randomized studies, which included 5 placebo-controlled and 4 active comparator-controlled studies (not mutually exclusive). The studies ranged from 6 weeks to 6 months in duration, at doses ranging from 20 mg to 80 mg once daily. A total of 5941 patients (3672 given Edarbi, 801 given placebo, and 1468 given active comparator) with mild, moderate or severe hypertension were studied. Overall, 51% of patients were male and 26% were 65 years or older; 67% were white and 19% were black.。
阿哌沙班说明书
核准日期：2013年1月22日修改日子期：2013年4月18日阿哌沙班片说明书请仔细阅读说明书并在医师指导下使用【药品名称】通用名称：阿哌沙班片商品名称：艾乐妥（Eliquis)英文名称：Apixaban Tablets汉语拼音：Apaishaban Pian【成份】本品活性成份：阿哌沙班化学名称：1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基）苯基]-4,5,6,7-四氢-1H-吡唑[3,4-c]吡啶-3-甲酰胺化学结构式：分子式：。
C25H25N5O4分子量：【性状】本品为黄色薄膜衣片，除去包衣后，显白色至类白色。
【适应症】用于髋关节或膝关节择期置换术的成年患者，预防静脉血栓栓塞事件（VTE）.【规格】?【用法用量】本品推荐剂量为每次,每日两次口服，以水送服，不受进餐影响。
首次服药时间应在手术后12?24小时之间。
在这个时间窗里决定服药具体时间点时，医生需同时考虑早期抗凝预防VTE的潜在益处和手术后出血的风险。
对于接受髋关节置换术的患者：推荐疗程为32到38天。
对于接受膝关节置换术的患者：推荐疗程为10到14天。
如果发生一次漏服，患者应立即服用本品，随后继续每日服药两次。
由注射用抗凝药转换为本品治疗时，可从下次给药时间点开始(反Z亦然)（参见【药物相互作用】）。
在一项Ⅱ期临床试验和三项Ⅲ期临床试验中评价了阿暇沙班的安全性，这些试验中共有5924例接受下肢骨科大手术（择期髋关节置换术或膝关节置换术）的患者，服用阿哌沙班，每日两次，最长接受38天的治疗。
接受每日两次阿哌沙班治疗的患者中，共计有11%发生了不良反应。
与其它抗凝药物一样，当存在相关的危险因素，如易导致出血的器官损伤时，阿哌沙班治疗过程中可能出现出血。
常见的不良反应包括贫血，出血，挫伤及恶心。
应结合手术背景对不良反应作出解释。
在下面的表1中，按照系统器官分类（MedDRA)和发生频率列出了上述II期、Ⅲ期临床试验中的不良反应。
抗高血压药物阿齐沙坦酯
抗高血压药物阿齐沙坦酯邢爱敏【期刊名称】《药学进展》【年(卷),期】2011(035)005【总页数】2页(P235-236)【关键词】azilsartan medoxomil;血管紧张素Ⅱ受体阻滞剂;高血压【作者】邢爱敏【作者单位】【正文语种】中文【中图分类】R972.4日本武田制药公司研发的血管紧张素Ⅱ受体阻滞剂阿齐沙坦酯(azilsartanmedoxomil，商品名:Edarbi)于2011年2月25日获美国FDA批准用于成人高血压的治疗。
该药目前有80 mg和40 mg两种规格，推荐剂量为80 mg，每日1次口服使用。
Ⅲ期临床试验显示，与FDA批准上市的其他两种抗高血压药物缬沙坦(商品名:Diovan)和奥美沙坦(商品名: Benicar)相比，阿齐沙坦酯在24小时内的降压效果更好。
但其产品标签上列有一则黑框警告，称:由于在孕期第2或第3个月时服用该药可使胎儿发育受到影响甚至导致其死亡，故孕妇禁用。
本品化学结构式:CAS:863031－21－4作用机制血管紧张素Ⅱ由血管紧张素Ⅰ经血管紧张素转换酶(ACE)催化产生，为肾素－血管紧张素系统的主要升压因子，可导致血管收缩，刺激醛固酮的合成、释放及肾脏对钠离子的重吸收。
阿齐沙坦酯在口服吸收后水解为阿齐沙坦，后者在血管平滑肌和肾上腺等多种组织中，可通过选择性阻断血管紧张素Ⅱ与AT1受体的结合而阻断血管紧张素Ⅱ的血管收缩和醛固酮分泌作用，故其作用不依赖于血管紧张素Ⅱ合成通路。
阿齐沙坦对AT1受体的亲和力是对AT2受体的1万倍以上。
由于其并不抑制ACE，故不会影响缓激肽水平，也不会结合并阻断其他与血管调节作用相关的受体或离子通道。
药动学阿齐沙坦酯口服后即水解为活性代谢物阿齐沙坦，故未能在血浆中检测到其原药。
在阿齐沙坦单剂量或多剂量(20～320 mg)给药后，AUC呈剂量依赖性，阿齐沙坦的绝对生物利用度约为60%，达峰时间为1.5～3 h，食物不影响其生物利用度;其在体内的分布容积约为16 L。
阿哌沙班说明书
核准日期：2013年1月22日修改日子期：2013年4月18日阿哌沙班片说明书请仔细阅读说明书并在医师指导下使用【药品名称】通用名称：阿哌沙班片商品名称：艾乐妥（Eliquis)英文名称：Apixaban Tablets汉语拼音：Apaishaban Pian【成份】本品活性成份：阿哌沙班化学名称：1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基）苯基]-4,5,6,7-四氢-1H-吡唑[3,4-c]吡啶-3-甲酰胺化学结构式：分子式：。
C25H25N5O4分子量：【性状】本品为黄色薄膜衣片，除去包衣后，显白色至类白色。
【适应症】用于髋关节或膝关节择期置换术的成年患者，预防静脉血栓栓塞事件（VTE）.【规格】«【用法用量】本品推荐剂量为每次,每日两次口服，以水送服，不受进餐影响。
首次服药时间应在手术后12〜24小时之间。
在这个时间窗里决定服药具体时间点时，医生需同时考虑早期抗凝预防VTE的潜在益处和手术后出血的风险。
对于接受髋关节置换术的患者：推荐疗程为32到38天。
对于接受膝关节置换术的患者：推荐疗程为10到14天。
如果发生一次漏服，患者应立即服用本品，随后继续每日服药两次。
由注射用抗凝药转换为本品治疗时，可从下次给药时间点开始(反Z亦然)（参见【药物相互作用】）。
在一项Ⅱ期临床试验和三项Ⅲ期临床试验中评价了阿暇沙班的安全性，这些试验中共有5924例接受下肢骨科大手术（择期髋关节置换术或膝关节置换术）的患者，服用阿哌沙班，每日两次，最长接受38天的治疗。
接受每日两次阿哌沙班治疗的患者中，共计有11%发生了不良反应。
与其它抗凝药物一样，当存在相关的危险因素，如易导致出血的器官损伤时，阿哌沙班治疗过程中可能出现出血。
常见的不良反应包括贫血，出血，挫伤及恶心。
应结合手术背景对不良反应作出解释。
在下面的表1中，按照系统器官分类（MedDRA)和发生频率列出了上述II期、Ⅲ期临床试验中的不良反应。
阿齐沙坦酯钾盐结构式
阿齐沙坦酯钾盐结构式
阿齐沙坦酯钾盐是一种用于治疗高血压的药物，其结构式如下所示：
分子式：C24H28N2O4·K·H2O
阿齐沙坦酯钾盐的分子结构由一个疏水性芳环和一系列极性基团组成，使其具有独特的药理作用。
其结构中的芳环部分可以与血管紧张素II受体结合，从而阻断血管紧张素II的作用，降低血压。
阿齐沙坦酯钾盐的制备方法主要有两种：一是通过阿齐沙坦与钾盐酸反应，二是通过阿齐沙坦与钾卤素反应。
这两种方法都需要在特定的反应条件下进行，以保证产物的纯度和质量。
阿齐沙坦酯钾盐具有明显的降压效果，可有效降低高血压患者的血压，且与其他降压药物相比，具有较少的副作用。
此外，阿齐沙坦酯钾盐还可用于治疗慢性肾病，能够减少蛋白尿，保护肾脏功能。
总的来说，阿齐沙坦酯钾盐的结构和药理作用使其成为一种重要的治疗高血压和慢性肾病的药物。