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2011年2月25日，美国食品药品监督管理局(FDA)批准了Edarbi片(有效成分azilsartan medoxomil)用于治疗成人高血压。临床研究显示相对于其他获得FDA批准的降压药如：Diovan (valsartan) 或Benicar (olmesartan)相比，Edarbi能更有效的全天候降低血压。
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 coadminister 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 www.fda.gov/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. No overall 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 cause excessive hypotension. In susceptible patients, e.g., with renal artery 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. Revised: 3/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE Edarbi 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 ADMINISTRATION 2.1 Recommended Dose The 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 Instructions Do not repackage Edarbi. Dispense and store Edarbi in its original container to protect Edarbi from light and moisture. 2.3 Special Populations No 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 STRENGTHS Edarbi 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 other 4 CONTRAINDICATIONS Do not coadminister aliskiren with Edarbi in patients with diabetes [see Drug Interactions (7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Fetal Toxicity Use 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 Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., 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 Function As 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 and angiotensin 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 REACTIONS 6.1 Clinical Trials Experience Because 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 six months; of these, 588 were treated for at least one 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: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic, and Mediastinal Disorders: cough 6.2 Clinical Laboratory Findings In 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 INTERACTIONS No 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, coadministration 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 POPULATIONS 8.1 Pregnancy Pregnancy Category D Use 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 renin-angiotensin 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 observe infants with histories of in utero exposure to Edarbi for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)]. 8.3 Nursing Mothers It 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 Use Neonates with a history of in utero exposure to Edarbi If oliguria or hypotension occurs, support blood pressure and renal function. Exchange transfusions or dialysis may be required. Safety and effectiveness in pediatric patients under 18 years of age have not been established. 8.5 Geriatric Use No 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 Impairment Dose 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 Impairment No 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 OVERDOSAGE Limited 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 seven 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 DESCRIPTION Edarbi (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 (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium salt. Its empirical formula is C30H23KN4O8 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.
Most of the antihypertensive effect occurs within the first two weeks of dosing. Figure 2 shows the 24-hour ambulatory systolic and diastolic blood pressure profiles at endpoint. Figure 2. Mean Ambulatory Blood Pressure at 6 Weeks by Dose and Hour
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture and light. Do not repackage; dispense and store in original container. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (17.2). 17.1 General Information Pregnancy Tell female patients of childbearing potential about the consequences of exposure to Edarbi during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible. 17.2 FDA-Approved Patient Labeling Patient Information Edarbi (eh-DAR-bee) (azilsartan medoxomil) Tablets Read this Patient Information leaflet before you start taking Edarbi and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=75b16bfc-38c1-4133-bd7d-13258d54edec 阿齐沙坦特点 阿齐沙坦作为新一代双重功能ARBs，不仅拮抗血管紧张素II的1型受体（AT1受体），还可能通过多种机制降低心血管疾病及糖尿病的风险。临床试验证明阿齐沙坦具有较好疗效，且不良反应发生率较低，依从性较好的特点。 阿齐沙坦的前药阿齐沙坦酯（azilsartan medoxomil）已经在美国及欧洲等国家和地区上市销售，通过动态血压监测（ABPM）测定，阿齐沙坦酯与两种常用ARB类处方药奥美沙坦酯（olmesartan medoxomil）（40 mg/天）和缬沙坦（valsartan）（320mg/天）最高批准剂量相比，EDARBI（80 mg/天）在降低临床收缩压（SBP）和24小时平均SBP方面有显著性统计学优势。 阿齐沙坦作为新一代的血管紧缩素II受体抑制剂，与血管紧张素转化酶抑制剂（ACEI）类降压药物相比，单独或联合用药均具有平稳降压、不会引起干咳的优点，平稳持久降血压作用。尽管已上市多个ARBs，但对于许多患者，仅抑制肾素-醛固酮系统（RAS）活性并不足以控制血压和降低心血管疾病及糖尿病的风险，而阿齐沙坦还能通过部分激活过氧化物酶体增殖物激活受体-γ（PPAR-γ）而对糖尿病患者产生潜在的保护作用，相关临床试验结果表明其临床效果要优于现在临床广泛使用的奥美沙坦酯和缬沙坦。 在一项为期24周的试验中，982例患者随机接受阿齐沙坦酯40mg/d（n=327）、80mg/d（n=329）或缬沙坦320mg/d（n=326）治疗。结果显示，与基线相比，阿齐沙坦酯两种剂量分别使主要的观察终点24h动态血压监控的平均收缩压分别降低了14.9mmHg和15.3mmHg；同样，次要终点临床谷血压测定，两种剂量的阿齐沙坦酯分别使收缩压降低了14.9mmHg和16.9mmHg；降压作用均明显强于320mg/d缬沙坦（分别为：11.3mmHg和11.6mmHg）。 | ||||||||||||||||||||||||||||||||||||||||||||||
