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英文名：azilsartan
中文名：阿齐沙坦酯片
藥理類別：血管收縮素II接受器拮抗
藥理類別：azilsartan medoxomil
孕婦用藥分級 D 級：
在對照的人體研究試驗中顯示該藥物對胚胎有不良影響，若此藥能帶來之效益遠超過其它藥物的使用，因此即使在其危險性的存在下，仍可接受此藥物用於懷孕婦女上。
結構式 
(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 
UpToDate UpToDate 連結 
药理作用
azilsartan medoxomil 是一种口服有效的前驱药，会快速转换成活性部分 azilsartan，azilsartan 会选择性地阻断血管收缩素 II 与多种组织裡的 AT1 受体结合，而拮抗其作用。
血管收缩素 II 是肾素 － 血管收缩素系统中最主要的升压剂，其作用包含血管收缩、刺激醛固酮的合成和释放、刺激心脏，以及钠在肾脏的再吸收。
阻断 AT1 受体，可抑制血管收缩素II对肾素分泌的负回馈调节作用，但增加的血浆肾素活性与血管收缩素 II 血中浓度，并无法抵消azilsartan的降血压作用。
适应症
治疗高血压。
用法用量
1. 建议起始剂量为每天一次，每次 20-40 mg。 须依病患臨床反应调整剂量，最大剂量为每天一次、每次 80 mg。
2. 易得平锭为口服使用，可与食物或空腹服用。
3. 2 周时可明显見到接近最大程度的降压效果，4周时可达到最大效果。
药动力学
口服给药后，在肠胃道的吸收过程中，azilsartan medoxomil 会迅速被水解为活性部分。 根据体外试验，carboxymethylenebutenolidase与肠道和肝脏裡的水解作用有关。 此外，azilsartan medoxomil 水解成 azilsartan 的过程涉及血浆酯酶。
吸收
根据 azilsartan 的血浆浓度，口服给予 azilsartan medoxomil 之后的绝对生体可用率估计值大约为 60%。 口服给予 azilsartan medoxomil 之后，大约 1.5 至 3 小时以内可到达 azilsartan 之最高血浆浓度(Cmax)。 食物不会影响 azilsartan 的生体可用率。
分布
azilsartan之分布体积大约为16L。 azilsartan极易与血浆蛋白质结合(>99%)，主要是血清白蛋白。 即使在远高于建议剂量所达到之azilsartan 血浆浓度，蛋白质结合率仍维持一定。
生物转换
azilsartan 有 2 种主要代谢物。 血浆内的主要代谢物是经由 o-去烷基反应形成，称为代谢物 M-II，次要代谢物则是由去羧基反应形成，称为代谢物 M-I。 人体体内主要代谢物与次要代谢物之全身性暴露量，分别约为 azilsartan 的 50% 与不到 1%。 M-I 与 M-II 并不贡献 Edarbi ®之药理活性。 azilsartan 主要由 CYP2C9 代谢。
排除
口服一剂 14C 标记之 azilsartan medoxomil 后，大约 55% 的放射活性排入粪便，约 42% 排入尿液，15% 的剂量以 azilsartan 的形式经尿液排出。 azilsartan 之排除半衰期约为 11 小时，肾脏廓清率约为 2.3mL/min。 采用每日一次的给药方式。 azilsartan 的血中浓度可在 5 天内达到稳定狀态，且不会蓄积在血浆内。
副作用
晕眩、腹泻、周边水肿。
交互作用
不建议并用锂盐并用
锂盐
与血管收缩素转化酶抑制剂(angiotensin-converting enzyme inhibitors)，曾有锂盐血清浓度与毒性可逆增加的报告。 血管收缩素II受体拮抗剂可能会有類似的作用。 由于缺乏 azilsartan medoxomil 并用锂盐的经验，故不建议并用。 若必须并用，建议小心监测锂盐的血清浓度。
需小心并用的组合
非類固醇類消炎药 (non-steroidal anti-inflammatory drug, NSAID)，包含选择性 COX-2 抑制剂、乙酰水杨酸（每日 > 3 g）与非选择性的 NSAID
血管收缩素II受体拮抗剂并用 NSAID(即选择性 COX-2 抑制剂、乙酰水杨酸［每日 > 3 g］与非选择性的 NSAID）时，降压效果可能会减弱。 此外，并用血管收缩素II受体拮抗剂与 NSAID 可能会增加肾功能惡化的风险，以及使血清钾浓度上升。 因此，建议在治療一开始，就要给予足够的水份补充与肾功能监测。
保钾利尿剂、钾补充剂、含钾的食盐替代品或其他可能会增加血钾浓度的药物
并用保钾利尿剂、钾补充剂、含钾的食盐替代品，或其他可能会增加血钾浓度的药物（例如肝素），可能会使血钾浓度上升。 应适时监测血清钾浓度。
肾素-血管收缩素系统(Renin-Angiotensin system)之双重阻断
相较于单一療法，本品与血管收缩素受体阻断剂(ARB)、血管收缩素转化酶抑制剂(ACEI)或aliskiren合并使用时所造成的“肾素-血管收缩素系统之双重阻断”，会导致出现低血压、高血钾及肾功能改变(包括急性肾衰竭) 的风险升高，因此，应针对同时使用本品与“其他会影响肾素-血管收缩素系统之药物”的患者监测血压、肾功能及电解质。
Aliskiren与本品不可合并使用于糖尿病患者。 此外，aliskiren与本品应避免合并使用在肾功能不全患者(GFR<60mL/min)。
临床试验数据显示，相较于使用单一作用于RAAS之药品，合并使用ACEIs、ARBs或含aliskiren成分药品来双重阻断RAAS，不良反应【例如：低血压、高钾血症及肾功能下降（包括急性肾衰竭）】之发生率较高。
禁忌
1. 对其活性物质或任何赋形剂过敏。
2. 全部孕期中妇女。
3. Aliskiren与本品不可合并使用于糖尿病患者。
4. 合并使用本品及含aliskiren成分药品于糖尿病患或肾功能不全患者 (GFR < 60 ml/min/1.73 m2)。
注意事项
根据其药效学特性，我们预期 azilsartan medoxomil 对驾驶及机械操作的能力，几乎没有影响。 但服用任何降压药物，皆应考虑到偶尔会有暈眩或疲倦的情况。
警语
双重阻断肾素－血管升压素－醛固酮系统（renin-angiotensin-aldosterone system, RAAS）：有证据显示，合并使用ACEIs、ARBs或含aliskiren成分药品会增加低血压、 高钾血症及肾功能下降（包括急性肾衰竭）之风险，故不建议合并使用ACEIs、ARBs或含aliskiren成分药品来双重阻断RAAS，若确有必要使用双重阻断治疗，应密切监测患者之肾功能、电解质及血压。 ACEIs及ARBs不应合并使用于糖尿病肾病变患者。
过量处理
症状
根据药理学特性，过量的主要表征可能是低血压和暈眩之症狀。 在健康受试者的对照臨床试验裡，曾使用每天一次、每次高达 320mg易得平锭之剂量，给予7天，耐受性良好。
处理方式
若出现低血压症狀，应给予支持性治療，并监测生命征象。 azilsartan不会经由透析排除。
药品保存方式
30℃以下。 请存放于原包装内，以避免光照及潮湿。
上市及在研情况
日本武田公司原研， 2012年4月在日本上市，商品名为“Azilva”,规格为20mg和40mg。目前没有在其他国家上市。阿齐沙坦酯为阿齐沙坦的前药，目前也已经在欧美上市，商品名为Edarbi 。
药理作用
阿齐沙坦选择性阻断血管紧张素Ⅱ与AT1 受体结合（阿齐沙坦对AT1受体的亲和力高出AT2受体的10000倍以上），从而阻断血管紧张素Ⅱ引起的血管收缩，醛固酮分泌等升血压效应。其作用不依赖于血管紧张素Ⅱ合成途径，故避免了ACEI对缓激肽水平的影响，几乎没有干咳等副作用。阻断血管紧张素Ⅱ受体可抑制血管紧张素Ⅱ对肾素分泌的负反馈调节，但所引起的血浆肾素活性及血管紧张素Ⅱ水平的增高，并不足以抵消阿齐沙坦的降压作用。

Edarbi 
(azilsartan medoxomil) Tablets

WARNING

FETAL TOXICITY

· When pregnancy is detected, discontinue Edarbi as soon as possible [see WARNINGS AND PRECAUTIONS].

· Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see WARNINGS AND PRECAUTIONS].

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 C30H23KN4O8and 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 tablet contains 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.

For Consumers

WHAT ARE THE POSSIBLE SIDE EFFECTS OF AZILSARTAN (EDARBI)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

· painful or difficult urination;

· little or no urinating;

· feeling tired or short of breath;

· a light-headed feeling, like you might pass out; or

· swelling in your feet or ankles.

Common side effects may include:

· diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at...

Read All Potential Side Effects and See Pictures of Edarbi »

Indications & Dosage

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

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].

Handling Instructions

Do not repackage Edarbi. Dispense and store Edarbi in its original container to protect Edarbi from light and moisture.

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].

HOW SUPPLIED

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

Storage And Handling

Edarbi tablets are unscored and white to nearly white, debossed with “ASL” on one side and “40” or “80” on the other.

Storage

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.

Manufactured by: Osaka, Japan. Manufactured for: Atlanta, GA 30328. Revised: Oct 2016

Side Effects & Drug Interactions

SIDE EFFECTS

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

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.

Postmarketing Experience

The following adverse reactions have been identified during the postmarketing use of EDARBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

· Nausea

· Muscle spasms

· Rash

· Pruritus

· Angioedema

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, withangiotensin 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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. 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).

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor agonists. Monitor serum lithium levels during concomitant use.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. Resultingoligohydramnios 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].

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.

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, Use in Specific Populations, and CLINICAL PHARMACOLOGY].

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.

Patient Counseling Information

See FDA-approved patient labeling.

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and two-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/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 two-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 seven (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 in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were 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. The major human metabolite, M-II was also positive in this assay during a 24-hour assay without metabolic 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.

Use In Specific Populations

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].

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.

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.

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].

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.

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].

Overdosage & Contraindications

OVERDOSE

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].

CONTRAINDICATIONS

Do not coadminister aliskiren-containing products with Edarbi in patients with diabetes [see DRUG INTERACTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Angiotensin 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, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan medoxomil is an orally administered prodrug that is rapidly converted by esterases during absorption to the active moiety, azilsartan. Azilsartan blocks the vasoconstrictor and aldosterone-secreting 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 with cardiovascular 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 of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit 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.

Pharmacodynamics

Azilsartan 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. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of Edarbi to healthy subjects; no clinically significant effects on serum potassium or sodium were observed.

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.

Pharmacokinetics

Absorption

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 (Cmax) 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 16 L. 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 M-II 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 five days, and no accumulation in plasma occurs with repeated once-daily dosing.

Special Populations

The 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 azilsartan

Animal Toxicology And/Or Pharmacology

Reproductive 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 M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.

Clinical Studies

The antihypertensive effects of Edarbi have been demonstrated in a total of seven double-blind, randomized studies, which included five placebo-controlled and four active comparator-controlled studies (not mutually exclusive). The studies ranged from six weeks to six 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.

Two 6-week, randomized, double-blind studies compared the effect on blood pressure of Edarbi at doses of 40 mg and 80 mg, with placebo and with active comparators. Blood pressure reductions compared to placebo based on clinic blood pressure measurements at trough and 24-hour mean blood pressure by ambulatory blood pressure monitoring (ABPM) are shown in Table 1 for both studies. Edarbi, 80 mg, was statistically superior to placebo and active comparators for both clinic and 24-hour mean blood pressure measurements.

Table 1: Placebo Corrected Mean Change from Baseline in Systolic/Diastolic Blood Pressure at 6 Weeks (mm Hg)

In a study comparing Edarbi to valsartan over 24 weeks, similar results were observed.

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

Other studies showed similar 24-hour ambulatory blood pressure profiles.

Edarbi has a sustained and consistent antihypertensive effect during long-term treatment, as shown in a study that randomized patients to placebo or continued Edarbi after 26 weeks. No rebound effect was observed following the abrupt cessation of Edarbi therapy.

Edarbi was effective in reducing blood pressure regardless of the age, gender, or race of patients, but the effect, as monotherapy, was smaller, approximately half, in black patients, who tend to have low renin levels. This has been generally true for other angiotensin II antagonists and ACE inhibitors.

Edarbi has about its usual blood pressure lowering effect size when added to a calcium channel blocker(amlodipine) or a thiazide-type diuretic (chlorthalidone).

There are no trials of Edarbi demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

Medication Guide

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.

What is the most important information I should know about Edarbi?

· Edarbi can cause harm or death to your unborn baby.

· Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.

· If you become pregnant while taking Edarbi, tell your doctor right away. Your doctor may switch you to a different medicine to treat your high blood pressure.

What is Edarbi?

Edarbi is a prescription medicine called an angiotensin II receptor blocker (ARB) used to treat high blood pressure (hypertension) in adults.

Your doctor may prescribe other medicines for you to take along with Edarbi to treat your high blood pressure.

It is not known if Edarbi is safe and effective in children under 18 years of age.

What should I tell my doctor before taking Edarbi?

Before you take Edarbi, tell your doctor if you:

· have been told that you have abnormal body salt (electrolytes) levels in your blood

· are pregnant or plan to become pregnant. See “What is the most important information I should know about Edarbi?”

· are breastfeeding or plan to breastfeed. It is not known if Edarbi passes into your breast milk. You and your doctor should decide if you will take Edarbi or breastfeed. You should not do both. Talk with your doctor about the best way to feed your baby if you take Edarbi.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Especially tell your doctor if you take:

· other medicines used to treat your high blood pressure or heart problem

· water pills (diuretic)

Ask your doctor if you are not sure if you are taking a medicine listed above.

Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine.

How should I take Edarbi?

· Your doctor will tell you how much Edarbi to take and when to take it. Follow his/her instructions.

· Edarbi can be taken with or without food.

· If you take too much Edarbi, call your doctor or go to the nearest hospital emergency room right away.

What are the possible side effects of Edarbi?

Edarbi may cause side effects, including:

· Harm or death to your unborn fetus if taken in the second or third trimester. See “What is the most important information I should know about Edarbi?”

· Low blood pressure (hypotension) and dizziness is most likely to happen if you also:

o take water pills (diuretics)

o are on a low-salt diet

o take other medicines that affect your blood pressure

o get sick with vomiting or diarrhea

o do not drink enough fluids

If you feel faint or dizzy, lie down and call your doctor right away.

These are not all the possible side effects with Edarbi. Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Edarbi?

· Store Edarbi at 59°F to 86°F (15°C to 30°C).

· Store Edarbi in the original container that you received from your pharmacist or doctor. Do not put Edarbi into a different container.

· Keep Edarbi in a tightly closed container, and keep Edarbi out of the light.

Keep Edarbi and all medicines out of the reach of children.

General information about Edarbi.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not give Edarbi to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Edarbi. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Edarbi that is written for health professionals.

For more information, go to www.edarbi.com or call 1-866-516-4950.

What is high blood pressure (hypertension)?

Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too great.

High blood pressure makes the heart work harder to pump blood through the body and causes damage to the blood vessels. Edarbi tablets can help your blood vessels relax so your blood pressure is lower. Medicines that lower your blood pressure may lower your chance of having a stroke or heart attack.

What are the ingredients in Edarbi?

Active ingredient: azilsartan medoxomil

Inactive ingredients: mannitol, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.