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Edarbi

Generic Name: Azilsartan Kamedoxomil
Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester-1-[[2′-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1′-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid, potassium salt
Molecular Formula: C30H23KN4O8
CAS Number: 863031-24-7

Medically reviewed on Dec 3, 2018

Warning

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 25 26 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue as soon as possible.1 25

Introduction

Angiotensin II receptor (AT1) antagonist (i.e., angiotensin II receptor blocker, ARB).1 4

Uses for Edarbi

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 3 4 5 6 1200

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 1200 1213

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).501 502 503 504 515 1200 1201

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.)

Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.1200 However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BPs to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.1200 These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.1200 1202 1210

Previous hypertension guidelines generally have based target BP goals on age and comorbidities.501 504 536 Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients501 504 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the current ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.1222 1223 1224 1229

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.1200 1220 1229

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.1200 1207 ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.1200

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).1200

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.1200

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.1200

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.1200 Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.1200

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.501 504 1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.1200

Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in hypertensive patients with diabetes mellitus or CKD; angiotensin II receptor antagonists also may be preferred, as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or post-MI.501 502 504 523 524 527 534 535 536 543 1200 1214 1215

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.12 13 15 16 17 535 536 1232

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure.524 528 800

Because of their established benefits, ACE inhibitors have been the preferred drugs for inhibition of the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); 524 however, some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.701 702 703 800

Angiotensin II receptor antagonists considered reasonable alternative therapy for those patients in whom an ACE inhibitor or ARNI is inappropriate.524 800 (See Sensitivity Reactions under Cautions.)

No additional therapeutic benefit when angiotensin II receptor antagonist used in combination with an ACE inhibitor.1 119

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800

Edarbi Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.1200

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.1216

  • If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic).1200 1216 Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.1200 1216 1220

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Must be dispensed and stored in the original manufacturer’s container.1

Dosage

Available as azilsartan kamedoxomil (the potassium salt of azilsartan medoxomil); dosage expressed in terms of azilsartan medoxomil.1

Adults

Hypertension
Oral

Usual dosage: Manufacturer states 80 mg once daily.1 Some experts state 40–80 mg once daily.1200 Consider initial dosage of 40 mg once daily in patients receiving high dosages of diuretics.1

Special Populations

Hepatic Impairment

No adjustment of initial azilsartan medoxomil dosage necessary in patients with mild to moderate hepatic impairment.1 Not studied in patients with severe hepatic impairment.1

Renal Impairment

No adjustment of initial azilsartan medoxomil dosage necessary in patients with mild to severe renal impairment or end-stage renal disease.1

Geriatric Patients

No adjustment of initial azilsartan medoxomil dosage is necessary.1

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of azilsartan therapy or initiate therapy using lower initial dosage (40 mg once daily).1

Cautions for Edarbi

Contraindications

  • Concomitant use of aliskiren and azilsartan in patients with diabetes mellitus.1 550 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when drugs that act directly on the renin-angiotensin system (e.g., angiotensin II receptor antagonists, ACE inhibitors) are used during the second and third trimesters of pregnancy.1 25 Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.1 ACE inhibitors also reported to increase the risk of major congenital malformations when administered during the first trimester of pregnancy.25 26 Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.1

Discontinue azilsartan as soon as possible when pregnancy is detected, unless continued use is considered life-saving.1 25 26 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.1 27

Sensitivity Reactions

Angioedema, pruritus, and rash reported during postmarketing experience.1

Other Warnings and Precautions

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics).1 (See Volume- and/or Salt-depleted Patients under Dosage and Administration.)

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized (e.g., with volume expansion).1

Malignancies

In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis found a modest but statistically significant increase in risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist compared with control.120 121 123 126 However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk.126 127 128 129 Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.126

Renal Effects

Possible oliguria, progressive azotemia and, rarely, acute renal failure and/or death in patients with severe heart failure, renal artery stenosis, or volume depletion.1

Increases in BUN and SCr possible in patients with renal artery stenosis.1

Specific Populations

Pregnancy

Category D.1

Can cause fetal and neonatal morbidity and death when administered to a pregnant woman.1 (See Boxed Warning.)

Lactation

Azilsartan is distributed into milk in rats; not known whether azilsartan is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Neonates with history of in utero exposure to azilsartan: If oliguria or hypotension occurs, support BP and renal function; exchange transfusions or dialysis may be required.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Safety and efficacy of azilsartan not established in pediatric patients.1

Geriatric Use

Increased incidence of elevated SCr in patients ≥75 years of age.1 No other differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Data lacking in patients with severe hepatic impairment.1

Renal Impairment

Increased incidence of abnormally high SCr in patients with moderate to severe renal impairment.1

Deterioration of renal function may occur.1 (See Renal Effects under Cautions.)

Black Patients

BP reduction with azilsartan monotherapy decreased by about 50% in black patients compared with patients of other races.1 (See Hypertension under Uses.)

Common Adverse Effects

Diarrhea;1 3 less common adverse effects include hypotension/orthostatic hypotension,1 nausea,1 asthenia,1 fatigue,1 3 5 muscle spasm,1 dizziness,1 3 4 5 postural dizziness,1 cough.1

Interactions for Edarbi

Metabolized principally by CYP2C9.1

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Increased risk of renal impairment, hyperkalemia, and hypotension1

Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly1

Aliskiren

Increased risk of renal impairment, hyperkalemia, and hypotension1 550

Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly1 550

Concomitant use contraindicated in patients with diabetes mellitus1 550

Avoid concomitant use in patients with GFR <60 mL/minute1 550

Amlodipine

Pharmacokinetic interactions unlikely1

Angiotensin II receptor antagonists

Increased risk of renal impairment, hyperkalemia, and hypotension1

Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly1

Antacids

Pharmacokinetic interactions unlikely1

Chlorthalidone

Pharmacokinetic interactions unlikely1

Greater reversible increases in SCr possible1

Digoxin

Pharmacokinetic interactions unlikely1

Diuretics, potassium-sparing

Possible increase in serum potassium concentrations9

Avoid concomitant administration9

Fluconazole

Pharmacokinetic interactions unlikely1

Glyburide

Pharmacokinetic interactions unlikely1

Hydrochlorothiazide

Greater reversible increases in SCr possible1

Ketoconazole

Pharmacokinetic interactions unlikely1

Lithium

Increased serum lithium concentrations and lithium toxicity reported with concomitant angiotensin II receptor antagonist therapy1

Monitor serum lithium concentrations during concomitant therapy1

Metformin

Pharmacokinetic interactions unlikely1

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors

Possible deterioration of renal function, including possible acute renal failure, in patients who are geriatric, volume-depleted, or have compromised renal function; effects usually reversible1

Possible attenuation of azilsartan antihypertensive effect1

Periodically monitor renal function1

Pioglitazone

Pharmacokinetic interactions unlikely1

Potassium supplements and potassium-containing salt substitutes

Possible increase in serum potassium concentrations9

Avoid concomitant administration9

Warfarin

Pharmacokinetic interactions unlikely1

Edarbi Pharmacokinetics

Absorption

Bioavailability

Azilsartan medoxomil (prodrug) is rapidly and completely hydrolyzed to azilsartan during absorption in the GI tract.1

Absolute bioavailability of azilsartan is about 60%.1

Peak plasma azilsartan concentration generally reached 1.5–3 hours following oral administration.1

Increases in AUC are dose proportional following single or multiple doses of azilsartan medoxomil in the range of 20–320 mg.1

Steady-state concentrations of azilsartan are achieved within 5 days.1

Onset

Most of the antihypertensive effect of azilsartan occurs within 2 weeks.1

Food

Food does not affect bioavailability of azilsartan.1

Special Populations

Modest increases in peak plasma azilsartan concentration and AUC reported in geriatric patients and in patients with mild to severe renal impairment or mild to moderate hepatic impairment; no dosage adjustment required.1 Not studied in patients with severe hepatic impairment.1

Distribution

Extent

Azilsartan crosses the placenta and is distributed in the fetus in rats.1

A minimal amount of azilsartan-associated radioactivity crosses the blood-brain barrier in rats.1

Azilsartan is distributed into milk in rats; not known whether azilsartan is distributed into human milk.1

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Azilsartan medoxomil undergoes rapid and complete hydrolysis to azilsartan.1

Azilsartan is metabolized primarily by CYP2C9.1

Azilsartan is metabolized to 2 primary metabolites, both of which are inactive; metabolite M-II (the major metabolite) is formed by O-dealkylation, and metabolite M-I (the minor metabolite) is formed by decarboxylation.1

Systemic exposures to M-II and M-I are approximately 50% and <1%, respectively, that of azilsartan.1

Elimination Route

Radiolabeled azilsartan medoxomil is eliminated mainly in feces (55%) and urine (42%, with 15% as azilsartan).1

Half-life

Approximately 11 hours.1

Stability

Storage

Oral

Tablets

25ºC (may be exposed to 15–30ºC).1 Dispense and store in tightly closed original container; protect from light and moisture.1

Actions

  • Azilsartan medoxomil, a prodrug, is hydrolyzed to azilsartan during absorption.1 31

  • Azilsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.1

  • Azilsartan should not affect bradykinin levels.1

Advice to Patients

  • Risk of hypotension.2 Importance of lying down and informing clinician immediately if lightheadedness or dizziness occurs.2

  • Importance of storing azilsartan medoxomil in the original container, tightly closed and protected from light and moisture.2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of discussing other options for hypertension treatment if pregnancy occurs.2 Importance of informing women of childbearing potential of risk of serious harm or death in the fetus and infant if azilsartan is used during the second or third trimester of pregnancy.1 2 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements.2

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Azilsartan Kamedoxomil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

40 mg (of azilsartan medoxomil)

Edarbi

Arbor

80 mg (of azilsartan medoxomil)

Edarbi

Arbor

AHFS DI Essentials™. © Copyright 2019, Selected Revisions December 3, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Arbor Pharmaceuticals. Edarbi (azilsartan medoxomil) tablets prescribing information. Atlanta, GA; 2014 Jul.

2. Arbor Pharmaceuticals. Edarbi (azilsartan medoxomil) tablets patient information. Atlanta, GA; 2014 Jul.

3. White WB, Weber MA, Sica D et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011; 57:413-20. http://www.ncbi.nlm.nih.gov/pubmed/21282560?dopt=AbstractPlus

4. Bakris GL, Sica D, Weber M et al. The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. J Clin Hypertens. 2011; 13:81-8.

5. Sica D, White WB, Weber MA et al. Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring. J Clin Hypertens. 2011; 13:467-72.

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12. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-62. http://www.ncbi.nlm.nih.gov/pubmed/8413456?dopt=AbstractPlus

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