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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

Warning(s)

  • 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 6 500

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 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).500 501 502 503 504 515

Angiotensin II receptor antagonists or ACE inhibitors may be preferred in hypertensive patients with diabetes mellitus or chronic kidney disease; 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.500 501 502 504 520 523 524 527 534 535 536 543

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.500 501 504 However, diminished response to an angiotensin II receptor antagonist is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

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 17 520 535 536

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 may be used as an alternative for those patients in whom an ACE inhibitor or ARNI is inappropriate.524 800

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

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

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

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: 80 mg once daily.1 Consider a reduced initial dosage of 40 mg once daily in patients receiving high dosages of diuretics.1

If BP is not adequately controlled, may add other antihypertensive agents.1

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Special Populations

Hepatic Impairment

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

Geriatric Patients

No adjustment of initial azilsartan 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 (See Boxed Warning.) ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.1 z25 26

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

Other Warnings and Precautions

Hypotension

Possible symptomatic hypotension with azilsartan, 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 azilsartan 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.1

Geriatric Use

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

Hepatic Impairment

Not studied 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

Azilsartan is 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 antihypertensive effect of azilsartan1

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 two 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

Azilsartan 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.2 Importance of informing women of childbearing potential of risk of serious harm or death in the fetus and infant if azilsartan medoxomil 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 2017, Selected Revisions May 3, 2017. 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

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