Irbesartan

Pronunciation

Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: 2 - Butyl - 3 - [[2′(1H - tetrazol - 5 - yl)[1,1′ - biphenyl] - 4 - yl]methyl] - 1,3 - diazaspiro[4.4]non - 1 - en - 4 - one
Molecular Formula: C25H28N6O3S•½C4H4 O4
CAS Number: 138402-11-6
Brands: Avapro, Avalide

Warning(s)

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 26 71 72 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue the drug as soon as possible.1 26 72

Introduction

Angiotensin II receptor (AT1) antagonist.1 2 4 5 6 21 22 23

Uses for Irbesartan

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 4 5 6 14 15 16 17 18 21 22 23 500

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

Slideshow: 2014 Update - First Time Brand-to-Generic Switches

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

Management of diabetic nephropathy manifested by elevated Scr and proteinuria (urinary protein excretion >300 mg daily) in patients with type 2 diabetes mellitus and hypertension.1

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.49 51 52 53 520 535 536

Heart Failure

Angiotensin II receptor antagonists are considered a reasonable alternative for inhibition of the renin-angiotensin system in patients with heart failure and reduced left ventricular ejection fraction (LVEF) who are intolerant of ACE inhibitors; because of their established benefits, ACE inhibitors are preferred.524 528

Irbesartan 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 21

Dosage

Adults

Hypertension
Irbesartan Therapy
Oral

JNC 8 expert panel recommends initial dosage of 75 mg once daily and target dosage of 300 mg once daily based on dosages used in randomized controlled studies.501

Manufacturer recommends initial dosage of 150 mg once daily in adults without intravascular volume depletion.1 In adults with depletion of intravascular volume, the usual initial dosage is 75 mg once daily.1 24

Manufacturer states usual dosage is 150–300 mg once daily; no additional therapeutic benefit with higher dosages or with twice-daily dosing.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

Irbesartan/Hydrochlorothiazide Fixed-combination Therapy
Oral

Manufacturer states fixed-combination preparation can be used for initial treatment of hypertension in patients who are likely to need multiple drugs to achieve their BP goals.26 Consider potential benefits and risks of initiating therapy with the fixed combination.26

If BP is not adequately controlled by monotherapy with irbesartan or hydrochlorothiazide, can switch to fixed-combination tablets (irbesartan 150 mg and 12.5 mg hydrochlorothiazide; then irbesartan 300 mg and hydrochlorothiazide 12.5 mg), administered once daily.26 Can increase dosage to irbesartan 300 mg and hydrochlorothiazide 25 mg daily, if needed, to control BP.26

In patients receiving fixed-combination tablets as initial therapy, the usual starting dosage is irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily.26 May increase dosage after 1–2 weeks of therapy to a maximum of irbesartan 300 mg and hydrochlorothiazide 25 mg once daily.26

Diabetic Nephropathy
Oral

Initial dosage of 75 mg once daily used in clinical trial.1 Increase dosage to target maintenance dosage of 300 mg once daily.1 No data available on effects of lower dosages.1

Special Populations

Hepatic Impairment

No initial dosage adjustments necessary.1 26

Renal Impairment

No initial dosage adjustments necessary.1 26

Irbesartan/hydrochlorothiazide fixed combination not recommended in patients with severe renal impairment.26

Geriatric Patients

No initial dosage adjustments necessary.1 26

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy using lower initial dosage (75 mg once daily).1 24 26 Fixed-combination tablets containing irbesartan and hydrochlorothiazide are not recommended as initial therapy in patients with intravascular volume depletion.26

Cautions for Irbesartan

Contraindications

  • Known hypersensitivity to irbesartan or any ingredient in the formulation.1 26

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 26 (See Boxed Warning.) ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.71 72

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.71 72

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.1 72 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.13

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics or undergoing dialysis).1 26 (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 26

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

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible;1 26 not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.73

General Precautions

Renal Effects

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe heart failure.1 26

Increases in BUN and Scr possible in patients with unilateral or bilateral renal artery stenosis.1 26

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.26

Specific Populations

Pregnancy

Category D.26 (See Boxed Warning.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 26 Discontinue nursing or the drug.1 26

Pediatric Use

Dosages of up to 4.5 mg/kg once daily did not appear to effectively lower BP in pediatric patients 6–16 years of age.1 Not studied in children <6 years of age.1

Safety and efficacy of the fixed-combination preparation containing irbesartan and hydrochlorothiazide not established.26

Geriatric Use

No substantial differences in safety or efficacy of irbesartan monotherapy or fixed-combination containing irbesartan and hydrochlorothiazide relative to younger adults, but increased sensitivity cannot be ruled out.1 26

Renal Impairment

Use with caution.1

Deterioration of renal function may occur.1 26 (See Renal Effects under Cautions.)

Use of irbesartan in fixed combination with hydrochlorothiazide is not recommended in patients with severe renal impairment.26

Black Patients

BP reduction may be smaller in black patients compared with nonblack patients.1 26 69 70 (See Hypertension under Uses.)

Common Adverse Effects

Diarrhea, dyspepsia/heartburn, fatigue; also, dizziness, orthostatic dizziness, and orthostatic hypotension in patients with diabetic nephropathy.1

Interactions for Irbesartan

Metabolized principally by CYP2C9.1 26 Does not substantially induce or inhibit CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.1 26

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased irbesartan metabolism) with CYP2C9 inhibitors.1 26

Specific Drugs

Drug

Interaction

Comments

Digoxin

Pharmacologic and/or pharmacokinetic interactions unlikely1 26

Hydrochlorothiazide

Pharmacokinetic interactions unlikely1 26

Additive hypotensive effects1 26

Nifedipine

Decreased irbesartan metabolism in vitro; alteration of irbesartan pharmacokinetics not observed in vivo1 26

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

Possible deterioration of renal function in geriatric, volume-depleted, or renally impaired patients1

Possible reduced antihypertensive effects1

Monitor renal function periodically1

Tolbutamide

Possible decreased irbesartan metabolism26

Warfarin

Pharmacologic and/or pharmacokinetic interaction unlikely1 26

Irbesartan Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration generally achieved 1.5–2 hours after oral dose.1 Absolute bioavailability is about 60–80%.1 26

Onset

Antihypertensive effect evident within 2 weeks, with maximum BP reduction after 2–4 weeks.1 26

Food

Food does not affect bioavailability.1 26

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.1 26

Crosses the blood-brain barrier poorly, if at all, in animals.1 15

Distributed into milk in rats; not known whether distributed into human milk.1 26

Plasma Protein Binding

90% (principally albumin and α1-acid glycoprotein).1 26

Elimination

Metabolism

Undergoes hepatic metabolism by glucuronide conjugation and oxidation (principally by CYP2C9) to inactive metabolites.1 26

Elimination Route

Eliminated in urine and feces (via bile).1 26

Half-life

Terminal elimination half-life: 11–15 hours.1

Special Populations

Not removed by hemodialysis.1 26 Pharmacokinetics not substantially altered by hemodialysis or renal impairment.1 26

Stability

Storage

Oral

Tablets

15–30°C.1 26

Actions

  • Blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.1 21 22 23 26

  • Does not interfere with response to bradykinins and substance P.1 5 6 21

  • Does not share the ACE inhibitor common adverse effect of dry cough.1 5 6 21 26

Advice to Patients

  • Risks of use during pregnancy.1 26

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 26

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 26

  • Importance of informing patients of other important precautionary information.1 26 (See Cautions.)

Preparations

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

Irbesartan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

75 mg

Avapro

Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

150 mg

Avapro

Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

300 mg

Avapro

Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

Irbesartan Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

150 mg with Hydrochlorothiazide 12.5 mg

Avalide

Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

300 mg with Hydrochlorothiazide 12.5 mg

Avalide

Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

300 mg with Hydrochlorothiazide 25 mg

Avalide

Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 12/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avalide 150-12.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$117.99 or 90/$336.99

Avalide 300-12.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$131.99 or 90/$378.98

Avalide 300-25MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$122.95 or 90/$345.09

Avapro 150MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$98.99 or 90/$269.98

Avapro 300MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$119.99 or 90/$327.98

Avapro 75MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$95.91 or 90/$253.93

Irbesartan 150MG Tablets (TEVA PHARMACEUTICALS USA): 30/$79.99 or 90/$219.97

Irbesartan-Hydrochlorothiazide 300-12.5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$115.99 or 90/$325.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 13, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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