Pronunciation

(ir be SAR tan)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Avapro: 75 mg, 150 mg, 300 mg

Generic: 75 mg, 150 mg, 300 mg

Brand Names: U.S.

• Avapro

Pharmacologic Category

• Angiotensin II Receptor Blocker
• Antihypertensive

Pharmacology

Irbesartan is an angiotensin receptor antagonist. Angiotensin II acts as a vasoconstrictor. In addition to causing direct vasoconstriction, angiotensin II also stimulates the release of aldosterone. Once aldosterone is released, sodium as well as water are reabsorbed. The end result is an elevation in blood pressure. Irbesartan binds to the AT1 angiotensin II receptor. This binding prevents angiotensin II from binding to the receptor thereby blocking the vasoconstriction and the aldosterone secreting effects of angiotensin II.

Absorption

Rapid and complete

Distribution

V_d: 53 to 93 L

Metabolism

Hepatic, via glucuronide conjugation and oxidation; oxidation occurs primarily by cytochrome P450 isoenzyme CYP2C9

Excretion

Feces (80%); urine (20%)

Onset of Action

Peak levels in 1 to 2 hours

Maximum effect: 3-6 hours postdose; with chronic dosing maximum effect: ~2 weeks

Time to Peak

Serum: 1.5 to 2 hours

Duration of Action

>24 hours

Half-Life Elimination

Terminal: 11 to 15 hours

Protein Binding

Plasma: 90%, primarily to albumin and alpha-1 acid glycoprotein

Special Populations: Race

In healthy black patients, AUC values were approximately 25% greater than white patients.

Use: Labeled Indications

Diabetic nephropathy: Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension.

Hypertension: Management of hypertension (alone or in combination with other antihypertensives).

Guideline recommendations:

Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8; James 2013]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:

• Patients ≥60 years with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg.

• Patients <60 years with SBP ≥140 mm Hg or DBP ≥90 mm Hg.

• Patients ≥18 years with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg.

• Patients ≥18 years with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg.

Coronary artery disease and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with coronary artery disease (CAD) recommends the use of an ARB (or ACE inhibitor) as part of a regimen in patients with hypertension and chronic stable angina if there is prior MI, LV systolic dysfunction, diabetes mellitus, or CKD. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

Diabetes and hypertension: The American Diabetes Association (ADA) guidelines recommend an ARB (or an ACE inhibitor) for patients with hypertension and diabetes with albuminuria (urinary albumin-to-creatinine ratio [UACR] ≥30 mg/g). For patients with hypertension and diabetes without albuminuria, any of the 4 classes of blood pressure medications (eg, ACE inhibitors, ARBs, thiazide-like diuretics, dihydropyridine calcium channel blockers) may be used and have shown beneficial cardiovascular outcomes (ADA 2017a).

Off Label Uses

Acute coronary syndrome (secondary prevention of cardiovascular events)

Based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of patients with ST-elevation myocardial infarction (STEMI), an ARB (eg, irbesartan) is recommended and effective in patients with NSTE-ACS or STEMI who have indications for but are intolerant of ACE inhibitors; this includes patients with heart failure, MI, or anterior MI who have a left ventricular ejection fraction (LVEF) ≤0.4. In post-STEMI patients, initiate within the first 24 hours.

Improve kidney outcomes in hypertensive patients with chronic kidney disease (CKD) (diabetic and nondiabetic population)

Based on the Eighth Joint National Committee (JNC 8) guidelines for the management of high blood pressure in adults, an ARB (eg, irbesartan) or an ACE inhibitor is effective and recommended to improve kidney outcomes in adult patients with CKD and hypertension. This recommendation applies to hypertensive CKD patients, with and without proteinuria, and regardless of race and diabetes status.

Based on the American Diabetes Association Standards of Medical Care in Diabetes, in CKD patients with diabetes and hypertension, an ARB (eg, irbesartan) or an ACE inhibitor is effective and strongly recommended in patients with an eGFR <60 mL/minute/1.73 m² and/or a UACR ≥300 mg/g for the prevention of CKD progression. In patients with modestly elevated UACR (30 to 299 mg/g), ARBs or ACE inhibitor are also recommended to reduce the progression to more advanced albuminuria.

Additional Off-Label Use:

Slow the rate of progression of aortic-root dilation in pediatric patients with Marfan syndrome

Contraindications

Hypersensitivity to irbesartan or any component of the formulation; concomitant use with aliskiren in patients with diabetes mellitus

Documentation of allergenic cross-reactivity for angiotensin receptor blockers is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with aliskiren in patients with moderate to severe renal impairment (GFR <60 mL/minute/1.73 m²); concomitant use with ACE inhibitors in patients with diabetic nephropathy; hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption; pregnancy; breastfeeding

Dosing: Adult

Hypertension: Oral: 150 mg once daily; patients may be titrated to 300 mg once daily; usual dosage range (ASH/ISH [Weber, 2014]): 150 to 300 mg daily; target dose (JNC 8 [James, 2013]): 300 mg once daily. Note: Starting dose in volume-depleted patients should be 75 mg.

Diabetic nephropathy: Oral: 300 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hypertension: Oral:

Children ≥6 to 12 years (off-label use): Initial: 75 mg once daily; may be titrated to a maximum of 150 mg once daily (NHBPEP, 2004).

Adolescents (off-label use): Initial: 150 mg once daily; may be titrated to a maximum dose of 300 mg once daily (NHBPEP, 2004).

Dosing: Renal Impairment

Mild to severe impairment: No dosage adjustment necessary unless the patient is also volume depleted.

Hemodialysis: Not removed by hemodialysis

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Administration

Administer with or without food.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II: Receptor Blockers may diminish the therapeutic effect of Angiotensin II. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Canagliflozin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Canagliflozin may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ciprofloxacin (Systemic): Angiotensin II Receptor Blockers may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

CycloSPORINE (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Monitor therapy

CYP2C9 Substrates (High risk with Inhibitors): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Drospirenone: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Heparin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Lornoxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lornoxicam. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Test Interactions

May lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016)

Adverse Reactions

Unless otherwise indicated, percentage of incidence is reported for patients with hypertension.

>10%: Endocrine & metabolic: Hyperkalemia (diabetic nephropathy: 19%; rarely seen in hypertension)

1% to 10%:

Cardiovascular: Orthostatic hypotension (diabetic nephropathy: 5%: hypertension: <1%)

Central nervous system: Dizziness (diabetic nephropathy: 10%), fatigue (4%)

Gastrointestinal: Diarrhea (3%), dyspepsia (2%)

Respiratory: Upper respiratory tract infection (9%)

<1%, postmarketing, and/or case reports: Abdominal distention, anemia (case report; Simonetti 2007), angina pectoris, angioedema, arthritis, auditory disturbance, bronchitis, bursitis, cardiac arrhythmia, cardiac failure, cerebrovascular accident, chills, conjunctivitis, constipation, decreased libido, depression, dermatitis, drowsiness, dyspnea, ecchymoses, epistaxis, erythema, facial edema, fever, flatulence, flushing, gastroenteritis, gout, hepatitis, hypertension, hypertensive crisis, hypotension, increased liver enzymes, increased serum transaminases, jaundice, muscle cramps, myalgia, myasthenia, myocardial infarction, nasal congestion, noncardiac chest pain, numbness, otalgia, otic infection, paresthesia, prostatic disease, pruritus, pulmonary congestion, renal failure, renal insufficiency, sexual disorder, sleep disorder, thrombocytopenia, transient ischemic attacks, tremor, upper extremity edema, urination disorder, urticaria, visual disturbance, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Angioedema has been reported rarely with some angiotensin II receptor antagonists (ARBs) and may occur at any time during treatment (especially following first dose). It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE-inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Discontinue therapy immediately if angioedema occurs. Aggressive early management is critical. Intramuscular (IM) administration of epinephrine may be necessary. Do not readminister to patients who have had angioedema with ARBs.

• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypotension: Symptomatic hypotension may occur upon initiation in patients who are salt- or volume-depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration. This transient hypotensive response is not a contraindication to further treatment with irbesartan.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, chronic kidney disease, severe heart failure, volume depletion) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution with preexisting renal insufficiency.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

• Surgical patients: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011). Based on current research and clinical guidelines in patients undergoing noncardiac surgery, continuing angiotensin-receptor blockers (ARB) is reasonable in the perioperative period. If ARBs are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).

Monitoring Parameters

Blood pressure, electrolytes, serum creatinine, BUN, urinalysis

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. The use of drugs which act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Use is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed in utero should be monitored for hyperkalemia, hypotension, and oliguria (exchange transfusions or dialysis may be needed). These adverse events are generally associated with maternal use in the second and third trimesters.

Untreated chronic maternal hypertension is also associated with adverse events in the fetus, infant, and mother. The use of angiotensin II receptor blockers is not recommended to treat chronic uncomplicated hypertension in pregnant women and should generally be avoided in women of reproductive potential (ACOG 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, diarrhea, or loss of strength and energy. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling), severe dizziness, passing out, angina, tachycardia, or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions,

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Further information

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