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Benazepril

Pronunciation

(ben AY ze pril)

Index Terms

  • Benazepril HCl
  • Benazepril Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Lotensin: 10 mg [DSC], 20 mg, 40 mg

Generic: 5 mg, 10 mg, 20 mg, 40 mg

Brand Names: U.S.

  • Lotensin

Pharmacologic Category

  • Angiotensin-Converting Enzyme (ACE) Inhibitor
  • Antihypertensive

Pharmacology

Competitive inhibition of angiotensin I being converted to angiotensin II, a potent vasoconstrictor, through the angiotensin I-converting enzyme (ACE) activity, with resultant lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion

Absorption

Rapid (37%); food does not alter significantly; metabolite (benazeprilat) itself unsuitable for oral administration due to poor absorption

Distribution

Vd: ~8.7 L (Balfour 1991)

Metabolism

Rapidly and extensively hepatic to its active metabolite, benazeprilat, via enzymatic hydrolysis; extensive first-pass effect

Excretion

Urine (trace amounts as benazepril; 20% as benazeprilat; 12% as other metabolites)

Clearance: Nonrenal clearance (ie, biliary, metabolic) appears to contribute to the elimination of benazeprilat (11% to 12%), particularly patients with severe renal impairment; hepatic clearance is the main elimination route of unchanged benazepril

Dialysis: ~6% of metabolite removed within 4 hours of dialysis following 10 mg of benazepril administered 2 hours prior to procedure; parent compound not found in dialysate

Onset of Action

Reduction in plasma angiotensin-converting enzyme (ACE) activity: Peak effect: 1 to 2 hours after 2 to 20 mg dose (Nussberger 1987; Nussberger 1989)

Reduction in blood pressure: Peak effect: Single dose: 2 to 4 hours; Continuous therapy: 2 weeks (Fogari 1990)

Time to Peak

Parent drug: 0.5 to 1 hour

Active metabolite (benazeprilat): Fasting: 1 to 2 hours; Nonfasting: 2 to 4 hours

Duration of Action

Reduction in plasma angiotensin-converting enzyme (ACE) activity: >90% inhibition for 24 hours after 5 to 20 mg dose (Balfour 1991)

Half-Life Elimination

Benazeprilat: Effective: 10 to 11 hours; Terminal: Children: 5 hours, Adults: 22 hours

Protein Binding

Benazepril: ~97%

Benazeprilat: ~95%

Special Populations: Renal Function Impairment

In those with CrCl 30 mL/minute or less, peak benazeprilat levels and initial half-life increase and time to steady state may be delayed.

Use: Labeled Indications

Hypertension: Management of hypertension

Guideline recommendations:

Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) 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 is ≥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 (CAD) 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 CAD recommends the use of an ACE inhibitor (or an ARB) 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 ACE inhibitor (or an ARB) for patients with HTN and diabetes with albuminuria (urinary albumin-to-creatinine ratio [UACR] ≥30 mg/g). For patients with hypertension and diabetes without albuminuria, any of the four 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

Heart failure

Data from a small, multicenter, randomized, double-blind, placebo-controlled trial in patients with chronic heart failure (NYHA classes II to IV) suggests that benazepril may be beneficial for the treatment of patients with this condition [Colfer 1992]. However, specific dosing cannot be recommended. Additional trials are necessary to further define the role of benazepril for the treatment of patients with heart failure.

Based on the American College of Cardiology/American Heart Association (ACCF/AHA) Guideline for the Management of Heart Failure, the use of ACE inhibitors along with other guideline directed medical therapies, is effective and recommended to prevent heart failure in patients with a reduced ejection fraction who have a history of MI (Stage B HF), to prevent heart failure in any patient with a reduced ejection fraction (Stage B HF), or to treat those with heart failure and reduced ejection fraction (Stage C HFrEF).

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 ACE inhibitor (eg, benazepril) or an ARB 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 ACE inhibitor (eg, benazepril) or an ARB is effective and strongly recommended in patients with an eGFR <60 mL/min/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), ACE inhibitors or ARBs are also recommended to reduce the progression to more advanced albuminuria.

Non–ST-elevation acute coronary syndrome

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), an ACE inhibitor (eg, benazepril) should be initiated and continued indefinitely after NSTE-ACS in patients with an LVEF ≤0.4 and in those with hypertension, diabetes mellitus, or stable CKD unless contraindicated. Use of an ACE inhibitor may also be useful in all other patients with cardiac or other vascular disease. In patients with stress (Takotsubo) cardiomyopathy, the use of ACE inhibitors (in combination with beta blockers, aspirin and diuretics) is recommended.

Contraindications

Hypersensitivity to benazepril, other ACE inhibitors, or any component of the formulation; history of angioedema (with or without prior ACE inhibitor therapy); concomitant use with aliskiren in patients with diabetes mellitus; coadministration with or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril).

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); pregnancy; breastfeeding; rare hereditary problems of galactose intolerance (eg, galactosemia, Lapp Lactase deficiency or glucose-galactose malabsorption).

Dosing: Adult

Hypertension: Oral: Initial: 10 mg once daily (5 mg once daily in patients receiving a diuretic); titrate to 40 mg daily based on blood pressure response; maintenance dose: 20 to 80 mg daily as a single dose or 2 divided doses; the need for twice-daily dosing should be assessed by monitoring peak (2 to 6 hours after dosing) and trough responses. Usual dosage (ASH/ISH [Weber 2014]): 10 to 40 mg daily.

Dosing: Geriatric

Oral: Consider lower initial doses (MacDonald 1993; Reid 1989).

Dosing: Pediatric

Hypertension: Children ≥6 years and Adolescents: Oral: Initial: 0.2 mg/kg once daily (maximum initial dose: 10 mg/day) as monotherapy; maintenance: 0.1 to 0.6 mg/kg once daily (maximum dose: 0.6 mg/kg/day or 40 mg/day).

Dosing: Renal Impairment

CrCl ≥30 mL/minute/1.73m2: No dosage adjustment necessary.

CrCl <30 mL/minute/1.73m2:

Adults: Initial: 5 mg once daily; maximum dose: 40 mg/day

Children ≥6 years and Adolescents: Use is not recommended (insufficient data exists; dose not established).

Hemodialysis: 25% to 50% of usual dose; supplemental dose is not necessary (Aronoff 2007)

Peritoneal dialysis: 25% to 50% of usual dose; supplemental dose is not necessary (Aronoff 2007)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Extemporaneously Prepared

A 2 mg/mL oral suspension may be made with tablets. Mix fifteen benazepril 20 mg tablets in an amber polyethylene terephthalate bottle with Ora-Plus 75 mL. Shake for 2 minutes, allow suspension to stand for ≥1 hour, then shake again for at least 1 additional minute. Add Ora-Sweet 75 mL to suspension and shake to disperse. Will make 150 mL of a 2 mg/mL suspension. Label “shake well” and “refrigerate”. Stable for 30 days.

Lotensin prescribing information, Validus Pharmaceuticals LLC, Parsippany, NJ, 2017.

Storage

Store at ≤30°C (86°F). Protect from moisture.

Drug Interactions

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

Aliskiren: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. 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

Allopurinol: Angiotensin-Converting Enzyme Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. 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 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

Aprotinin: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

AzaTHIOprine: Angiotensin-Converting Enzyme Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. 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

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

Canagliflozin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Canagliflozin may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Ciprofloxacin (Systemic): Angiotensin-Converting Enzyme Inhibitors may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

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

Dipeptidyl Peptidase-IV Inhibitors: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: Angiotensin-Converting Enzyme Inhibitors 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-Converting Enzyme Inhibitors. Monitor therapy

Everolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy

Ferric Hydroxide Polymaltose Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. Monitor therapy

Gold Sodium Thiomalate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Monitor therapy

Grass Pollen Allergen Extract (5 Grass Extract): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Consider therapy modification

Heparin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. 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

HydroCHLOROthiazide: May enhance the hypotensive effect of Benazepril. HydroCHLOROthiazide may enhance the nephrotoxic effect of Benazepril. Benazepril may decrease the serum concentration of HydroCHLOROthiazide. Monitor therapy

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

Icatibant: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Iron Dextran Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Consider therapy modification

Lanthanum: May decrease the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Consider therapy modification

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

Lithium: Angiotensin-Converting Enzyme Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification

Loop Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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-Converting Enzyme Inhibitors. 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-Converting Enzyme Inhibitors 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 antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. 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-Converting Enzyme Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Pregabalin: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. 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

Sacubitril: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination

Salicylates: May enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sodium Phosphates: Angiotensin-Converting Enzyme Inhibitors 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 ACEIs, 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

Temsirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

TiZANidine: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. 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

1% to 10%:

Central nervous system: Headache (6%), dizziness (4%), drowsiness (2%), orthostatic dizziness (2%)

Renal: Increased serum creatinine (2%), renal insufficiency (may occur in patients with bilateral renal artery stenosis or hypovolemia)

Respiratory: Cough (1% to 10%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Agranulocytosis, alopecia, anaphylactoid reaction, angina pectoris, angioedema (includes head, neck, and intestinal angioedema), arthralgia, arthritis, asthma, dermatitis, dyspnea, ECG changes, eosinophilia, flushing, gastritis, hemolytic anemia, hyperbilirubinemia, hyperglycemia, hyperkalemia, hypersensitivity, hypertonia, hyponatremia, hypotension, impotence, increased blood urea nitrogen (transient), increased serum transaminases, increased uric acid, insomnia, leukopenia, myalgia, neutropenia, orthostatic hypotension, palpitations, pancreatitis, paresthesia, pemphigus, peripheral edema, proteinuria, pruritus, shock, skin photosensitivity, skin rash, Stevens-Johnson syndrome, syncope, thrombocytopenia, vomiting

Eosinophilic pneumonitis, anaphylaxis, neutropenia, agranulocytosis, renal insufficiency, and renal failure have been reported with other ACE inhibitors. In addition, a syndrome including fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia, and elevated ESR has been reported to be associated with ACE inhibitors.

ALERT: U.S. Boxed Warning

Fetal toxicity:

When pregnancy is detected, discontinue benazepril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to a developing fetus.

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Any time during treatment (especially following first dose) angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African Americans and patients with idiopathic or hereditary angioedema may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) therapy or a neprilysin inhibitor (eg, sacubitril). 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. Aggressive early and appropriate management is critical. Contraindicated in patients with history of angioedema with or without prior ACE inhibitor therapy.

• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis; discontinue if marked elevation of hepatic transaminases or jaundice occurs.

• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.

• Hematologic effects: Another ACE inhibitor, captopril, has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with differential in these patients.

• Hyperkalemia: May occur with ACE inhibitors; 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 periodically.

• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in BUN and serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) 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 (Bakris 2000).

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.

• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.

• Diabetes: Use with caution in patients with diabetes receiving insulin or oral antidiabetic agents; may be at increased risk for episodes of hypoglycemia.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (ACCF/AHA [Gersh 2011]).

• 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 in preexisting renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.

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:

• Black patients: ACE inhibitors effectiveness is less in black patients than in non-blacks. In addition, ACE inhibitors cause a higher rate of angioedema in black than in non-black patients.

• 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 ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. 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 non-cardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).

Monitoring Parameters

Blood pressure; BUN, serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential.

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. Benazepril crosses the placenta. Drugs that 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. Their use in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester, although this finding may be confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant and mother. ACE inhibitors are not recommended for the treatment of uncomplicated hypertension in pregnancy (ACOG 2013) and they are specifically contraindicated for the treatment of hypertension and chronic heart failure during pregnancy by some guidelines (Regitz-Zagrosek 2011). In addition, ACE inhibitors should generally be avoided in women of reproductive age (ACOG 2013). If treatment for hypertension or chronic heart failure in pregnancy is needed, other agents should be used (ACOG 2013; Regitz-Zagrosek 2011).

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 headache. Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling), severe dizziness, passing out, persistent cough, shortness of breath, excessive weight gain, swelling of arms or legs, severe abdominal pain, severe nausea, vomiting, or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (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 health care 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.

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