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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(ben AY ze pril)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypertension, either alone or in combination with other antihypertensive agents
Pregnancy Risk Factor
D
Pregnancy Considerations
Due to adverse events observed in humans, benazepril is considered pregnancy category D. Benazepril crosses the placenta. First trimester exposure to ACE inhibitors may cause major congenital malformations. An increased risk of cardiovascular and/or central nervous system malformations was observed in one study; however, an increased risk of teratogenic events was not observed in other studies. Second and third trimester use of an ACE inhibitor is associated with oligohydramnios. Oligohydramnios due to decreased fetal renal function may lead to fetal limb contractures, craniofacial deformation, and hypoplastic lung development. The use of ACE inhibitors during the second and third trimesters is also associated with anuria, hypotension, renal failure (reversible or irreversible), skull hypoplasia, and death in the fetus/neonate. Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant. ACE inhibitors are not recommended during pregnancy to treat maternal hypertension or heart failure. Those who are planning a pregnancy should be considered for other medication options if an ACE inhibitor is currently prescribed or the ACE inhibitor should be discontinued as soon as possible once pregnancy is detected. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed to an ACE inhibitor in utero, especially during the second and third trimester, should be monitored for hyperkalemia, hypotension, and oliguria.[U.S. Boxed Warning]: Based on human data, ACE inhibitors can cause injury and death to the developing fetus. ACE inhibitors should be discontinued as soon as possible once pregnancy is detected.
Lactation
Enters breast milk
Breast-Feeding Considerations
Small amounts of benazepril and benazeprilat are found in breast milk.
Contraindications
Hypersensitivity to benazepril or any component of the formulation; patients with a history of angioedema (with or without prior ACE inhibitor therapy)
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
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. 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 1-4 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.
• 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 closely.
• 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.
• Neutropenia/agranulocytosis: Another ACE Inhibitor, captopril, has been associated with rare cases of agranulocytosis, neutropenia, or leukopenia with myeloid hypoplasia. 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.
• 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, 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.
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.
• 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 pre-existing renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Concurrent drug therapy issues:
• Angiotensin receptor blockers: Concurrent use of angiotensin receptor blockers may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia).
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Based on human data, ACEIs can cause injury and death to the developing fetus when used in the second and third trimesters. ACEIs should be discontinued as soon as possible once pregnancy is detected.
Other warnings/precautions:
• Surgery: 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.
Adverse Reactions
1% to 10%:
Cardiovascular: Postural dizziness (2%)
Central nervous system: Headache (6%), dizziness (4%), somnolence (2%)
Renal: Serum creatinine increased (2%), worsening of renal function 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, angioedema (includes head, neck and intestinal angioedema), arthralgia, arthritis, asthma, BUN increased (transient), dermatitis, dyspnea, ECG changes, eosinophilia, flushing, gastritis, hemolytic anemia, hyperbilirubinemia, hyperglycemia, hyperkalemia, hypersensitivity, hypertonia, hyponatremia, hypotension, impotence, insomnia, leukopenia, myalgia, neutropenia, palpitations, pancreatitis, paresthesia, pemphigus, peripheral edema, photosensitivity, postural hypotension, proteinuria, pruritus, rash, shock, Stevens-Johnson syndrome, syncope, thrombocytopenia, transaminases increased, uric acid increased, vomiting
Eosinophilic pneumonitis, anaphylaxis, 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.
Drug Interactions
Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk D: Consider therapy modification
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Antacids: May decrease the serum concentration of ACE Inhibitors. Management: Separate fosinopril administration from antacids by at least 2 hours. US and Canadian recommendations for use of other ACE- inhibitors with antacids may vary. Consult appropriate labeling. Monitor for decreased therapeutic effects of ACE-inhibitors. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
AzaTHIOprine: ACE Inhibitors may enhance the neutropenic effect of AzaTHIOprine. Risk C: Monitor therapy
CycloSPORINE: ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk D: Consider therapy modification
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Iron Dextran Complex: ACE 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. Risk D: Consider therapy modification
Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: ACE 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 ACE Inhibitors. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: Monitor therapy
Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Sodium Phosphates: ACE 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. Risk D: Consider therapy modification
Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Thiazide Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may have increased antihypertensive effect).
Storage
Store at ≤30°C (86°F). Protect from moisture.
Mechanism of Action
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
Pharmacodynamics/Kinetics
Reduction in plasma angiotensin-converting enzyme (ACE) activity:
Onset of action: Peak effect: 1-2 hours after 2-20 mg dose
Duration: >90% inhibition for 24 hours after 5-20 mg dose
Reduction in blood pressure:
Peak effect: Single dose: 2-4 hours; Continuous therapy: 2 weeks
Absorption: Rapid (37%); food does not alter significantly; metabolite (benazeprilat) itself unsuitable for oral administration due to poor absorption
Distribution: Vd: ~8.7 L
Protein binding:
Benazepril: ~97%
Benazeprilat: ~95%
Metabolism: Rapidly and extensively hepatic to its active metabolite, benazeprilat, via enzymatic hydrolysis; extensive first-pass effect
Half-life elimination: Benazeprilat: Effective: 10-11 hours; Terminal: Children: 5 hours, Adults: 22 hours
Time to peak: Parent drug: 0.5-1 hour
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
Dosage
Oral: Hypertension:
Children ≥6 years: Initial: 0.2 mg/kg/day (up to 10 mg/day) as monotherapy; dosing range: 0.1-0.6 mg/kg/day (maximum dose: 40 mg/day)
Adults: Initial: 10 mg/day in patients not receiving a diuretic; 20-80 mg/day as a single dose or 2 divided doses; the need for twice-daily dosing should be assessed by monitoring peak (2-6 hours after dosing) and trough responses.
Note: Patients taking diuretics should have them discontinued 2-3 days prior to starting benazepril. If they cannot be discontinued, then initial dose should be 5 mg; restart after blood pressure is stabilized if needed.
Elderly: Oral: Initial: 5-10 mg/day in single or divided doses; usual range: 20-40 mg/day; adjust for renal function; also see Note in adult dosing.
Dosing interval in renal impairment: Clcr <30 mL/minute:
Children: Use is not recommended.
Adults: Administer 5 mg/day initially; maximum daily dose: 40 mg.
Hemodialysis: Moderately dialyzable (20% to 50%); administer dose postdialysis or administer 25% to 35% supplemental dose.
Peritoneal dialysis: Supplemental dose is not necessary.
Monitoring Parameters
Blood pressure; serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential
Patient Education
Take first dose at bedtime. Do not take potassium supplements or salt substitutes containing potassium without consulting prescriber. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, lightheadedness, postural hypotension, nausea, vomiting, abdominal pain, dry mouth, or transient loss of appetite; report if these side effects persist. Report mouth sores; fever or chills; swelling of extremities, face, mouth, or tongue; or respiratory difficulty or unusual cough.
Geriatric Considerations
Due to frequent decreases in glomerular filtration (also Clcr) with aging, elderly patients may have exaggerated responses to ACE inhibitors; differences in clinical response due to hepatic changes are not observed. ACE inhibitors may be preferred agents in elderly patients with congestive heart failure and diabetes mellitus. Diabetic proteinuria is reduced and insulin sensitivity is enhanced. In general, the side effect profile is favorable in elderly and causes little or no CNS confusion; use lowest dose recommendations initially. Many elderly may be volume depleted due to diuretic use and/or blunted thirst reflex resulting in inadequate fluid intake.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: In patients on chronic ACE inhibitor 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. Episodes of intraoperative hypotension may be managed by fluid administration and/or modest doses of alpha-adrenergic agents. Severe hypotension may occur in patients who are sodium- and/or volume-depleted, initiate lower doses and monitor closely when starting therapy in these patients. ACE inhibitor therapy may elicit an increase in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin-receptor blocker therapy instituted. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures. Aging patients with a decrease in glomerular filtration (also creatinine clearance), severe heart failure, and renal failure may experience an exaggerated response with administration of ACE inhibitors. Diabetic proteinuria is reduced and insulin sensitivity is enhanced.
Evidence-Based Information: ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, decompensated heart failure. ACE inhibitors are also indicated in patients postmyocardial infarction in whom left ventricular ejection fraction is <40%. When used in patients with heart failure, the target dose or maximum tolerated dose should be achieved, if possible. Lower daily doses of ACE inhibitors have not demonstrated the same cardioprotective effects. ACE inhibitors have renal protective effects in patients with diabetic proteinuria. The HOPE trial examined the use of ramipril at a dose of between 2.5-10 mg daily in patients without heart failure at high risk for cardiovascular events and documented a significant improvement in cardiovascular outcome compared to placebo.
Cardiovascular Considerations
Heart Failure: The ACC/AHA 2009 Heart Failure Guidelines recommend that ACE inhibitors be used in patients with a reduced EF (with or without heart failure symptoms) unless contraindicated. ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, congestive heart failure. When used in patients with heart failure, the target dose should be achieved, if possible. Lower daily doses of ACE inhibitors have demonstrated the same mortality effects as high doses, but have not decreased hospitalizations to the extent that high-dose ACE inhibitors have, as demonstrated in the ATLAS study (Packer M, 1999).
Hypertension: The ALLHAT study (ALLHAT Collaborative Group, 2002) compared CV outcomes of lisinopril, amlodipine, and chlorthalidone in hypertensive patients having at least one other risk factor for coronary heart disease. Investigators found no difference between the groups on the primary outcome of fatal coronary disease or nonfatal MI. The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors or angiotensin receptor blockers (ARBs) can be beneficial in patients with hypertension and LVH without symptoms of heart failure. JNC 7 suggests that patients can benefit from treatment with an ACE inhibitor if they have hypertension and heart failure, acute myocardial infarction, high coronary disease risk, diabetes, chronic kidney disease, or history of stroke.
Vascular Disease: The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors can be useful in preventing heart failure in patients who have a history of atherosclerotic vascular disease, diabetes, or hypertension with associated cardiovascular risk factors. The HOPE trial (Heart Outcomes Prevention Evaluation Study Investigators, 2000) investigated the value of an ACE inhibitor (ramipril 5-10 mg daily) versus placebo in patients who had evidence of vascular disease or diabetes (one other cardiovascular risk factor) and were at least 55 years of age. Patients were excluded if they had a low ejection fraction, heart failure, or were on an ACE inhibitor. The primary outcome was a composite of death from cardiovascular cause, myocardial infarction, or stroke; 9297 patients were enrolled and randomized. Ramipril significantly reduced the risk of death from CV causes, MI, or stroke over placebo. New cases of diabetes were also reduced in the ramipril group. In the EUROPA trial, patients with stable coronary artery disease (at low-risk for cardiovascular events) received perindopril or placebo and were evaluated for incidence of cardiovascular events after 4 years of treatment. In this randomized, placebo-controlled, prospective study, 12,218 patients received either perindopril (8 mg/day, n=6110) or placebo (n=6108) and were assessed for the primary endpoint of a cardiovascular event, defined as cardiovascular death, myocardial infarction, or cardiac arrest. The study population was well balanced with respect to baseline demographics and concomitant medication use (including beta-blockers, platelet inhibitors, antihyperlipidemics, calcium channel blockers, nitrates, and diuretics). Intent-to-treat analysis revealed that 603 (10%) of placebo patients experienced the primary endpoint of a cardiovascular event compared to 488 (8%) of perindopril-receiving patients, for a 20% relative risk reduction (p=0.0003). This result was not influenced by presence of other comorbidities (eg, diabetes, hypertension) or concomitant beta-blocker, calcium channel blocker, or lipid-lowering therapies. Withdrawal from the study (postrandomization) due to adverse reactions was similar between treatment groups. The number needed to treat analysis suggests that treatment of 50 patients over a 4-year period will prevent one major cardiovascular event.
Acute Coronary Syndromes: In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or CHF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended for all post-ACS individuals (Class IIa). According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion, or LVEF <0.4, in the absence of hypotension or known contraindications to this class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. The VALIANT trial evaluated the effects of valsartan (target dose: 160 mg twice daily), captopril (target dose: 50 mg twice daily), and the combination (target doses: valsartan 80 mg twice daily and captopril 150 mg once daily) in a randomized, double-blind trial of patients with acute MI (0.5-10 days post-MI) complicated by left ventricular systolic dysfunction, heart failure, or both. Enrollment in the study numbered 14,703 patients and followed for a median of 24.7 months. There was no difference in the primary endpoint (all cause mortality) among the three groups. There was no difference in incidence of CV death, recurrent MI, or hospitalization for heart failure either. Hypotension and renal dysfunction occurred significantly more often in the valsartan group than with captopril alone. Cough, rash, and taste disturbances occurred more often in the captopril group. The authors (Pfeffer MA, 2003) concluded that valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after MI. Combining valsartan with captopril increased the rate of adverse events without improving survival.
Potential Adverse Events: ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, ARB therapy instituted. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.
Drug Interactions: Concomitant indomethacin therapy may blunt the reduction in sitting and 24-hour ambulatory diastolic blood pressure. Use of NSAIDs should be avoided or limited, with monitoring of blood pressure control in this setting. In patients with heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness
Mental Health: Effects on Psychiatric Treatment
May decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Blood pressure should be monitored after first doses and periodically throughout.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as hydrochloride: 5 mg, 10 mg, 20 mg, 40 mg
Lotensin®: 5 mg, 10 mg, 20 mg, 40 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Benazepril HCl)
5 mg (90): $64.97
10 mg (30): $25.99
20 mg (30): $25.99
40 mg (30): $23.99
Tablets (Lotensin)
5 mg (30): $62.80
10 mg (30): $67.99
20 mg (30): $72.99
40 mg (30): $67.99
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, Novartis Pharmaceuticals Corporation, Suffern, NY, 2009.
References
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, “Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),” JAMA, 2002, 288(23):2981-97.
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2011,” Diabetes Care, 2011, 34(Suppl 1):11-61.
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine,” J Am Coll Cardiol, 2007, 50(7):e1-e157.
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636. Available at http://www.circulationaha.org/cgi/content/full/110/5/588
Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.
Chase MP, Fiarman GS, Scholz FJ, et al, “Angioedema of the Small Bowel Due to an Angiotensin-Converting Enzyme Inhibitor,” J Clin Gastroenterol, 2000, 31(3):254-7.
Chobanian AV, Bakris GL, Black HR, et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,” JAMA, 2003, 289(19):2560-71.
Conlin P, Moore T, Swartz S, et al, “Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients,” Hypertension, 2000, 36(3):461-5.
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International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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