Professional Information

Angiotensin-converting Enzyme (ACE Inhibitors Systemic)

This monograph includes information on the following:

1) Benazepril
2) Captopril
3) Cilazapril ^*
4) Enalapril
5) Fosinopril
6) Lisinopril
7) Moexipril ^†
8) Perindopril
9) Quinapril
10) Ramipril
11) Trandolapril

VA CLASSIFICATION
Benazepril
Primary: CV800
Secondary: CV409; CV900

Captopril
Primary: CV800
Secondary: CV409; CV900

Cilazapril
Primary: CV800
Secondary: CV409; CV900

Enalapril
Primary: CV800
Secondary: CV409; CV900

Enalaprilat
Primary: CV800
Secondary: CV409; CV900

Fosinopril
Primary: CV800
Secondary: CV409; CV900

Lisinopril
Primary: CV800
Secondary: CV409; CV900

Moexipril
Primary: CV800
Secondary: CV409; CV900

Perindopril
Primary: CV800
Secondary: CV409; CV900

Quinapril
Primary: CV800
Secondary: CV409; CV900

Ramipril
Primary: CV800
Secondary: CV409; CV900

Trandolapril
Primary: CV800
Secondary: CV409; CV900

Commonly used brand name(s): Accupril⁹; Aceon⁸; Altace¹⁰; Capoten²; Coversyl⁸; Inhibace³; Lotensin¹; Mavik¹¹; Monopril⁵; Prinivil⁶; Univasc⁷; Vasotec⁴; Zestril⁶.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Antihypertensive—Benazepril; Captopril; Cilazapril; Enalapril; Enalaprilat; Fosinopril; Lisinopril; Moexipril; Perindopril; Quinapril; Ramipril; Trandolapril;

Vasodilator, congestive heart failure—Benazepril; Captopril; Cilazapril; Enalapril; Fosinopril; Lisinopril; Quinapril; Ramipril; Trandolapril;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hypertension (treatment)—Angiotensin-converting enzyme (ACE) inhibitors are indicated, alone or in combination with a thiazide diuretic, in the treatment of hypertension ^{03} ^{237} ^{243} ^{246} ^{251} ^{286}.
—ACE inhibitors are also used for [treatment of malignant, refractory, or accelerated hypertension]¹ , and for treatment of renovascular hypertension ^{243} (except in patients with bilateral renal artery stenoses or renal artery stenosis in a solitary kidney—See Medical considerations/contraindications ).
—Enalaprilat intravenous injection is for the treatment of hypertension when oral therapy is not practical. ^{293}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

Congestive heart failure (treatment)—[ Benazepril]¹ ^{152} ^{153} ^{154} captopril ^{107} ^{290}, [cilazapril] ^{309}, enalapril ^{108} ^{292} ^{294}, fosinopril ^{295} ^{296}, lisinopril, ^{236} ^{297} ^{298} quinapril ^{158} ^{159} ^{303} ^{304}, and [ramipril]¹ ^{160} ^{161} ^{162} ^{163} are also indicated, in combination with diuretics and digitalis therapy, for treatment of congestive heart failure not responding to other measures.

Congestive heart failure, post–myocardial infarction (treatment) —Ramipril ^{305} ^{306}, and trandolapril ^{307} ^{308} are indicated in stable patients with clinical signs of congestive heart failure within the first few days after sustaining an acute myocardial infarction. Ramipril and trandolapril have been shown to decrease the risk of cardiovascular death and also the risk of heart failure–related hospitalization ^{305} ^{306} ^{307} ^{308}

Left ventricular dysfunction, asymptomatic (treatment) ¹—Enalapril is indicated for the treatment of left ventricular dysfunction (ejection fraction £ 35%) in clinically stable patients who are asymptomatic. ^{263} ^{264} ^{292} Enalapril has been shown to decrease the rate of development of overt heart failure and decrease the frequency of hospitalization secondary to heart failure. ^{263} ^{264} ^{292}

Left ventricular dysfunction, post–myocardial infarction (treatment)—Captopril and trandolapril are indicated following myocardial infarction in clinically stable patients with left ventricular dysfunction to improve survival and decrease the incidence of overt heart failure and subsequent hospitalization for congestive heart failure. ^{258} ^{259} ^{260} ^{290} ^{291} ^{307} ^{308} Left ventricular dysfunction was determined by ejection fraction £ 40% for the captopril study ^{290} ^{291}, and by identification of wall motion abnormalities for the trandolapril study ^{307} ^{308}.

Myocardial infarction, acute—Lisinopril is indicated for the treatment of hemodynamically stable patients within 24 hours of an acute myocardial infarction to improve survival ^{297} ^{298} ^{299} ^{300}

Diabetic nephropathy (treatment)—Captopril may be used in the treatment of nephropathy in patients with Type 1 insulin-dependent diabetes mellitus (IDDM). ^{62} ^{279} ^{290} ^{291} Captopril has been shown to slow the progression of diabetic nephropathy in normotensive and hypertensive IDDM patients with documented diabetic retinopathy, a serum creatinine concentration of £ 2.5 mg per deciliter, and urinary protein excretion of ³ 500 mg in 24 hours. ^{62} The greatest effect has been seen in those patients with poorer renal function at baseline (mean serum creatinine concentration ³ 1.5 mg per deciliter). ^{62} ^{277} ^{278}

Risk reduction for myocardial infarction, stroke and death from cardiovascular causes¹—Ramipril is indicated in patients 55 years of age and older who are at high risk of developing a major cardiovascular event with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Ramipril can be used in addition to other needed treatment such as antihypertensive, antiplatelet or lipid-lowering therapy.
^{317}
[Scleroderma, hypertension in (treatment) ]¹or
[Scleroderma, renal crisis in (treatment) ]¹—ACE inhibitors are also used for treatment of hypertension or renal crisis in scleroderma ^{49} ^{202} ^{203} ^{204} ^{205} ^{206} ^{207} ^{208} ^{209} ^{210}.

Acceptance not established
Captopril has been studied for the treatment of congestive heart failure and hypertension in neonates. However, there are insufficient data to establish its efficacy for these indications; therefore, further studies, especially randomized controlled studies, are warranted^{318}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Benazepril hydrochloride: 460.96 ^{97} ^{288}
    Captopril: 217.29 ^{290}
    Cilazapril: 435.52 ^{310}
    Enalapril: 492.52. ^{97}
    Enalaprilat (active metabolite): 384.43 ^{97} ^{293}
    Fosinopril sodium: 585.65 ^{295}
    Lisinopril: 441.52 ^{97} ^{297}
    Moexipril hydrochloride: 535.04 ^{305}
    Perindopril erbumine: 441.61 ^{313}
    Quinapril hydrochloride: 474.98 ^{97}
    Ramipril: 416.52 ^{97}
    Trandolapril: 430.54 ^{307}

pKa—
    Captopril: 3.7 and 9.8 (apparent)

Mechanism of action/Effect:

Benazepril—Benazeprilat (active metabolite) ^{86} ^{90} ^{91}

Captopril—Not a prodrug ^{107}

Cilazapril—Cilazaprilat (active metabolite) ^{309}

Enalapril—Enalaprilat (active metabolite) ^{108}

Fosinopril—Fosinoprilat (active metabolite) ^{110} ^{123} ^{124} ^{127} ^{128}

Lisinopril—Not a prodrug ^{109}

Moexipril—Moexiprilat (active metabolite) ^{301}

Perindopril—Perindoprilat (active metabolite) ^{302}^{313}

Quinapril—Quinaprilat (active metabolite) ^{89} ^{93} ^{94} ^{95} ^{303} ^{98}

Ramipril—Ramiprilat (active metabolite) ^{112} ^{113} ^{115} ^{117} ^{118} ^{119}

Trandolapril—Trandolaprilat (active metabolite) ^{307}

Antihypertensive—Exact mechanism of antihypertensive action is unknown but is thought to be related to competitive inhibition of angiotensin I–converting enzyme (ACE) activity, resulting in a decreased rate of conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Decreased angiotensin II concentrations result in a secondary increase in plasma renin activity (PRA), through removal of the negative feedback of renin release ^{49} ^{242}, and a direct reduction in aldosterone secretion resulting in small increases in serum potassium, sodium, and fluid loss ^{286}. ACE inhibitors may be less effective in control of blood pressures among low renin hypertensives, predominantly the black patient population, as compared to normal or high renin hypertensive patients. ^{286} ACE inhibitors reduce peripheral arterial resistance. ^{286} In addition, a possible effect on the kallikrein-kinin system (interference with degradation and resulting increased concentrations of bradykinin) and an increase in prostaglandin synthesis have been suggested but not proven ^{03} ^{05}.

Vasodilator, congestive heart failure—Decrease in peripheral vascular (afterload) resistance, pulmonary capillary wedge pressure (preload), and pulmonary vascular resistance; and improved cardiac output and exercise tolerance ^{251}.

Other actions/effects:

Captopril may reduce proteinuria in hypertensive patients with diabetic nephropathy. ^{215} ^{216} ^{217} ^{218} ^{219} ^{220} ^{290}This effect may be due to the beneficial change in intrarenal hemodynamics (renal vasodilatation and reduced filtration pressure) produced by captopril resulting in decreased urinary protein excretion ^{215} ^{217}.

Absorption:

Benazepril—At least 37% absorbed from the gastrointestinal tract ^{86} ^{91}; presence of food does not affect the extent of absorption but may increase the time to peak concentration ^{288}.

Captopril—Rapidly and at least 75% absorbed from the gastrointestinal tract. Absorption is reduced by 30 to 55% in the presence of food. ^{107} ^{193}

Cilazapril—Rapidly; about 57% absorbed from the gastrointestinal tract. ^{309} Absorption is reduced by 14% and peak is delayed by 1 hour in the presence of food; however, this has little influence on plasma ACE inhibition. ^{309}

Enalapril—Approximately 60%; not affected by the presence of food. ^{108} ^{199} ^{200} ^{292}

Fosinopril—Slowly; about 36% absorbed from the gastrointestinal tract. ^{110} ^{130} ^{131} ^{147} Absorption rate may be decreased in presence of food, but extent of absorption is not affected. ^{110} ^{130} ^{295}

Lisinopril—Approximately 25%, but widely variable between individuals (6 to 60%) ^{243}; not affected by the presence of food. ^{51} ^{243} ^{297}

Moexipril—Approximately 13% absorbed from the gastrointestinal tract ^{301}; presence of food reduces the extent of absorption by 40%, and approximately 10% more is reduced with high fat content foods. ^{301}

Perindopril—Rapidly, at least 65% to 75% from the gastrointestinal tract; presence of food does not affect the rate or extent of absorption of perindopril, but absolute bioavailability of perindoprilat is reduced 35%^{313}. ^{302}

Quinapril—Approximately 60% ^{93} ^{94} ^{95} ^{98} ^{303}; presence of food does not affect extent of absorption, ^{93} ^{94} ^{95} but may increase the time to peak drug concentration. ^{95} ^{303} High-fat meals may moderately decrease, 25–30%, the rate and extent of absorption. ^{303}

Ramipril—Rapidly and at least 50 to 60% absorbed from the gastrointestinal tract. ^{111} ^{113} ^{116} ^{305} Extent of absorption is not affected by the presence of food ^{111} ^{119}; however, the rate of absorption is reduced. ^{111} ^{305}

Trandolapril—Approximately 10%; presence of food slows the rate but not the extent of absorption. ^{307}

Protein binding:

Benazepril—Very high (96.7%). ^{86} ^{90} ^{91} ^{92}

Benazeprilat (active metabolite)—Very high (95.3%). ^{86} ^{90} ^{91} ^{92}

Captopril—Low (25 to 30%), primarily to albumin ^{21} ^{22} ^{107}.

Enalaprilat—Moderate (50 to 60%).

Fosinoprilat (active metabolite)—Very high (97 to 98%). ^{110} ^{127} ^{130} ^{131}

Lisinopril—None ^{243}.

Moexiprilat—Moderate (50%). ^{301}

Perindopril—Moderate (60%).^{313}^{314}

Perindoprilat (active metabolite)—Low (10% to 20%). ^{313} ^{314}

Quinaprilat (active metabolite)—Very high (97%). ^{93} ^{94} ^{95} ^{303}

Ramipril—High (73%). ^{111} ^{113} ^{115} ^{119}

Ramiprilat (active metabolite)—High (56%). ^{111} ^{113} ^{115} ^{119}

Trandolapril—High (80%), concentration independent. ^{307}

Trandolaprilat (active metabolite)—Moderate to high (65 to 94%), concentration dependent. ^{307}

Biotransformation:

Benazepril—Hepatic, to benazeprilat, the active metabolite. ^{86} ^{87} ^{91} ^{106}

Captopril—Hepatic.

Enalapril—Hepatic, by hydrolysis, to enalaprilat, the active metabolite. ^{200}

Enalaprilat—None.

Fosinopril—Hepatic, gastrointestinal mucosa; by hydrolysis to fosinoprilat, the active metabolite. ^{128} ^{130} ^{147}

Lisinopril—None ^{243}.

Moexipril—Converted in various organs and hepatically to moexiprilat, the active metabolite. ^{312}

Perindopril—Hepatic, by hydrolysis, to perindoprilat, the active metabolite, and to other metabolites by glucuronidation and cyclization via dehydration. ^{313}

Quinapril—Hepatic, gastrointestinal tract, extravascular tissue; by hydrolysis to quinaprilat, the active metabolite. ^{89} ^{95} ^{98} ^{99}

Ramipril—Hepatic. ^{111} ^{112} ^{117} ^{119}

Trandolapril—Hepatic, by hydrolysis to trandolaprilat, the active metabolite. ^{307}

Half-life:

Benazepril—0.6 hours. ^{92}

Benazeprilat (active metabolite)—Effective accumulation half-life is 10 to 11 hours. ^{86} ^{88} ^{91} ^{92}

Captopril—Less than 3 hours; increased in renal failure (3.5 to 32 hours). ^{107}

Enalaprilat (active metabolite)—11 hours; increased in renal failure. ^{108} ^{200}

Fosinoprilat (active metabolite)—Effective accumulation half-life is approximately 11.5 hours. ^{110} ^{147}

Lisinopril—12 hours ^{243}; increased in renal failure.

Moexipril—1.3 hours ^{301}

Moexiprilat (active metabolite)—Functional elimination half-life of approximately 12 hours. ^{301}

Quinapril—Approximately 1 to 2 hours. ^{93} ^{94} ^{98}

Quinaprilat (active metabolite)—Effective accumulation half-life is approximately 3 hours. ^{95} ^{303} ^{100} ^{104}

Perindopril—Approximately 0.8 to 1 hour. ^{313}

Perindoprilat (active metabolite)— Apparent mean half–life of 3 to 10 hours; terminal elimination half-life of 30 to 120 hours.^{313}

Ramipril—5.1 hours. ^{114}

Ramiprilat (active metabolite)—Effective accumulation half-life is 13 to 17 hours; ^{111} ^{115} increased in renal failure. ^{117} ^{118}

Trandolapril—6 hours ^{307}

Trandolaprilat (active metabolite)—10 hours ^{307}

Onset of action:

Single dose:

Benazepril: Within 1 hour. ^{91}

Captopril: 15 to 60 minutes. ^{290}

Enalapril: 1 hour ^{03}.

Enalaprilat (intravenous): 15 minutes. ^{248}

Fosinopril: Within 1 hour. ^{110}

Lisinopril: 1 hour. ^{243}

Moexipril: 1 hour. ^{301}

Perindopril: Within 1 to 2 hours. ^{315}

Quinapril: Within 1 hour. ^{94} ^{95} ^{96}

Ramipril: Within 1 to 2 hours. ^{111} ^{113}

Trandolapril: 2 hours. ^{308}

Time to peak serum concentration

Benazepril—0.5 to 1 hour. ^{86} ^{88} ^{90} ^{91} ^{92}

Benazeprilat (active metabolite)—1 to 1.5 hours. ^{86} ^{88} ^{90} ^{91} ^{92}

Captopril—30 to 90 minutes. ^{107}

Enalapril—1 hour (3 to 4 hours for enalaprilat). ^{108}

Enalaprilat (intravenous)—15 minutes. ^{194}

Fosinoprilat (active metabolite)—2 to 4 hours. ^{110} ^{126} ^{130} ^{131} ^{147}

Lisinopril—7 hours ^{243}.

Moexiprilat (active metabolite)—1.5 hours. ^{301}

Perindoprilat (active metabolite)—3 to 7 hours. ^{313}

Quinapril—Within 1 hour. ^{94} ^{95} ^{303}

Quinaprilat (active metabolite)—Within 2 hours. ^{94} ^{95} ^{303} ^{98} ^{104}

Ramipril—Within 1 hour. ^{111} ^{114} ^{115}

Ramiprilat (active metabolite)—3 hours. ^{114} ^{115}

Trandolapril—1 hour. ^{307}

Trandolaprilat (active metabolite)—4 to 10 hours. ^{307}

Time to peak effect:

Single dose:

Benazepril: 2 to 4 hours. ^{91}

Captopril: 60 to 90 minutes. ^{107}

Enalapril: 4 to 6 hours. ^{108}

Enalaprilat (intravenous): 1 to 4 hours ^{248}.

Fosinopril: 2 to 6 hours. ^{110}

Moexipril: 3 to 6 hours. ^{301}

Lisinopril: 6 hours ^{243}.

Perindopril: 3 to 7 hours.^{313}^{316}

Quinapril: 2 to 4 hours. ^{303}

Ramipril: 4 to 6.5 hours. ^{120} ^{121}

Trandolapril: Approximately 8 hours. ^{308}

Multiple doses:

The full therapeutic effect may not be noticed until several weeks after initiation of oral therapy.

Duration of action:

Single dose—:

Benazepril: Approximately 24 hours. ^{91}

Captopril: Approximately 6 to 12 hours; dose related.

Enalapril: Approximately 24 hours. ^{108}

Enalaprilat (intravenous): Approximately 6 hours. ^{248}

Fosinopril: Approximately 24 hours. ^{110} ^{126} ^{129}

Lisinopril: Approximately 24 hours. ^{243}

Perindopril: Approximately 24 hours.^{313}

Moexipril: Approximately 24 hours. ^{301}

Quinapril: Up to 24 hours; dose related. ^{95} ^{98}

Ramipril: Approximately 24 hours. ^{111} ^{115} ^{120} ^{121}

Trandolapril: Approximately 24 hours. ^{307}

Elimination:

Benazepril—
        Predominantly renal. ^{86} ^{87} ^{91}
        Nonrenal (biliary): 11 to 12%. ^{91}
        In dialysis: Benazeprilat is slightly removable by hemodialysis. ^{91}

Captopril—
        Renal: More than 95% ^{107}; 40 to 50% unchanged (may be less in patients with congestive heart failure ^{252}); remainder as metabolites ^{107}.
        In dialysis: Captopril is removable by hemodialysis.

Enalapril—
        Renal: 60% (20% as enalapril and 40% as enalaprilat). ^{200}
        Fecal: 33% (6% as enalapril and 27% as enalaprilat). ^{200}
        In dialysis: Enalaprilat is removable by hemodialysis ^{11}, at the rate of 62 mL per minute, and by peritoneal dialysis ^{254}.

Enalaprilat—
        Renal: 100% unchanged ^{248}.
        In dialysis: Enalaprilat is removable by hemodialysis at the rate of 62 mL per minute ^{248}.

Fosinopril—
        Renal: 44 to 50%. ^{110} ^{127} ^{131} ^{147}
        Fecal: 46 to 50%. ^{110} ^{127} ^{131} ^{147}
        In dialysis: Fosinopril is not well dialyzed. ^{110} Fosinoprilat clearance by hemodialysis and peritoneal dialysis is approximately 2% and 7%, respectively, of urea clearance. ^{110}

Lisinopril—
        Renal: 100% unchanged ^{243}.
        In dialysis: Lisinopril is removable by hemodialysis ^{50}.

Moexipril—
        Renal: 13% (1% as moexipril, 7% as moexiprilat, and 5% as other metabolites). ^{301}
        Fecal: 53% (52% as moexiprilat and 1% as moexipril). ^{301}
        In dialysis: It is not known whether moexipril or moexiprilat is removable by hemodialysis. ^{301}

Perindopril—
        Renal: 75%^{314} (4% to 12% as perindopril^{313}, 4.5% to 22% as perindoprilat^{314}).
        Fecal: 25%^{314}
        In dialysis: Mean dialysis clearance of perindopril is 52 mL per minute; perindoprilat mean dialysis clearance is 67.2 mL per minute. ^{313}

Quinapril—
        Renal: 61% (56% as quinapril and quinaprilat). ^{93} ^{94}
        Fecal: 37%. ^{93} ^{94}
        In dialysis: Minimal effect on the elimination of quinapril and quinaprilat. ^{303}

Ramipril—
        Renal: Approximately 60%. ^{111} ^{115} ^{116}
        Fecal: Approximately 40%. ^{111} ^{115} ^{116}
        In dialysis: It is not known whether ramipril or ramiprilat is removable by hemodialysis. ^{111}

Trandolapril—
        Renal: 33% (15% as trandolaprilat). ^{308}
        Fecal: 66% (38% as trandolaprilat). ^{308}
        In dialysis: Minimal effect on the elimination of trandolapril and trandolaprilat. ^{307}

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one ACE inhibitor also may be sensitive to another.

Carcinogenicity

Benazepril—Studies in mice and rats given doses of 150 mg per kg of body weight (mg/kg) per day (110 times the maximum recommended human dose by weight) for up to 2 years revealed no evidence of carcinogenicity. ^{91}

Captopril—Two-year studies in mice and rats at doses of 50 to 1350 mg/kg per day showed no evidence of carcinogenicity.

Enalapril—Studies in rats for 106 weeks and in mice for 94 weeks at doses up to 150 and 300 times the maximum daily human dose (based on a patient weight of 50 kg), respectively, found no evidence of tumorigenicity or carcinogenicity ^{01}.

Enalaprilat (intravenous)—Studies have not been done. However, since actions of enalapril maleate are caused by enalaprilat, the active metabolite, the same information would be expected to apply ^{49}.

Fosinopril—Studies in mice and rats given doses up to 400 mg/kg per day for up to 24 months revealed no evidence of carcinogenicity. However, a slightly higher incidence of mesentery/omentum lipomas was found in male rats given the highest dose level (about 250 times the maximum human dose by weight). ^{110}

Lisinopril—Studies in male and female rats for 105 weeks at doses up to 56 times the maximum recommended human daily dose (based on a patient weight of 50 kg) and in male and female mice for 92 weeks at doses up to 84 times the maximum recommended human daily dose (based on a patient weight of 50 kg) found no evidence of tumorigenicity ^{245}.

Moexipril—Long-term studies in mice and rats given doses up to 14 or 27.3 times the maximum recommended human daily dose (based on a milligrams per square meter of body surface area) found no evidence of carcinogenicity. ^{301}

Perindopril—Long-term studies in mice and rats given doses up to 20 times (based on milligrams per kilogram) or 2 to 4 times (based on a milligrams per square meter of body surface area) the proposed clinical dose of 16 milligrams per day found no evidence of carcinogenicity.^{313}

Quinapril—Studies in mice and rats given doses up to 75 or 100 mg/kg per day (50 to 60 times the maximum recommended human daily dose by weight) for 104 weeks revealed no evidence of carcinogenicity. However, female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. ^{96}

Ramipril—Studies in rats and mice given doses up to 500 mg/kg per day for 24 months and up to 1000 mg/kg per day for 18 months, respectively, revealed no evidence of tumorigenicity. Renal juxtaglomerular apparatus hypertrophy was found in mice, rats, dogs, and monkeys given doses greatly in excess of recommended human doses. ^{111}

Trandolapril—Long-term studies in mice at doses up to 25 mg/kg per day and in rats at doses up to 8 mg/kg per day, showed no evidence of carcinogenicity. ^{307}

Mutagenicity

Benazepril—No evidence of mutagenicity was found in tests including the Ames bacterial assay (with or without metabolic activation), an in vitro test for forward mutations in cultured mammalian cells, and a nucleus anomaly test. ^{91}

Enalapril and enalaprilat— No evidence of mutagenicity was found in tests including the Ames bacterial assay with or without metabolic activation, rec-assay, reverse mutation assay with E. coli , sister chromatid exchange with cultured mammalian cells, the micronucleus test with mice, and in an in vivo cytogenic study using mouse bone marrow.

Fosinopril—No evidence of mutagenicity was found in tests including the Ames bacterial assay, the mouse lymphoma forward mutation assay, and a mitotic gene conversion assay. No evidence of genotoxicity was found in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo . An increased frequency of chromosomal aberrations was found in the Chinese hamster ovary cell cytogenetic assay at toxic cell concentrations tested without metabolic activation. However, this increase was not found at lower drug concentrations without metabolic activation or at any other concentration with metabolic activation. ^{110}

Lisinopril—No evidence of mutagenicity was found in tests including the Ames bacterial assay with or without metabolic activation, forward mutation assay using Chinese hamster lung cells, in vitro alkaline elution rat hepatocyte assay, and chromosomal aberration studies in vitro in Chinese hamster ovary cells and in vivo in mouse bone marrow ^{243}.

Moexipril—No evidence of mutagenicity was found in the Ames test and microbial reverse mutation assay, with and without activation, or in an in vivo nucleus anomaly test. ^{301} However, at 20 hours harvest time, increased chromosomal aberration frequency in Chinese hamster ovary cells was detected under metabolic activation conditions. ^{301}

Perindopril—No evidence of mutagenicity was found in the Ames bacterial assay, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests, and Chinese hamster bone marrow assay.^{313}

Quinapril—No evidence of mutagenicity was found in the Ames bacterial assay with or without metabolic activation. ^{96}

Ramipril—No evidence of mutagenicity was found in tests including the Ames bacterial assay, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, and a forward gene-mutation assay in a Chinese hamster ovary cell line. ^{111}

Trandolapril—No evidence of mutagenicity was found in the Ames test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. ^{307}

Pregnancy/Reproduction
Fertility—
Benazepril: No adverse effect on the reproductive performance of male and female rats was found. ^{91}

Captopril: No impairment of fertility was found in rats. ^{107}

Enalapril: No adverse effects on reproductive performance were found in male and female rats given 10 to 90 mg/kg of enalapril per day . ^{108}

Fosinopril: No adverse reproductive effects were found in male and female rats given doses up to 60 mg/kg per day (about 38 times the maximum recommended human dose by weight). However, a slight increase in pairing time was observed in rats given a toxic dose of 240 mg/kg per day (150 times the maximum recommended human dose by weight). ^{110}

Lisinopril: No adverse effects on reproductive performance were found in male and female rats given doses up to 300 mg/kg per day of lisinopril. ^{109}

Moexipril: No evidence of impaired fertility, reproductive toxicity, or teratogenicity was detected in reproduction studies performed in rabbits and rats at doses up to 0.7 and 90.9 times the maximum recommended human dose, respectively, on a mg per square meter basis. ^{301}

Perindopril: No adverse effects on reproductive performance or fertility were found in male and female rats given doses 30 times (based on milligrams per kilogram) or 6 times (milligrams per square meter) the proposed maximum clinical dose of perindopril.^{313}

Quinapril: No adverse effects on fertility or reproduction were found in rats given doses up to 100 mg/kg per day (60 times the maximum daily human dose based on weight). ^{96}

Ramipril: No impairment of fertility was found in rats given doses up to 500 mg/kg per day. ^{111}

Trandolapril: No impairment of fertility was found in rats administered doses of up to 100 mg/kg per day, which is 1250 times the maximum recommended human dose based on weight. ^{307} ^{308}

Pregnancy—
In humans, ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. ^{91} ^{96} ^{107} ^{108} ^{109} ^{110} ^{111} ACE inhibitors should be discontinued as soon as possible when pregnancy is detected. ^{286}

ACE inhibitors cross the placenta. ^{91} ^{107} ^{109} ^{110} ^{254} Fetal exposure to ACE inhibitors during the second and third trimesters can cause hypotension ^{132} ^{133} ^{136} ^{137}, renal failure ^{132} ^{133} ^{135} ^{136} ^{137}, anuria ^{132} ^{133} ^{135} ^{136} ^{137}, skull hypoplasia ^{132} ^{133}, and even death in the newborn ^{132} ^{133} ^{136} ^{137}. Maternal oligohydramnios has also been reported, probably reflecting decreasing fetal renal function ^{132} ^{133} ^{135} ^{136} ^{250} ^{286}.

Enalapril and lisinopril have been removed from neonatal circulation by peritoneal dialysis ^{108} ^{134} ^{236} ^{254} ^{261}. Captopril is not removable by peritoneal dialysis. There are inadequate data concerning the effectiveness of hemodialysis and there is no information concerning use of exchange transfusion for removing captopril from general circulation. ^{107} There has been no experience with hemodialysis, peritoneal dialysis, or exchange transfusion for removing benazepril, fosinopril, perindopril, quinapril, or ramipril from neonatal circulation. ^{91} ^{96} ^{109} ^{110} ^{111}^{313}

It is recommended that infants exposed in utero to ACE inhibitors be closely observed for hypotension, oliguria, and hyperkalemia ^{254}. Oliguria should be treated with support of blood pressure and renal perfusion by administration of fluids and pressors as appropriate ^{91} ^{96} ^{110} ^{111} ^{245} ^{247} ^{254}.

Benazepril: Studies in pregnant rats, mice, and rabbits at doses 300, 90, and more than 3 times, respectively, the maximum recommended human dose by weight, revealed no embryotoxic, fetotoxic, or teratogenic effects. ^{91}

Captopril: Several cases of intrauterine growth retardation, fetal distress and hypotension, and one case of cranial malformation have been reported. Neonatal deaths have occurred in rats at up to 400 times the recommended human dose. Fetal deaths have occurred when rabbits were given 2 to 70 times the maximum recommended human dose, and a low incidence of cranial malformations occurred in offspring. No teratogenicity has been noted in hamsters or rats.

Enalapril: Fetal toxicity (decrease in average fetal weight) has occurred in rats at doses of enalapril 2000 times the maximum daily human dose, and maternal and fetal toxicity has occurred in rabbits at doses almost double the maximum daily human dose. In some cases, saline supplementation prevented maternal and fetal toxicity. No teratogenicity has been noted in rabbits and neither fetal toxicity nor teratogenicity occurred in rats at doses up to 333 times the maximum daily human dose.

Fosinopril: Maternal toxicity was evident in pregnant rabbits given doses up to 40 mg/kg per day (about 50 times the maximum recommended human dose). Fosinopril at doses up to 40 mg/kg per day (about 50 times the maximum recommended human dose) was embryocidal in rabbits, probably due to marked decreases in blood pressure secondary to ACE inhibition in this species. There was no evidence of teratogenicity in rabbits at any dosage level. ^{110} Maternal toxicity was evident in pregnant rats at all dose levels tested up to 400 mg/kg per day (about 500 times the maximum recommended human dose). Furthermore, all dose levels produced slight reductions in placental weights and some degree of skeletal ossification. High doses resulted in reduced fetal body weight. Three similar orofacial malformations and one fetus with situs inversus occurred in animals given fosinopril. It is uncertain whether these anomalies were associated with drug treatment. ^{110}

Lisinopril: Lisinopril was not teratogenic in mice given doses up to 625 times the maximum recommended human dose on days 6 to 15 of gestation; an increase in fetal resorptions occurred at doses of 62.5 times the maximum recommended human dose, but was prevented at doses of 625 times the maximum recommended human dose by saline supplementation. No fetotoxicity or teratogenicity occurred in rats given doses up to 188 times the maximum recommended human dose on days 6 to 17 of gestation, but an increased incidence of pup deaths and a lower average birth weight (both preventable by saline supplementation) occurred postpartum in rats given lisinopril on day 15 of gestation through day 21 postpartum. Lisinopril crosses the placenta in rats but has not been found in the fetus. Lisinopril did not cause teratogenicity in saline-supplemented rabbits given doses up to 1 mg/kg per day but did cause fetotoxicity (increased fetal resorptions, increased incidence of incomplete ossification). ^{243}

Moexipril: No teratogenicity was observed in rats or rabbits given up to 90.9 and 0.7 times the maximum recommended human dose, respectively, on a mg per square meter basis. ^{301}

Perindopril:No teratogenicity was observed after exposure to doses 6 times, 670 times, 50 times, and 17 times the maximum recommended human dose (MRHD) in mice, rats, rabbits, or monkeys, based on a mg per square meter basis, respectively. . On a mg/kg basis, the values are 60 times, 3750 times, 150 times, and 50 times the MRHD, respectively^{313}

Quinapril: Quinapril at doses as high as 300 mg/kg per day (180 times the maximum daily human dose by weight) did not produce fetotoxic or teratogenic effects in rats, despite maternal toxicity at 150 mg/kg per day. However, reduced offspring body weight was observed at doses greater than 25 mg/kg per day, and changes in renal histology (juxtaglomerular cell hypertrophy, tubular/pelvic dilation, glomerulosclerosis) were seen in dams and offspring given 150 mg/kg per day when tested later in gestation and during lactation. Quinapril did not produce teratogenic effects in rabbits. However, in some rabbits maternal toxicity and embryotoxicity were observed at doses as low as 0.5 mg/kg per day (one time the recommended human dose) and 1.0 mg/kg per day. ^{96}

Ramipril: Studies in rats, mice, monkeys, and rabbits at doses up to 2500 times (in rats and mice), more than 12 times, and more than 2 times, respectively, the maximum recommended human dose by weight, revealed an increased incidence of dilated renal pelvises in rat fetuses and retarded birth weights in mice. However, these studies did not show ramipril to produce terata or to affect fertility, reproductive performance, or pregnancy. ^{111}

Trandolapril: Teratogenic effects were not observed in rabbits given doses of 0.8 mg/kg per day, in rats given doses of 1000 mg/kg per day, or in monkeys given doses of 25 mg/kg per day. ^{307} These doses represent 10, 1250, and 312 times the maximum recommended human dose by weight, respectively. ^{307}

For all ACE inhibitors:
FDA Pregnancy Category C—First trimester.

FDA Pregnancy Category D—Second and third trimesters.

Breast-feeding

Benazepril—Benazepril and benazeprilat are distributed into breast milk. A nursing infant would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat. ^{91}

Cilazapril—It is not known whether cilazapril is distributed into human breast milk; cilazaprilat appears to distribute into the milk of lactating rats. However, problems in humans have not been documented.^{309}

Captopril—Captopril is distributed into breast milk; concentrations in breast milk are approximately 1% of maternal blood concentrations. However, problems in humans have not been documented.

Enalapril— Enalapril and enalaprilat are distributed into breast milk. However, problems in humans have not been documented. ^{292}

Fosinopril—Fosinoprilat (active metabolite) is distributed into breast milk. Detectable levels of fosinoprilat in breast milk were found following ingestion of 20 mg per day for 3 days. ^{110}

Lisinopril—It is not known whether lisinopril is distributed into human breast milk; it appears to distribute into the milk of lactating rats. However, problems in humans have not been documented. ^{243}

Moexipril—It is not known whether moexipril is distributed into breast milk. ^{301} However, problems in humans have not been documented. ^{301}

Perindopril—It is not known whether perindopril is distributed into human breast milk; it appears to distribute into the milk of lactating rats. However, problems in humans have not been documented.^{313}

Quinapril—It is not known whether quinapril or its metabolites are distributed into human breast milk; quinapril appears to distribute into the milk of lactating rats. However, problems in humans have not been documented. ^{96}

Ramipril—A 10-mg dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, multiple doses may produce low milk concentrations. ^{111}

Trandolapril—It is not known whether trandolapril is distributed into breast milk. ^{307} Trandolapril and/or its metabolites are distributed into the milk of lactating rats. ^{307} However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of ACE inhibitors have not been done in the pediatric population. ^{286} However, the use of ACE inhibitors in a limited number of neonates and infants has identified some potential pediatrics-specific problems. In neonates and infants, there is a risk of oliguria and neurologic abnormalities, possibly as a result of decreased renal and cerebral blood flow secondary to marked and prolonged reductions in blood pressure caused by ACE inhibitors ^{66} ^{67} ^{68} ^{170} ^{286}; a lower initial dose and close monitoring are recommended.

Geriatrics

ACE inhibitors are thought to be most effective in reducing blood pressure in patients with normal or high plasma renin activity. Since plasma renin activity appears to decline with increasing age, elderly individuals may be less sensitive to the hypotensive effects of ACE inhibitors. However, elevated serum ACE inhibitor concentrations resulting from age-related decline in renal function may compensate for the lower renin dependence ^{13} ^{14} ^{15} ^{46} ^{55} ^{140} ^{150}. Pharmacokinetic studies with lisinopril, perindopril, quinapril, and ramipril have revealed higher peak serum concentrations and area under the curve (AUC) in elderly patients given doses similar to those given to younger adults ^{96} ^{109} ^{111} ^{243} ^{246}^{313}. The net result is that no significant differences in blood pressure response or side/adverse effects have been noted in elderly patients receiving ACE inhibitors. ^{91} ^{96} ^{110} ^{111} ^{139} ^{140} ^{141} ^{142} ^{143} ^{144} ^{145} ^{307} ^{308} Nevertheless, some elderly patients may be more sensitive to the hypotensive effects of these medications and may require caution when receiving an ACE inhibitor. ^{91} ^{96} ^{110} ^{111} ^{286}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

For all ACE inhibitors
» Alcohol ^{301} or
» Diuretics ^{91}^{303} ^{107} ^{108} ^{109} ^{110} ^{111} ^{173} ^{286} ^{287}^{313} or
Hypotension-producing medications, other (see Appendix II )    (concurrent use with ACE inhibitors may produce additive hypotensive effects )

    (antihypertensive agents that cause renin release or affect sympathetic activity have the greatest additive effect ^{107} ^{108} ^{290} ^{309}; concurrent use of captopril with beta-adrenergic blocking agents produces an increased but less than fully additive effect ^{107}; although some antihypertensive and/or diuretic combinations may be used for therapeutic advantage, dosage adjustments may be necessary during concurrent use or when one drug is discontinued)

    (if significant systemic absorption of ophthalmic beta-blockers occurs, hypotensive effects of ACE inhibitors may be potentiated)

    (sudden and severe hypotension may occur within the first 1 to 5 ^{49} hours after the initial dose of an ACE inhibitor, particularly in patients who are sodium- and volume-depleted as a result of diuretic therapy. Withdrawal of the diuretic or increase of salt intake approximately 1 week before start of captopril ^{107} therapy or 2 to 3 days before start of benazepril,^{91} enalapril ^{292}, fosinopril ^{110}, lisinopril ^{109}, quinapril ^{96}, perindopril ^{313}, or ramipril ^{111} therapy, or initiating ACE inhibitor therapy in lower doses, will minimize the reaction; this reaction does not usually recur with subsequent doses, although caution in increasing doses is recommended ^{49}; diuretics may be reinstituted as necessary ^{26} ^{30} ^{31} ^{32} ^{43})

    (risk of renal failure may be increased in patients who are sodium- and volume-depleted as a result of diuretic therapy ^{287})

    (ACE inhibitors may reduce the secondary aldosteronism and hypokalemia caused by diuretics)

Antacids ^{295} ^{308}    (concurrent use with fosinopril and trandolapril reduced serum levels and urinary excretion of fosinopril and trandolapril as compared with the ACE inhibitors administered alone, which suggests antacids may impair the absorption of ACE inhibitors; if concurrent use is indicated, dosing should be separated by 2 hours. ^{295})

Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin ^{107} ^{109} ^{286} ^{297}    (concurrent use of these agents may reduce the antihypertensive effects of ACE inhibitors; indomethacin, and possibly other NSAIDs, may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention ^{05} ^{16}; the patient should be carefully monitored to confirm that the desired effect is being obtained)

Blood from blood bank (may contain up to 30 mEq [mmol] of potassium per liter of plasma or up to 65 mEq [mmol] per liter of whole blood when stored for more than 10 days) or
Cyclosporine or
» Diuretics, potassium-sparing ^{16} ^{21} ^{22} ^{23} ^{24} ^{25} ^{91} ^{303} ^{107} ^{108} ^{109} ^{110} ^{111} ^{290} ^{309}^{313} or
» Low-salt milk (may contain up to 60 mEq [mmol] of potassium per liter) or
» Potassium-containing medications or
» Potassium supplements or substances containing high concentrations of potassium or ^{107} ^{108} ^{109} ^{110} ^{111} ^{287}^{313} ^{292}^{313}
» Salt substitutes (most contain substantial amounts of potassium) ^{16} ^{303} ^{107} ^{108} ^{109} ^{307}    (concurrent administration with ACE inhibitors may result in hyperkalemia since reduction of aldosterone production induced by ACE inhibitors may lead to elevation of serum potassium; frequent determination of serum potassium concentrations is recommended if concurrent use of these agents is necessary; concurrent use is not recommended in patients with congestive heart failure ^{251})

Allopurinol or
Cytostatic agents or
Procainamide or
Systemic corticosteroids ^{308} or
Bone marrow depressants (see Appendix II )    (concurrent administration with an ACE inhibitor may result in an increased risk of development of potentially fatal neutropenia and/or agranulocytosis ^{16} ^{17} ^{18} ^{19} ^{20} ^{290})

Lithium    (reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use with ACE inhibitors; frequent monitoring of serum lithium concentrations is recommended during concurrent use ^{91} ^{303} ^{107} ^{108} ^{109} ^{110} ^{111} ^{164} ^{171} ^{172} ^{256} ^{286} ^{297})

^{313}
Sympathomimetics    (concurrent use of these agents may reduce the antihypertensive effects of ACE inhibitors; the patient should be carefully monitored to confirm that the desired effect is being obtained ^{287} ^{288})

For quinapril only
Tetracyclines or
Other drugs that interact with magnesium ^{303}    (concurrent use of these agents with quinapril may reduce their absorption; absorption of tetracycline is reduced by approximately 28 to 37%, possibly due to the high magnesium content in Accupril brand of quinapril tablets ^{303} ^{226} ^{286})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
For all ACE inhibitors
Iodohippurate sodium I 123/I 131 renal imaging ^{85} or
Technetium Tc 99m pentetate renal imaging    (in patients with renal artery stenosis, captopril [and probably all ACE inhibitors] may cause a reversible decrease in localization and excretion of iodohippurate I 123/I 131 ^{85} or technetium Tc 99m pentetate ^{48} ^{79} ^{80} ^{81} ^{82} ^{83} in the affected kidney; may cause confusion as to whether decreased renal function is drug-related ^{48} ^{49})

For captopril only
Urinary acetone test ^{107} ^{196} ^{290}    (captopril may produce false-positive results)

For fosinopril only
Digoxin levels    (fosinopril may cause a false low serum digoxin level with the Digi-Tab RIA Kit ^{110} ^{295})

With physiology/laboratory test values
For benazepril only
ECG changes ^{286}For quinapril only
Hematuria ^{304}For all ACE inhibitors
Alkaline phosphatase, serum and
Bilirubin, serum and
Transaminases, serum ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{304} ^{305} ^{306} ^{307} ^{308}^{313}    (concentration increases have been reported ^{183} ^{184} ^{238} ^{286})

Antinuclear antibody (ANA) titer ^{107} ^{108} ^{109} ^{110} ^{181}    (positive ANA has been reported)

Blood urea nitrogen (BUN) and
Creatinine, serum ^{91} ^{108} ^{109} ^{110} ^{111} ^{288} ^{301}^{303} ^{304} ^{306} ^{307}^{313}    (concentrations may be transiently increased, especially in patients with renal parenchymal and renovascular ^{02} disease in patients who are volume- or sodium-depleted ^{107} ^{238}, in patients with renal artery stenosis ^{107} ^{108} ^{109}, or after rapid reduction of long-standing or severe high blood pressure ^{107})

Glucose, serum    (may be elevated ^{286} ^{289} ^{306} ^{309})

Hematocrit or
Hemoglobin    (may rarely be slightly decreased ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{251} ^{286} ^{292} ^{296} ^{297}^{313})

Lymphocytes ^{304} or
Neutrophiles    (may be lowered ^{286})

Protein, urinary ^{296} ^{305} ^{306}    (concentration may be transiently increased in patients with pre-existing proteinuria or diabetes mellitus ^{301})

Potassium, serum ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{286} ^{288} ^{293}^{303} ^{307}^{313}    (concentrations may be slightly increased as a result of reduced circulating aldosterone concentrations and concomitant reduction in glomerular filtration rate [GFR], especially in patients with renal function impairment)

Sodium, serum ^{107} ^{108} ^{110} ^{190} ^{195} ^{286} ^{290} ^{293}    (concentrations may be slightly decreased, especially during initial therapy )

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist

For all ACE inhibitors:
» Angioedema, ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{286}^{303} history of, related to previous ACE inhibitor therapy ^{247} ^{287} or
» Hereditary angioedema ^{180} or
» Idiopathic angioedema ^{174} ^{179}    (increased risk for development of ACE inhibitor–related angioedema )

Aortic stenosis ^{286} ^{296} or
Cerebrovascular disease or
Ischemic heart disease    (reduction in blood pressure from ACE inhibitor therapy could aggravate these conditions ^{301} ^{307})

Autoimmune disease, severe, especially systemic lupus erythematosus (SLE), other collagen vascular diseases, ^{287} or scleroderma ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{288}^{303}    (increased risk for development of neutropenia or agranulocytosis)

Bone marrow depression ^{290}    (increased risk for agranulocytosis and neutropenia)

Diabetes mellitus ^{173} ^{301}    (increased risk of hyperkalemia, insulin sensitivity and/or increased glucose tolerance has been reported in diabetic patients receiving ACE inhibitors ^{301})

» Hyperkalemia ^{290}
» Renal artery stenosis, bilateral or in a solitary kidney ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{290} ^{292} ^{302}^{303} or
» Renal transplant    (increased risk of renal function impairment; increased risk of agranulocytosis and neutropenia when immunosuppressants are also administered to the patient ^{288})

» Renal function impairment ^{286} ^{287} ^{288} ^{290} ^{292}    (decreased elimination of active ACE inhibitor [except fosinopril], resulting in higher plasma concentrations ^{10} ^{11} ^{110}; increased risk of hyperkalemia ^{91} ^{108} ^{109} ^{110} ^{111} ^{303}or, for captopril, proteinuria, neutropenia, and agranulocytosis ^{107}. Patients with impaired renal function may require lower or less frequent doses and smaller increments in dose ^{10} ^{175}. However, dosage adjustment may not be necessary with fosinopril since total body drug clearance even in severe renal function impairment is not decreased significantly, possibly due to compensatory hepatobiliary elimination. ^{110} If a diuretic is also required, a loop diuretic ^{49} is recommended instead of a thiazide diuretic in patients with severe renal function impairment )

Sensitivity to the ACE inhibitor prescribed, or any other ACE inhibitor ^{91} ^{107} ^{286} ^{287}
» Caution is required also in patients on severe dietary sodium restriction or dialysis; these patients may be volume-depleted, and sudden reduction by the initial dose of ACE inhibitor in the angiotensin II levels that have been maintaining them at a near-normotensive state may result in sudden and severe hypotension ^{02} ^{26} . In addition, the risk of ACE inhibitor–induced renal failure may be increased in patients who are sodium- and volume-depleted, especially those with congestive heart failure.
For benazepril, captopril, enalapril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril (in addition to the above):
» Hepatic function impairment ^{301} ^{307}^{313}    (may reduce metabolism of captopril and may reduce conversion of prodrug to active moiety with benazepril, enalapril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)

Leukocyte count determinations, total and differential    (recommended prior to initiation of ACE inhibitor therapy and periodically thereafter; recommended every month for the first 3 to 6 months of therapy, and at periodic intervals thereafter for a period of up to 1 year in patients at increased risk for neutropenia [i.e., those with renal function impairment or collagen vascular disease] or receiving high doses ^{57}; also recommended at the first sign of infection. It is recommended that ACE inhibitor therapy be withdrawn if neutropenia [neutrophil count less than 1000 per cubic millimeter (1 × 10 ⁹/L)] is confirmed ^{107})

Liver function tests    (recommended baseline for patients with pre-existing liver abnormalities and for patients on captopril; also for patients taking ACE inhibitors when experiencing any unexplained symptoms during the first weeks or months of treatment ^{290} ^{301} ^{309})

Potassium, serum    (recommended periodically in patients at risk for hyperkalemia, such as those with renal insufficiency, or diabetes mellitus, or for patients on concurrent potassium-sparing diuretic therapy, potassium supplements, and/or potassium containing salt substitutes ^{301} ^{307}^{313})

Renal function determinations    (recommended at periodic intervals, especially in patients who are sodium- and volume-depleted as a result of diuretic therapy or who have severe congestive heart failure ^{58})

Urinary protein estimates by means of dipstick on first morning urine ^{107}    (recommended prior to initiation of therapy and at periodic intervals thereafter for up to 1 year in patients with renal function impairment or those receiving doses of captopril greater than 150 mg per day; if excessive or increasing proteinuria occurs, it is recommended that ACE inhibitor therapy be re-evaluated )

Side/Adverse Effects

Note: Proteinuria has occurred in about 1% of patients receiving greater than 150 mg of captopril per day. ^{197} This adverse effect is thought to be due to the sulfhydryl moiety of captopril. ^{28} However, whether this is a true causal relationship is unknown. ^{28} Proteinuria usually occurs in patients with existing renal function impairment within 8 months of initiation of captopril therapy and usually reverses within 6 months even with continuation of therapy. ^{107} Membranous glomerulopathy has been reported in some of these patients, especially with doses of captopril greater than 150 mg per day. Proteinuria has also been reported in patients receiving enalapril and lisinopril. ^{28} ^{222} Reported incidences range from 0% to 1.4% for enalapril and 0.7% for lisinopril. ^{28} ^{221} ^{222}
There have been reports of reversible renal failure during ACE inhibitor therapy, especially in patients with bilateral renal artery stenoses or renal artery stenosis in a solitary kidney ^{05} ^{07} ^{08}. There is also evidence that renal failure may be related to sodium and volume depletion from previous diuretic therapy or severe sodium restriction, especially in patients with congestive heart failure ^{02} ^{04} ^{05} ^{06} ^{26} ^{33} ^{59}.
Hepatotoxicity has been reported rarely in patients receiving captopril, ^{265} ^{266} ^{267} ^{268} ^{270} ^{272} ^{273} enalapril, ^{267} ^{271} ^{273} ^{274} and lisinopril ^{269}. Cholestasis has been reported most frequently, ^{265} ^{266} ^{268} ^{270} ^{273} although hepatic necrosis and hepatocellular injury have also been reported. ^{267} ^{269} ^{271} The most common presenting symptoms are jaundice, pruritus, and abdominal tenderness. ^{275} ACE inhibitor–associated hepatotoxicity is usually reversible upon discontinuation of therapy. ^{268} ^{270} ^{274} ^{275} Apparent cross-reactivity has been reported between captopril and enalapril and between lisinopril and enalapril. ^{267} ^{273} ^{275}

Severe, life-threatening, anaphylactoid reactions have occurred in two patients using ACE inhibitors during desensitization protocols involving hymenoptera venom. Additionally, some patients treated with ACE inhibitors who have been exposed to either high-flux membrane dialysis or low-density lipoprotein apheresis with dextran sulfate absorption have also experienced anaphylactoid-like reactions^{313}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent

Hypotension (dizziness, light-headedness, or fainting)— especially following the initial dose in sodium- or volume-depleted patients ^{26} ^{27} ^{28} ^{29} ^{174} ^{286} ^{301}^{303} ^{307} or in patients receiving an ACE inhibitor for congestive heart failure ^{42} ^{174}

skin rash, with or without itching, fever, or joint pain ^{03}^{107}^{174}

Note: Maculopapular or, rarely, urticarial rash usually occurs during the first 4 weeks of the therapy with captopril and usually disappears with dosage reduction or withdrawal, or administration of an antihistamine ^{107}; between 7 and 10% of these patients may show eosinophilia and/or positive antinuclear antibody (ANA) titers. ^{107} The reaction may also occur, less frequently, with the other ACE inhibitors. ^{91} ^{108} ^{109} ^{110} ^{111} ^{243}^{303}
Rarely, a persistent lichenoid or pemphigoid reaction, possibly with a photosensitive factor ^{174}, has been reported with captopril.

Incidence rare

Angioedema of the extremities, face, lips, mucous membranes, tongue, glottis, and/or larynx ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{177} ^{178} ^{301}^{303}^{307} (sudden trouble in swallowing or breathing ^{251}; swelling of face, mouth, hands, or feet; hoarseness ^{238})—especially following the initial dose ^{177}

chest pain

hyperkalemia ^{174} ^{301} ^{303}^{307} (confusion; irregular heartbeat; nervousness; numbness or tingling in hands, feet, or lips; shortness of breath or difficult breathing; weakness or heaviness of legs )

neutropenia or agranulocytosis ^{185} ^{186} ^{187}^{303} (fever and chills)

pancreatitis ^{226} ^{227} ^{228} ^{229} ^{301} ^{307} (abdominal pain; nausea; vomiting; abdominal distention; fever)

Note: Angioedema involving the tongue, glottis, or larynx may cause airway obstruction ^{176}, which could be fatal ^{91} ^{107} ^{108} ^{109} ^{110} ^{111} ^{238}^{303}.
Chest pain is usually associated with severe hypotension ^{60}.
Incidence of neutropenia or agranulocytosis is much higher in patients with renal function impairment (0.2% for captopril) or collagen vascular disease ^{03} ^{187} ^{191} (e.g., SLE or scleroderma) (3.7% for captopril). Neutropenia appears to be dose-related ^{174} and may begin within 3 months after initiation of therapy, with the nadir of the leukocyte count occurring after 10 to 30 days and persisting about 2 weeks after withdrawal. Deaths from pancytopenia and sepsis have been reported with captopril in patients with and without autoimmune disease.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Cough, dry, persistent ^{34} ^{35} ^{36} ^{37} ^{38} ^{39} ^{40} ^{41} ^{52} ^{69} ^{70} ^{174} ^{188} ^{189} ^{251} ^{301}^{303} ^{307}

headache ^{01} ^{91} ^{96} ^{107} ^{108} ^{109} ^{110} ^{111} ^{174} ^{301} ^{307}

Note: Cough usually occurs within the first week of therapy (onset varies from 24 hours to several weeks after initiation) ^{69}, persists throughout therapy, and disappears within a few days after withdrawal of the ACE inhibitor ^{69}. Characteristically the cough begins as a tickling sensation in the back of the throat leading to a dry, nonproductive, persistent cough ^{69}; may be worse at night or in the supine position ^{69}; onset can be paroxysmal and course may be episodic or intermittent ^{69}; may occasionally lead to hoarseness or vomiting ^{69}.

Incidence less frequent

Diarrhea ^{01} ^{91} ^{107} ^{108} ^{109} ^{110} ^{111}^{303}

dysgeusia (loss of taste)^{107}^{111}^{174}^{191}^{287}

fatigue (unusual tiredness)^{01}^{91}^{107}^{108}^{109}^{110}^{111}^{174}^{301}^{303}^{307}

nausea ^{01} ^{91} ^{107} ^{108} ^{109} ^{110} ^{111}^{303}

Note: Loss of taste is usually reversible after 2 to 3 months even with continued treatment, and may be associated with weight loss.

Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Treatment of overdose consists of volume expansion for correction of hypotension^{05}^{09} and established procedures for treating dehydration and electrolyte imbalance.^{313} Captopril, enalaprilat, lisinopril, trandolaprilat ^{286}, and perindoprilat^{302}^{313} are removable by hemodialysis. Benazeprilat is slightly removable by hemodialysis. ^{288}

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Angiotensin-converting Enzyme (ACE) Inhibitors .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to any ACE inhibitor

Pregnancy—ACE inhibitors cross the placenta; ACE inhibitor-associated fetal hypotension, oliguria, and death reported in humans; fetotoxicity found in animals

Breast-feeding—Benazepril, captopril, and fosinopril are distributed into breast milk
Other medications, especially alcohol, diuretics (particularly potassium-sparing), potassium-containing medications, or potassium supplements

Use of low-salt milk or salt substitutes
Other medical problems, especially angioedema related to previous ACE inhibitor therapy, hepatic function impairment, hyperkalemia, renal artery stenosis, renal transplant, renal function impairment, or sodium and volume depletion

Proper use of this medication
Compliance with therapy; taking medication at the same time each day to maintain the therapeutic effect

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

For captopril and moexipril
For best results, taking on an empty stomach 1 hour before meals

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake ^{223}; risks associated with sodium depletion; not taking salt substitutes or using low-salt milk unless approved by physician

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension

» Proper storage

Precautions while using this medication
Making regular visits to physician to check progress

Receiving immediate medical attention for any signs of facial or extremity swelling and/or difficulty in swallowing or breathing, because of the risk of angioedema ^{286}

» Notifying physician immediately if pregnancy is suspected ^{286}

Caution when driving or doing other things requiring alertness, because of possible dizziness, especially after initial dose of ACE inhibitor in patients taking diuretics

Checking with physician if severe nausea, vomiting, or diarrhea occurs and continues, because of the risk of dehydration, which may result in hypotension ^{71} ^{72} ^{73}

Caution when exercising or during exposure to hot weather because of the risk of dehydration (due to excessive perspiration), which may result in hypotension ^{01} ^{239}

Caution if any kind of surgery (including dental surgery) or emergency treatment is required

Reporting any signs of infection (chills, fever, or sore throat) to physician, because of the risk of neutropenia ^{286} ^{301} ^{307}

For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician ^{223}

For captopril and fosinopril
Caution if any laboratory tests required; possible interference with test results

Side/adverse effects
Signs of potential side effects, especially hypotension, skin rash (with or without itching, fever, or joint pain), angioedema, chest pain, hyperkalemia, neutropenia or agranulocytosis, and pancreatitis.

General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response.

The hypotensive effect of ACE inhibitors is about the same in both standing and supine positions. ^{107} ^{109} ^{110} ^{111}

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery may be undesirable. However, the anesthesiologist must be aware of such therapy. ^{262}

If increased blood urea nitrogen (BUN) and creatinine concentrations occur, reduction in dosage of the ACE inhibitor and/or withdrawal of the diuretic may be required. The possibility of renovascular hypertension should also be considered, especially in the presence of a solitary kidney, transplanted kidney, or bilateral renal artery stenosis ^{61}.

Caution is recommended in initiating ACE inhibitor therapy for congestive heart failure in patients who have been receiving digitalis glycosides and/or diuretics. If the patient is sodium- and water-depleted, a lower initial dosage should be used.

If symptomatic hypotension occurs, dosage reduction of the ACE inhibitor or withdrawal of the ACE inhibitor or diuretic may be necessary ^{251}.

For treatment of adverse effects
For angioedema with swelling confined to the face, mucous membranes of the mouth, lips, and extremities, treatment other than withdrawal of the medication is usually not necessary, although antihistamines may relieve the symptoms ^{238} ^{240}.
Treatment of angioedema involving the tongue, glottis, or larynx ^{240} may include the following:

   • Withdrawal of the ACE inhibitor and hospitalization of the patient ^{04}.
   • Subcutaneous (or, rarely, intravenous) epinephrine.
   • Intravenous diphenhydramine hydrochloride.
   • Intravenous hydrocortisone.

BENAZEPRIL

Summary of Differences

Precautions:
Breast-feeding—Benazepril and benazeprilat are distributed into breast milk.

Additional Dosing Information
See also General Dosing Information .

It is recommended that previous diuretic therapy be withdrawn 2 to 3 days before benazepril therapy is initiated ^{91}, except in patients with accelerated or malignant hypertension or hypertension that is difficu


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