MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Benazepril may be confused with Benadryl®
Lotensin® may be confused with Lioresal®, lovastatin
International issues:
Lotensin® may be confused with Latensin® which is a brand name for bacillus cereus in Germany
U.S. BRAND NAMES — Lotensin®
PHARMACOLOGIC CATEGORY
Angiotensin-Converting Enzyme (ACE) Inhibitor
DOSING: ADULTS — Hypertension: Oral: 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.
DOSING: PEDIATRIC — Hypertension: Children ≥ 6 years: Oral: 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)
(For additional information see “Benazepril: Pediatric drug information”)
DOSING: 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: 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.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as hydrochloride: 5 mg, 10 mg, 20 mg, 40 mg
Lotensin®: 5 mg, 10 mg, 20 mg, 40 mg
DOSAGE FORMS: CONCISE
Tablet: 5 mg, 10 mg, 20 mg, 40 mg
Lotensin®: 5 mg, 10 mg, 20 mg, 40 mg
GENERIC EQUIVALENT AVAILABLE — Yes
USE — Treatment of hypertension, either alone or in combination with other antihypertensive agents
ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Cardiovascular: Postural dizziness (2%)
Central nervous system: Headache (6%), dizziness (4%), fatigue (2%), somnolence (2%)
Gastrointestinal: Nausea (1%)
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% (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, pruritis, 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.
CONTRAINDICATIONS — Hypersensitivity to benazepril or any component of the formulation; angioedema or serious hypersensitivity related to previous treatment with an ACE inhibitor
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. Use in patients with previous angioedema associated with ACE inhibitor therapy is contraindicated. 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.
Special populations: Pediatrics: Safety and efficacy have not been established in children. 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.
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. Risk C: Monitor therapy
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
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. 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
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 effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
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
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
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).
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — 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.
PRICING — (data from drugstore.com)
Tablets (Benazepril HCl)
5 mg (90): $64.97
10 mg (30): $23.99
20 mg (30): $23.99
40 mg (30): $23.99
Tablets (Lotensin)
5 mg (30): $57.14
10 mg (30): $57.14
20 mg (30): $61.54
40 mg (30): $57.14
MONITORING PARAMETERS — Blood pressure; serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential
CANADIAN BRAND NAMES — Apo-Benazepril®; Lotensin®
INTERNATIONAL BRAND NAMES — Benace (IN); Boncordin (AR); Cibacen (AE, AT, BB, BE, BF, BG, BH, BJ, BM, BS, BZ, CH, CI, CY, DE, DK, EG, ES, ET, GH, GM, GN, GR, GY, ID, IE, IL, IQ, IR, IT, JM, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, NL, OM, PH, PT, QA, SA, SC, SD, SL, SN, SR, SY, TN, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Cibacen Cor (DE); Cibacene (FR); Labopal (ES); Lotensin (BR, CL, HN, HU, MX, PE, PL, UY, VE); Zaprace (CL)
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
PATIENT INFORMATION — May be taken without regard to meals. Do not stop therapy except under prescriber advice. Do not add a salt substitute (potassium) without advice of prescriber. May cause dizziness, fainting, and lightheadedness, especially in first week of therapy. Sit and stand up slowly. May cause changes in taste or rash. Report persistent cough or other side effects.