Criteria for Outpatient Use Guidelines

Table 2
Maximum Dosage Recommendations for
ACE Inhibitor Combination Therapy in Adults

DRUG	MAXIMUM DAILY DOSAGE
Amlodipine/Benazepril (Lotrel ®, generics)     2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg,     10 mg/40 mg capsules	hypertension: 10 mg/40 mg
Benazepril/Hydrochlorothiazide (Lotensin HCT®, generics) 5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg tablets	hypertension: 40 mg/50 mg
Captopril/Hydrochlorothiazide (generics) 25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg tablets	hypertension: 150 mg/50 mg
Enalapril/Hydrochlorothiazide (Vaseretic®, generics) 5 mg/12.5 mg, 10 mg/25 mg tablets	hypertension: 20 mg/50 mg
Fosinopril/Hydrochlorothiazide (generics) 10 mg/12.5 mg, 20 mg/12.5 mg tablets	hypertension: 20 mg/12.5 mg
Lisinopril/Hydrochlorothiazide (Prinzide®, Zestoretic®, generics) 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg tablets	hypertension: 80 mg/50 mg
Moexipril/Hydrochlorothiazide (Uniretic®, generics)      7.5 mg/12.5 mg, 15 mg/12.5 mg, 15 mg/25 mg tablets	hypertension: 30 mg/50 mg
Quinapril/Hydrochlorothiazide (Accuretic®, generics) 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg tablets	hypertension: 40 mg/25 mg
Trandolapril/Verapamil (Tarka®, generics) 1 mg/240 mg, 2 mg/180 mg, 2 mg/240 mg, 4 mg/240 mg extended-release tablets	hypertension: 8 mg/240 mg

 

Pediatrics
Select ACE inhibitors are FDA-approved for use to manage hypertension in pediatric patients.  Maximum recommended ACE inhibitor doses for pediatric patients are summarized in Table 3.  Dosages exceeding these recommendations will be reviewed.

Table 3
Maximum Recommended Doses for
ACE inhibitors in Pediatric Patients

DRUG	MAXIMUM DAILY DOSAGE
Benazepril	hypertension: 6 years of age and older:  0.6 mg/kg/day up to 40 mg/day
Enalapril	hypertension: 1 month of age and older:  0.58 mg/kg/day up to 40 mg/day
Fosinopril	hypertension: 6 to 16 years of age, > 50 kg:  40 mg daily
Lisinopril	hypertension:  6 years of age and older:  0.61 mg/kg/day up to 40 mg/day

2. Duration of Therapy

There is no basis for limiting ACE inhibitor therapy duration when utilized to manage hypertension, heart failure, and proteinuria associated with diabetic nephropathy, as these conditions require chronic treatment.  Additionally, the American College of Cardiology (ACC)/American Heart Association 2007 guidelines for ST-elevation myocardial infarction (STEMI) recommend indefinite therapy with ACE inhibitors for these patients, while the ACC/AHA 2007 guidelines for unstable angina/non-STEMI patients recommend prolonged use of ACE inhibitors in select patients.

3.*Duplicative Therapy

The use of two or more ACE inhibitors concurrently is not justified.  Additional therapeutic benefit is not realized when ACE inhibitors are used in combination.  Patient profiles documenting the receipt of multiple ACE inhibitors will be reviewed.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

Drug-drug interactions considered clinically significant for ACE inhibitors are summarized in Table 4.  Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life-threatening which have not yet been classified will be reviewed:

Table 4
ACE Inhibitor Drug-Drug Interactions

TARGET DRUG	INTERACTING DRUG	INTERACTION	RECOMMENDATION	CLINICAL SIGNIFICANCE*+
ACE inhibitors	aliskiren	potential for additive hypotensive effects; increased risk of hyperkalemia with this drug combination as both decrease serum aldosterone levels	administer drug combination cautiously; monitor serum potassium levels closely	moderate (DrugReax) 3-moderate (CP)
ACE inhibitors	antidiabetic agents	potential for enhanced hypoglycemic effects due to improved insulin sensitivity by ACE inhibitors	closely monitor blood glucose levels; reduced antidiabetic doses may be necessary	moderate (DrugReax) 3-moderate (CP) 2 (DIF)
ACE inhibitors	azathioprine	increased risk of anemia, leukopenia with drug combination; mechanism unknown	avoid combination, if possible; if combined therapy necessary, monitor for myelosuppression	major (DrugReax) 2-major (CP)
lisinopril	clozapine	potential for increased serum clozapine levels and enhanced pharmacologic, adverse effects; lisinopril may decrease clozapine renal elimination through unknown mechanism	assess clinical response, monitor serum clozapine levels if drug combination utilized	3-moderate (CP) 4 (DIF)
ACE inhibitors	cyclosporine	increased risk of acute renal failure, hyperkalemia with drug combination due to ACE inhibition, which causes decreased angiotensin II and aldosterone	closely monitor renal function and serum potassium levels with ACE inhibitor-cyclosporine drug combination	moderate (DrugReax) 3-moderate (CP)
ACE inhibitors	entecavir	potential for increased entecavir serum levels and enhanced pharmacologic/adverse effects due to ACE inhibitor effects on renal function	monitor for increased adverse events if drug combination is administered	3-moderate (CP)
ACE inhibitors	eplerenone	increased risk of hyperkalemia as both agents decrease aldosterone levels	closely monitor serum potassium levels	2-major (CP)
ACE inhibitors	heparin	increased risk of hyperkalemia due to additive suppression of aldosterone synthesis	administer drug combination cautiously; closely monitor serum potassium levels	3-moderate (CP)
ACE inhibitors	lithium	potential for increased serum lithium levels and enhanced pharmacologic, toxic effects, possibly due to decreased lithium clearance	avoid combination, if possible; if drug combination necessary, monitor serum lithium levels and observe for signs of lithium toxicity	moderate (DrugReax) 3-moderate (CP) 2 (DIF)
ACE inhibitors	monoamine oxidase inhibitors	potential for additive hypotensive effects	monitor blood pressure closely, if drug combination utilized	3-moderate (CP)
ACE inhibitors	NSAIDs, salicylates, COX-2 inhibitors	potential for decreased antihypertensive effects, increased renal impairment risk (especially in patents dependent on renal prostaglandins for perfusion), with combined therapy due to inhibition of prostaglandin synthesis	monitor blood pressure, renal function, and clinical status if drug combination utilized; low-dose aspirin less likely to reduce ACE inhibitor antihypertensive, cardioprotective effects	moderate (DrugReax) 3-moderate (CP) 2, 4 (DIF)
ACE inhibitors	potassium-sparing diuretics, potassium salts	ACE inhibitors reduce aldosterone concentrations, resulting in increased potassium concentrations; increased risk of hyperkalemia with drug combination due to additive pharmacologic effects	monitor serum potassium levels and monitor patients for signs/symptoms of hyperkalemia if drug combination administered; patients with renal failure, diabetes, advanced age may be at increased risk; use combination cautiously in heart failure patients	major (DrugReax) 2-major (CP) 1 (DIF)
ACE inhibitors	pregabalin	combined therapy may increase risk of developing life-threatening angioedema with respiratory compromise	observe patients closely if drug combination utilized	2-major (CP)
ACE inhibitors	trimethoprim	combined therapy may increase risk of additive hyperkalemia due to decreased aldosterone synthesis by ACE inhibitor and potassium-sparing effect on distal nephron by trimethoprim	monitor serum potassium levels and monitor patients for signs/symptoms of hyperkalemia if drug combination administered	2-major (CP)

*CP = Clinical Pharmacology
+Drug Interaction Facts

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