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Trandolapril

Pronunciation

(tran DOE la pril)

Dosage Forms

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

Tablet, Oral:

Mavik: 1 mg [scored]

Mavik: 2 mg, 4 mg [DSC]

Generic: 1 mg, 2 mg, 4 mg

Brand Names: U.S.

  • Mavik

Pharmacologic Category

  • Angiotensin-Converting Enzyme (ACE) Inhibitor
  • Antihypertensive

Pharmacology

Trandolapril is an ACE inhibitor which prevents the formation of angiotensin II from angiotensin I. Trandolapril must undergo enzymatic hydrolysis, mainly in liver, to its biologically active metabolite, trandolaprilat. A CNS mechanism may also be involved in the hypotensive effect as angiotensin II increases adrenergic outflow from the CNS. Vasoactive kallikreins may be decreased in conversion to active hormones by ACE inhibitors, thus reducing blood pressure.

Absorption

Slowed with food

Distribution

Trandolapril: ~18 L

Metabolism

Hepatically hydrolyzed to active metabolite, trandolaprilat and at least 7 other metabolites

Excretion

Urine (~33% as trandolapril and trandolaprilat); feces (~66%)

Renal clearance: 1 to 4 L/hour (dose dependent); reduced in renal impairment

Time to Peak

Trandolapril: ~1 hour; Trandolaprilat: 4 to 10 hours

Half-Life Elimination

Trandolapril: ~6 hours; Trandolaprilat: Effective: 22.5 hours

Protein Binding

Trandolapril: ~80%; Trandolaprilat: 65% to 94% (concentration dependent)

Special Populations: Renal Function Impairment

Plasma trandolapril and trandolaprilat are approximately 2-fold greater and renal Cl is decreased ~85% in patients with CrCl <30 mL/minute and in hemodialysis patients.

Special Populations: Hepatic Function Impairment

In patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were 9- and 2-fold greater, respectively, but inhibition of ACE activity was not affected.

Special Populations: Elderly

Plasma concentration of trandolapril is increased.

Use: Labeled Indications

Hypertension: Management of hypertension alone or in combination with other antihypertensive agents

Post-myocardial infarction (MI) heart failure or left-ventricular dysfunction: Treatment of post-MI heart failure (HF) in patients who are symptomatic from HF within the first few days after sustaining acute MI or post-MI left ventricular (LV) dysfunction in stable patients who have evidence of left-ventricular systolic dysfunction (identified by wall motion abnormalities).

Guideline recommendations:

Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:

• Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age with SBP ≥140 mm Hg or DBP is ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with CAD recommends the use of an ACE inhibitor (or an ARB) as part of a regimen in patients with hypertension and chronic stable angina if there is prior MI, LV systolic dysfunction, diabetes mellitus, or CKD. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

Heart failure: The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 heart failure guidelines recommend the use of ACE inhibitors, along with other guideline directed medical therapies, to prevent heart failure in patients with a reduced ejection fraction who have a history of MI (Stage B HF), to prevent heart failure in any patient with a reduced ejection fraction (Stage B HF), or to treat those with heart failure and reduced ejection fraction (Stage C HFrEF) (ACCF/AHA [Yancy 2013]).

STEMI: The 2013 ACCF/AHA guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) states that an ACE inhibitor should be initiated within the first 24 hours after STEMI in patients with anterior MI, heart failure, or left ventricular ejection fraction (LVEF) of 0.4 or less. It is also reasonable to initiate an ACE inhibitor in all patients with STEMI (O’Gara 2013).

Use: Unlabeled

To delay the progression of nephropathy and reduce risks of cardiovascular events in hypertensive patients with type 1 or 2 diabetes mellitus

Contraindications

Hypersensitivity to trandolapril or any component of the formulation; coadministration with aliskiren in patients with diabetes; hereditary/idiopathic angioedema; history of angioedema related to previous treatment with an ACE inhibitor.

Documentation of allergenic cross-reactivity for Angiotensin-Converting Enzyme Inhibitors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Women who are pregnant or planning to become pregnant; breast-feeding; concomitant use with aliskiren in patients with moderate to severe renal impairment (GFR <60 mL/minute/1.73 m2); hypotensive or hemodynamically unstable states; hemodynamically significant bilateral artery stenosis or severe artery stenosis of a solitary functioning kidney; concomitant use with angiotensin II receptor blockers (ARBs) in patients with diabetic nephropathy; hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

Dosing: Adult

Hypertension: Oral:

Patients not receiving a diuretic:

US labeling: Initial: 1 mg once daily (2 mg daily in black patients). Adjust dosage at intervals of ≥1 week according to blood pressure response; usual dosage (ASH/ISH [Weber 2014]): 2 to 8 mg daily. There is little experience with doses >8 mg daily. Patients inadequately treated with once daily dosing at 4 mg may be treated with twice daily dosing. If blood pressure is not adequately controlled with trandolapril monotherapy, a diuretic may be added.

Canadian labeling: Initial: 1 mg once daily. Adjust dosage at intervals of 2 to 4 weeks according to blood pressure response; usual maintenance dose: 1 mg to 2 mg once daily (maximum: 4 mg/day).

Patients receiving a diuretic: Consider discontinuing diuretic therapy 2 to 3 days before initiating trandolapril if possible; if blood pressure is not controlled by trandolapril alone, diuretic therapy should be resumed; if unable to discontinue diuretic, initiate trandolapril 0.5 mg once daily and monitor closely until blood pressure is stable; titrate to response as tolerated.

Post-MI heart failure or LV dysfunction: Oral:

US labeling: Initial: 1 mg once daily; titrate (as tolerated) toward target dose of 4 mg once daily. If 4 mg dose is not tolerated, patients may continue therapy with the greatest tolerated dose. The American College of Cardiology Foundation/American Heart Association guidelines recommend the use of a 0.5 mg test dose with titration up to 4 mg daily as tolerated (O’Gara 2013).

Canadian labeling: Initial (beginning ≥3 days after acute MI): 1 mg once daily; after 2 days may increase to 2 mg once daily as tolerated for 1 month and then increase to 4 mg once daily; patients unable to tolerate a dose increase may be maintained at the previously tolerated dose.

Heart failure with reduced ejection fraction (HFrEF) (off-label use): Oral: Initial: 1 mg once daily; target dose: 4 mg once daily (ACCF/AHA [Yancy 2013]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

US labeling:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.

CrCl <30 mL/minute: Initial: 0.5 mg once daily; titrate as tolerated to optimal response.

Canadian labeling:

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

CrCl <30 to ≥ 10 mL/minute/1.73 m2: Initial: 0.5 mg once daily; titrate as tolerated (maximum: 1 mg/day)

CrCl <10 mL/minute/1.73 m2: Initial: 0.5 mg once daily (maximum: 0.5 mg/day)

Dosing: Hepatic Impairment

US labeling:

Mild to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; consider lower doses in patients with hepatic impairment.

Cirrhosis: Initial: 0.5 mg once daily; titrate as tolerated to optimal response.

Canadian labeling:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Initial: 0.5 mg once daily; titrate as tolerated to optimal response.

Administration

Oral: Administer without regard to meals.

Dietary Considerations

Use potassium-containing salt substitutes cautiously in patients with diabetes, renal impairment, or those maintained on potassium supplements or potassium-sparing diuretics.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

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

Aliskiren: May enhance the hyperkalemic effect of ACE Inhibitors. Aliskiren may enhance the hypotensive effect of ACE Inhibitors. Aliskiren may enhance the nephrotoxic effect of ACE Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of ACE Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

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

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Ciprofloxacin (Systemic): ACE Inhibitors may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of ACE Inhibitors. Monitor therapy

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

DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: ACE Inhibitors may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

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

Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

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

Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. 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. Monitor therapy

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

Heparin: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. 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. 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. Consider therapy modification

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

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

Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

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

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

Nicorandil: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

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

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

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

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Pregabalin: ACE Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Monitor therapy

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

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

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

Salicylates: May enhance the nephrotoxic effect of ACE Inhibitors. Salicylates may diminish the therapeutic effect of ACE Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. 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. Consider therapy modification

Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

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

TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with HF. However, the frequency of adverse effects associated with placebo is also increased in this population.

>1%:

Cardiovascular: Hypotension (<1% to 11%), syncope (6%), bradycardia (<1% to 5%), cardiogenic shock (4%), intermittent claudication (4%)

Central nervous system: Dizziness (1% to 23%), stroke (3%)

Endocrine & metabolic: Uric acid increased (15%), hyperkalemia (5%), hypocalcemia (5%)

Gastrointestinal: Gastritis (4%), diarrhea (1%)

Neuromuscular & skeletal: Myalgia (5%), weakness (3%)

Renal: BUN increased (9%), serum creatinine increased (1% to 5%)

Respiratory: Cough (2% to 35%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Agranulocytosis, alopecia, angina, angioedema, arrhythmia, AV block (first-degree), bronchitis, cardiac failure, depression, epistaxis, fever, gout, hallucinations, hepatitis, hyponatremia, hypotension (symptomatic), impotence, insomnia, leukopenia, myocardial infarction, myocardial ischemia, neutropenia, pancreatitis, pancytopenia, paresthesia, pemphigus, pharyngitis, pruritus, rash, renal failure, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, transaminases increased, transient ischemic attack, upper respiratory tract infection, ventricular tachycardia, vertigo

Worsening of renal function may occur in patients with bilateral renal artery stenosis or hypovolemia. In addition, a syndrome which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia and positive ANA, and elevated ESR has been reported with ACE inhibitors. Eosinophilic pneumonitis has also been reported with other ACE inhibitors.

ALERT: U.S. Boxed Warning

Fetal toxicity:

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

Warnings/Precautions

Concerns related to adverse reactions:

• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising the airway) or the intestine (presenting with abdominal pain). African-Americans and patients with idiopathic or hereditary angioedema may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus, sirolimus, temsirolimus) therapy. 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 (some fatal); discontinue if marked elevation of hepatic transaminases or jaundice occurs.

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

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

• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium 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.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in BUN and serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small benign increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (Bakris 2000).

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with aortic stenosis; may reduce coronary perfusion resulting in ischemia. The Canadian labeling contraindicates use in patients with hemodynamically significant bilateral artery stenosis or severe artery stenosis of a solitary functioning kidney.

• 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. The Canadian labeling contraindicates use in patients with hypotensive or hemodynamically unstable states.

• 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.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment recommended in patients with cirrhosis and lower doses should be considered in patients with hepatic impairment.

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

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended in patients with CrCl <30 mL/minute. Avoid rapid dosage escalation, which may lead to further renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

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

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

Dosage forms specific issues:

• Lactose: Formulation may contain lactose. The Canadian labeling contraindicates use in patients with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Other warnings/precautions:

• Surgery: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).

Monitoring Parameters

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

2013 ACCF/AHA Heart Failure guideline recommendations: Within 1 to 2 weeks after initiation and periodically thereafter, reassess renal function and serum potassium especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements (ACCF/AHA [Yancy 2013]).

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. The use of these drugs in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester, although this finding may be confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), severe dizziness, passing out, cough that will not go away, bradycardia, severe abdominal pain, severe nausea, vomiting, or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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