Trandolapril (Monograph)

Brand name: Mavik
Drug class: Angiotensin-Converting Enzyme Inhibitors
- ACE Inhibitors
VA class: CV800
Chemical name: 1-Ethyl ester (2S,3aR,7aS)-1-[(S)-N-[(S)-1-carboxy-3-phenylpropyl] alanyl]hexahydro-2-indolinecarboxylic acid
Molecular formula: C₂₄H₃₄N₂O₅
CAS number: 87679-37-6

Medically reviewed by Drugs.com on Feb 23, 2024. Written by ASHP.

Introduction

Nonsulfhydryl ACE inhibitor.

Uses for Trandolapril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).

ACE inhibitors are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115..

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to ACE inhibitors. However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.

ACE inhibitors may be preferred in hypertensive patients with heart failure, ischemic heart disease, diabetes mellitus, CKD, or cerebrovascular disease or post-MI.

Heart Failure or Left Ventricular Dysfunction After Acute MI

Reduction of the risk of mortality (mainly cardiovascular mortality) and risk of heart failure-associated hospitalization following MI in hemodynamically stable patients who have evidence of left ventricular systolic dysfunction or who have demonstrated clinical signs of heart failure within a few days following acute MI.

Expert guidelines recommend initiation of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarct, heart failure, or ejection fraction ≤40% who do not have any contraindications (e.g., hypotension, shock, renal dysfunction). Use with caution (and with gradual upward titration) during initial postinfarction period because of the possibility of hypotension or renal dysfunction.

Continue therapy indefinitely in patients with left ventricular dysfunction or other compelling indications (e.g., hypertension, diabetes mellitus, CKD).

Heart Failure

Management of heart failure^{† [off-label]}, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers).

Some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria^{† [off-label]} who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.

Related/similar drugs

amlodipine, lisinopril, metoprolol, aspirin, losartan, furosemide, carvedilol

Trandolapril Dosage and Administration

General

BP Monitoring and Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

• If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

• If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic). Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.

Administration

Oral Administration

Administer orally once or twice daily.

Administer trandolapril/verapamil fixed combination with food; manufacturer makes no specific recommendation regarding administration of trandolapril with meals.

Dosage

In patients currently receiving diuretic therapy, discontinue diuretic or cautiously increase salt intake prior to initiating trandolapril. If diuretic cannot be discontinued, initiate trandolapril at a reduced dosage. (See Hypotension under Cautions and see the individual dosage sections in Dosage and Administration.)

Adults

Hypertension

Trandolapril Therapy

Oral

Initially, 2 mg once daily in black patients and 1 mg once daily in patients of other races as monotherapy. Adjust dosage based on BP response, usually at intervals of ≥1 week.

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating trandolapril. May resume diuretic therapy if BP not controlled adequately with trandolapril alone. If diuretic cannot be discontinued, initiate trandolapril therapy at 0.5 mg once daily under close medical supervision for several hours until BP has stabilized.

Usual maintenance dosage: Manufacturer states 2–4 mg once daily. Some experts state 1–4 mg once daily.

If 4 mg once daily does not adequately control BP, consider administering drug in 2 divided doses.

Limited clinical experience with dosages >8 mg daily.

Trandolapril/Verapamil Fixed-combination Therapy

Oral

Manufacturer states fixed-combination preparation should not be used for initial antihypertensive therapy.

May be used after adequate response is not achieved with trandolapril or verapamil monotherapy.

May be initiated in patients who experience dose-limiting adverse effects with either trandolapril or verapamil monotherapy.

For patients receiving verapamil (up to 240 mg) and trandolapril (up to 8 mg) in separate tablets once daily, replacement with the fixed combination can be attempted using tablets containing the same component doses.

Heart Failure or Left Ventricular Dysfunction After Acute MI

Oral

Manufacturer recommends initial dose of 1 mg.

Some experts recommend initiation of therapy within the first 24 hours of MI with a test dose of 0.5 mg.

Following initial dose, titrate as tolerated to a target dosage of 4 mg once daily; if 4 mg once daily is not tolerated, may continue therapy at the highest tolerated dosage.

Prescribing Limits

Adults

Hypertension

Oral

Limited clinical experience with dosages >8 mg daily.

Heart Failure† [off-label]

Oral

ACCF and AHA recommend maximum dosage of 4 mg once daily.

Special Populations

Hepatic Impairment

Hypertension

Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with hepatic cirrhosis; titrate subsequent dosage according to BP response.

Heart Failure or Left Ventricular Dysfunction after Acute MI

Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with hepatic cirrhosis; titrate subsequent dosage as tolerated according to response.

Renal Impairment

Hypertension

Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with severe renal impairment (Cl_cr <30 mL/minute); titrate subsequent dosage according to BP response.

Heart Failure or Left Ventricular Dysfunction after Acute MI

Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with severe renal impairment (Cl_cr <30 mL/minute); titrate subsequent dosage as tolerated according to response.

Cautions for Trandolapril

Contraindications

• Known hypersensitivity (e.g., history of angioedema) to trandolapril or another ACE inhibitor.

• History of hereditary/idiopathic angioedema.

• Concomitant therapy with aliskiren in patients with diabetes mellitus.

• Concomitant use (within 36 hours) of a neprilysin inhibitor (e.g., sacubitril).

Warnings/Precautions

Warnings

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics or undergoing dialysis, patients with diarrhea or vomiting). Risk of marked hypotension, sometimes associated with oliguria, azotemia, and rarely, death in patients with heart failure with or without associated renal insufficiency.

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical conditions. May minimize potential for hypotension by correcting volume and/or salt depletion prior to initiating trandolapril therapy. (See Dosage under Dosage and Administration.)

Initiate therapy in patients with heart failure (with or without associated renal insufficiency) under close medical supervision; monitor closely for first 2 weeks following initiation of trandolapril or any increase in trandolapril or diuretic dosage.

Take care to avoid hypotension in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.

If symptomatic hypotension occurs, place patient in supine position and, if necessary, administer IV infusion of 0.9% sodium chloride injection. Transient hypotension is not a contraindication to additional doses; however, consider reinitiating therapy at reduced doses of trandolapril and/or diuretic.

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy. (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.

Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.

Hematologic Effects

Neutropenia and agranulocytosis reported with captopril; risk of neutropenia appears to depend principally on presence of renal impairment and presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma); risk with trandolapril is unknown.

Consider monitoring leukocytes in patients with collagen vascular disease, especially if renal impairment exists.

Sensitivity Reactions

Anaphylactoid reactions and/or head and neck angioedema possible; angioedema associated with laryngeal edema may be fatal. Concomitant use of an ACE inhibitor and a mammalian target of rapamycin (mTOR) inhibitor or neprilysin inhibitor (e.g., sacubitril) may increase the risk of angioedema. If angioedema occurs, promptly discontinue trandolapril and observe patient until swelling disappears. Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.

Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption or following initiation of hemodialysis that utilized high-flux membrane.

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.

Contraindicated in patients with a history of angioedema associated with ACE inhibitors.

General Precautions

Renal Effects

Transient increases in BUN and S_cr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy. Possible increases in BUN and S_cr in patients with unilateral or bilateral renal artery stenosis; generally reversible following discontinuance of ACE inhibitor and/or diuretic.

Possible oliguria, progressive azotemia, and rarely, acute renal failure and/or death in patients with severe heart failure.

Closely monitor renal function following initiation of therapy in hypertensive patients with unilateral or bilateral renal artery stenosis. Some patients may require dosage reduction or discontinuance of ACE inhibitor and/or diuretic.

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes). (See Specific Drugs under Interactions.)

Monitor serum potassium concentration carefully in these patients.

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.

Specific Populations

Pregnancy

Category D.

Can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. (See Boxed Warning.)

Lactation

Distributed into milk in rats. Use not recommended.

Pediatric Use

If oliguria or hypotension occurs in neonates with a history of in utero exposure to trandolapril, support BP and renal function; exchange transfusions or dialysis may be required.

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults; however, possibility exists of greater sensitivity to the drug in some geriatric individuals.

Hepatic Impairment

Consider dosage reduction. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Deterioration of renal function may occur. (See Renal Effects under Cautions.)

Initial dosage adjustment recommended in patients with Cl_cr <30 mL/minute. (See Renal Impairment under Dosage and Administration.)

Black Patients

BP reduction may be smaller in black patients compared with patients of other races. (See Hypertension under Uses.)

Higher incidence of angioedema reported with ACE inhibitors in black patients compared with other races.

Common Adverse Effects

Patients with hypertension: Cough, dizziness, diarrhea.

Patients with left ventricular dysfunction after acute MI: Cough, dizziness, hypotension, elevated serum uric acid concentrations, elevated BUN, percutaneous transluminal coronary angioplasty (PTCA) or CABG, dyspepsia, syncope, hyperkalemia.

Drug Interactions

Specific Drugs

Trandolapril Pharmacokinetics

Absorption

Bioavailability

Prodrug; has little pharmacologic activity until hydrolyzed to trandolaprilat. Absolute bioavailability following oral administration of trandolapril is about 10% as trandolapril and 70% as trandolaprilat.

Peak concentrations of trandolapril and trandolaprilat are achieved within 1 and 4–10 hours, respectively, following administration in fasted state.

Onset

A single 2-mg dose results in approximately 70–85% inhibition of plasma ACE activity at 4 hours after administration.

During chronic therapy, maximum antihypertensive effect with any dosage is achieved within 1 week.

Duration

Following a single 2-mg dose, inhibition of plasma ACE activity declines by about 10% at 24 hours and by about one-half after 8 days.

Food

Food decreases rate of absorption but does not affect extent of absorption or peak plasma concentration.

Special Populations

In patients with mild to moderate alcoholic cirrhosis, plasma trandolapril and trandolaprilat concentrations are increased approximately 9- and 2-fold, respectively.

In patients with Cl_cr <30 mL/minute, plasma trandolapril and trandolaprilat concentrations are increased approximately 2-fold.

Distribution

Extent

Distributed into milk in rats.

Plasma Protein Binding

Trandolapril: 80% (independent of concentration).

Trandolaprilat: Concentration-dependent binding (65% at 1000 ng/mL and 94% at 0.1 ng/mL).

Elimination

Metabolism

Metabolized in the liver to an active metabolite, trandolaprilat. At least 7 other metabolites, principally glucuronide conjugates or de-esterification products, have been identified.

Elimination Route

Eliminated in urine (33%), principally as trandolaprilat, and in feces (66%).

Half-life

Elimination half-life of trandolapril: 6 hours.

Effective half-life of trandolaprilat: 22.5 hours.

Stability

Storage

Oral

Tablets

20–25°C.

Actions

• Prodrug; has little pharmacologic activity until hydrolyzed in the liver to trandolaprilat.

• Suppresses the renin-angiotensin-aldosterone system.

Advice to Patients

• Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions. Importance of reporting sensitivity reactions (e.g., edema of face, eyes, lips, tongue, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.

• Importance of reporting signs of infection (e.g., sore throat, fever).

• Risk of hypotension. Importance of informing clinicians promptly if lightheadedness or fainting occurs.

• Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.

• Risks of use during pregnancy. (See Boxed Warning.)

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium), as well as any concomitant illnesses.

• Importance of patients informing clinicians that they are receiving an ACE inhibitor with a long duration of action prior to undergoing surgery and/or anesthesia.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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