VA Class:CV800
Trandolapril is an angiotensin-converting enzyme (ACE) inhibitor.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17
Trandolapril is used alone or in combination with drugs from other classes of antihypertensive agents in the management of hypertension.1, 3, 5, 11, 13, 14, 15, 16, 17, 1200 Trandolapril also is used to reduce the risk of mortality (mainly cardiovascular mortality) as well as to reduce the risk of heart failure-associated hospitalization following myocardial infarction (MI) in hemodynamically stable patients who have evidence of left ventricular systolic dysfunction (identified by wall motion abnormalities) or who demonstrated clinical signs of heart failure within a few days following acute MI.1, 32
Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease) or in patients receiving immunosuppressive therapy, the possibility that similar adverse effects may occur with trandolapril should be considered since current evidence is insufficient to rule out such risk.1 (See Cautions: Hematologic Effects, in Captopril 24:32.04)
Trandolapril is used alone or in combination with drugs from other classes of antihypertensive agents in the management of hypertension.1, 3, 5, 11, 13, 14, 15, 16, 17, 1200 ACE inhibitors are considered one of several preferred antihypertensive drugs 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.501, 502, 503, 504, 1200 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.501, 502, 504, 1200, 1213 (See Uses: Hypertension, in Captopril 24:32.04.) ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease (CKD), or cerebrovascular disease or following MI.501, 502, 504, 523, 524, 525, 526, 527, 534, 535, 536, 543, 1200, 1214, 1215 (See Uses: Hypertension, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.)
In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1218 However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200, 1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors.24, 56, 57, 79, 80, 501, 504, 1200 Although ACE inhibitors have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low-renin hypertension.24, 25, 56, 57 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.1, 57, 1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.)
In controlled clinical trials, verapamil in fixed combination with trandolapril (2 or 4 mg trandolapril and 180 or 240 mg verapamil, respectively) administered once daily decreased placebo-corrected seated systolic blood pressure by about 7-12 mm Hg and diastolic blood pressure by about 6-8 mm Hg 24 hours after dosing.29 Blood pressure reductions were greater with fixed combination of 240 mg of verapamil and 4 mg of trandolapril than with either drug alone.29 Efficacy was not affected by age or gender, and antihypertensive effects have continued during long-term therapy (i.e., at least 1 year).29
For additional information on the role of ACE inhibitors in the management of hypertension, see Uses in Captopril 24:32.04 and Enalaprilat/Enalapril 24:32.04. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Heart Failure or Left Ventricular Dysfunction After Acute Myocardial Infarction
Trandolapril is used to reduce the risk of mortality (mainly cardiovascular mortality) and reduce the risk of heart failure-associated hospitalization following MI in hemodynamically stable patients who have evidence of left ventricular systolic dysfunction (identified by wall motion abnormalities) or clinical signs of heart failure within the first few days following acute MI.1, 32, 524 In these patients, when compared with those receiving placebo, trandolapril therapy initiated 3-7 days after acute MI reduced the risk of mortality from any cause by approximately 16% (mainly cardiovascular mortality); the risk of progression of heart failure (defined by heart failure-associated hospitalization, death, or requirement of an ACE inhibitor for the treatment of heart failure) was reduced by 20%.1, 32 This evidence of efficacy was obtained from a large, multicenter, randomized, double-blind, placebo-controlled, long-term (2-4 years) study (the Trandolapril Cardiac Evaluation; TRACE) in Caucasian patients.1, 32 Heart failure developed substantially earlier in patients receiving placebo compared with those receiving trandolapril.1 Trandolapril did not appear to reduce the rates of reinfarction,1, 32 although there was a trend to fewer such events when compared with placebo.1, 32 Trandolapril therapy was not associated with substantial effects on subsequent hospitalization, exercise tolerance, ventricular function, ventricular dimensions, or New York Heart Association (NYHA) heart failure status.1, 32
Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI.527, 803, 1100 The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia).527, 805, 1100 In addition to their effects on mortality, ACE inhibitors also are used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular “remodeling”) following acute MI.44, 45, 46, 47, 48, 49, 50, 524 Evidence regarding the efficacy of such therapy has been somewhat conflicting,35, 36, 37, 38, 39, 40, 41, 44, 45, 46, 47, 48, 49, 50 particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction.33, 34, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 47, 48, 49, 50 (See Uses: Left Ventricular Dysfunction After Acute Myocardial Infarction in Enalaprilat/Enalapril 24:32.04) However, the preponderance of evidence has shown a benefit of early oral therapy with ACE inhibitors, even in patients with no baseline dysfunction.1, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50
Current expert guidelines recommend the use of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction).527 While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction.527, 1100 ACE inhibitor therapy generally should be continued indefinitely in all patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, CKD).525, 1100 The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.527
ACE inhibitors have been used in the management of heart failure†, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers).60, 61, 62, 63, 64, 524, 800
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524, 701, 703, 800 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.524, 800 Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524, 800 In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.800 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction,524 some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization.702, 800 ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced 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.800 However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised.800 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.800 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.800 For additional information on the use of ACE inhibitors in the management of heart failure, see Uses: Heart Failure, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.
Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria†, 74, 75, 76, 77, 78, 1232 and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion.535, 536, 1232 The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.70 For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see Diabetic Nephropathy under Uses: Nephropathy, in Captopril 24:32.04.
Trandolapril is administered orally.1 Although food may decrease the rate (but not the extent) of absorption of the drug, no clinically important effects have been demonstrated and the manufacturer makes no specific recommendations for administering the drug with regard to meals.1, 92
Dosage of trandolapril must be adjusted according to patient tolerance and response.1 Because of the risk of inducing hypotension, initiation of trandolapril therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances.1 If therapy is initiated in a patient already receiving a diuretic, symptomatic hypotension may occur following the initial dose of the angiotensin-converting enzyme (ACE) inhibitor.1 To minimize the possibility of hypotension, especially in patients in whom diuretic therapy was recently initiated, it is recommended that diuretic therapy be discontinued or salt intake increased cautiously prior to initiating trandolapril therapy.600 If diuretic therapy cannot be discontinued, the initial dosage of trandolapril should be reduced.600 Dosage also should be adjusted carefully under close medical supervision in patients with heart failure, with or without associated renal insufficiency, because of the risk of hypotension; such patients should be followed closely for at least 2 weeks after initiation of trandolapril or diuretic therapy or dosage adjustment of either drug.1 (See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.) For additional information on initiating trandolapril in patients receiving diuretic therapy, see the disease-specific dosage sections in Dosage and Administration.
For the management of hypertension in adults not receiving a diuretic, the usual initial dosage of trandolapril is 1 mg once daily in nonblack patients and 2 mg once daily in black patients.31, 600 In patients currently receiving diuretic therapy, the diuretic should be discontinued 2-3 days before initiating trandolapril, if possible.600 If blood pressure is not adequately controlled with trandolapril alone, the diuretic may be resumed.600 If the diuretic cannot be discontinued, trandolapril therapy should be initiated at a reduced dosage of 0.5 mg daily under close medical supervision for several hours until blood pressure has stabilized.600
The manufacturer states that the usual maintenance dosage of trandolapril in adults is 2-4 mg once daily.600 Some experts state that the usual dosage range is 1-4 mg once daily.1200 Dosage of the drug should be adjusted according to blood pressure response.600 If the blood pressure response is not adequate with administration of trandolapril 4 mg once daily, giving the drug in 2 divided doses daily (e.g., 2 mg twice daily) should be considered.28, 600 Dosage generally is adjusted no more rapidly than at 1-week intervals.600 The safety and efficacy of dosages exceeding 8 mg daily have not been established.600 If blood pressure is not controlled with trandolapril alone, a second antihypertensive agent (e.g., a diuretic600 ) may be added.1200
Trandolapril/Verapamil Fixed-combination Therapy
The manufacturer states that the commercially available preparation containing trandolapril in fixed combination with verapamil should not be used for initial therapy of hypertension.601 The fixed-combination preparation generally should be used in adults after an adequate response is not achieved with trandolapril or verapamil monotherapy.601 Alternatively, therapy with the fixed-combination preparation may be initiated in patients who experience dose-limiting adverse effects with either trandolapril or verapamil monotherapy.601 For patients receiving verapamil (up to 240 mg) and trandolapril (up to 8 mg) in separate tablets once daily, replacement with the fixed-combination preparation can be attempted using tablets containing the same component doses.29 Clinical trials with the verapamil and trandolapril fixed combination have investigated only once-daily dosing.29 The fixed-combination tablets contain verapamil hydrochloride in an extended-release component and trandolapril in an immediate-release component.29 The antihypertensive effect or the adverse effects of adding 4 mg once daily of trandolapril to extended-release verapamil (240 mg twice daily) have not been studied, nor have the effects of adding 180 mg of verapamil extended-release tablets daily to 2 mg of trandolapril twice daily been evaluated.601 Over the dosage range of extended-release verapamil of 120-240 mg once daily and trandolapril 0.5-8 mg once daily, the effects of the fixed combination increase with increasing doses of either component.29
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with ACE inhibitor monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with trandolapril, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501, 504, 536 a 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
Heart Failure or Left Ventricular Dysfunction After Acute Myocardial Infarction
When used after acute myocardial infarction (MI) in adults with clinical signs of heart failure, the manufacturer recommends an initial trandolapril dose of 1 mg.1, 602 Some clinicians recommend initiation of therapy within the first 24 hours following MI with a test dose of 0.5 mg.527 Following the initial dose, trandolapril should be titrated, as tolerated, to a target dosage of 4 mg once daily.602 If a dosage of 4 mg once daily is not tolerated, therapy may be continued at the highest tolerated dosage.602
If trandolapril is used in patients with impaired renal function, dosage must be modified in response to the degree of renal impairment,1, 16 and, as with other ACE inhibitors, the theoretical risk of neutropenia must be considered.1
In hypertensive adults with creatinine clearances less than 30 mL/minute per 1.73 m2, the usual initial dosage of trandolapril is 0.5 mg daily.1, 3, 4, 16, 17 If an adequate response is not achieved, dosage may then be increased gradually until blood pressure is controlled or a maximum dosage of 4 mg daily is reached.1, 28 If concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic is preferred to a thiazide diuretic.28
In patients with hepatic cirrhosis, dosage of trandolapril should be initiated at 0.5 mg daily.1, 16 If an adequate response is not achieved, dosage may then be increased gradually16 until blood pressure is controlled or a maximum dosage of 4 mg daily is reached.1, 28
History of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor treatment.1
History of hereditary/idiopathic angioedema.603
Known hypersensitivity to trandolapril, other ACE inhibitors, or any ingredient in the formulation.1
Concomitant aliskiren therapy in patients with diabetes mellitus.603
Concomitant use (within 36 hours) of a neprilysin inhibitor (e.g., sacubitril).603 (See Drug Interactions: Neprilysin Inhibitors.)
When verapamil is used in fixed combination with trandolapril, the usual cautions, precautions, and contraindications associated with verapamil must be considered in addition to those associated with trandolapril.29 (See Cautions, in Verapamil 24:28.92.)
Like other ACE inhibitors, trandolapril rarely is associated with hypotension in patients with uncomplicated hypertension.1 Symptomatic hypotension may occur; patients at particular risk include those with severe volume and/or salt depletion secondary to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.1 Volume and/or salt depletion should be corrected before starting trandolapril therapy.1
Marked hypotension, which may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death, may occur in patients with heart failure (with or without associated renal impairment).1 In patients with heart failure, trandolapril therapy should be started at the recommended dose under close medical supervision with close monitoring for the first 2 weeks of treatment and whenever the dosage of trandolapril or diuretic is increased.1 (See Dosage and Administration: Dosage.) Hypotension also should be avoided in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.1
If symptomatic hypotension occurs, the patient should be placed in the supine position, and if necessary, an IV infusion of 0.9% sodium chloride injection to expand fluid volume should be administered.1 Transient hypotension is not a contraindication to further trandolapril therapy.1 The drug usually may be continued following restoration of blood pressure and volume; however, a reduction in dosage of trandolapril or concomitant diuretic therapy should be considered.1
Neutropenia/agranulocytosis, particularly in patients with renal impairment (especially those with concomitant collagen vascular disease [e.g., systemic lupus erythematosus, scleroderma]), reported with captopril.1 Data insufficient to rule out similar incidence of agranulocytosis with trandolapril in patients without prior reactions with other ACE inhibitors.1 Monitoring of leukocytes in patients with collagen vascular disease, especially if renal impairment exists, should be considered.1, 29
Fetal/Neonatal Morbidity and Mortality
Drugs that act on the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.1, 21, 22, 23, 24, 30, 603 ACE inhibitors also increase the risk of major congenital malformations when administered during the first trimester of pregnancy.81, 82 Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.603 Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.603 ACE inhibitors (e.g., trandolapril) should be discontinued as soon as possible when pregnancy is detected unless continued use is considered life-saving for the mother.82, 603 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.1, 21 For additional information on the risk of ACE inhibitors during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.
Rare ACE inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur; may progress to fulminant hepatic necrosis and is potentially fatal.1, 29 Patients receiving an ACE inhibitor, including trandolapril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring.1, 29
Sensitivity reactions, including anaphylactoid reactions and angioedema (including laryngeal angioedema, and tongue edema) are potentially fatal.1, 29 Head and neck angioedema involving the tongue, glottis, or larynx may cause airway obstruction.1, 29 If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, trandolapril should be discontinued and appropriate therapy (e.g., epinephrine) should be initiated immediately.1, 29 Angioedema has been reported at a higher rate in black patients compared with patients of other races receiving an ACE inhibitor.603 In addition, concomitant use of an ACE inhibitor and a mammalian target of rapamycin (mTOR) inhibitor or a neprilysin inhibitor (e.g., sacubitril) may increase the risk of angioedema.603
Intestinal angioedema (occasionally without a prior history of facial angioedema or elevated serum levels of complement 1 [C1] esterase inhibitor) also has been reported in patients receiving ACE inhibitors.1 Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery;1 symptoms usually have resolved after discontinuance of the ACE inhibitor.1 Intestinal angioedema should be considered in the differential diagnosis of patients who develop abdominal pain during therapy with an ACE inhibitor.1
Life-threatening anaphylactoid reactions have been reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.1, 29 When ACE inhibitors were temporarily discontinued before desensitization with the venom, anaphylactoid reactions did not recur; however, such reactions recurred after inadvertent rechallenge.1, 29 Anaphylactoid reactions also have been reported in patients following initiation of hemodialysis that used a high-flux membrane in patients receiving an ACE inhibitor.1, 29 In addition, anaphylactoid reactions have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption.1, 29
Inhibition of the renin-angiotensin-aldosterone (RAA) system may cause renal impairment and rarely renal failure and/or death in susceptible patients (e.g., those whose renal function depends on the activity of the RAA system such as patients with severe heart failure).1, 29
Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations may occur following administration of ACE inhibitor therapy, particularly in hypertensive patients with unilateral or bilateral renal-artery stenosis, preexisting renal impairment, or concomitant diuretic therapy.1 This effect usually was reversible following discontinuance of ACE inhibitor and/or diuretic therapy.1 Renal function should be monitored closely during the first few weeks of therapy and periodically thereafter in such patients.1
Hyperkalemia can develop, especially in those 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).1
Persistent and nonproductive; resolves after drug discontinuance.1
Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension.1 Hypotension in such patients may be corrected by volume expansion.1
Category D.603 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality, under Warnings/Precautions: Warnings, in Cautions.)
Trandolapril and its metabolites are distributed into milk in rats.1 Because of the potential for serious adverse reactions from trandolapril in nursing infants, the manufacturer states that the drug should not be used in nursing women.1
If oliguria or hypotension occurs in neonates with a history of in utero exposure to perindopril, blood pressure and renal function should be supported; exchange transfusions or dialysis may be required.603
The manufacturer states that efficacy and safety of trandolapril in children younger than 18 years of age have not been established.1, 28 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients in the Thiazides General Statement 40:28.20.
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1
Renal function may decrease with ACE inhibitor therapy in susceptible patients.1 Use with caution in those with renal impairment.1 (See Dosage and Administration: Special Populations and also Renal Effects under Warnings/Precautions: General Precautions, Renal Effects, in Cautions.)
ACE inhibitors generally are not as effective in black patients compared with other races.1 (See Uses: Hypertension.)
Adverse effects reported in more than 1% of patients receiving trandolapril for the treatment of hypertension include cough,1 dizziness,1 diarrhea,1 headache,1 and fatigue.1 Adverse effects reported in more than 1% of patients receiving trandolapril for the treatment of left ventricular dysfunction after acute myocardial infarction (MI) include cough,1 dizziness,1 hypotension,1 hyperuricemia,1 elevated BUN concentrations,1 percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG),1, 1 dyspepsia,1 syncope,1 hyperkalemia,1 bradycardia,1 hypocalcemia,1 myalgia,1 elevated serum creatinine concentrations,1 gastritis,1 cardiogenic shock,1 intermittent claudication,1 stroke,1 and asthenia.1 Adverse effects reported in more than 1% of patients receiving trandolapril in fixed combination with verapamil include first-degree atrioventricular (AV) block,29 bradycardia,29 bronchitis,29 chest pain,29 constipation,29 cough,29 diarrhea,29 dizziness,29 dyspnea,29 edema,29 fatigue,29 headache,29 elevated serum hepatic enzyme concentrations,29 nausea,29 extremity pain,29 back pain,29 joint pain,29 upper respiratory tract infection,29 and upper respiratory tract congestion.29
Concomitant use of an angiotensin-converting enzyme (ACE) inhibitor and an antidiabetic agent (insulin or oral hypoglycemic agent) may result in an increased blood glucose-lowering effect and increase the risk of hypoglycemia.603
Potential pharmacokinetic and pharmacologic interaction (hypotensive effect).1
Drugs that Block the Renin-Angiotensin System
Dual blockade of the renin-angiotensin system with angiotensin receptor blocking agents, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared with monotherapy.603 Most patients receiving the combination of 2 renin-angiotensin system blocking agents do not obtain additional benefit compared with monotherapy.603 Concomitant use of 2 renin-angiotensin system blocking agents generally should be avoided.603 Blood pressure, renal function, and electrolytes should be closely monitored in patients receiving trandolapril and other agents that affect the renin-angiotensin system.603 Concomitant use of trandolapril with aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m2).603
Drugs Increasing Serum Potassium Concentration
Potential pharmacologic interaction (additive hyperkalemic effect).1 Includes potassium-sparing diuretics, potassium supplements, and other drugs that can cause hyperkalemia.1
Nitroid reactions (manifestations include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients receiving therapy with injectable gold (sodium aurothiomalate) and an ACE inhibitor.603
Potential pharmacokinetic interaction (increased lithium concentrations and clinical toxicity).1
Mammalian Target of Rapamycin Inhibitors
Concomitant use of an ACE inhibitor and a mammalian target of rapamycin (mTOR) inhibitor (e.g., everolimus, sirolimus, temsirolimus) may increase the risk of angioedema.603
Increased risk of angioedema.603 Trandolapril should not be administered within 36 hours of a neprilysin inhibitor.603 (See Contraindications.)
Nonsteroidal Anti-inflammatory Agents
In geriatric patients, patients who are volume depleted (including those who are receiving diuretic therapy), or patients with compromised renal function, concomitant use of nonsteroidal anti-inflammatory agents (NSAIAs), including cyclooxygenase-2 (COX-2) inhibitors, and ACE inhibitors may result in the deterioration of renal function, including possible renal failure.603 These effects are usually reversible.603 Renal function should be monitored periodically in patients receiving concomitant trandolapril and NSAIA therapy.603
Trandolapril is an angiotensin-converting enzyme (ACE, bradykininase, kininase II) inhibitor.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 Unlike captopril or lisinopril, but similar to benazepril, enalapril, fosinopril, moexipril, perindopril, quinapril, and ramipril, trandolapril is a prodrug2, 9 and has little pharmacologic activity until hydrolyzed in the liver3, 4, 8, 17 to trandolaprilat.1, 3, 4, 5, 7, 12, 16, 17, 83, 84, 85, 86, 87, 88, 89, 90, 91 Like benazepril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, and ramipril, but unlike captopril, trandolapril does not contain a sulfhydryl group.1, 3, 4, 5, 7, 8, 11, 12, 13, 16, 17, 83, 84, 85, 86, 87, 88, 89, 90, 91
Risk of angioedema, anaphylactoid, and other sensitivity reactions and importance of discontinuing the drug and reporting suggestive manifestations (e.g., edema of face, eyes, lips, or tongue; swallowing or breathing with difficulty) to a clinician.1
Risk of hypotension (e.g., lightheadedness, syncope), especially during initial therapy or with volume depletion secondary to excessive perspiration, vomiting, or diarrhea.1 Importance of adequate fluid intake.1 Importance of discontinuing drug and contacting clinician if symptoms of syncope occur.1
Importance of contacting a clinician promptly if manifestations of infection or neutropenia (e.g., sore throat, fever) develop.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Risk of hyperkalemia.1 Importance of avoiding the use of potassium supplements or salt substitutes containing potassium without consultation with a clinician.1
Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1, 82 Risk of use during first, second, and third trimesters of pregnancy.1, 81, 82
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturers' labelings should be consulted. It is essential that the manufacturers' labelings be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 1 mg* | Mavik® (scored) | |
Trandolapril Tablets | ||||
2 mg* | Mavik® | AbbVie | ||
Trandolapril Tablets | ||||
4 mg* | Mavik® | AbbVie | ||
Trandolapril Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release core (containing verapamil hydrochloride 240 mg), film-coated | 1 mg with Verapamil Hydrochloride 240 mg | AbbVie | |
Tablets, extended-release core (containing verapamil hydrochloride 180 mg), film-coated | 2 mg with Verapamil Hydrochloride 180 mg | Tarka® | AbbVie | |
Tablets, extended-release core (containing verapamil hydrochloride 240 mg), film-coated | 2 mg with Verapamil Hydrochloride 240 mg | Tarka® | AbbVie | |
Tablets, extended-release core (containing verapamil hydrochloride 240 mg), film-coated | 4 mg with Verapamil Hydrochloride 240 mg | Tarka® | AbbVie |
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