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Trandolapril

Class: Angiotensin-Converting Enzyme 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
Brands: Mavik, Tarka

Warning(s)

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 81 82 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue trandolapril as soon as possible.1 82

Introduction

Nonsulfhydryl ACE inhibitor.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Uses for Trandolapril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 3 5 11 13 14 15 16 17 500

ACE inhibitors are recommended as one of several preferred agents for the initial management of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.500 501 502 504 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).500 501 502 503 504 515

ACE inhibitors may be preferred in hypertensive patients with heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease, or cerebrovascular disease or post-MI.500 501 502 504 520 523 524 525 526 527 534 535 536 543

Slideshow: 2014 Update - First Time Brand-to-Generic Switches

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to ACE inhibitors.24 56 57 79 80 500 501 504 However, diminished response to an ACE inhibitor is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.24 26 27 500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

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.1 32

Heart Failure

Management of symptomatic heart failure, usually in conjunction with cardiac glycosides, diuretics, and β-adrenergic blocking agents.58 60 61 62 63 64

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria 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.74 75 76 77 78 520 535 536

Trandolapril Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer orally once or twice daily.1

Administer trandolapril/verapamil fixed combination with food;29 manufacturer makes no specific recommendation regarding administration of trandolapril with meals.1

Dosage

In patients currently receiving diuretic therapy, discontinue diuretic or cautiously increase salt intake prior to initiating trandolapril.600 If diuretic cannot be discontinued, initiate trandolapril at a reduced dosage.600 (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.600 Adjust dosage based on BP response, usually at intervals of ≥1 week.600

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating trandolapril.600 May resume diuretic therapy if BP not controlled adequately with trandolapril alone.600 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.600

Usual maintenance dosage: 2–4 mg once daily.600

If 4 mg once daily does not adequately control BP, consider administering drug in 2 divided doses.28 600

Limited clinical experience with dosages >8 mg daily.600

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Trandolapril/Verapamil Fixed-combination Therapy
Oral

Manufacturer states fixed-combination preparation should not be used for initial antihypertensive therapy.601

May be used after adequate response is not achieved with trandolapril or verapamil monotherapy.601

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 can be attempted using tablets containing the same component doses.29

Heart Failure or Left Ventricular Dysfunction after Acute MI
Oral

Initially, 1 mg once daily;1 32 therapy may be initiated about 3–5 days after acute MI.1 32

Titrate dosage as tolerated to a target dosage of 4 mg once daily; if 4 mg daily is not tolerated, may continue therapy at the highest tolerated dosage.1

Prescribing Limits

Adults

Hypertension
Oral

Limited clinical experience with dosages >8 mg daily.600

Special Populations

Hepatic Impairment

Hypertension
Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with hepatic cirrhosis;1 16 titrate subsequent dosage according to BP response.1

Heart Failure or Left Ventricular Dysfunction after Acute MI
Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with hepatic cirrhosis;1 16 titrate subsequent dosage as tolerated according to response.1

Renal Impairment

Hypertension
Oral

Reduced initial dosage (0.5 mg once daily) recommended in patients with severe renal impairment (Clcr <30 mL/minute);1 3 4 16 17 titrate subsequent dosage according to BP response.1

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 (Clcr <30 mL/minute); titrate subsequent dosage as tolerated according to response.1

Cautions for Trandolapril

Contraindications

  • Known hypersensitivity (e.g., history of angioedema) to trandolapril or another ACE inhibitor.1

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).1 Risk of marked hypotension, sometimes associated with oliguria, azotemia, and rarely, death in patients with heart failure with or without associated renal insufficiency.1

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.1

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical conditions.1 May minimize potential for hypotension by correcting volume and/or salt depletion prior to initiating trandolapril therapy.1 (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.1

Take care to avoid hypotension in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.1

If symptomatic hypotension occurs, place patient in supine position and, if necessary, administer IV infusion of 0.9% sodium chloride injection.1 Transient hypotension is not a contraindication to additional doses; however, consider reinitiating therapy at reduced doses of trandolapril and/or diuretic.1

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.1 21 22 23 24 30 81 82 (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.82

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.81 82

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.82 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.1 21

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.1 29

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.1 29

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.1

Consider monitoring leukocytes in patients with collagen vascular disease, especially if renal impairment exists.1 29

Sensitivity Reactions

Anaphylactoid reactions and/or head and neck angioedema possible; angioedema associated with laryngeal edema may be fatal.1 29 If angioedema occurs, promptly discontinue trandolapril and observe patient until swelling disappears.1 Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.1 29

Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.1

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.1 29

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.1 29

Contraindicated in patients with a history of angioedema associated with ACE inhibitors.1

General Precautions

Renal Effects

Transient increases in BUN and Scr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.1 Possible increases in BUN and Scr in patients with unilateral or bilateral renal artery stenosis; generally reversible following discontinuance of ACE inhibitor and/or diuretic.1 29

Possible oliguria, progressive azotemia, and rarely, acute renal failure and/or death in patients with severe heart failure.1

Closely monitor renal function following initiation of therapy in hypertensive patients with unilateral or bilateral renal artery stenosis.1 29 Some patients may require dosage reduction or discontinuance of ACE inhibitor and/or diuretic.1

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).1 (See Specific Drugs under Interactions.)

Monitor serum potassium concentration carefully in these patients.1

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.1

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).1 (See Boxed Warning.)

Lactation

Distributed into milk in rats.1 Use not recommended.1

Pediatric Use

Safety and efficacy not established.1

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.1

Hepatic Impairment

Consider dosage reduction.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Deterioration of renal function may occur.1 (See Renal Effects under Cautions.)

Initial dosage adjustment recommended in patients with Clcr <30 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Black Patients

BP reduction may be smaller in black patients compared with nonblack patients.24 25 56 57 (See Hypertension under Uses.)

Higher incidence of angioedema reported with ACE inhibitors in black patients compared with other races.1 57 500

Common Adverse Effects

Patients with hypertension: Cough, dizziness, diarrhea.1

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.1

Interactions for Trandolapril

Specific Drugs

Drug

Interaction

Comments

Cimetidine

Possible increase in plasma trandolapril concentrations but no change in plasma trandolaprilat concentrations and no change in ACE inhibition1

Digoxin

Pharmacokinetic interaction unlikely1

Diuretics

Increased hypotensive effect1

If possible, discontinue diuretic before initiating trandolapril1 (See Dosage under Dosage and Administration)

Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)

Enhanced hyperkalemic effect1

Use with caution; monitor serum potassium concentrations frequently1

Lithium

Increased serum lithium concentrations; possible toxicity1

Use with caution; monitor serum lithium concentrations frequently1

Nifedipine

Pharmacokinetic interaction unlikely29

Potassium supplements or potassium-containing salt substitutes

Enhanced hyperkalemic effect1

Use with caution; monitor serum potassium concentrations frequently1

Warfarin

Pharmacologic interaction unlikely1

Trandolapril Pharmacokinetics

Absorption

Bioavailability

Prodrug;2 9 has little pharmacologic activity until hydrolyzed to trandolaprilat.1 3 4 5 7 12 16 17 Absolute bioavailability following oral administration of trandolapril is about 10% as trandolapril and 70% as trandolaprilat.1

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

Onset

A single 2-mg dose results in approximately 70–85% inhibition of plasma ACE activity at 4 hours after administration.1

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

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.1

Food

Food decreases rate of absorption but does not affect extent of absorption or peak plasma concentration.1

Special Populations

In patients with mild to moderate alcoholic cirrhosis, plasma trandolapril and trandolaprilat concentrations are increased approximately 9- and 2-fold, respectively.1

In patients with Clcr <30 mL/minute, plasma trandolapril and trandolaprilat concentrations are increased approximately 2-fold.1

Distribution

Extent

Distributed into milk in rats.1

Plasma Protein Binding

Trandolapril: 80% (independent of concentration).1

Trandolaprilat: Concentration-dependent binding (65% at 1000 ng/mL and 94% at 0.1 ng/mL).1

Elimination

Metabolism

Metabolized in the liver3 4 8 17 to an active metabolite, trandolaprilat.1 3 4 5 6 12 16 17 At least 7 other metabolites, principally glucuronide conjugates or de-esterification products, have been identified.1

Elimination Route

Eliminated in urine (33%), principally as trandolaprilat, and in feces (66%).1

Half-life

Trandolapril: 6 hours.1

Trandolaprilat: 10 hours.1

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • Prodrug;2 9 has little pharmacologic activity until hydrolyzed in the liver3 4 8 17 to trandolaprilat.1 3 4 5 6 12 16 17

  • Suppresses the renin-angiotensin-aldosterone system.1

Advice to Patients

  • Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.1 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.1

  • Importance of reporting signs of infection (e.g., sore throat, fever).1

  • Risk of hypotension.1 Importance of informing clinicians promptly if lightheadedness or fainting occurs.1

  • Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.1

  • Risks of use during pregnancy.1 81 82 (See Boxed Warning.)

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • 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.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

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

Trandolapril

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1 mg*

Mavik (scored)

AbbVie

Trandolapril Tablets

2 mg*

Mavik

AbbVie

Trandolapril Tablets

4 mg*

Mavik

AbbVie

Trandolapril Tablets

Trandolapril Combinations

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

Tarka

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Mavik 1MG Tablets (ABBOTT): 100/$139.99 or 300/$397.95

Mavik 2MG Tablets (ABBOTT): 30/$56.99 or 90/$137.97

Mavik 4MG Tablets (ABBOTT): 30/$56.99 or 90/$137.97

Tarka 1-240MG Controlled-release Tablets (ABBOTT): 30/$105.99 or 90/$285.96

Tarka 2-180MG Controlled-release Tablets (ABBOTT): 30/$113.99 or 90/$329.97

Tarka 2-240MG Controlled-release Tablets (ABBOTT): 30/$113.99 or 90/$319.98

Tarka 4-240MG Controlled-release Tablets (ABBOTT): 30/$115.99 or 90/$334.98

Trandolapril 2MG Tablets (LUPIN PHARMACEUTICALS): 100/$110.98 or 300/$310.97

Trandolapril 4MG Tablets (LUPIN PHARMACEUTICALS): 100/$112.00 or 300/$315.95

Trandolapril-Verapamil HCl 2-180MG Controlled-release Tablets (GLENMARK PHARMACEUTICALS): 30/$89.99 or 90/$249.97

Trandolapril-Verapamil HCl 2-240MG Controlled-release Tablets (GLENMARK PHARMACEUTICALS): 30/$89.99 or 90/$249.97

Trandolapril-Verapamil HCl 4-240MG Controlled-release Tablets (GLENMARK PHARMACEUTICALS): 30/$89.99 or 90/$249.97

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions January 26, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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