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Generic Name: 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

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 Mavik

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 3 5 11 13 14 15 16 17 31

One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high coronary disease risk, diabetes mellitus, chronic renal failure, and/or cerebrovascular disease.59

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

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.59

Heart Failure or Left Ventricular Dysfunction after AMI

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 CHF within a few days following AMI.1 32

CHF

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

Diabetic Nephropathy

A first-line agent in the treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus.31 72 73 74 75 76 77 78

Mavik Dosage and Administration

General

Hypertension

  • Trandolapril/verapamil fixed combination should not be used for initial treatment of hypertension.31

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

Adults

Hypertension
Oral

Initially, 2 mg once daily in black patients and 1 mg once daily in patients of other races as monotherapy.1 31 59 Adjust dosage at intervals of ≥1 week.1

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating trandolapril.1 May cautiously resume diuretic therapy if BP not controlled adequately with trandolapril alone.1 If diuretic cannot be discontinued, initiate therapy at 0.5 mg daily under close medical supervision for several hours until BP has stabilized.1

Usual dosage: 2–4 mg once daily.1 31 59

If 4 mg once daily does not adequately control BP, consider administering drug in 2 divided doses.1 If trandolapril monotherapy does not adequately control BP, consider adding a diuretic.1

Limited clinical experience with dosages >8 mg daily.1 28

Trandolapril/Verapamil Combination Therapy
Oral

Adjust dosage by first administering each drug separately.18 31 55 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 AMI
Oral

Initially, 1 mg once daily;1 32 therapy may be initiated about 3–5 days after AMI.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.1 28

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 AMI
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 AMI
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 Mavik

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 CHF 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 CHF (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 31 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 CHF.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.)

Blacks

BP reduction may be smaller in black patients compared with nonblack patients;24 25 56 57 however, no apparent population difference during combined therapy with ACE inhibitor and thiazide diuretic.24 26 27 31 Use in combination with a diuretic.24 26 27 31

Higher incidence of angioedema reported with ACE inhibitors in blacks compared with other races.1 57 59

Common Adverse Effects

Patients with hypertension: Cough, dizziness, diarrhea.1

Patients with left ventricular dysfunction after AMI: Cough, dizziness, hypotension, elevated serum uric acid concentrations, elevated BUN, percutaneous transluminal coronary angioplasty (PTCA) or CABG, dyspepsia, syncope, hyperkalemia.1

Interactions for Mavik

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

Mavik 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.

Trandolapril

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1 mg

Mavik (with povidone; scored)

Abbott

2 mg

Mavik (with povidone)

Abbott

4 mg

Mavik (with povidone)

Abbott

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 (with povidone)

Abbott

Tablets, extended-release core (containing verapamil hydrochloride 180 mg), film-coated

2 mg with Verapamil Hydrochloride 180 mg

Tarka (with povidone)

Abbott

Tablets, extended-release core (containing verapamil hydrochloride 240 mg), film-coated

2 mg with Verapamil Hydrochloride 240 mg

Tarka (with povidone)

Abbott

Tablets, extended-release core (containing verapamil hydrochloride 240 mg), film-coated

4 mg with Verapamil Hydrochloride 240 mg

Tarka (with povidone)

Abbott

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. 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, 2004-2014, Selected Revisions April 1, 2008. 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.

References

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48. Oldroyd KG, Pye MP, Ray SG et al. Effects of early captopril administration on infarct expansion, left ventricular remodeling and exercise capacity after acute myocardial infarction. Am J Cardiol. 1991; 68:713-8. [IDIS 288996] [PubMed 1892076]

49. Sharpe N, Murphy J, Smith H et al. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet. 1988; 1:255-9. [IDIS 238337] [PubMed 2893080]

50. Pfeffer MA, Lamas GA, Vaughan DE et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988; 319:80-6. [IDIS 243316] [PubMed 2967917]

51. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

52. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

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