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Trandolapril

Pronunciation: tran-DOL-a-pril
Class: ACE inhibitor

Trade Names

Mavik
- Tablets, oral 1 mg
- Tablets, oral 2 mg
- Tablets, oral 4 mg

Pharmacology

Reduces the formation of the vasopressor hormone angiotensin II by inhibiting ACE, resulting in decreased BP and reduced sodium reabsorption and potassium retention.

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Pharmacokinetics

Absorption

Food slows absorption but does not affect AUC. Plasma concentration and AUC are dose-proportional. Bioavailability is 10% as trandolapril and 70% as trandolaprilat (metabolite). T max is 1 h for trandolapril and 4 to 10 h for trandolaprilat.

Distribution

Trandolapril is 80% protein bound. Binding of trandolaprilat is concentration-dependent (from 65% to 94%). Vd is 18 L.

Metabolism

Trandolaprilat is the major metabolite and is 8 times more active than trandolapril. Other metabolites are glucuronides or deesterification products.

Elimination

33% of parent drug and metabolites are recovered in urine and 66% in feces. Trandolapril half-life is 6 h. The steady-state half-life of trandolaprilat is 22.5 h.

Peak

Time to peak effect is 4 h.

Duration

Duration of action is 24 h.

Special Populations

Renal Function Impairment

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

Hepatic Function Impairment

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

Elderly

In patients 65 y and older with hypertension, plasma concentration of trandolapril is increased.

Indications and Usage

To decrease the risk of death or hospitalization in stable patients who have evidence of left ventricular systolic dysfunction (identified by wall motion abnormalities) or who are symptomatic from CHF within the first few days after sustaining an acute MI; treatment of hypertension either alone or in combination with other antihypertensive drugs.

Contraindications

Hypersensitivity to any component of the product; hereditary/idiopathic angioedema; history of angioedema with any ACE inhibitor.

Dosage and Administration

Heart failure post-MI/left ventricular dysfunction post-MI
Adults

PO 1 mg/day. Following initial dose, titrate patients (as tolerated) toward a target dosage of 4 mg once daily.

Hypertension
Adults

PO 1 mg once daily in nonblack patients and 2 mg in black patients initially with usual maintenance dosages of 2 to 4 mg once daily. In patients receiving a diuretic that cannot be discontinued, the initial dose should be 0.5 mg, with careful medical supervision for several hours until BP has stabilized. Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing.

Renal/Hepatic function impairment

PO For patients with a CrCl less than 30 mL/min or with hepatic cirrhosis, starting dosage is 0.5 mg/day.

Storage/Stability

Store between 68° and 77°F.

Drug Interactions

Aldosterone blockers (eg, eplerenone)

The risk of serious hyperkalemia may be increased, resulting in cardiac arrhythmias or arrest. Periodic monitoring of serum potassium level is recommended until the effect of the aldosterone blocker is established. Dose reduction of the aldosterone blocker may be necessary to decrease potassium levels.

Aliskiren

The risk of hyperkalemia may be increased. Coadministration is contraindicated in diabetic patients because of an increased risk of renal impairment, hypotension, and hyperkalemia. Avoid coadministration in patients with CrCl less than 60 mL/min. Closely monitor potassium concentrations and renal function in patients who receive this combination.

Anesthetic agents

The hypotensive effect of inhalational anesthetic agents that produce hypotension may be increased. If this interaction is suspected, it can be corrected by volume expansion.

Angiotensin II receptor antagonists (eg, telmisartan)

Coadministration may be associated with an increased risk of renal dysfunction. Use with caution. Monitor renal function.

Capsaicin

Cough associated with trandolapril may be exacerbated.

Cimetidine

Coadministration increases the trandolaprilat C max by approximately 44% but does not affect the pharmacokinetics of trandolaprilat or ACE inhibition.

Clozapine

An additive or synergistic hypotensive effect with postural syncope may occur. In addition, clozapine concentrations may be increased. Use with caution. Monitor BP and adjust the trandolapril dose as needed.

COX-2 inhibitors (eg, celecoxib), NSAIDs (eg, indomethacin), salicylates (eg, aspirin)

May reduce hypotensive effects, especially in low-renin or volume-dependent hypertensive patients. If an interaction is suspected, discontinue the NSAID or salicylate or use an alternative antihypertensive agent. In addition, the risk of deterioration of renal function may be increased with concurrent use of NSAIDs. Periodically monitor renal function.

Diuretics

Possible hypotensive effect. If the diuretic cannot be discontinued 2 to 3 days prior to starting trandolapril, use a lower starting dose of trandolapril.

Food

Food slows the absorption of trandolapril but does not affect trandolaprilat AUC or C max , or the trandolapril C max .

Gold salts (eg, sodium aurothiomalate)

The risk of gold salt–induced nitritoid reactions (eg, flushing, sweating, dizziness, nausea, malaise, weakness, hypotension) may be increased. Closely observe patients for signs and symptoms of nitritoid reactions. If an interaction occurs, one of the agents may need to be discontinued.

Insulin, sulfonylureas (eg, glyburide)

The risk of hypoglycemia may be increased. Monitor blood glucose and observe the patient for symptoms of hypoglycemia. Adjust the insulin or sulfonylurea dose as needed.

Lithium

Lithium serum concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity (eg, neurotoxicity). Use with caution and closely monitor lithium concentrations.

Loop diuretics (eg, furosemide)

Effects of loop diuretics may be decreased. In addition, coadministration may cause more acute renal dysfunction than trandolapril alone. If fluid and sodium retention occur, consider increasing the dosage of the loop diuretic. If renal function deteriorates, stop both agents.

mTOR inhibitors (eg, everolimus, sirolimus)

Risk of angioedema may be increased. If an interaction is suspected, stop one or both drugs.

Potassium preparations (eg, potassium chloride), potassium supplements, or potassium-sparing drugs (eg, spironolactone)

May increase serum potassium levels, increasing the risk of hyperkalemia. Closely monitor serum potassium concentrations and adjust treatment as needed.

Thiazide diuretics (eg, chlorothiazide)

Trandolapril can attenuate potassium loss caused by thiazide diuretics. Monitor serum potassium and adjust treatment as needed. In addition, the risk of renal failure may be increased. Monitor renal function, especially in elderly patients and patients with impaired renal function. If an interaction is suspected, stop one or both agents.

Tizanidine

The pharmacologic effects of trandolapril may be increased, possibly resulting in severe hypotension. Use with caution and closely monitor BP. If hypotension occurs, supportive treatment may be necessary.

Trimethoprim

The risk of serious hyperkalemia may be increased, resulting in cardiac arrhythmias or arrest. Closely monitor serum potassium level and the clinical response of the patient. If an interaction occurs, discontinuation of one or both drugs may be necessary.

Adverse Reactions

Cardiovascular

Hypotension (11%); percutaneous transluminal coronary angioplasty or coronary artery bypass graft (7%); syncope (6%); bradycardia (5%); cardiogenic shock, intermittent claudication (4%); stroke (3%); angina pectoris, arrhythmia, cardiac failure, MI, myocardial ischemia, tachycardia, transient ischemic attack, ventricular tachycardia (postmarketing).

CNS

Dizziness (23%); asthenia (3%); cerebral hemorrhage, depression, hallucination (postmarketing).

Dermatologic

Alopecia, Stevens-Johnson syndrome, sweating, TEN (postmarketing).

GI

Dyspepsia (6%); gastritis (4%); diarrhea (1%); dry mouth, pancreatitis (postmarketing).

Hematologic

Agranulocytosis, pancytopenia (postmarketing).

Hepatic

Hepatitis, increased AST, jaundice (postmarketing).

Lab Tests

Elevated serum uric acid (15%); elevated BUN (9%); elevated creatinine (5%).

Metabolic

Hyperkalemia, hypocalcemia (5%).

Musculoskeletal

Myalgia (5%).

Respiratory

Cough (35%); bronchitis (postmarketing).

Miscellaneous

Fever, malaise, renal failure (postmarketing).

Precautions

Warnings

Fetal toxicity

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


Monitor

Consider monitoring WBC in patients with collagen-vascular disease and/or renal disease. Monitor renal function during the first few weeks of therapy in patients with renal artery stenosis.


Pregnancy

Category D . Can cause injury or death to the fetus if used during the second or third trimesters.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Greater sensitivity of some older individual patients cannot be ruled out.

Hypersensitivity

Anaphylactoid reactions have occurred in patients taking ACE inhibitors undergoing desensitization, and in patients being dialyzed with high-flux membranes or undergoing LDL apheresis with dextran sulfate absorption.

Renal Function

Reduce dosage in patients with CrCl less than 30 mL/min. In patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN may occur.

Angioedema

Angioedema involving the extremities, face, lips, tongue, glottis, or larynx may occur. Intestinal angioedema has also been reported.

Cough

A persistent, nonproductive cough has been reported with all ACE inhibitors.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and, sometimes, death.

Hyperkalemia

Elevations in serum potassium have been observed; risk factors include renal insufficiency, diabetes, and concomitant use of potassium supplements or drugs known to increase serum potassium.

Hypotension/First-dose effect

Significant decreases in BP may occur following the first dose, especially in severely salt- or volume-depleted patients (such as those receiving diuretics) or those with heart failure.

Neutropenia or agranulocytosis

Has occurred with other ACE inhibitors; risk appears greater with renal impairment, especially if they also have a collagen-vascular disease.

Renal effects

Use with caution in patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe CHF); use may be associated with oliguria, progressive azotemia, acute renal failure, and/or death.

Surgery/Anesthesia

Risk of hypotension may be increased; if hypotension occurs, it can be corrected by volume expansion.

Overdosage

Symptoms

Hyperkalemia, renal failure, severe hypotension.

Patient Information

  • Advise patients to take the prescribed dose without regard to meals but to take with food if stomach upset occurs.
  • Inform hypertensive patients that this drug controls, but does not cure, hypertension, and that they should continue taking the drug as prescribed, even when BP is not elevated.
  • Instruct patients to continue taking other medications for their condition as prescribed by health care provider.
  • Advise patients to monitor and record BP and pulse at home and to inform their health care provider if abnormal measurements are noted. Also advise patients to take a record of their BP and pulse to each follow-up visit.
  • Cautions patient to avoid sudden position changes to prevent orthostatic hypotension.
  • Instruct patients to lie or sit down if experiencing dizziness or light-headedness when standing.
  • Emphasize to hypertensive patients the importance of the following other modalities on BP control: weight control, regular exercise, smoking cessation, and moderate intake of alcohol and salt.
  • Emphasize to heart failure patients the importance of the following other modalities that can help control heart failure symptoms: weight control, progressive exercise program, smoking cessation, and moderate intake of alcohol and salt.
  • Advise heart failure patients to weigh themselves daily, keep a record of daily weights, and notify their health care provider if rapid weight gain (eg, 5 lb in 1 wk) is noted or if edema or shortness of breath gets worse.
  • Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in BP, resulting in light-headedness or fainting.
  • Advise patients that medication may cause dizziness or light-headedness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Instruct patients to stop taking the drug and immediately report any of the following symptoms to their health care provider: chest pains; difficulty breathing; fainting; fever; irregular heartbeat; sore throat; fever; swelling of the face, lips, eyelids, or tongue; swelling of the hands or feet.
  • Instruct patients to inform their health care provider if a persistent cough develops while taking this medication.
  • Instruct patients not to use potassium supplements or salt substitutes containing potassium without consulting their health care provider.
  • Inform female patients of childbearing age about the consequences of exposure to trandolapril during pregnancy. Tell patients to report pregnancies to their health care provider as soon as possible.

Copyright © 2009 Wolters Kluwer Health.

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