Trandolapril

Pronunciation: (tran-DOE-la-pril)
Class: ACE inhibitor

Trade Names

Mavik
- Tablets 1 mg
- Tablets 2 mg
- Tablets 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.

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 and is independent of concentration. 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 de-esterification products.

Elimination

33% of parent drug and metabolites are recovered in urine and 66% in feces. Trandolapril half-life is 6 h. The half-life of trandolaprilat is 10 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 of age and older with hypertension, plasma concentration of trandolapril is increased.

Indications and Usage

Heart Failure Post-MI/Left Ventricular Dysfunction Post-MI

For 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.

Hypertension

Treatment of hypertension either alone or in combination with other antihypertensive drugs.

Contraindications

Hypersensitivity or 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/day.

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.

Hypertension
Adults

PO 1 to 2 mg every day initially with usual maintenance dosages of 2 to 4 mg every day.

Storage/Stability

Store tablets 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. Use with caution. Closely monitor potassium concentrations.

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. If severe coughing develops, consider discontinuing one or both drugs.

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.

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.

Everolimus

The risk of angioedema may be increased. If an interaction is suspected, discontinue one or both agents.

Gold salts (eg, sodium aurothiomalate)

The risk of gold salt–induced nitritoid reactions, characterized by flushing, sweating, dizziness, nausea, malaise, weakness, and 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.

Iron salts, parenteral (eg, iron dextran)

The risk of adverse reactions to parenteral iron (eg, arthralgia, fever) may be increased. If these agents must be used concurrently, closely monitor the patient. If an interaction is suspected, discontinue one of the agents.

Lithium salts

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

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.

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.

Pergolide

An additive or synergistic effect, resulting in profound hypotension, may occur. Use with caution. Consider starting with a low dose of pergolide. Closely monitor BP. If BP falls, dosage reduction may be needed.

Phenothiazines

Increased hypotensive effect with postural syncope. Use with caution. Monitor BP and adjust the trandolapril dose as needed.

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

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

Sulfonylureas (eg, glyburide)

The risk of hypoglycemia may be increased. Monitor blood glucose and observe the patient for symptoms of hypoglycemia. Adjust the sulfonylurea dose 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 in 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%); syncope (6%); bradycardia (5%); cardiogenic shock, intermittent claudication (4%); stroke (3%).

CNS

Dizziness (23%).

GI

Dyspepsia (6%); gastritis (4%); diarrhea (1%).

Lab Tests

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

Metabolic

Hyperkalemia, hypocalcemia (5%).

Musculoskeletal

Myalgia (5%).

Respiratory

Cough (35%).

Miscellaneous

Asthenia (3%); angioedema (0.13%); anaphylactoid reactions.

Precautions

Warnings

Pregnancy

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue therapy as soon as possible.

Pregnancy

Category D (second and third trimester); Category C (first trimester).

Lactation

Undetermined. Avoid use in breast-feeding women, if possible.

Children

Safety and efficacy not established.

Elderly

Reduce doses if needed.

Renal Function

Reduce dosage. Decreases in renal function may occur if renal function is dependent on the renin-angiotensin system; patients with renal artery stenosis may experience acute renal failure.

Anaphylactoid reactions

Angioedema and anaphylactoid reactions are rarely reported, but are potentially life-threatening.

Angioedema

Use with extreme caution in patients with hereditary angioedema.

Cough

Chronic nonproductive cough may occur.

Hepatic failure

May occur. Discontinue drug if patient develops jaundice.

Hypotension/First-dose effect

Hypotension may occur during initiation of therapy, especially in patients with severe salt or volume depletion or those with CHF.

Neutropenia or agranulocytosis

Has occurred with other ACE inhibitors; the risk appears greater in patients with renal dysfunction, heart failure, or immunosuppression. Periodically monitor WBC in these patients.

Overdosage

Symptoms

Hypotension.

Patient Information

Advise patient to take the prescribed dose without regard to meals, but to take with food if stomach upset occurs.
Advise patient to try to take each dose at about the same time each day.
Inform hypertensive patients that this drug controls, but does not cure, hypertension, and to continue taking drug as prescribed, even when BP is not elevated.
Caution patient not to change the dose or stop taking unless advised by health care provider.
Instruct patients to continue taking other medications for their condition as prescribed by health care provider.
Instruct patient in BP and pulse measurement skills.
Advise patient to monitor and record BP and pulse at home and to inform health care provider if abnormal measurements are noted. Also advise patient to take record of BP and pulse to each follow-up visit.
Caution patient to avoid sudden position changes to prevent orthostatic hypotension.
Instruct patient to lie or sit down if experiencing dizziness or light-headedness when standing.
Emphasize to hypertensive patient 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 patient to weigh themselves daily, keep a record of daily weights, and notify health care provider if rapid weight gain (eg, 5 lb in 1 wk) is noted or if edema or shortness of breath are getting worse.
Caution patient that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in BP, resulting in light-headedness or fainting.
Advise patient 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 patient to stop taking the drug and immediately report any of the following symptoms to health care provider: chest pains; difficulty breathing; fainting; fever; irregular heartbeat; sore throat; swelling of the face, lips, eyelids, or tongue; swelling of the hands or feet.
Instruct patient to inform health care provider if a persistent cough develops while taking this medication.