trandolapril 2 mg tablet generic mavik

Uses

Trandolapril is used alone or in combination with drugs from other classes of antihypertensive agents in the management of hypertension. 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 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 myocardial infarction.

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.

Hypertension

Trandolapril is used alone or in combination with drugs from other classes of antihypertensive agents in the management of hypertension. ACE inhibitors are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. 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. 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, or cerebrovascular disease or following myocardial infarction. (See Uses: Hypertension in and in )

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors. 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; however, this population difference in response does not appear to occur during combined therapy with an ACE inhibitor and a thiazide diuretic or calcium-channel blocker. In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied. (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses in and in )

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. Blood pressure reductions were greater with fixed combination of 240 mg of verapamil and 4 mg of trandolapril than with either drug alone. Efficacy was not affected by age or gender, and antihypertensive effects have continued during long-term therapy (i.e., at least 1 year).

For additional information on the role of ACE inhibitors in the management of hypertension, and . For information on overall principles and expert recommendations for treatment of hypertension,

Heart Failure after Acute Myocardial Infarction or Left Ventricular Dysfunction after Acute Myocardial Infarction

Trandolapril 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 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 myocardial infarction. In these patients, when compared with those receiving placebo, trandolapril therapy initiated 3-7 days after acute myocardial infarction 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%. 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. Heart failure developed substantially earlier in patients receiving placebo compared with those receiving trandolapril. Trandolapril did not appear to reduce the rates of reinfarction, although there was a trend to fewer such events when compared with placebo. 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.

ACE inhibitors have been used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular remodeling) following acute myocardial infarction. However, current evidence regarding the efficacy of such therapy is conflicting, particularly when therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction. and

Heart Failure

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).

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. 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. 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. 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. 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, 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. 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. 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. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of ACE inhibitors in the management of heart failure, and in

Diabetic Nephropathy

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, 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. The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed. For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see

Dosage and Administration

Administration

Trandolapril is administered orally. 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.

Dosage

Dosage of trandolapril must be adjusted according to patient tolerance and response. 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. 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. 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. If diuretic therapy cannot be discontinued, the initial dosage of trandolapril should be reduced. 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.(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.

Hypertension

Trandolapril Therapy

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. In patients currently receiving diuretic therapy, the diuretic should be discontinued 2-3 days before initiating trandolapril, if possible. If blood pressure is not adequately controlled with trandolapril alone, the diuretic may be resumed. 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.

The usual maintenance dosage of trandolapril in adults is 2-4 mg once daily. Dosage of the drug should be adjusted according to blood pressure response. 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. Dosage generally is adjusted no more rapidly than at 1-week intervals. The safety and efficacy of dosages exceeding 8 mg daily have not been established. If blood pressure is not controlled with trandolapril alone, a second antihypertensive agent (e.g., a diuretic) may be added.

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months.

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with trandolapril monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added. In patients who experience intolerable adverse effects with trandolapril, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the ACE inhibitor and initiate another class of antihypertensive agent.

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. The fixed-combination preparation generally should be used in adults after an adequate response is not achieved with trandolapril or verapamil monotherapy. Alternatively, therapy with the fixed-combination preparation may be initiated in patients who experience dose-limiting adverse effects with either trandolapril or verapamil monotherapy. 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. Clinical trials with the verapamil and trandolapril fixed combination have investigated only once-daily dosing. The fixed-combination tablets contain verapamil hydrochloride in an extended-release component and trandolapril in an immediate-release component. 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. 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.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of trandolapril is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting trandolapril dosage in the management of hypertension,

Heart Failure after Acute Myocardial Infarction or Left Ventricular Dysfunction after Acute Myocardial Infarction

When used after acute myocardial infarction in adults with clinical signs of heart failure, the manufacturer recommends a trandolapril dosage of 1 mg once daily. Trandolapril therapy may be initiated several days after myocardial infarction. Following the initial dose, the dosage should be titrated, as tolerated, to a target dosage of 4 mg once daily. If a dosage of 4 mg once daily is not tolerated, therapy may be continued at the highest tolerated dosage.

Special Populations

If trandolapril is used in patients with impaired renal function, dosage must be modified in response to the degree of renal impairment, and, as with other ACE inhibitors, the theoretical risk of neutropenia must be considered.

In hypertensive adults with creatinine clearances less than 30 mL/minute per 1.73 m, the usual initial dosage of trandolapril is 0.5 mg daily. 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. If concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic is preferred to a thiazide diuretic.

In patients with hepatic cirrhosis, dosage of trandolapril should be initiated at 0.5 mg daily. 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.

Cautions

Contraindications

History of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor treatment.

Known hypersensitivity to trandolapril, other ACE inhibitors, or any ingredient in the formulation.

Warnings/Precautions

Warnings

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.

Cardiovascular Effects

Like other ACE inhibitors, trandolapril rarely is associated with hypotension in patients with uncomplicated hypertension. 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. Volume and/or salt depletion should be corrected before starting trandolapril therapy.

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). 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.(See Dosage and Administration: Dosage.) Hypotension also should be avoided in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.

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. Transient hypotension is not a contraindication to further trandolapril therapy. 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.

Hematologic Effects

Neutropenia/agranulocytosis, particularly in patients with renal impairment (especially those with concomitant collagen vascular disease [e.g., systemic lupus erythematosus, scleroderma]), reported with captopril. Data insufficient to rule out similar incidence of agranulocytosis with trandolapril in patients without prior reactions with other ACE inhibitors. Monitoring of leukocytes in patients with collagen vascular disease, especially if renal impairment exists, should be considered.

Fetal/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. ACE inhibitors also increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy. For additional information on the risk of ACE inhibitors during pregnancy, and in .

Hepatic Effects

Rare ACE inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur; may progress to fulminant hepatic necrosis and is potentially fatal. Patients receiving an ACE inhibitor, including trandolapril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring.

Sensitivity Reactions

Sensitivity reactions, including anaphylactoid reactions and angioedema (including laryngeal angioedema, and tongue edema) are potentially fatal. Head and neck angioedema involving the tongue, glottis, or larynx may cause airway obstruction. 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.

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. Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery; symptoms usually have resolved after discontinuance of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of patients who develop abdominal pain during therapy with an ACE inhibitor.

Life-threatening anaphylactoid reactions have been reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom. When ACE inhibitors were temporarily discontinued before desensitization with the venom, anaphylactoid reactions did not recur; however, such reactions recurred after inadvertent rechallenge. Anaphylactoid reactions also have been reported in patients following initiation of hemodialysis that used a high-flux membrane in patients receiving an ACE inhibitor. In addition, anaphylactoid reactions have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption.

General Precautions

Renal Effects

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).

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. This effect usually was reversible following discontinuance of ACE inhibitor and/or diuretic therapy. Renal function should be monitored closely during the first few weeks of therapy and periodically thereafter in such patients.

Effects on Potassium

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).

Cough

Persistent and nonproductive; resolves after drug discontinuance.

Surgery/Anesthesia

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension. Hypotension in such patients may be corrected by volume expansion.

Specific Populations

Pregnancy

Category C (first trimester); Category D (second and third trimesters).(See Fetal/Neonatal Morbidity and Mortality, under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Trandolapril and its metabolites are distributed into milk in rats. 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.

Pediatric Use

The manufacturer states that efficacy and safety of trandolapril in children younger than 18 years of age have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Renal Impairment

Renal function may decrease with ACE inhibitor therapy in susceptible patients. Use with caution in those with renal impairment.(See Dosage and Administration: Special Populations and also Renal Effects under Warnings/Precautions: General Precautions, Renal Effects, in Cautions.)

Black Patients

ACE inhibitors generally are not as effective in black patients compared with other races.(See Uses: Hypertension.)

Common Adverse Effects

Adverse effects reported in more than 1% of patients receiving trandolapril for the treatment of hypertension include cough, dizziness, diarrhea, headache, and fatigue. Adverse effects reported in more than 1% of patients receiving trandolapril for the treatment of left ventricular dysfunction after acute myocardial infarction include cough, dizziness, hypotension, hyperuricemia, elevated BUN concentrations, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG), dyspepsia, syncope, hyperkalemia, bradycardia, hypocalcemia, myalgia, elevated serum creatinine concentrations, gastritis, cardiogenic shock, intermittent claudication, stroke, and asthenia. Adverse effects reported in more than 1% of patients receiving trandolapril in fixed combination with verapamil include first-degree atrioventricular (AV) block, bradycardia, bronchitis, chest pain, constipation, cough, diarrhea, dizziness, dyspnea, edema, fatigue, headache, elevated serum hepatic enzyme concentrations, nausea, extremity pain, back pain, joint pain, upper respiratory tract infection, and upper respiratory tract congestion.

Drug Interactions

Diuretics

Potential pharmacokinetic and pharmacologic interaction (hypotensive effect).

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (additive hyperkalemic effect). Includes potassium-sparing diuretics, potassium supplements, and other drugs that can cause hyperkalemia.

Lithium

Potential pharmacokinetic interaction (increased lithium concentrations and clinical toxicity).