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enalapril-hydrochlorothiazide 10-25 mg tablet

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Uses

Hypertension

Enalapril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Enalaprilat is used in the management of hypertension when oral therapy is not practical. 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 enalapril or enalaprilat should be considered since current experience is insufficient to rule out such risk. Enalapril has occasionally been used without recurrence of adverse effect in patients who developed intolerable adverse effects (i.e., rash, taste disturbances) during captopril therapy. Further studies are needed to evaluate the possible risks associated with the long-term use of enalapril. The hypotensive efficacy of enalapril in hypertensive patients is similar to that of captopril or β-adrenergic blocking agents (β-blockers). Enalapril may have a greater effect on systolic blood pressure at rest (but not with exercise) than do β-blockers, but additional study is necessary to establish the comparative efficacy of enalapril and β-blockers.

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of 4 classes of antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular protection. However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines. Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs). Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.

Considerations in Initiating Antihypertensive Therapy

Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., life-style modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.

While the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended antihypertensive drug therapy in all patients with systolic/diastolic blood pressure of 140/90 mm Hg or higher who fail to respond to lifestyle/behavioral modifications, other experts, including the panel members appointed to the Eighth Joint National Committee (JNC 8 expert panel), recommend a higher systolic blood pressure threshold for older individuals (e.g., the JNC 8 expert panel recommends a threshold of 150 mm Hg for patients 60 years of age or older).

In addition, there is some variation in the blood pressure thresholds and treatment goals recommended for patients with diabetes mellitus or chronic kidney disease. In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had blood pressures of 130/80 mm Hg or higher; however, current hypertension management guidelines generally recommend the same blood pressure threshold of 140/90 mm Hg for initiating antihypertensive drug therapy in these individuals as for the general population of patients without these conditions, although a lower goal (e.g., less than 130/80 mm Hg) may still be considered.

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension; when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies. For additional details,

Antihypertensive drug therapy generally should be initiated gradually and titrated at intervals of approximately 2-4 weeks to achieve the target blood pressure. The goal is to reduce blood pressure to levels below the threshold used for initiating drug therapy. Addition of a second drug should be initiated when use of monotherapy in adequate dosages fails to achieve goal blood pressure. Some experts state that initial antihypertensive therapy with a combination of drugs may be considered in patients with systolic/diastolic blood pressure greater than 20/10 mm Hg above goal blood pressure. Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly). Initial combined therapy may be particularly useful in patients with markedly high baseline blood pressures and those with additional risk factors.

Initial Drug Therapy

In current hypertension management guidelines, ACE inhibitors are recommended as one of several preferred drugs for the initial treatment 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 Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors under Uses: Hypertension.)

Follow-up and Maintenance Therapy

Several strategies are recommended for the titration and combination of antihypertensive drugs; these strategies include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination). In patients who fail to respond adequately to initial monotherapy with an ACE inhibitor, the JNC 8 expert panel states that a thiazide diuretic or a calcium-channel blocker may be added. If goal blood pressure is not achieved with maximum dosages of these 2 drugs, a third antihypertensive agent from one of the recommended drug classes may be added; if more than 3 drugs are required, other antihypertensive agents (e.g., β-blockers, aldosterone antagonists, centrally acting agents) may be considered. Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects. If the blood pressure goal cannot be achieved using the above recommended strategies, consultation with a hypertension specialist should be considered.

Thus, enalapril can be used for the management of hypertension as initial monotherapy or as a component of a multiple-drug regimen. When enalapril alone is used but the hypertension does not respond adequately, addition of a thiazide diuretic often adequately controls blood pressure. Such combined therapy generally produces additive reduction in blood pressure and may permit dosage reduction of either or both drugs and minimize adverse effects while maintaining blood pressure control.

Enalapril may be effective in the management of hypertension resistant to other drugs. Although enalapril occasionally may be effective alone in patients with severe hypertension, it is usually necessary to use the drug in conjunction with a diuretic.(See Drug Interactions: Hypotensive Agents and Diuretics.) Enalapril has been used in some diabetic hypertensive patients with no adverse effect on control or therapy of diabetes; however, hypoglycemia has occasionally occurred when the drug was used in patients whose diabetes had been controlled with insulin or oral hypoglycemic agents.(See Drug Interactions: Other Drugs.)

Tolerance to the hypotensive effect of enalapril apparently does not occur during long-term administration, particularly if the drug is used with a diuretic.

IV enalaprilat may be used in the management of hypertension when oral therapy is not practical. Enalaprilat generally produces a prompt reduction in blood pressure, usually without an orthostatic response, and with a slight reduction in heart rate. Occasional hypotension, or symptomatic postural hypotension in volume-depleted patients, might be anticipated. Enalaprilat also has been used effectively to control blood pressure in adults with severe hypertension or hypertensive emergencies(see Hypertensive Crises under Uses: Hypertension) and in a small number of neonates with severe hypertension.

As with other antihypertensive agents, treatment with enalapril or enalaprilat is not curative; after withdrawal of the drug, blood pressure returns to pretreatment levels. Abrupt withdrawal of enalapril or enalaprilat therapy results in a gradual return of hypertension; rapid increases in blood pressure have not been reported to date.

Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors

Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.

Ischemic Heart Disease

The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics. Many experts recommend the use of an ACE inhibitor (or an angiotensin II receptor antagonist) and/or a β-blocker in hypertensive patients with stable ischemic heart disease because of the cardioprotective benefits of these drugs; all patients who have survived a myocardial infarction should be treated with a β-blocker because of the demonstrated mortality benefit of these agents. Other antihypertensive drugs such as calcium-channel blockers or thiazide diuretics may be added to the regimen as necessary to achieve blood pressure goals.

Heart Failure

While ACE inhibitors as single therapies are not superior to other antihypertensive agents in the reduction of cardiovascular outcomes, ACE inhibitors, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers, have been shown to reduce morbidity and mortality in patients with existing heart failure.(See Uses: Heart Failure.) ACE inhibitors also have been used to prevent subsequent heart failure and reduce morbidity and mortality in patients with systolic dysfunction following acute myocardial infarction.(See Uses: Left Ventricular Dysfunction after Myocardial Infarction.)

Diabetes Mellitus

ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics have all been recommended for initial antihypertensive therapy in patients with diabetes mellitus, although certain agents may be preferred. Results of several studies indicate that adequate control of blood pressure in patients with type 2 diabetes mellitus reduces the development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease). There also is evidence demonstrating the benefits of ACE inhibitors in reducing the development or progression of microvascular or macrovascular complications in hypertensive patients with type 1 or type 2 diabetes mellitus. The American Diabetes Association (ADA) states that the antihypertensive regimen of patients with diabetes and hypertension should include an ACE inhibitor or angiotensin II receptor antagonist because of the cardiovascular benefits of these drugs; the renoprotective effect of these drugs provides another compelling reason for their use in diabetic patients who may have albuminuria or renal insufficiency.(See Uses: Diabetic Nephropathy.) If additional blood pressure control is required, a calcium-channel blocker or thiazide diuretic may be added. Because ACE inhibitors and angiotensin II receptor antagonists tend not to be as effective in black patients, some experts recommend a thiazide diuretic or a calcium-channel blocker as the initial antihypertensive drug of choice in black patients with diabetes.(See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.)

Chronic Kidney Disease

Hypertensive patients with chronic kidney disease (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure. Use of ACE inhibitors or angiotensin II receptor antagonists is recommended in patients with diabetic or nondiabetic chronic kidney disease; these drugs have been shown to slow the progression of kidney disease, but evidence of a cardiovascular benefit is not as clear. Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria. Although ACE inhibitors and angiotensin II receptor antagonists generally are not recommended as the drugs of first choice for initial antihypertensive therapy in black patients, some experts suggest that these drugs be used for their renoprotective effects in black patients with chronic kidney disease and proteinuria because of the high likelihood that these patients will progress to end-stage renal disease. Diuretics also may be useful in the management of chronic kidney disease, and may potentiate the effects of ACE inhibitors, angiotensin II receptor antagonists, and other antihypertensive agents when used in combination.

Cerebrovascular Disease

Blood pressure goals in patients with ischemic stroke or transient ischemic attack (TIA) should be individualized, but generally are similar to those recommended for the general population (i.e., systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg). In patients with a recent lacunar stroke, the American Heart Association (AHA) and the American Stroke Association (ASA) suggest that a lower systolic blood pressure goal of 130 mm Hg may be reasonable based on results of a randomized open-label study (the Secondary Prevention of Small Subcortical Strokes [SPS3] trial). Although experts state that the optimal choice of drug for the management of hypertension in patients with a previous TIA or ischemic stroke is uncertain, the available data indicate that a diuretic or the combination of a diuretic and an ACE inhibitor may be used. Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower recurrent stroke rates.

Hypertension Associated with Scleroderma Renal Crisis

Enalapril has been effective for the management of hypertension associated with scleroderma renal crisis in a limited number of patients who were unable to tolerate captopril because of adverse effects. Maintenance therapy with enalapril (5-30 mg daily) controlled blood pressure in these patients and was accompanied by improvement in renal function. Some clinicians consider ACE inhibitors the drugs of choice for this condition.

Other Special Considerations for Antihypertensive Therapy

Race

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with ACE inhibitors. In a prespecified subgroup analysis of the ALLHAT study, a thiazide-type diuretic was more effective than an ACE inhibitor in improving cerebrovascular and cardiovascular outcomes in black patients; when compared with a calcium-channel blocker, the ACE inhibitor was less effective in reducing blood pressure and was associated with a 51% higher rate of stroke. However, such diminished response to an ACE inhibitor is largely eliminated when the drug is administered concomitantly with a thiazide diuretic or calcium-channel blocker. In addition, some experts state that when use of ACE inhibitors is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.

Although enalapril has lowered blood pressure in all races studied, monotherapy with enalapril 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 enalapril and a thiazide diuretic. In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.

Renovascular or Malignant Hypertension

Enalapril also has been effective in the management of renovascular or malignant hypertension, renal hypertension secondary to renal-artery stenosis, and, in some patients, hypertension associated with chronic renal failure. In addition to the drugs' hypotensive effect, ACE inhibitors also have stabilized or improved effective renal blood flow and glomerular filtration rate and decreased proteinuria in some hypertensive patients with moderately impaired renal function, moderate to severe renal disease, or diabetic nephropathy. However, enalapril should be used with caution in patients with impaired renal function, especially those with bilateral renal-artery stenosis or with renal-artery stenosis in a solitary kidney.(See Cautions: Renal Effects and see Hematologic Effects and see Precautions and Contraindications.)

Hypertensive Crises

Enalaprilat has been used effectively to reduce blood pressure in adults with severe hypertension or hypertensive emergencies.

Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage. Such emergencies include hypertensive encephalopathy, acute myocardial infarction, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, and unstable angina pectoris. Patients with hypertensive emergencies require hospitalization and are treated initially with an appropriate parenteral agent. Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy.

Acute enalaprilat therapy (e.g., 1.25-5 mg IV, repeated every 6 hours as necessary) is one of several parenteral regimens currently recommended for rapidly reducing blood pressure in patients with hypertensive crises in whom reduction of blood pressure is considered an emergency. However, reduction of blood pressure in a prompt but controlled manner may be more easily achieved with short-acting antihypertensive agents administered by continuous IV infusion (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside), and some clinicians state that such agents generally are preferred.

Enalaprilat also has been used for rapid reduction of blood pressure in pediatric patients 1-17 years of age with hypertensive urgencies or emergencies.

The risks of overly aggressive therapy in any hypertensive crisis must always be considered, as excessive falls in blood pressure may precipitate renal, cerebral, or coronary ischemia.

Heart Failure

Enalapril is used in the management of symptomatic heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and 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. In patients with prior or current symptoms of chronic heart failure with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [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 (e.g., sacubitril/valsartan) 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 an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure with reduced LVEF (New York Heart Association [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.

Some clinicians state that ACE inhibitors usually are prescribed in clinical practice at dosages lower than those determined as target dosages in clinical trials, although results of several studies suggest that high dosages are associated with greater hemodynamic, neurohormonal, symptomatic, and prognostic benefits than lower dosages. Results of a large, randomized, double-blind study (Assessment of Treatment with Lisinopril and Survival [ATLAS] study) in patients with heart failure (NYHA class II-IV) indicate that high lisinopril dosages (32.5-35 mg daily) were associated with a 12% lower risk of death or hospitalization for any cause and 24% fewer hospitalizations for heart failure than low dosages (2.5-5 mg) of the drug.

Once ACE inhibitor therapy is initiated for heart failure, it generally is continued indefinitely, if tolerated, since withdrawal of an ACE inhibitor may lead to clinical deterioration. Patients with NYHA class II or III heart failure who are tolerating therapy with an ACE inhibitor may be switched to therapy containing an ARNI to further reduce morbidity and mortality; however, the ARNI should not be administered concomitantly with an ACE inhibitor or within 36 hours of the last dose of an ACE inhibitor.

Current evidence supports the use of ACE inhibitors and β-blocker therapy to prevent development of left ventricular dilatation and dysfunction (''ventricular remodeling'') in patients with heart failure.(See Uses: Asymptomatic Left Ventricular Dysfunction.) The addition of other agents such as diuretics, cardiac glycosides, aldosterone antagonists, and/or sinoatrial modulators in the management of heart failure should be individualized. Unless contraindicated, diuretics are recommended in all patients with heart failure and reduced ejection fraction who have evidence of fluid retention to improve symptoms. Digoxin may be beneficial to patients with heart failure with reduced ejection fraction to decrease hospitalization for heart failure, especially in those with persistent symptoms despite treatment with guideline-directed medical therapy. The addition of a sinoatrial modulator (i.e., ivabradine) is recommended in selected patients with chronic heart failure and reduced LVEF who are already receiving guideline-directed medical therapy, to reduce heart failure-related hospitalizations.

Results of a randomized, multicenter, double-blind, placebo-controlled study (Randomized Aldactone Evaluation Study [RALES]) indicate that addition of low-dosage spironolactone (25-50 mg daily) to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside) in patients with severe (NYHA class IV within 6 months before enrollment and NYHA class III or IV at the time of enrollment) heart failure and an LVEF of 35% or less, was associated with decreases in overall mortality and hospitalization (for worsening heart failure) rates of approximately 30 and 35%, respectively, compared with standard therapy and placebo. Based on the results of RALES and other studies, ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure (NYHA class II-IV) and reduced LVEF (35% or less) who are already receiving standard therapy to reduce morbidity and mortality.

Many patients with heart failure respond to enalapril with improvement in cardiac function indexes, symptomatic (e.g., dyspnea, fatigue) relief, improved functional capacity, and increased exercise tolerance. In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 4 months. In some patients, beneficial effects have been sustained for up to 2-21 months. Enalapril also has been effective in conjunction with cardiac glycosides and diuretics for the management of heart failure resistant to or inadequately controlled by cardiac glycosides, diuretics, and vasodilators. In a multicenter, placebo-controlled study in patients with severe heart failure (NYHA class IV), the addition of enalapril to the therapeutic regimen (which included cardiac glycosides, diuretics, and/or vasodilators) was associated with a 40% reduction in overall mortality at 6 months and a 31% reduction at 12 months compared with patients who did not receive an ACE inhibitor, although the incidence of sudden cardiac death did not differ. In addition, there was a substantial improvement in NYHA functional class for patients receiving enalapril in this study. Follow-up of surviving patients 2 years after completion of the blinded, placebo-controlled phase showed a carry-over effect of enalapril on mortality reduction despite the availability of enalapril therapy for all surviving patients (whether treated initially with the drug or not) and the poorer clinical condition of the initial enalapril-treated group at the outset of follow-up; during follow-up, the carry-over effect on mortality reduction of initial enalapril therapy persisted for 15 months.

In 2 multicenter, controlled studies, enalapril substantially reduced mortality in patients with mild to moderate heart failure (NYHA class I-III) when added to a conventional therapeutic regimen (most commonly cardiac glycosides and diuretics); in these patients, enalapril therapy also may substantially reduce the rate of hospitalization. In one of these studies, the reduction in mortality was substantially greater with enalapril than with combined hydralazine and isosorbide dinitrate, although the latter regimen produced substantially greater improvement in exercise performance and left ventricular function. The beneficial effects of enalapril on reduction in mortality may result from a delay in worsening of heart failure, although other mechanisms (e.g., on causes of sudden death) may be involved. Analysis of the results of these studies according to racial subgroup indicates that white patients had substantially greater reductions in blood pressure and the risk of hospitalization for heart failure than black patients receiving similar dosages of enalapril.(See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.) However, the risk of death in either racial subgroup was not altered by enalapril therapy.

It has not been determined whether addition of a vasodilator (e.g., hydralazine) to an ACE inhibitor is more effective than an ACE inhibitor alone. The efficacy of enalapril appears to be similar to that of captopril. However, because of enalapril's relatively long duration of action compared with captopril, enalapril may produce more prolonged hypotensive effects, particularly at high dosages, which potentially could result in adverse cerebral and renal effects. In addition, because the renin-angiotensin system appears to substantially contribute to preservation of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, therapy with an ACE inhibitor in such patients may adversely affect renal function.(See Cautions: Renal Effects.)

ACE inhibitors also are used in patients with ACCF/AHA stage B heart failure (see Uses: Asymptomatic Left Ventricular Dysfunction) to prevent symptomatic heart failure and have been shown to reduce mortality after myocardial infarction or acute coronary syndrome.(See Uses: Left Ventricular Dysfunction after Acute Myocardial Infarction.)

Asymptomatic Left Ventricular Dysfunction

Enalapril is used in clinically stable asymptomatic patients with left ventricular dysfunction (manifested as an ejection fraction of 35% or less) in an effort to decrease the rate of development of overt heart failure and subsequent hospitalizations for heart failure in these patients. AHA recommends use of ACE inhibitors in these patients. Experts recommend that all asymptomatic patients with reduced LVEF (ACCF/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. If ACE inhibitors are not tolerated, then an angiotensin II receptor antagonist is recommended as an alternative.

Enalapril's beneficial effect in preventing the development of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction may result either from relieving symptoms that otherwise would have become apparent or from slowing the progression of asymptomatic ventricular dysfunction to overt, symptomatic disease. In a multicenter, placebo-controlled study in patients with left ventricular dysfunction who did not have symptomatic heart failure (NYHA class I and II) and were not being treated for such at initiation of ACE inhibitor therapy, enalapril reduced the incidence of heart failure and rate of related hospitalizations relative to those receiving placebo during an average of 37.4 months of follow-up. Patients with higher ejection fractions and black patients appeared to benefit less from enalapril therapy than those with lower fractions and white patients, respectively. The effect of enalapril in preventing the development of heart failure was evident within 3 months after initiation of the drug and continued to increase for the remaining study period (approximately 3 years). Mortality rates increased substantially in patients who developed overt heart failure, suggesting the possibility of a secondary benefit on prognosis from prevention of symptomatic progression. In a follow-up study, treatment with enalapril for 3-4 years led to a sustained improvement in survival (11-12 years) in patients with reduced LVEF, including those who were asymptomatic at baseline.

Left Ventricular Dysfunction after Acute Myocardial Infarction

ACE inhibitors, including enalapril and enalaprilat, have been used to minimize or prevent the development of left ventricular dilatation and dysfunction following acute myocardial infarction. However, evidence regarding the efficacy of such therapy has been somewhat conflicting, particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction. While the preponderance of evidence (including a large, multinational, multicenter study) has shown a benefit of early oral therapy involving other ACE inhibitors, even in patients with no baseline dysfunction, one large study involving parenteral and oral enalapril found little if any early (within several months) benefit, particularly in terms of survival, from such therapy. In this multicenter, controlled study, IV enalaprilat (followed by oral enalapril) was initiated within 24 hours of the onset of chest pain associated with acute myocardial infarction and continued for up to approximately 6 months; there was no evidence of improved survival from enalapril therapy during the 6-month period after myocardial infarction and, in some patients, an actual worsening of heart failure was observed. In addition, enalapril therapy was associated with a substantial risk of hypotensive episodes, and long-term mortality was higher among patients who experienced hypotension with the first dose of enalapril than among other patients receiving the drug or among those who experienced hypotension with placebo. The lack of survival benefit observed in this study applied overall as well as to subgroups of patients (e.g., those with Q-wave infarction, anterior infarction, previous infarction, or current infarction complicated by pulmonary edema or heart failure). The results of this study are in contrast to other studies involving other ACE inhibitors initiated within 24 hours to 4 weeks after acute myocardial infarction in which a beneficial effect was observed, in terms of effects on left ventricular volume, infarct expansion, and/or survival.

The reason for the differences in potential benefit observed between studies involving enalapril and those involving other ACE inhibitors (e.g., captopril, lisinopril, ramipril) is unclear, but the lack of benefit in the enalapril study may have resulted in part from an early adverse effect of ACE inhibition (e.g., inhibition of angiotensin II-stimulated protein synthesis involved in healing) combined with a rapid decrease in blood pressure associated with the initial administration of enalaprilat and with an inadequate period of follow-up to detect a delayed beneficial effect. While use of parenteral ACE inhibitors during the early postinfarction period is not recommended, an oral ACE inhibitor should be initiated (starting with low doses) and titrated upward gradually during the initial postinfarction period. Early treatment with an ACE inhibitor following myocardial infarction has been shown to be beneficial in patients with or without left ventricular dysfunction or heart failure, although the benefits of these drugs appear to be greatest in patients with anterior myocardial infarction or evidence of prior infarction, heart failure, or tachycardia. Some clinicians state that ACE inhibitor therapy generally can be discontinued if there are no patient complications or evidence of symptomatic or asymptomatic left ventricular dysfunction by 4-6 weeks postinfarction in patients in whom such therapy was initiated prophylactically. However, long-term therapy with oral ACE inhibitors has been used to prevent cardiovascular events in patients with diabetes mellitus or a history of cardiovascular disease or myocardial infarction.

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

Oral Administration

Enalapril maleate alone or in fixed combination with hydrochlorothiazide is administered orally. For patients unable to swallow tablets, enalapril maleate may be administered orally as an extemporaneously prepared suspension. The drug can be given before, during, or after meals since food does not appear to substantially affect the rate or extent of absorption of enalapril.

An extemporaneous suspension containing enalapril maleate 1 mg/mL can be prepared in the following manner. First, 50 mL of sodium citrate dihydrate (Bicitra) is added to a polyethylene terephthalate (PET) bottle containing ten 20-mg tablets of enalapril maleate, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for 60 minutes following reconstitution, and then should be shaken for an additional minute. The concentrated suspension of enalapril maleate should be diluted with 150 mL of syrup (Ora-Sweet SF), and the container then shaken to disperse the ingredients. The suspension should be shaken before dispensing of each dose.

IV Administration

Enalaprilat is administered by slow IV infusion over a period of at least 5 minutes. The drug should not be administered by other parenteral routes of administration. Enalaprilat may be administered by slow, direct IV infusion, or the injection can be diluted in up to 50 mL of compatible IV infusion solution for administration.(See Chemistry and Stability: Stability.) Enalaprilat injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

Dosage of enalapril maleate and enalaprilat must be adjusted according to the patient's tolerance and response.Since enalapril maleate is a prodrug of enalaprilat and is well absorbed following oral administration, dosage of the two drugs is not identical and clinicians must give careful attention to dosage when converting from oral to IV therapy or vice versa.

Because of the risk of inducing hypotension, initiation of enalapril maleate or enalaprilat 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 patients already receiving a diuretic, symptomatic hypotension may occur following the initial dose of the angiotensin-converting enzyme (ACE) inhibitor. The possibility of hypotension may be minimized by discontinuing the diuretic, reducing the diuretic dosage, or cautiously increasing salt intake prior to initiation of oral enalapril maleate or IV enalaprilat therapy.(See Cautions: Cardiovascular Effects.) For information on initiating oral enalapril maleate or IV enalaprilat therapy when diuretic therapy is not being withheld, see the disease-specific dosage sections in Dosage and Administration: Dosage.

Hypertension

Oral Dosage

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. Based on such information, an initial adult enalapril maleate dosage of 5 mg daily and a target dosage of 20 mg daily (given as a single dose or in 2 divided doses) are recommended. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months.

The manufacturer states that the usual initial adult dosage of enalapril maleate for the management of hypertension in patients not receiving a diuretic is 5 mg once daily. In patients who are receiving a diuretic, it is recommended that diuretic therapy be discontinued, if possible, 2-3 days before initiating therapy.(See Cautions: Precautions and Contraindications.) If blood pressure is not adequately controlled with the ACE inhibitor alone, diuretic therapy may be resumed cautiously. If diuretic therapy cannot be discontinued, an initial enalapril maleate dose of 2.5 mg should be administered under medical supervision for at least 2 hours and until blood pressure has stabilized for at least an additional hour.

The usual initial pediatric (1 month to 16 years of age) dosage of enalapril maleate is 0.08 mg/kg once daily, up to 5 mg. Dosages of enalapril maleate exceeding 0.58 mg/kg or in excess of 40 mg have not been studied in pediatric patients.

Dosage of enalapril maleate should be adjusted according to the patient's blood pressure response. If the blood pressure response diminishes toward the end of the dosing interval during once-daily administration, increasing the dosage or giving the drug in 2 divided doses daily should be considered. Because the reduction in blood pressure may be gradual, some clinicians suggest that enalapril maleate dosage generally be titrated at 2- to 4-week intervals if necessary. The usual maintenance dosage of enalapril maleate in adults is 10-40 mg daily, given as a single dose or in 2 divided doses daily, although most patients can be maintained on once-daily dosing. Optimum blood pressure reduction may require several weeks of therapy in some patients. If blood pressure is not adequately controlled with enalapril alone, a second antihypertensive agent (e.g., a diuretic) may be added.

When oral therapy is initiated following IV enalaprilat therapy in adults not receiving a diuretic, the recommended initial dosage of enalapril maleate is 5 mg once daily with subsequent dosage adjustment as necessary. When oral therapy is initiated following IV enalaprilat therapy in adults receiving a diuretic, the recommended initial dosage of enalapril maleate in those who responded to enalaprilat 0.625 mg every 6 hours is 2.5 mg once daily with subsequent dosage adjustment as necessary.

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with enalapril 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 enalapril, 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.

Enalapril/Hydrochlorothiazide Fixed-combination Oral Therapy

To minimize the likelihood of adverse effects, therapy with the commercially available preparations containing enalapril in fixed combination with hydrochlorothiazide should only be initiated in adults after an adequate response is not achieved with enalapril or hydrochlorothiazide monotherapy. Alternatively, the fixed combination containing enalapril with hydrochlorothiazide may be used in adults who had been receiving the drugs separately and in whom dosage of the individual drugs has been adjusted. The recommended initial adult dosage of the commercially available fixed-combination tablets is 5 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide or 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide once daily. Further increases of either or both drugs depend on clinical response; however, generally, dosage of hydrochlorothiazide should not be increased for about 2-3 weeks after initiation of therapy. Because the suggested maximum adult dosage of enalapril maleate and hydrochlorothiazide during combined antihypertensive therapy is 20 or 50 mg daily, respectively, the combined dosage of enalapril maleate and hydrochlorothiazide in the fixed combination should not exceed these respective levels.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of enalapril maleate 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.(See Considerations in Initiating Antihypertensive Therapy under Uses: Hypertension.)

IV Dosage

When oral therapy is not feasible, the recommended initial IV enalaprilat dosage in adults not receiving a diuretic or in those converting from enalapril maleate therapy (without concomitant diuretic therapy) is 1.25 mg every 6 hours. Reduction in blood pressure usually occurs within 15 minutes, but the maximal hypotensive response after the first dose may not occur for up to 4 hours after administration. The maximum effects of the second and subsequent doses may exceed those of the first dose. Although no regimen has been shown to be more effective than 1.25 mg every 6 hours, dosages as high as 5 mg every 6 hours were well tolerated for up to 36 hours in controlled clinical studies. Experience with dosages greater than 20 mg daily is insufficient. In studies of patients with hypertension, enalaprilat was not administered for longer than 48 hours, but in other studies it has been administered for as long as 7 days.

When oral therapy is not feasible in adults receiving a diuretic, the recommended initial IV enalaprilat dose is 0.625 mg. A reduction in blood pressure usually occurs within 15 minutes. Although most of the effect is usually apparent within the first hour, the maximal hypotensive response may not occur for up to 4 hours after the initial dose. If the blood pressure response after 1 hour is inadequate, another dose of 0.625 mg may be given. Additional doses of 1.25 mg may be administered at 6-hour intervals.

To reduce blood pressure rapidly in adults with a hypertensive emergency, an IV enalaprilat dosage of 1.25-5 mg, repeated every 6 hours as necessary, has been recommended. If IV enalaprilat is used in the management of a hypertensive emergency in adults, the initial goal of such therapy is to reduce mean arterial blood pressure by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia. If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours. Patients with aortic dissection should have their systolic pressure reduced to less than 100 mm Hg if tolerated.

For rapid reduction of blood pressure in pediatric patients (1-17 years of age) with severe hypertension, some experts recommend administration of a direct IV enalaprilat injection of 0.05-0.1 mg/kg per dose, up to 1.25 mg per dose.

For information on converting patients from IV to oral therapy, see Oral Dosage under Dosage: Hypertension, in Dosage and Administration.

Heart Failure

Because of the risk of severe hypotension, enalapril maleate therapy for heart failure should be initiated under very close medical supervision (e.g., in a hospital setting) with consideration given to recent diuretic therapy and the possibility of severe sodium and/or fluid depletion. ACE inhibitor therapy should be initiated with caution in patients with very low systemic blood pressure (systolic blood pressure less than 80 mm Hg), markedly increased serum concentrations of creatinine (greater than 3 mg/dL), bilateral renal artery stenosis, or elevated concentrations of serum potassium (greater than 5 mEq/L). Experts recommend that renal function and serum potassium be assessed within 1-2 weeks of initiation of therapy and periodically thereafter in patients receiving an ACE inhibitor, especially in those with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia, or in those taking potassium supplements. Use of low initial enalapril maleate dosages and reduction of the dosage of concomitantly administered diuretics may decrease the initial risk of hypotension. However, the long-term hemodynamic benefit of low enalapril maleate dosages (e.g., 10-20 mg daily) in this condition has not been established.

It should be recognized that although symptoms of heart failure may improve within 48 hours after initiating ACE inhibitor therapy in some patients, such improvement usually is not evident for several weeks or months after initiating ACE inhibitor therapy. In addition, it should be considered that such therapy may reduce the risk of disease progression even if symptomatic improvement is not evident. Therefore, dosages generally should be titrated to a prespecified target (i.e., at least 20 mg of enalapril daily) or highest tolerated dosage rather than according to response.

For the management of symptomatic heart failure, enalapril maleate often is administered in conjunction with other agents such as a cardiac glycoside, a diuretic, and a β-blocker. Enalapril maleate dosage for heart failure should be initiated at low doses and titrated gradually upward if lower doses have been well tolerated. The usual initial enalapril maleate dosage for the management of heart failure in adults with normal renal function and serum sodium concentration is 2.5 mg twice daily. After the initial dose, the patient should be monitored closely for at least 2 hours and for at least one additional hour after blood pressure has stabilized. Hypotension occurring after the initial dose does not preclude the administration of subsequent doses of the drug, provided due caution is exercised and the hypotension has been managed effectively. To minimize the likelihood of hypotension, the dosage of any diuretic given concomitantly with enalapril should be reduced, if possible. The usual maintenance dosage of enalapril maleate for heart failure is 2.5-20 mg twice daily. The maximum recommended daily dosage of the drug is 40 mg, given in 2 divided doses.

Asymptomatic Left Ventricular Dysfunction

When used in adults with asymptomatic left ventricular dysfunction, enalapril maleate therapy has been initiated using a dosage of 2.5 mg twice daily. Therapy is then titrated as tolerated to a target daily dosage of 20 mg given in divided doses. After the initial dose of enalapril, the patient should be closely observed for at least 2 hours and for at least one additional hour after blood pressure has stabilized. To minimize the likelihood of hypotension, the dosage of any concomitant diuretic should be reduced, if possible. The appearance of hypotension after the initial dose of enalapril does not preclude subsequent carefully titrated doses of the drug after the hypotension has been effectively managed.

Dosage in Renal or Hepatic Impairment, Hyponatremia, Pediatric Patients, and Geriatric Patients

If enalapril maleate or enalaprilat is used in patients with impaired renal function, dosage must be modified in response to the degree of renal impairment, and the theoretical risk of neutropenia must be considered.(See Cautions: Hematologic Effects.)

The manufacturer states that hypertensive adults with moderate renal impairment (i.e., creatinine clearances greater than 30 mL/minute) may receive the usual dosage of enalapril maleate. In adults with severe renal impairment (i.e., creatinine clearances of 30 mL/minute or less), dosage of enalapril maleate should be initiated at 2.5 mg daily. If an adequate response is not achieved, dosage may then be gradually increased until blood pressure is controlled or a maximum dosage of 40 mg daily is reached. Alternatively, some clinicians suggest that patients with creatinine clearances of 10-50 mL/minute can receive 75-100% of the usual dosage and those with creatinine clearances less than 10 mL/minute can receive 50% of the usual dosage. Patients undergoing hemodialysis should receive a supplemental dose of the drug after dialysis. The manufacturer recommends that hemodialysis patients be given a dose of 2.5 mg on dialysis days; on days between dialysis periods, enalapril maleate dosage should be adjusted according to the patient's blood pressure response.

For hypertensive adults with moderate renal impairment (i.e., creatinine clearances greater than 30 mL/minute) in whom oral therapy is not feasible, the recommended dosage of IV enalaprilat is 1.25 mg every 6 hours. In adults with severe renal impairment (i.e., creatinine clearances of 30 mL/minute or less), the initial dose of IV enalaprilat should be 0.625 mg; if the blood pressure response is inadequate after 1 hour, another dose of 0.625 mg may be given. Additional doses of 1.25 mg may be administered at 6-hour intervals. For patients undergoing dialysis, the initial dosage of IV enalaprilat should be 0.625 mg every 6 hours. When oral therapy is initiated following IV enalaprilat therapy, the recommended initial dosage of enalapril maleate is 5 mg once daily in patients with creatinine clearances greater than 30 mL/minute and 2.5 mg once daily in patients with creatinine clearances of 30 mL/minute or less. Dosage is subsequently adjusted according to the patient's blood pressure response.

The manufacturer states that adults with heart failure and hyponatremia (serum sodium concentration less than 130 mEq/L) or serum creatinine concentration greater than 1.6 mg/dL should receive an initial enalapril maleate dosage of 2.5 mg daily under close monitoring (see Dosage: Heart Failure, in Dosage and Administration). Subsequent dosage may be increased gradually as necessary, usually at intervals of 4 or more days, to 2.5 mg twice daily, then 5 mg twice daily, and then higher, provided excessive hypotension or deterioration of renal function is not present at the time of intended dosage adjustment; dosage should not exceed 40 mg daily.

If concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic is preferred to a thiazide diuretic. Therefore, use of commercially available preparations containing enalapril maleate in fixed combination with hydrochlorothiazide is not recommended for patients with severe renal impairment. The manufacturers state that dosage adjustment of commercially available preparations containing enalapril maleate in fixed combination with hydrochlorothiazide is not needed in patients with renal impairment whose creatinine clearance exceeds 30 mL/minute per 1.73 m.

Enalapril maleate is not recommended for neonates or for pediatric patients who have a glomerular filtration rate of less than 30 mL/minute per 1.73 m, since no data are available in such patients.

Since it is not known whether geriatric patients 65 years of age or older respond the same to enalapril in fixed combination with hydrochlorothiazide as younger adults, the manufacturer suggests that patients in this age group receive initial dosages of the fixed combination in the lower end of the usual range.

Cautions

Adverse reactions to enalapril usually are mild and transient but have required discontinuance of therapy in about 3 or 6% of patients receiving the drug for the management of hypertension or heart failure, respectively. Enalaprilat usually is well tolerated. Since enalapril is metabolized to enalaprilat, administration of enalaprilat can be expected to produce adverse effects associated with enalapril therapy. Overall, the frequency of many adverse effects produced by enalapril appears to be similar to or less than that produced by captopril. However, unlike captopril, enalapril lacks the sulfhydryl group which has been associated with certain captopril-induced adverse effects (e.g., cutaneous reactions, taste disturbances, proteinuria), and the risk of these effects may be decreased during enalapril therapy. Additional experience to determine the relative safety of enalapril is necessary, and the possibility that the risk may be similar should be considered. Because of enalapril's long duration of action, the risk of some adverse effects (e.g., hypotension, deterioration in renal function) may be increased compared with short-acting ACE inhibitors, particularly in patients whose cardiovascular and renal systems have increased dependency on the renin-angiotensin system (e.g., those with severe heart failure).

Adverse nervous system effects (e.g., headache, dizziness, fatigue) occur most frequently during enalapril therapy for hypertension. Although adverse effects of enalapril generally are mild, discontinuance of the drug has been necessary in about 6% of patients, principally because of dizziness, headache, hypotension, or rash. The manufacturer states that the incidence of the most frequently reported adverse effects was similar in patients receiving enalapril or placebo in clinical trials. In patients with heart failure, symptomatic hypotension, deterioration in renal function, and increased serum potassium concentration appear to occur most frequently, particularly during initiation of enalapril therapy in volume- and/or sodium-depleted patients (e.g., those receiving concomitant diuretic therapy).

The frequency of some adverse reactions may be increased during therapy with enalapril in fixed combination with hydrochlorothiazide compared with either drug alone, but the manufacturer states that adverse reactions reported to date with the combination have been reported previously with the individual drugs. No reactions peculiar to the combination have been reported.

Nervous System Effects

Headache and dizziness occur in about 5% of patients receiving enalapril alone for hypertension, requiring discontinuance in 0.4 and 0.3% of patients, respectively, and occur in about 6 and 9%, respectively, of hypertensive patients receiving the drug in fixed combination with hydrochlorothiazide. In patients receiving enalapril for heart failure, dizziness and headache occurred in approximately 8 and 2% of patients, respectively, and required discontinuance of the drug in 0.6 and 0.1%, respectively. Headache has been reported in about 3% of patients receiving enalaprilat. Fatigue has occurred in about 3% of patients receiving the drug alone for hypertension, requiring discontinuance in less than 0.1%, and has occurred in about 4% of hypertensive patients receiving the drug in fixed combination with hydrochlorothiazide. Fatigue, fever, and dizziness have been reported in 0.5-1% of patients receiving enalaprilat. Vertigo has occurred in about 2% of patients receiving enalapril for heart failure and required discontinuance in about 0.1% of patients. Insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia, asthenia, and somnolence occur in about 0.5-2% of patients receiving enalapril alone or in fixed combination with hydrochlorothiazide. Hyperesthesia of the oral mucosa, CNS depression, malaise, nightmares, confusion, ataxia, and coldness of the extremities have been reported rarely.

GI Effects

Diarrhea and nausea occur in about 1-2% of patients with hypertension receiving enalapril alone or in fixed combination with hydrochlorothiazide and in patients with heart failure receiving the drug, and have required discontinuance of the drug in 0.2% or less of patients. Nausea has been reported in about 1% of patients receiving enalaprilat. Abdominal pain, vomiting, stomatitis, and dyspepsia occur in 0.5-2% of patients receiving enalapril, and ulceration of the oral mucosa, ileus, melena, anorexia, glossitis, dry mouth, and flatulence have been reported rarely. Constipation has been reported in 0.5-1% of patients receiving enalaprilat.

Hepatic Effects

A clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (which occasionally may be fatal), has been reported rarely in patients receiving ACE inhibitors. The mechanism of this reaction is not known.

Cardiovascular Effects

The most frequent adverse cardiovascular effect of enalapril or enalaprilat is hypotension (including postural hypotension and other orthostatic effects), which occurs in about 1-2% of patients with hypertension and in about 5-7% of those with heart failure, following an initial dose or during extended therapy. Syncope occurred in approximately 0.5 or 2% of patients with hypertension or heart failure, respectively. Hypotension or syncope has required discontinuance of therapy in about 0.1 or 2% of patients with hypertension or heart failure, respectively, receiving enalapril.

Hypotensive effects, including excessive and/or symptomatic hypotension, appear to occur more frequently in patients receiving enalapril for heart failure rather than for uncomplicated hypertension. Some reduction in blood pressure occurs in most patients receiving the drug for heart failure and generally is beneficial when secondary to afterload reduction; however, pronounced hypotension can occur and may adversely affect renal and myocardial perfusion (see later discussion in this section). Enalapril-induced hypotension may occasionally be alleviated by dosage reduction, but severe hypotension has also occurred after low doses (i.e., a single 2.5- or 5-mg dose) of the drug.

The value of initiating enalapril therapy at low doses to decrease the risk of hypotension has not been fully elucidated, but such dosing has been suggested, particularly for patients at risk (e.g., those with heart failure). Orthostatic hypotension appears to occur more frequently during initiation of therapy and in patients with sodium depletion or hypovolemia. Transient hypotension in patients with heart failure or with hypertension may occur after any of the first several doses (i.e., with the first 24-48 hours), and sometimes is associated with dizziness, blurred vision, nausea, syncope, and, rarely, bradycardia. Patients who are volume and/or sodium depleted such as those receiving diuretics, especially those in whom diuretic therapy was recently initiated (e.g., patients with severe congestive heart failure), those whose sodium intake is severely restricted, and those who are undergoing dialysis, may occasionally experience a precipitous reduction in blood pressure within the first 3-4 hours after a dose of enalapril. The risk of orthostatic hypotension associated with concomitant use of enalapril and a diuretic may be affected by the sequence of initiation of therapy with each drug; the risk may be higher when enalapril is added to diuretic therapy than when a diuretic is added to enalapril therapy. Symptomatic hypotension that occurs later in a course of enalapril therapy (e.g., after the first 48 hours) may indicate the presence of sodium depletion (e.g., secondary to restriction of sodium intake or increased diuretic dosage).

When enalapril was used in fixed combination with hydrochlorothiazide in clinical trials in hypertensive patients, hypotension, orthostatic hypotension, and other orthostatic effects occurred in 0.9, 1.5, and 2.3% of patients, respectively. Syncope occurred in 1.3% of patients receiving the fixed combination, but the frequency of this effect can be minimized by proper titration of each drug separately and substitution with the combination preparation only when the optimum dosages correspond to the fixed ratio in the preparation.

Severe enalapril-induced hypotension may be associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure, myocardial ischemia, and/or death in patients with heart failure, hyponatremia, or severe sodium or volume depletion of any etiology; patients undergoing dialysis; and those receiving high-dose or recent intensive diuretic therapy or in whom the diuretic dosage was recently increased. In such patients, it may be advisable to discontinue diuretic therapy (except in patients with heart failure), reduce the diuretic dosage, or cautiously increase salt intake, if possible, prior to initiating therapy with enalapril. Patients at risk for excessive hypotension should be closely monitored after an initial dose of the drug, and should be followed closely for 2 weeks after initiation of enalapril therapy and whenever dosage of enalapril and/or a concomitantly administered diuretic is increased. Some experts state that patients with heart failure should be under very close medical supervision (e.g., in a hospital setting) when enalapril therapy is initiated, since severe hypotension could potentially compromise the patient's hemodynamic status. The risk of hypotension and potential detrimental hemodynamic and clinical effects in patients with severe heart failure appears to be higher during therapy with a long-acting ACE inhibitor such as enalapril than with a short-acting inhibitor.

If hypotension occurs in patients receiving enalapril, the patient should be placed in the supine or Trendelenburg's position; if hypotension is severe or prolonged, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered. Transient hypotension is not a contraindication to additional doses of enalapril, and therapy with the drug can usually be cautiously reinitiated after blood pressure has been stabilized (e.g., with volume expansion); enalapril dosage reduction and/or dosage reduction or discontinuance of concomitantly administered diuretics may be necessary. Some clinicians state that asymptomatic hypotension often does not require specific therapy and may be well tolerated with continued enalapril therapy. However, severe hypotension occasionally may require discontinuance of enalapril therapy, and the possibility should be considered that hypotension may persist for prolonged periods (e.g., for a week or longer) after discontinuance because of the drug's long duration of action. Patients with heart failure or those undergoing dialysis may be at particular risk of prolonged hypotension. The possibility of severe hypotension may be minimized by withholding diuretic therapy and/or increasing sodium intake for 2-3 days prior to initiating enalapril therapy.

Hypotension also may occur in enalapril-treated patients during major surgery or during anesthesia with agents that produce hypotension. This hypotensive effect results from inhibition by enalapril of the angiotensin II formation that occurs subsequent to compensatory renin release, and, if it is thought to be caused by enalapril, can generally be corrected with fluid volume expansion.

Palpitation and chest pain occur in about 0.5-2% of patients with hypertension receiving enalapril alone or in fixed combination with hydrochlorothiazide. Tachycardia, bradycardia, and development or worsening of Raynaud's phenomenon have been reported rarely in patients receiving the drug. Cardiac arrest or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients, pulmonary embolism and infarction, pulmonary edema, rhythm disturbances (including atrial tachycardia and bradycardia), flushing, and atrial fibrillation have been reported in about 0.5-1% of patients with hypertension or heart failure. Angina or myocardial infarction was reported in about 1-1.5% of patients receiving enalapril for heart failure in controlled and uncontrolled studies, and required discontinuance in about 0.1-0.3% of patients, but a similar incidence for these effects was reported in patients receiving placebo in controlled studies. Myocardial infarction was reported in 0.5-1% of patients receiving enalaprilat.

Renal Effects

Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations, has occurred in about 20% of patients with renovascular hypertension, especially those with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney. This effect was usually reversible following discontinuance of enalapril and/or diuretic therapy. Renal function should be monitored closely during the first few weeks of therapy in these patients.(See Cautions: Precautions and Contraindications.) Transient increases in BUN and serum creatinine concentrations have also occurred in about 0.2% of patients with hypertension, but without preexisting renal vascular disease, who were receiving enalapril alone. These effects occur more frequently in patients receiving concomitant diuretic therapy, in patients with heart failure, and in patients with some degree of preexisting renal dysfunction. Dosage reduction of enalapril and/or dosage reduction or discontinuance of diuretic therapy may be necessary. The rapidity of onset and magnitude of enalapril-induced renal insufficiency in patients with heart failure may depend in part on the degree of sodium depletion. About 5-15 or 15-30% of patients with mild to moderate or severe heart failure, respectively, treated with an ACE inhibitor develop substantial elevations of serum creatinine concentrations (e.g., greater than 5 mg/dL). Acute reversible renal failure, flank pain, oliguria, uremia, glycosuria, and proteinuria have been reported rarely in patients receiving enalapril. Urinary tract infection has been reported in about 1% of patients receiving enalapril for heart failure in controlled and uncontrolled studies, but this effect occurred in about 2% of patients receiving placebo in controlled studies.

Because the renin-angiotensin system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly during therapy with an ACE inhibitor in these patients. Such drug-induced deterioration is generally well tolerated, and does not usually necessitate discontinuance of effective therapy with the drug when symptomatic improvement of the heart failure occurs. In addition, the magnitude of deterioration in renal function can usually be ameliorated by reducing the dosage of concomitantly administered diuretics and/or by liberalizing dietary sodium intake, since concomitant diuretic therapy and/or sodium restriction potentially increase the role of angiotensin II in maintaining glomerular filtration in these patients. In patients in whom renal perfusion pressure is very low and is further reduced by ACE-inhibitor therapy, however, deterioration in renal function may be clinically important. Patients with concomitant underlying diabetes mellitus may be at particular risk for developing renal insufficiency during ACE-inhibitor therapy. In some patients with severe heart failure, with or without associated renal insufficiency, treatment with an ACE inhibitor, including enalapril, may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. The risk of developing functional renal insufficiency appears to be higher during therapy with a long-acting ACE inhibitor such as enalapril than with a short-acting inhibitor.

Dermatologic and Sensitivity Reactions

The most frequent adverse dermatologic effect of enalapril is rash, which occurs in about 1.5% of patients and is usually maculopapular and rarely urticarial. Rash may sometimes be accompanied by pruritus, erythema, or eosinophilia, and has required discontinuance of the drug in approximately 0.3% of patients. A patient who developed enalapril-induced rash was subsequently treated with captopril without recurrence. However, the frequency of enalapril-induced rash appears to be less than that of captopril, possibly because enalapril lacks the sulfhydryl group, and several patients who developed captopril-induced rash have subsequently been treated with enalapril without recurrence of rash. Rash has been reported in 0.5-1% of patients receiving enalaprilat.

Pruritus, without rash, and excessive sweating have been reported in 0.5-2% of patients receiving enalapril alone or in fixed combination with hydrochlorothiazide. Alopecia has been reported in 0.5-1% of patients receiving enalapril. A symptom complex, consisting of positive ANA titer, increased erythrocyte sedimentation rate (ESR), arthralgias and/or arthritis, myalgias, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash, and other dermatologic reactions has been reported in 0.5-1% of patients receiving enalapril therapy. Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, and erythema multiforme have been reported rarely in patients receiving enalapril therapy.

Severe, sudden anaphylactoid reactions, which can be fatal, have been reported following initiation of hemodialysis that utilized a high-flux polyacrylonitrile [PAN] membrane (e.g., AN 69) in patients receiving an ACE inhibitor. Manifestations of these reactions included nausea, abdominal cramps, burning, angioedema, and shortness of breath; progression to severe hypotension can develop rapidly. Dialysis should be stopped immediately and aggressive supportive and symptomatic therapy should be initiated as indicated. Antihistamines do not appear to be effective in providing symptomatic relief. While it currently does not seem to be necessary to exclude the use of ACE inhibitors in patients undergoing hemodialysis that involves PAN membranes, caution should be exercised during concomitant use. The mechanism of this interaction has not been established, and the incidence and risk of its occurrence remain to be elucidated. The possibility that ACE inhibitors may precipitate similar reactions in patients undergoing hemodialysis involving other membrane types (new or reprocessed) should be considered. In addition, anaphylactoid reactions also have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption. Manifestations of these reactions included flushing, dyspnea, bradycardia, and hypotension. It has been postulated that these reactions may be associated with accumulation of polypeptides (e.g., bradykinin) since endogenous concentration of such polypeptides may be increased by LDL-apheresis with dextran sulfate and their metabolism may be decreased by ACE inhibitors. To avoid these anaphylactoid reactions, some clinicians recommend withdrawal of ACE inhibitors 12-30 hours before apheresis, while others state that ACE inhibitors should not be used in patients treated with LDL apheresis.

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 24 hours before desensitization with the venom, anaphylactoid reactions did not recur; however, such reactions recurred after inadvertent rechallenge.

Angioedema of the face, lips, tongue, larynx, glottis, or extremities has occurred in patients receiving ACE inhibitor therapy, including enalapril.(See Cautions: Precautions and Contraindications.) In addition, intestinal angioedema (occasionally without a prior history of facial angioedema or elevated serum levels of complement 1 [C1] esterase inhibitor) 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; manifestations 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.

Hematologic Effects

Decreases in hemoglobin and hematocrit averaging approximately 0.3 g/dL and 1%, respectively, occur frequently in hypertensive patients receiving enalapril alone or in fixed combination with hydrochlorothiazide, but rarely are clinically important unless another cause of anemia also exists. Enalapril-induced anemia has required discontinuance of therapy in less than 0.1% of patients. Hemolytic anemia, including cases of hemolysis in a few patients with glucose-6-phosphate-dehydrogenase (G-6-PD) deficiency, has been reported in patients receiving enalapril maleate therapy; a causal relationship has not been established.

Neutropenia (less than 1000 neutrophils/mm) and agranulocytosis, both associated with myeloid hypoplasia, have occurred rarely in patients receiving captopril. Several cases of neutropenia, agranulocytosis, or thrombocytopenia have been reported, and a causal relationship to enalapril cannot be excluded. Because of pharmacologic and structural similarities between captopril and enalapril and the current lack of sufficient data to establish the relative risk of these adverse hematologic effects in patients receiving enalapril, the possibility that bone marrow depression, neutropenia, and agranulocytosis could occur in patients receiving enalapril should be considered. Experience with captopril indicates that patients with renal impairment, especially those with collagen vascular disease, appear to be at increased risk of these adverse hematologic effects, and complete and differential leukocyte counts should be performed periodically during enalapril therapy in these patients. Enalapril lacks a sulfhydryl group, the structural feature suggested as being associated with this toxicity in patients receiving captopril; however, this structural relationship has not been established and the lack of this group in enalapril may not exclude the possibility of these effects in patients receiving the drug.

Effects on Taste

Loss of taste perception and decrease in taste acuity have been reported infrequently during enalapril therapy. Hyperesthesia of the oral mucosa has occurred in at least one patient receiving enalapril but was reversible following discontinuance of the drug. Patients with intolerable captopril-induced taste disturbances may tolerate enalapril better.

Effects on Potassium

Although small increases (i.e., by an average of 0.2 mEq/L) in serum potassium concentrations frequently occur in patients receiving enalapril without a thiazide diuretic, hyperkalemia (i.e., increases to greater than 5.7 mEq/L) occurs in approximately 1 or 4% of patients with hypertension or heart failure, respectively, receiving the drug. In most cases, these were isolated increases that resolved despite continued therapy with the drug; however, hyperkalemia required discontinuance of enalapril therapy in about 0.3% of patients receiving the drug for hypertension. Hyperkalemia is less frequent in patients receiving enalapril and hydrochlorothiazide concomitantly, occurring in about 0.1% of patients. Patients with diabetes mellitus, impaired renal function, or heart failure and patients concomitantly receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes) may be at increased risk of developing hyperkalemia during enalapril therapy; serum potassium concentration should be monitored frequently in these patients, and potassium intake should be controlled and therapy with drugs that can increase serum potassium modified or discontinued as necessary. The manufacturer recommends that potassium-sparing diuretics generally not be used in patients receiving enalapril for heart failure.

Respiratory Effects

Cough has been reported in 1.3 or 3.5% of patients receiving enalapril alone or in fixed combination with hydrochlorothiazide for hypertension, respectively, and in about 2% of those receiving the drug for heart failure; discontinuance of the drug was required in less than 0.5% of patients. Nonproductive cough, particularly at night, may occur more frequently, especially in patients with chronic obstructive pulmonary disease. Some clinicians state that cough often is overlooked as a potential adverse effect of ACE inhibitors and may occur more frequently (in about 5-15% of patients). The cough generally is persistent and nonproductive, is not associated with other respiratory symptoms, and is reversible following discontinuance of the drug. Nasal congestion also has been reported. It has been suggested that accumulation of kinins in the respiratory tract secondary to ACE inhibition may in part be responsible for cough and nasal congestion. Concomitant therapy with a nonsteroidal anti-inflammatory agent (i.e., sulindac) appeared to minimize cough in a few patients, but additional study of the safety (e.g., effects on renal function) of such combined therapy is necessary. If cough develops in a patient receiving enalapril, ACE inhibitor-induced cough should be considered as part of the differential diagnosis.

Dyspnea and wheezing, which may persist if therapy with the drug is continued, have been reported in about 1% or less of patients receiving enalapril. Pneumonia or bronchitis has been reported in about 1% of patients receiving enalapril for heart failure. Asthma, upper respiratory infection, bronchospasm, pulmonary infiltrates, eosinophilic pneumonitis, and rhinorrhea also have been reported in patients receiving enalapril maleate therapy. Angioedema has occurred in 0.2 or 0.6% of patients receiving enalapril alone or in fixed combination with hydrochlorothiazide, respectively, and, if associated with laryngeal edema, may be fatal. ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.(See Cautions: Precautions and Contraindications.)

Other Adverse Effects

Muscle cramps, and impotence have been reported in 0.5-1% of patients receiving enalapril alone, and decreased libido has been reported rarely. These effects have occurred more frequently when the drug was administered in fixed combination with hydrochlorothiazide. Hearing loss, which was reversible following discontinuance of the drug, has been reported rarely; however, the mechanism of this adverse effect is not known. Pancreatitis, hepatitis or cholestatic jaundice, hepatic failure, sore throat, hoarseness, anosmia, conjunctivitis, dry eyes, tearing eyes, gynecomastia, and myalgia have been reported in patients receiving enalapril. Vulvovaginal pruritus, burning urination, and dysuria were reported in at least one patient receiving enalapril.

Although a definite causal relationship to enalapril has not been established, elevations of serum hepatic enzymes and/or bilirubin concentrations have been reported rarely when enalapril was administered alone or in fixed combination with hydrochlorothiazide.

Precautions and Contraindications

Since enalapril is metabolized to enalaprilat, both drugs share the same cautions, precautions, and contraindications. Because captopril, another ACE inhibitor, can cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease), the possibility that similar adverse effects may occur with enalapril should be considered. Periodic monitoring of leukocyte counts should be considered in these patients.(See Cautions: Hematologic Effects.) Patients should be instructed to notify their clinician if any sign or symptom of infection such as fever or sore throat occurs. When enalapril is used in fixed combination with hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with enalapril. To minimize dose-independent adverse effects, it is recommended that therapy with enalapril in fixed combination with hydrochlorothiazide only be initiated in patients in whom an adequate response is not achieved with enalapril or hydrochlorothiazide monotherapy.

Renal function should be evaluated prior to initiation of enalapril therapy, and the drug should be used with caution in patients with renal impairment, particularly those with known or suspected renovascular disease. Reduction of enalapril dosage, reduction in dosage or discontinuance of diuretic therapy, and/or adequate sodium repletion may be necessary in some patients who develop impaired renal function during enalapril therapy. Because of an increased risk of reducing renal perfusion to a critically low level, enalapril should be used with caution and renal function monitored closely for the first few weeks of therapy in patients with bilateral renal-artery stenosis and those with renal-artery stenosis in a solitary kidney. Serum creatinine and electrolyte concentrations should be evaluated prior to and 1 week following initiation of therapy with ACE inhibitors in patients with heart failure. In patients with heart failure who have some degree of renal impairment (baseline serum creatinine concentrations less than 2 mg/dL) or more severe renal impairment (baseline serum creatinine concentrations exceeding 2 mg/dL), an increase in serum creatinine concentration exceeding 0.5 or 1 mg/dL, respectively, should prompt consideration of discontinuing ACE inhibitor therapy while additional renal evaluation and corrective action is undertaken. The possibility that ACE inhibitors might precipitate severe, sudden, potentially life-threatening anaphylactoid reactions in patients undergoing hemodialysis involving a high-flux membrane should be considered.(See Cautions: Dermatologic and Sensitivity Reactions.)

Enalapril should be used with caution in patients with sodium depletion or hypovolemia, those receiving diuretics, and those undergoing dialysis since severe hypotension may occur. The drug should also be used with caution in patients in whom excessive hypotension may have serious consequences (e.g., patients with coronary or cerebrovascular insufficiency). Because of the potential decrease in blood pressure in patients with heart failure, enalapril therapy should be initiated under very close medical supervision in these patients.(See Cautions: Cardiovascular Effects.) Like all vasodilators, enalapril should be administered with caution in patients with obstruction in the outflow tract of the left ventricle (e.g., aortic stenosis, hypertrophic cardiomyopathy). Patients at risk for excessive hypotension should be monitored closely for the first 2 weeks of therapy and whenever the dosage of enalapril and/or a concomitantly administered diuretic is increased. Patients receiving enalapril therapy should be informed that vomiting, diarrhea, excessive perspiration, and dehydration may lead to an exaggerated decrease in blood pressure because of fluid volume reduction; patients should notify their clinician if any of these conditions occurs. Patients should also be warned to report light headedness, especially during the first few days of therapy; if actual syncope occurs, they should discontinue enalapril therapy and contact their clinician. Since therapy with ACE inhibitors has been associated with development of a rare syndrome that usually is manifested initially by cholestatic jaundice, which may progress to fulminant hepatic necrosis and occasionally may be fatal, patients receiving an ACE inhibitor, including enalapril, who develop jaundice or marked elevations of hepatic enzymes should discontinue the drug and receive appropriate medical follow-up.(See Cautions: Hepatic Effects.)

Angioedema may occur, especially following the first dose of enalapril, and, if associated with laryngeal edema, may be fatal. If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, enalapril should be discontinued and the patient carefully observed until swelling disappears. If swelling is confined to the face and lips, the condition generally responds without treatment; however, antihistamines may provide symptomatic relief. Swelling of the tongue, glottis, or larynx may cause airway obstruction, and appropriate therapy (e.g., epinephrine, maintenance of patent airway) should be initiated immediately. Patients should be informed that swelling of the face, eyes, lips, or tongue or difficulty in breathing may be signs and symptoms of angioedema, and that they should discontinue enalapril and notify their clinician immediately if any of these conditions occurs. The possibility that patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving the drugs should be considered. Enalapril is contraindicated in patients with a history of angioedema related to ACE inhibitor therapy and those with hereditary or idiopathic angioedema. Enalapril also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Antihypertensive effects of enalapril maleate have been established in hypertensive pediatric patients 1 month to 16 years of age. Enalapril maleate is not recommended for neonates or for pediatric patients with a glomerular filtration rate of less than 30 mL/minute per 1.73 m, since no data are available. The adverse effect profile of enalapril maleate in pediatric patients is similar to that in adults. Safety and efficacy of enalaprilat injection or of enalapril in fixed combination with hydrochlorothiazide in children have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Geriatric Precautions

Clinical studies of enalapril in fixed combination with hydrochlorothiazide did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. Enalapril is substantially eliminated by the kidneys; because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of toxicity, renal function should be monitored and dosage should be selected carefully.

Mutagenicity and Carcinogenicity

No evidence of enalapril- or enalaprilat-induced mutagenicity or of mutagenicity induced by concomitant testing of enalapril and hydrochlorothiazide was seen with an in vitro microbial test system (Ames test) with or without metabolic activation. Enalapril alone or combined with hydrochlorothiazide also was not mutagenic in several other in vitro test systems, including mammalian systems, and in in vivo cytogenetic tests using mouse bone marrow.

No evidence of carcinogenesis was seen in rats or in male and female mice receiving enalapril maleate dosages up to 90 or 90 and 180 mg/kg daily, respectively (about 26 or 13 times the maximum daily human dosage on a mg/m basis, respectively), for 106 or 94 weeks, respectively. Carcinogenicity studies have not been performed with enalaprilat.

While an excess rate of GI cancer relative to placebo has been observed in several large trials in patients receiving prolonged ACE-inhibitor therapy, a causal relationship to the drugs has not been established. Some evidence suggests that such a relationship is unlikely since the observed risk did not increase with increasing exposure to the drugs and because of the heterogeneity of the reported cancers (involving the rectum, cecum, colon, esophagus, stomach, gallbladder, pancreas, or liver). However, the possibility of a causal relationship cannot be excluded, and additional study to further elucidate any possible relationship between use of ACE inhibitors and these cancers is necessary.

Pregnancy, Fertility, and Lactation

Pregnancy

Fetal and neonatal morbidity and mortality have been reported in at least 50 pregnant women who were receiving ACE inhibitors during pregnancy. Very limited epidemiologic data indicate that the rate of fetal and neonatal morbidity resulting from exposure to ACE inhibitors during the second and third trimesters may be as high as 10-20%. Hypotension, reversible or irreversible renal failure, anuria, skull hypoplasia (defective skull ossification in some cases), and/or death were reported in neonates whose mothers had received ACE inhibitors during the second and third trimesters of pregnancy. In one premature neonate (35 weeks' gestation) born with acute, reversible renal failure following exposure to enalapril for several weeks prior to delivery, plasma ACE activity was completely suppressed at birth, and plasma active and total renin concentrations and renin activity were substantially increased in the neonate; the renal failure was managed with peritoneal dialysis, which was discontinued after 10 days. Other adverse effects associated with such use included oligohydramnios, presumably due to decreased renal function in the fetus, prematurity, fetal death, and patent ductus arteriosus; however, it is not known whether these effects were associated with ACE inhibition or underlying maternal disease. Oligohydramnios has been associated with contractures of the limbs, craniofacial deformities, hypoplasia of the lungs, and intrauterine growth retardation.

Although fetal exposure limited to the first trimester previously was considered not to be associated with substantial risk, data from an epidemiologic study have shown that infants whose mothers had taken an ACE inhibitor during the first trimester of pregnancy have an increased risk of major congenital malformations compared with infants who had not undergone first trimester exposure to ACE inhibitors. The risk of major congenital malformations, primarily affecting the cardiovascular and central nervous systems, was increased by about 2.7 times in infants whose mothers had taken an ACE inhibitor during the first trimester of pregnancy compared with infants who had not undergone such exposure. Every effort should be made to discontinue enalapril or enalaprilat therapy as soon as possible in any woman who becomes pregnant while receiving either of the drugs, regardless of the period of gestation. In addition, all women of childbearing potential who are receiving an ACE inhibitor should be advised to report pregnancy to their clinician as soon as possible. Women of childbearing potential who are receiving an ACE inhibitor also should be advised to inform their clinician if they are planning to become pregnant or think they might be pregnant. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy. Rarely (probably less frequently than once in every 1000 pregnancies), no adequate alternative can be identified; in such rare cases, the woman should be informed of the potential hazard to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is present, enalapril therapy should be discontinued, unless use of the drug is considered life-saving for the woman.Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling may be performed, if appropriate depending on the period of gestation. However, both clinicians and patients should realize that oligohydramnios may not become apparent until after irreversible fetal injury already has occurred.

Infants exposed in utero to ACE inhibitors should be observed closely for hypotension, oliguria, and hyperkalemia. If oliguria occurs, supportive measures (e.g., administration of fluids and pressor agents) to correct hypotension and renal perfusion should be considered. Exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for impaired renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit. The manufacturer states that the drug theoretically may be removed by exchange transfusion; however, this latter procedure has not been used to date.

Reproduction studies in rats using enalapril maleate dosages up to 200 mg/kg daily (about 333 times the maximum daily human dosage) have not revealed evidence of teratogenicity or fetotoxicity. Decreases in average fetal weight occurred in rats receiving enalapril maleate dosages of 1200 mg/kg daily, but fetotoxicity did not occur when rats received a diet supplemented with sodium chloride. Fetotoxicity (decreased fetal weight) has been observed in rats receiving oral dosages up to 90 mg/kg of enalapril maleate combined with 10 mg/kg of hydrochlorothiazide daily (representing 26 and 1.6 times the maximum recommended human daily dosage of enalapril maleate and hydrochlorothiazide, respectively, on a mg/m basis) and in mice receiving combined oral therapy with up to 30 and 10 mg/kg daily of enalapril maleate and hydrochlorothiazide, respectively (representing 4.3 and 0.8 times the maximum recommended human daily dosage of enalapril maleate and hydrochlorothiazide, respectively, on a mg/m basis), but did not occur when lower dosages of enalapril maleate (30 and 10 mg/kg daily, respectively) were combined with 10 mg/kg of hydrochlorothiazide daily in these animals. Reproduction studies in rabbits receiving enalapril maleate dosages up to 30 mg/kg daily during days 6-18 of gestation did not reveal evidence of teratogenicity, but maternotoxicity and fetotoxicity occurred in rabbits at dosages of 1 mg/kg daily. Fetotoxicity and maternotoxicity did not occur in rabbits receiving enalapril maleate dosages of 3-10 mg/kg daily when their diet was supplemented with sodium chloride, but did occur at dosages of 30 mg/kg daily even when the diet was supplemented.

Fertility

Reproduction studies in male and female rats using enalapril maleate dosages of 10-90 mg/kg daily (representing up to 4.3 and 0.8 times the maximum recommended human daily dosage of enalapril maleate and hydrochlorothiazide, respectively, on a mg/m basis) have not revealed adverse effects on reproductive performance. Impotence and decreased libido have been reported occasionally in patients receiving enalapril alone or in fixed combination with hydrochlorothiazide.

Lactation

Because enalapril alone or thiazide diuretics alone are distributed into human milk and potentially may cause serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or enalapril (either alone or in fixed combination with hydrochlorothiazide), taking into account the importance of the drug(s) to the woman.

Drug Interactions

In addition to the drug interactions described, the possibility that other drug interactions reported with other angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril) might occur with enalapril should be considered.

Hypotensive Agents and Diuretics

When enalapril is administered with diuretics or other hypotensive drugs, the hypotensive effect of enalapril is increased. The effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly.

Enalapril and diuretics appear to have additive hypotensive effects; however, severe hypotension and reversible renal insufficiency may occasionally occur, especially in volume- and/or sodium-depleted patients.(See Cautions: Cardiovascular Effects; and Renal Effects.) Hypotensive drugs that cause release of renin (e.g., diuretics) will increase the hypotensive effect of enalapril. Reduction of enalapril dosage and/or dosage reduction or discontinuance of diuretic therapy may be necessary. Patients should be monitored closely during initiation and dosage adjustment of concomitant therapy with enalapril and a diuretic; in patients already receiving diuretics, the risk of these effects may be minimized by withholding diuretic therapy and/or increasing sodium intake for 2-3 days prior to initiating enalapril therapy. If diuretic therapy cannot be withheld, the patient should be under medical supervision for at least 2 hours after the initial dose of enalapril and until blood pressure has stabilized for at least an additional hour.

Drugs Increasing Serum Potassium Concentration

Potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes should be used with caution and serum potassium should be determined frequently in patients receiving enalapril, since hyperkalemia may occur. Dosage of the potassium-sparing diuretic and/or potassium supplement should be reduced or the diuretic and/or supplement discontinued as necessary. The manufacturer recommends that potassium-sparing diuretics generally not be used in patients receiving enalapril for heart failure. However, ACE inhibitors have been administrated with low-dosage spironolactone therapy and hyperkalemia was reported rarely.(See Uses: Heart Failure.) Patients should be advised to not use potassium-containing salt substitutes unless otherwise instructed by their clinician. Patients with renal impairment may be at increased risk of hyperkalemia.

Nonsteroidal Anti-inflammatory Agents

Because ACE inhibitors may promote kinin-mediated prostaglandin synthesis and/or release, concomitant administration of drugs that inhibit prostaglandin synthesis (e.g., aspirin, ibuprofen) may reduce the blood pressure response to ACE inhibitors, including enalapril. Limited data indicate that concomitant administration of ACE inhibitors with nonsteroidal anti-inflammatory agents (NSAIAs) occasionally may result in acute reduction of renal function; however, the possibility cannot be ruled out that one drug alone may cause such an effect. Blood pressure should be monitored carefully when an NSAIA is initiated in patients receiving ACE inhibitor therapy; in addition, clinicians should be alert for evidence of impaired renal function. Some clinicians suggest that if a drug interaction between an ACE inhibitor and an NSAIA is suspected, the NSAIA should be discontinued, or a different hypotensive agent used or, alternatively, the dosage of the hypotensive agent should be modified.

Aspirin and other NSAIAs also can attenuate the hemodynamic actions of ACE inhibitors in patients with heart failure. Because ACE inhibitors share and enhance the effects of the compensatory hemodynamic mechanisms of heart failure, with aspirin and other NSAIAs interacting with the compensatory mechanisms rather than with a given ACE inhibitor per se, these desirable mechanisms are particularly susceptible to the interaction and a subsequent potential loss of clinical benefits. As a result, the more severe the heart failure and the more prominent the compensatory mechanisms, the more appreciable the interaction between NSAIAs and ACE inhibitors. Even if optimal dosage of an ACE inhibitor is used in the treatment of heart failure, the potential cardiovascular and survival benefit may not be seen if the patient is receiving an NSAIA concomitantly. In several multicenter studies, concomitant administration of a NSAIA (i.e., a single 350-mg dose of aspirin) in patients with heart failure inhibited favorable hemodynamic effects associated with ACE inhibitors, attenuating the favorable effects of these drugs on survival and cardiovascular morbidity. However, these findings have not been confirmed by other studies. In one retrospective analysis of pooled data, patients who received an ACE inhibitor concomitantly with aspirin (160- 325 mg daily) during the acute phase following myocardial infarction had proportional reductions in 7- and 30-day mortality rates comparable to patients who received an ACE inhibitor alone. Some clinicians have questioned the results of this study because of methodologic concerns (e.g., unsubstantiated assumptions about aspirin therapy [dosage, time of initiation, duration]; disparate distribution of patients). Although it has been suggested that patients requiring long-term management of heart failure avoid the concomitant use of ACE inhibitors and aspirin (and perhaps substitute another platelet-aggregation inhibitor for aspirin [e.g., clopidogrel, ticlopidine]), some clinicians state that existing data are insufficient to recommend a change in the current prescribing practices of clinicians concerning the use of aspirin in patients receiving therapy with an ACE inhibitor.

Lithium

Lithium toxicity has occurred following concomitant administration of enalapril and lithium carbonate and was reversible following discontinuance of both drugs. In one patient, the toxicity was associated with elevated plasma lithium concentration and was manifested as ataxia, dysarthria, tremor, confusion, and altered EEG; bradycardia and T-wave depression also occurred. Moderate renal insufficiency (serum creatinine of 2.2 mg/dL) or acute renal failure has also occurred in these patients. The exact mechanism of this interaction remains to be established, but it has been suggested that enalapril may decrease renal elimination of lithium, possibly by increasing sodium excretion secondary to decreased aldosterone secretion or by altering renal function secondary to ACE inhibition. Renal function has returned to baseline within 2-4 days after discontinuing enalapril, and plasma lithium concentrations have returned to within normal limits following discontinuance of enalapril and temporary withdrawal of lithium therapy. The manufacturer of enalapril recommends that serum lithium concentrations be monitored frequently when enalapril and lithium are administered concomitantly.

Other Drugs

Enalapril may reduce fasting blood glucose concentrations in nondiabetic individuals and may produce hypoglycemia in diabetic patients whose diabetes has been controlled with insulin or oral antidiabetic agents. Further studies are needed to evaluate the hypoglycemic effect of enalapril; however, similar effects have been reported in patients receiving captopril, and the risk of precipitating hypoglycemia should be considered when therapy with an ACE inhibitor is initiated in diabetic patients.

Concomitant use of enalapril and some vasodilating agents (e.g., nitrates) or anesthetic agents may cause an exaggerated hypotensive response. Patients receiving enalapril concomitantly with nitrates or with anesthetic agents that produce hypotension should be observed for possible additive hypotensive effects. Fluid volume expansion can correct hypotension during surgery or anesthesia if it is thought to result from an enalapril-induced inhibition of the angiotensin II formation that occurs secondary to compensatory renin release.

Pharmacokinetics

Absorption

Enalapril maleate, unlike enalaprilat, is well absorbed following oral administration. Although enalaprilat is a more potent angiotensin-converting enzyme (ACE) inhibitor than enalapril, it is poorly absorbed from the GI tract because of its high polarity, with only about 3-12% of an orally administered dose being absorbed. Approximately 55-75% of an oral dose of enalapril maleate is rapidly absorbed from the GI tract in healthy individuals and hypertensive patients. Food does not appear to substantially affect the rate or extent of absorption of enalapril maleate. Following oral administration, enalapril maleate appears to undergo first-pass metabolism principally in the liver, being hydrolyzed to enalaprilat. Concomitant oral administration of enalapril maleate and hydrochlorothiazide has little, if any, effect on the bioavailability of either drug. Oral administration of the commercially available fixed combination containing the drugs reportedly is bioequivalent to concurrent administration of the drugs as individual preparations.(See Pharmacokinetics: Elimination.)

Peak serum enalapril concentrations of 40-80 ng/mL occur within about 0.5-1.5 hours following oral administration of a single 10-mg dose of enalapril maleate in healthy individuals or hypertensive patients. Peak serum enalaprilat concentrations reportedly increase proportionally with oral doses of enalapril maleate ranging from 2.5-40 mg. Following oral administration of a single 2.5-, 5-, 10-, 20-, or 40-mg dose of enalapril maleate in these patients, average peak serum enalaprilat concentrations of 6-8, 15-28, 37-50, 70-80, or 123-150 ng/mL, respectively, occur within about 3-4.5 hours. Steady-state serum concentrations of enalaprilat were reached within 30-60 hours in patients with normal renal function receiving oral enalapril maleate dosages of 10 mg daily for 8 days; appreciable accumulation of the metabolite did not occur.

The hypotensive effect of a single oral dose of enalapril maleate is usually apparent within 1 hour and maximal in 4-8 hours. The hypotensive effect of usual doses of the drug generally persists for 12-24 hours but may diminish toward the end of the dosing interval in some patients. The reduction in blood pressure may be gradual, and several weeks of therapy may be required before the full effect is achieved. Following IV administration of enalaprilat, the hypotensive effect is usually apparent within 5-15 minutes with maximal effect occurring within 1-4 hours; the duration of hypotensive effect appears to be dose related, but with the recommended doses, the duration of action in most patients is approximately 6 hours. Plasma ACE inhibition and reduction in blood pressure appear to be correlated to a plasma enalaprilat concentration of 10 ng/mL, a concentration at which maximal blockade of plasma ACE is achieved. After withdrawal of enalapril or enalaprilat, blood pressure gradually returns to pretreatment levels; rebound hypertension following abrupt withdrawal of the drug has not been reported to date.

The onset and duration of hemodynamic effects of enalapril maleate appear to be slower and more prolonged than those of captopril. In patients with heart failure, the hemodynamic effects of enalapril maleate are generally apparent within 2-4 hours and may persist for up to 24 hours after an oral dose.

Distribution

Distribution of enalapril into human body tissues and fluids has not been fully characterized.

Approximately 50-60% of enalaprilat is bound to plasma proteins. Two binding sites have been identified, a low-affinity, high-capacity site and a high-affinity, low-capacity site. Drug bound to the latter site may represent enalaprilat bound to circulating serum ACE, possibly accounting for the prolonged terminal elimination of the drug.

Information on distribution into the CNS is limited, but enalapril appears to cross the blood-brain barrier poorly, if at all, and enalaprilat does not appear to distribute into the CNS. The drug did not accumulate in any tissue following multiple-dose administration in animals. The drug crosses the placenta. In a premature neonate (35 weeks' gestation) whose mother received 20 mg of enalapril maleate daily for 17 days prior to delivery, plasma enalaprilat concentration soon after birth in the neonate was 28 ng/mL. Enalapril and enalaprilat are distributed into milk in trace amounts.

Elimination

Following oral administration, the half-life of unchanged enalapril appears to be less than 2 hours in healthy individuals and in patients with normal hepatic and renal functions, but may be increased in patients with heart failure. Following oral administration of a single 5- or 10-mg dose of enalapril maleate in patients with heart failure, the half-life of enalapril was 3.4 or 5.8 hours, respectively. Serum concentrations of enalaprilat, the active metabolite of enalapril, appear to decline in a multiphasic manner. Elimination of enalaprilat may also be prolonged in patients with heart failure or impaired hepatic function compared with healthy individuals and patients with hypertension. Observations of serum concentrations of enalaprilat over long periods following oral or IV administration suggest that enalaprilat has an average terminal half-life of about 35-38 hours (range: 30-87 hours). The observed prolonged terminal phase may actually reflect enalaprilat binding to the high-affinity, low-capacity binding site of circulating serum ACE. The effective half-life for accumulation of enalaprilat (determined from urinary recovery) has been reported to average about 11 or 14 hours in healthy adults with normal renal function or in hypertensive pediatric patients, respectively.

Peak and trough enalaprilat concentrations and areas under the serum concentration-time curves (AUCs) may increase, time to peak and steady-state serum concentration may be delayed, and the effective half-life for accumulation may be prolonged in patients with impaired renal function. In patients with creatinine clearances less than 30 mL/minute, the effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is prolonged. In patients with moderate renal impairment (i.e., creatinine clearances of 30-60 mL/minute), this half-life is not substantially prolonged, and there appears to be a lack of correlation between AUCs and creatinine clearance. Decreased urinary excretion of enalapril may increase the extent of hydrolysis of enalapril to enalaprilat or may increase extrarenal elimination of the drug (e.g., via biliary excretion).

About 60% of an absorbed dose of enalapril is extensively hydrolyzed to enalaprilat, principally in the liver via esterases. About 20% appears to be hydrolyzed on first pass through the liver; this hydrolysis does not appear to occur in plasma in humans. Enalaprilat is a more potent ACE inhibitor than enalapril. There is no evidence of other metabolites of enalapril in humans, rats, or dogs. However, a despropyl metabolite of enalaprilat was identified in urine in rhesus monkeys, accounting for 13% of an oral dose of enalapril maleate. Hydrolysis of enalapril to enalaprilat may be delayed and/or impaired in patients with severe hepatic impairment, but the pharmacodynamic effects of the drug do not appear to be significantly altered.

Following oral administration, enalapril and enalaprilat are excreted in urine and feces. In healthy individuals, a mean of 60-78% (a mean of 43-56% as enalaprilat and the remainder as unchanged drug) of a 10-mg oral dose of enalapril maleate is excreted in urine within 24-48 hours after administration and approximately 33% (about 27% as enalaprilat and 6% as unchanged drug) is excreted in feces within 24-48 hours. In a multiple-dose study (10 mg daily) in healthy individuals with normal renal function, urinary excretion of enalaprilat and total drug increased during the first 4 days of therapy and then stabilized; urinary excretion of the metabolite averaged 45% of the cumulative dose and that of total drug averaged 62%. In a multiple-dose study (0.07-0.14 mg/kg of enalapril maleate daily) in hypertensive pediatric patients (2 months to 16 years), 67% (64-76% as enalaprilat and the remainder as unchanged drug) of the administered dose is recovered in urine within 24 hours. It is not known whether enalapril and enalaprilat excreted in feces represent unabsorbed drug or that excreted via biliary elimination. Biliary excretion of enalapril and enalaprilat occurs in animals; however, this route of elimination has not been demonstrated in humans.

Renal clearance of enalaprilat and enalapril are reported to be approximately 100-158 and 300 mL/minute, respectively, in adults with normal renal function. The higher renal clearance of enalapril compared with that of the metabolite may indicate some degree of active tubular secretion of unchanged drug. Renal clearance may be decreased in hypertensive patients. In geriatric individuals, renal clearance and/or volume of distribution may decrease.

Enalaprilat is removed by hemodialysis. The amount of drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate); however, the hemodialysis clearance of enalaprilat is reportedly 62 mL/minute. Enalaprilat also appears to be removed by peritoneal dialysis.

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