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captopril 25 mg tablet

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Uses

Hypertension

Captopril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Because captopril can 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 drug was previously reserved for hypertension (usually severe) that was not manageable with maximal therapeutic dosages of other hypotensive agents in combination regimens (e.g., usually a diuretic, a β-adrenergic blocking agent [β-blocker], and a vasodilator) or when such regimens produced intolerable adverse effects. However, clinical experience with low dosages (up to 150 mg daily) has shown captopril to have a favorable benefit-to-risk ratio in the management of mild to moderate hypertension and the drug may currently be used as initial therapy in patients with normal renal function, in whom the risk of adverse hematologic effects is relatively low. In patients with impaired renal function, especially those with collagen vascular disease, captopril should be reserved for patients in whom other antihypertensive agents produce intolerable adverse effects or who do not have an adequate response to combination regimens of antihypertensive agents.

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of 4 classes of antihypertensive agents (angiotensin-converting enzyme [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., lifestyle 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, captopril can be used for the management of hypertension as initial monotherapy or as a component of a multiple-drug regimen. When captopril is used alone 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.

Captopril may be effective in the management of hypertension resistant to other drugs. Although captopril occasionally may be effective alone in patients with severe hypertension, it is usually necessary to use it in conjunction with a diuretic. (See Drug Interactions: Hypotensive Agents and Diuretics.)

Tolerance to the hypotensive effect of captopril apparently does not occur during long-term administration, particularly if the drug is used with a diuretic. As with other hypotensive agents, treatment with captopril is not curative; after withdrawal of the drug, blood pressure returns to pretreatment levels. Abrupt withdrawal of captopril 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 shown to prevent subsequent heart failure and reduce morbidity and mortality in patients with systolic dysfunction following an acute myocardial infarction.(See Uses: Left Ventricular Dysfunction after Acute Myocardial Infarction.)

Diabetes Mellitus

ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics have all been recommended for use as 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: 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.

Other Special Considerations for Antihypertensive Therapy

Race

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers 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 captopril has lowered blood pressure in all races studied, monotherapy with this agent 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 captopril 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

Captopril also has been effective in the management of renovascular or malignant hypertension and, in some patients, in the management of hypertension associated with chronic renal failure.

Hypertensive Crises

Captopril has been used orally for rapidly reducing blood pressure in patients with hypertensive crises in whom reduction of blood pressure was considered urgent (hypertensive urgencies) or an emergency (hypertensive emergencies). Because even oral therapy for hypertensive crises can result in profound hypotension and associated adverse cardiovascular effects (e.g., myocardial ischemia or infarction, cerebrovascular hypoperfusion or stroke), captopril should not be used indiscriminately, and the benefits versus risks of rapidly reducing blood pressure with the drug must be weighed carefully.

Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage. Such urgencies include the upper levels of stage 2 hypertension associated with severe headache, shortness of breath, epistaxis, or severe anxiety. Hypertensive urgencies generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen or with oral doses of short-acting antihypertensive agents such as captopril followed by several hours of observation; however, there is no evidence suggesting that failure to aggressively reduce blood pressure in these patients is associated with any short-term risk. In fact, overly aggressive management of severe elevations in blood pressure not associated with impending or progressing organ damage can sometimes lead to cumulative hypotensive effects.

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. Although oral therapy with captopril has been used to rapidly reduce blood pressure in such emergencies, patients with hypertensive emergencies should be hospitalized and treated initially with appropriate parenteral antihypertensive therapy (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside).

For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Nephropathy

Captopril may be used in patients with nephropathy, including diabetic nephropathy. Use of ACE inhibitors or angiotensin II receptor antagonists is recommended in the management of diabetic or nondiabetic chronic kidney disease to slow progression of the disease. ACE inhibitors have stabilized or improved effective renal blood flow and glomerular filtration rate and decreased proteinuria in hypertensive or normotensive patients with moderately impaired renal function, moderate to severe renal disease, or diabetic nephropathy. Short-term administration of captopril improved blood flow and glomerular filtration rate in some hypertensive patients with moderately impaired renal function; however, long-term captopril therapy has not maintained sustained improvement in renal blood flow and glomerular filtration rate. In general, captopril should be used with caution in patients with impaired renal function, especially those with bilateral renal-artery stenosis or renal-artery stenosis in a solitary kidney.(See Cautions: Renal Effects and see Cautions: Hematologic Effects, and also see Precautions and Contraindications.) Captopril appears to be ineffective in the management of hypertension in anephric patients.(See Pharmacology: Renal and Electrolyte Effects.)

Diabetic Nephropathy

Captopril is used in the management of diabetic nephropathy manifested by proteinuria (urinary protein excretion exceeding 500 mg per 24 hours) in patients with type 1 (insulin dependent, IDDM) diabetes mellitus and diabetic retinopathy.

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 per 24 hours) or higher (exceeding 300 mg per 24 hours) levels of urinary albumin excretion. Comparative trials evaluating the efficacy of ACE inhibitors and angiotensin II receptor antagonists for improving renal outcomes in diabetic patients are lacking. Evidence supporting use of ACE inhibitors generally is based on studies in patients with type 1 diabetes mellitus, while evidence supporting use of angiotensin II receptor antagonists generally is based on studies in patients with type 2 diabetes mellitus. Findings from these studies indicate that both drug classes delay progression of increased urinary albumin excretion in patients with diabetes mellitus and also may slow the decline in renal function. Because the available data are consistent, some experts suggest that the effects of both drug classes in improving renal outcomes in patients with diabetes mellitus and proteinuria are likely to be similar. Drugs that inhibit the renin-angiotensin system (i.e., ACE inhibitors, angiotensin II receptor antagonists) also have been shown to delay the onset of albuminuria in patients with type 2 diabetes mellitus and hypertension who have normal levels of urinary albumin excretion. Although combined therapy with ACE inhibitors and angiotensin II receptor antagonists appears to have additive effects in reducing albuminuria, such combinations provide no additional cardiovascular benefit and increase the risk of adverse effects (e.g., impaired renal function, hyperkalemia).

In a multicenter, controlled study in hypertensive and normotensive individuals who had type 1 diabetes mellitus for at least 7 years, diabetic retinopathy, proteinuria, and a serum creatinine concentration of 2.5 mg/dL or less, deterioration in renal function was substantially less pronounced in patients receiving long-term captopril therapy (median: 3 years [range: 1.8-4.8 years]) than in those receiving placebo. Patients with hypertension received hypotensive agents (e.g., diuretics, β-blockers, α-adrenergic blocking agents, vasodilators) as needed. Overall, patients receiving captopril had a 48% reduction in the risk of doubling of serum creatinine concentration. Captopril therapy was especially useful in patients with more advanced renal disease (i.e., baseline serum creatinine exceeding 1.5 mg/dL). Captopril therapy was associated with a 30% reduction in urinary protein excretion within 3 months and was evident throughout the study. In addition, patients receiving captopril had a 50% reduction in the risk of death and need for dialysis or renal transplantation, particularly in those with more advanced renal disease. It has been suggested that captopril and other ACE inhibitors may slow the progression of renal nephropathy by a mechanism independent of its antihypertensive properties.

Captopril also has been shown to delay the onset of diabetic nephropathy in normotensive patients with diabetes mellitus and microalbuminuria. In multicenter controlled studies in normotensive patients with type 1 diabetes mellitus, retinopathy, and microalbuminuria (20-200 mcg/minute), treatment with captopril (50 mg twice daily) for 2 years was associated with a substantial reduction in the risk of developing diabetic nephropathy (based on progression of microalbuminuria to proteinuria). In one study, albumin excretion rate increased from a mean baseline value of 52 to 76 mcg/minute at 2 years in patients receiving placebo, while rates determined at the same time points in patients receiving captopril decreased from 52 to 41 mcg/minute. While clinical studies indicate that treatment with captopril can postpone the development of diabetic nephropathy in normotensive type 1 diabetic patients with microalbuminuria, the long-term clinical benefit of reducing the progression of microalbuminuria to proteinuria has not been determined.

Heart Failure

Captopril is used in the management of 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. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure with reduced LVEF, ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and 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.

Diuretics are recommended in all patients with heart failure and reduced ejection fraction who have evidence of fluid retention, unless contraindicated, 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 manufacturer states that most experience from controlled studies has been with combined captopril, cardiac glycoside, and diuretic therapy; however, the manufacturer also states that the beneficial effect of captopril does not require concomitant cardiac glycoside 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 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 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 captopril with improvement in cardiac function indexes, symptomatic relief, improved functional capacity, and increased exercise tolerance. In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 6 months. In some patients, beneficial effects have been sustained for up to 1 year or longer. Captopril also has been effective in conjunction with cardiac glycosides and diuretics in the management of heart failure resistant to or inadequately controlled by cardiac glycosides, diuretics, and vasodilators.

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

In patients with heart failure in whom renal perfusion is severely compromised, the renin-angiotensin system appears to substantially contribute to preservation of glomerular filtration; therefore, therapy with an ACE inhibitor may adversely affect renal function in such patients.(See Cautions: Renal Effects.)

Left Ventricular Dysfunction after Acute Myocardial Infarction

Captopril is used in an effort to improve survival following acute myocardial infarction in clinically stable patients with left ventricular dysfunction (manifested as an ejection fraction of 40% or less) and to reduce the incidence of overt heart failure and subsequent hospitalizations for heart failure in these patients. ACE inhibitors have been shown to reduce mortality rates in diabetic patients with left ventricular dysfunction, and the American College of Cardiology (ACC) and the AHA recommend use of these drugs in diabetic patients with acute coronary syndromes (i.e., unstable angina or non-ST-segment elevation myocardial infarction).

ACE inhibitors, including captopril, have been used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular ''remodeling'') 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 captopril and other ACE inhibitors (e.g., lisinopril, zofenopril [not commercially available in the US]), even in patients with no baseline dysfunction, one large study involving enalapril therapy initiated within 24 hours of infarction (parenteral enalaprilat followed by oral enalapril) found little if any early (within several months) benefit, particularly in terms of survival, from such therapy. However, in a multicenter, controlled study involving captopril in which initiation of therapy with the drug was delayed until 3-16 days after acute myocardial infarction and limited to patients with low ejection fractions (40% or less), long-term (mean: 42 months; range: 24-60 months) therapy with the drug was associated with a reduction in overall mortality as well as a reduction in morbidity and mortality secondary to cardiovascular causes. In addition, in a large, controlled, long-term (average: 15 months; range: 6-46 months) study, ramipril (another ACE inhibitor) was associated with a reduction in overall mortality as well as in the risk of progression to severe heart failure and heart failure-associated hospitalization when given within an average of 5 (range: 2-9) days following acute myocardial infarction in patients who had clinical signs of heart failure. In several other studies involving captopril in which the drug was initiated within 24 hours to 4 weeks after acute myocardial infarction, a beneficial effect also was observed, at least in terms of effects on left ventricular volume and/or infarct expansion.

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 involved in healing) combined with a rapid decrease in blood pressure associated with the initial administration of IV 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 such 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 ACE inhibitor 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. ()

Asymptomatic Left Ventricular Dysfunction

ACE inhibitors have been used to attenuate left ventricular enlargement and prevent progression to symptomatic dysfunction in asymptomatic patients with heart failure (ACCF/AHA stage B heart failure). Captopril has reduced the development of symptomatic heart failure and associated morbidity and mortality in such patients. The drug's beneficial effect in preventing the development of symptomatic heart failure in these patients 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. If an ACE inhibitor is not tolerated, then an angiotensin II receptor antagonist is recommended as alternative therapy.

Other Uses

Captopril has been shown to increase digital circulation in one patient with Raynaud's phenomenon and decrease the orthostatic sodium and water retention in several women with idiopathic edema. Therefore, it has been suggested that the drug may be useful in the treatment of these conditions; however, additional evaluation is necessary.

ACE inhibitors have been used to reduce the risk of cardiovascular events in patients 55 years of age or older who are at high risk for cardiovascular events (e.g., diabetes mellitus, history of cardiovascular disease, stroke, peripheral vascular disease, dyslipidemia, smoking, microalbuminuria, hypertension).

Dosage and Administration

Administration

Captopril is administered orally. The manufacturer recommends that the drug be taken 1 hour before meals to ensure maximum absorption.(See Pharmacokinetics: Absorption.)

Dosage

Dosage of captopril must be adjusted according to the patient's tolerance and response.

Hypertension

Because of the risk of inducing hypotension, initiation of captopril therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. Except in patients with severe hypertension, it is recommended that other antihypertensive therapy be discontinued, if possible, 1 week before initiating captopril to minimize the possibility of severe hypotension. If captopril therapy is initiated in patients already receiving a diuretic, treatment with the drug should be initiated under close supervision, following the usual dosage and titration recommendations.

Concomitant sodium restriction may be helpful when captopril is used alone.

Captopril Therapy

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 captopril dosage of 50 mg daily (given in 2 divided doses) and a target dosage of 150-200 mg daily (given 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 captopril for the management of hypertension in adults with normal renal function is 25 mg 2 or 3 times daily. However, lower initial dosages (e.g., 6.25 mg twice daily to 12.5 mg 3 times daily) may be effective in some patients, particularly in those already receiving a diuretic. Because the reduction in blood pressure may be gradual, most clinicians do not increase dosage during the first 1-2 weeks of captopril therapy. If blood pressure is not adequately controlled after 1-2 weeks, dosage may be increased to 50 mg 2 or 3 times daily. Similar dosages generally have been used in the management of hypertension in geriatric patients, although dosages of 6.25-12.5 mg 1-4 times daily have occasionally been used. The manufacturer states that it usually is not necessary to exceed a captopril dosage of 150 mg daily; if blood pressure is not adequately controlled after 1-2 weeks at a dosage of 50 mg 3 times daily, a thiazide diuretic should also be administered in a low dosage (e.g., 15 mg of hydrochlorothiazide daily). Because the full effect of a combined dose of therapy with captopril and a diuretic may not be attained for 6-8 weeks, dosage of either drug in a combined regimen generally should be increased no more frequently than every 6 weeks, unless the clinical situation requires more rapid adjustment. Diuretic dosage may be increased until its maximum usual antihypertensive dose is reached. If further reduction of blood pressure is necessary, dosage of captopril may be increased to 100 mg 2 or 3 times daily and, if necessary, to 150 mg 2 or 3 times daily, while continuing diuretic therapy. Although a β-adrenergic blocking agent (β-blocker) may be used with captopril, the hypotensive effects are less than additive and this combination is rarely employed. (See Uses: Hypertension.) For further information on dosage of captopril used in combination therapy, see Captopril/Hydrochlorothiazide Fixed-combination Therapy under Dosage: Hypertension. The usual adult maintenance dosage of captopril recommended by the manufacturers is 25-150 mg 2 or 3 times daily, and the maximum dosage is 450 mg daily.

Some experts have recommended a lower usual captopril dosage range of 25-100 mg daily given in 2 divided doses; the rationale for this reduced dosage is that it usually is preferable to add another antihypertensive agent to the regimen than to continue increasing captopril dosage since the patient may not tolerate such continued increases.

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with captopril 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 captopril, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the angiotensin-converting enzyme (ACE) inhibitor and initiate another class of antihypertensive agent.

The need for divided (2 or 3 doses) daily dosing of captopril may deter patient compliance and adequate blood pressure control throughout the day; optimally, the antihypertensive drug or dosage form should provide 24-hour efficacy with once-daily dosing, with at least 50% of the peak antihypertensive effect remaining at the end of the dosing interval.

Clinical experience with captopril in children is limited (see Cautions: Pediatric Precautions), and dosage must be carefully titrated. In general, dosage for children has been reduced in proportion to body weight. Some experts have recommended a usual initial dosage for children of 0.9-1.5 mg/kg daily (given as 0.3-0.5 mg/kg 3 times daily). Dosage may be increased as necessary to a maximum dosage of 6 mg/kg daily. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

Captopril/Hydrochlorothiazide Fixed-combination Therapy

When combination therapy is required for the management of hypertension, dosage first can be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, the fixed combination may be used. Alternatively, certain fixed-combination preparations containing low doses of captopril and hydrochlorothiazide can be used initially, thereby potentiating the antihypertensive effect of either drug alone while minimizing the likelihood of dose-related adverse effects. If combination therapy is initiated with the fixed-combination preparation, the initial adult dosage is 25 mg of captopril and 15 mg of hydrochlorothiazide once daily. Subsequent dosage can be adjusted by administering each drug separately or by advancing the once-daily administered fixed-combination preparation to that containing captopril and hydrochlorothiazide 50 and 15 mg, respectively; 25 and 25 mg, respectively; or 50 and 25 mg, respectively. The manufacturer states that dosage adjustments generally should be made at 6-week intervals. It may be necessary to administer captopril separately in divided doses in order to maintain adequate trough (prior to a dose) blood pressure control. Generally, combined dosage of captopril and hydrochlorothiazide in adults should not exceed 150 and 50 mg daily, respectively.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of captopril 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.)

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

Hypertensive Crises

In adults with severe hypertension (e.g., accelerated or malignant hypertension) in whom prompt blood pressure reduction is indicated or in whom temporary discontinuance of current antihypertensive therapy is not practical or desirable, diuretic therapy should be continued, other hypotensive agents should be discontinued, and captopril should be initiated promptly at a dosage of 25 mg 2 or 3 times daily, under close supervision with frequent monitoring of the patient's blood pressure.

When necessary, dosage of captopril may be increased at intervals of 24 hours or less under continuous supervision until the optimum blood pressure response is attained or 450 mg daily is given; in this regimen, a diuretic such as furosemide may also be necessary. If adequate control of blood pressure is not attained initially with captopril alone or in combination with a diuretic, some clinicians believe that temporary, adjunctive therapy with other hypotensive agents may be necessary.

Although acute captopril therapy (e.g., 12.5-25 mg, repeated once or twice if necessary at intervals of 30-60 minutes or longer) has been used orally in adults with hypertensive crises, including those with severe hypertension in whom reduction of blood pressure was considered urgent (hypertensive urgencies) or an emergency (hypertensive emergencies), other management methods generally are preferred for patients with these conditions.(See Hypertensive Crises under Uses: Hypertension.)

Diabetic Nephropathy

The recommended dosage of captopril for the long-term treatment of diabetic nephropathy is 25 mg 3 times daily. If adequate control of blood pressure is not attained with captopril alone, additional hypotensive agents (e.g., diuretics, β-blockers, calcium-channel blocking agents) may be administered concomitantly.

Heart Failure

For the management of symptomatic heart failure, captopril usually is administered in conjunction with other agents such as a cardiac glycoside, a diuretic, and a β-blocker. Captopril therapy must be initiated under very close medical supervision 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 should be assessed within 1-2 weeks of initiation of therapy and periodically thereafter, especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia, or in those taking potassium supplements.

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., 150 mg of captopril daily) or highest tolerated dosage rather than according to response.

The usual initial adult dosage of captopril recommended by the manufacturer for the management of heart failure in patients with normal renal function is 25 mg 3 times daily. In patients with normal or low blood pressure who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, an initial dosage of 6.25 or 12.5 mg 3 times daily may minimize the magnitude or duration of the hypotensive effect; titration to the usual daily dosage can then be made within the next several days. Dosage is increased gradually according to the patient's tolerance and response. After a dosage of 50 mg 3 times daily is reached, further increases in dosage should be delayed when possible for at least 2 weeks to determine if an adequate response occurs.

Alternatively, the American College of Cardiology (ACC) and American Heart Association (AHA) recommend that captopril be initiated at low dosage (i.e., 6.25 mg 3 times daily) and titrated gradually upward as tolerated to a maximum dosage of 50 mg 3 times daily. It has been recommended that therapy with ACE inhibitors be titrated upwards to dosages that have been shown to reduce the risk of cardiovascular events in clinical trials rather than titrating based on a patient's therapeutic response. Most patients have an adequate response with 50 or 100 mg 3 times daily. The manufacturer states that a maximum dosage of 450 mg daily should not be exceeded. Some experts suggest a maximum dosage of 50 mg 3 times daily in patients with chronic heart failure.

Alternatively, for the management of heart failure in geriatric patients, some clinicians have initiated captopril therapy at a dosage of 6.25 mg twice daily; if necessary, dosage was increased to 25 mg twice daily after 2 weeks and was subsequently increased if heart failure was not adequately controlled after 4 weeks of therapy at this dosage. The median dosage after 12 weeks of therapy in these geriatric patients was 75 mg daily in 2 divided doses.

Left Ventricular Dysfunction after Acute Myocardial Infarction

When used following acute myocardial infarction in adults with left ventricular dysfunction, the manufacturer states that captopril therapy may be initiated as early as 3 days following myocardial infarction. When this approach is followed, an initial 6.25-mg dose of captopril should be given followed by 12.5 mg 3 times daily. During the next several days, dosage should be increased to 25 mg 3 times daily and then, during the next several weeks as tolerated, dosage should be increased to 50 mg 3 times daily. Alternatively, some clinicians state that captopril therapy can be initiated as soon as oral therapy is feasible within 24 hours after myocardial infarction, provided initial doses are low and dosage is titrated gradually to achieve a full dose 24-48 hours after infarction. When this regimen is followed, captopril therapy should be initiated with a 6.25-mg dose, followed by 12.5 mg 2 hours later, 25 mg 10-12 hours later, and then 50 mg twice daily as tolerated. The recommended maintenance dosage for long-term use following myocardial infarction is 50 mg 3 times daily.

Dosage in Renal Impairment

If captopril is used in patients with impaired renal function, doses and/or frequency of administration must be modified in response to the degree of renal impairment and the risk of neutropenia must be considered.(See Cautions: Precautions and Contraindications.) The initial dosage of captopril should be reduced in these patients (i.e., less than 75 mg daily), and dosage should be slowly increased in small increments at 1- to 2-week intervals. After the desired therapeutic effect has been attained, dosage should be slowly decreased to the minimum effective level. It has been suggested that, after the minimum effective daily dosage has been determined in patients with impaired renal function, the dosing interval may be increased with appropriate dose modification; however, criteria for dosage adjustment have not been clearly established. Some clinicians suggest that patients with creatinine clearances of 10-50 mL/minute can receive 75% of the usual captopril dosage or the usual dose can be administered every 12-18 hours, and that those with creatinine clearances less than 10 mL/minute can receive 50% of the usual dosage or the usual dose can be administered every 24 hours. Patients undergoing hemodialysis may require a supplemental dose after dialysis.

When combination therapy with captopril and hydrochlorothiazide is required for the management of hypertension in patients with impaired renal function, the risk of precipitating hypotension during initiation of combined therapy should be considered. (See Cautions: Cardiovascular Effects and see Precautions and Contraindications.) Dosages of the drugs should be titrated carefully by slowly increasing the dosage of each drug separately in small increments. After the desired therapeutic effect has been attained, the manufacturer recommends that the dosing interval be increased and/or the doses decreased until the minimal effective daily dosage has been achieved. If after careful titration of each drug separately it is determined that the optimum maintenance dosage corresponds to the ratio in commercial combination preparation, the fixed combination may be substituted but should be replaced with the individual drugs if subsequent dosage adjustment is necessary. If concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic such as furosemide is preferred to a thiazide diuretic. Therefore, use of commercially available preparations containing captopril in fixed combination with hydrochlorothiazide is usually not recommended for patients with severe renal impairment.

Cautions

Captopril is generally well tolerated in most patients; however, serious adverse effects (e.g., neutropenia, agranulocytosis, proteinuria, aplastic anemia) have been reported rarely, mainly in patients with renal impairment (especially those with collagen vascular disease). Captopril-induced adverse effects are often alleviated by dosage reduction, occasionally disappear despite continued treatment and without dosage reduction, and are usually reversible following discontinuance of the drug. The most common adverse effects of captopril are rash and loss of taste perception. Adverse effects requiring discontinuance of captopril therapy occur in about 4-12% of patients.

Hematologic Effects

Neutropenia (less than 1000 neutrophils/mm) and agranulocytosis, both associated with myeloid hypoplasia, have occurred rarely in patients receiving captopril. In addition to myeloid hypoplasia, erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia) were frequently observed in patients with captopril-induced neutropenia; anemia and thrombocytopenia also occurred occasionally in these patients. Systemic or oral cavity infections or other effects associated with agranulocytosis occurred in about half of the patients who developed neutropenia.

Neutropenia has occurred within 3-12 weeks after beginning treatment with captopril. The risk of captopril-induced neutropenia appears to depend principally on the degree of renal impairment and the presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma). In clinical studies in patients with some degree of renal impairment (serum creatinine concentration of at least 1.6 mg/dL), neutropenia occurred in about 0.2% of patients, a frequency greater than 15 times that in patients with uncomplicated hypertension who have normal renal function. Most of the patients with renal impairment received relatively high dosages, particularly in relation to their renal function; in some reports, the neutropenia was associated with concomitant administration of allopurinol while in other reports this association was not apparent. In clinical studies, neutropenia has occurred in about 3.7% of patients with collagen vascular disease and renal impairment. Neutropenia has also occurred in some patients receiving captopril for the management of heart failure and the risk factors appear to be similar; about 50% of the patients developing neutropenia had impaired renal function and about 75% were receiving procainamide concomitantly.

Following discontinuance of captopril and other drugs, the neutrophil count generally returned to normal in about 2 weeks. Serious infections have been limited to patients with complex clinical conditions. Death has occurred in about 13% of patients who developed neutropenia, but almost all deaths occurred in patients with serious illness who had collagen vascular disease, renal failure, and/or heart failure and/or who were receiving immunosuppressive therapy. Although a few patients have been rechallenged with captopril (usually with lower dosages) without recurrence, others have reportedly experienced recurrence, even with lower dosages. Although a causal relationship to captopril has not been established, anemia (e.g., aplastic, hemolytic) has been reported in some patients receiving the drug.

Renal Effects

Proteinuria (total urinary proteins exceeding 1 g/day) has occurred in about 0.7% of patients receiving captopril, and nephrotic syndrome occurred in about one-fifth of these patients. About 90% of patients who have developed proteinuria during captopril therapy had evidence of prior renal disease and/or received relatively high dosages of the drug (greater than 150 mg daily). If proteinuria develops, it usually occurs by the eighth month of treatment with captopril, consists mainly of albumin, and is rarely accompanied by increases in BUN or serum creatinine concentrations. Renal biopsies in some patients who developed proteinuria showed that membranous glomerulopathy was present; however, it was not definitely established that this effect was caused by the drug since these patients did not have pretreatment renal biopsies, and membranous glomerulopathy has occurred in hypertensive patients who did not receive the drug. Proteinuria usually subsides or clears within 6 months whether or not captopril therapy is continued; however, in some patients, it may persist.

Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations may occur following administration of captopril, especially in patients with impaired renal function, sodium depletion, or hypovolemia; patients with renovascular hypertension, particularly those with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney; or patients with chronic or severe hypertension in whom the glomerular filtration rate may decrease transiently. This effect was usually reversible following discontinuance of captopril and/or diuretic therapy. Acute reversible renal failure also may occur. Renal function should be monitored closely during the first few weeks of therapy and periodically thereafter in patients with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney. (See Cautions: Precautions and Contraindications.) About 5-15% or 15-30% of patients with mild to moderate or severe heart failure, respectively, treated with an angiotensin-converting enzyme (ACE) inhibitor develop substantial elevations of serum creatinine concentrations (e.g., exceeding 5 mg/dL) and BUN. Some patients with heart failure, including those with severe preexisting renal disease, may require discontinuance of angiotensin-converting enzyme (ACE) inhibitor therapy, including captopril, because of progressively increasing serum creatinine concentration. The rapidity of onset and magnitude of captopril-induced renal insufficiency in patients with heart failure may depend in part on the degree of sodium depletion.

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 risk for developing renal insufficiency during ACE-inhibitor therapy; however, ACE inhibitors, including captopril, have been beneficial in the management of diabetic nephropathy.

Although a definite causal relationship to captopril has not been established, renal insufficiency, polyuria, oliguria, and urinary frequency have been reported in about 0.1-0.2% of patients.

Dermatologic and Sensitivity Reactions

The most common adverse effect of captopril is rash, which occurs in about 4-7% of patients (depending on renal function and dosage) and is usually maculopapular and rarely urticarial. Rash is often accompanied by pruritus and erythema and sometimes by fever, arthralgia, eosinophilia, and/or positive antinuclear antibody (ANA) titers. Eosinophilia and/or positive ANA titers have been reported in 7-10% of patients with captopril-induced rash. The rash occurs most frequently on the upper extremities and trunk but may occur at other sites. It generally occurs during the first 4 weeks of therapy and has occurred rarely within 30 minutes after the initial dose of the drug. The rash is usually mild and disappears within a few days after dosage reduction, short-term treatment with an oral antihistamine, and/or discontinuance of the drug. In some patients, the rash may disappear despite continued treatment and without dosage adjustment. Although the cause has not been clearly determined, it has been suggested that the rash may be a reaction mediated by kinins. Pruritus without rash occurs in about 2% of patients receiving captopril.

Photosensitivity has occurred, and captopril has been associated with reversible, pemphigoid lesions. Bullous pemphigoid also has been reported; however, a causal relationship to the drug has not been established.

Angioedema of the face, mucous membranes, lips, tongue, larynx, glottis, or extremities has occurred in about 0.1% of patients and may be reversible following discontinuance of therapy.(See Cautions: Precautions and Contraindications.) Intestinal angioedema (occasionally without a prior history of facial angioedema or elevated serum levels of complement 1 [C1] esterase inhibitor) also has been reported in patients receiving ACE inhibitors. Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery; 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.

Other hypersensitivity reactions have included vasculitis and hypersensitivity pneumonitis, which was associated with eosinophilia and pulmonary infiltrates. Rarely, a serum sickness type of reaction with rash or other dermatologic manifestations, fever, myalgia, arthralgia, interstitial nephritis, increased erythrocyte sedimentation rate (ESR), and/or difficulty in breathing has been reported in patients receiving captopril. Alopecia has occurred, but a causal relationship to the drug has not been established.

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. In these patients, consideration should be given to using a different type of dialysis membrane or a drug other than an ACE inhibitor. In addition, anaphylactoid reactions also have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption, a procedure utilizing devices not approved in the US. 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.

Onycholysis and dystrophic changes in the fingernails have occurred rarely in patients receiving captopril. In at least one patient, these changes were associated with other manifestations of zinc deficiency (e.g., alopecia, asteatosis, dysgeusia, cutaneous eruptions). Although serum zinc concentrations were within the normal range in this patient, manifestations of zinc deficiency showed some improvement when captopril dosage was reduced and then gradually resolved when supplemental zinc therapy was initiated. However, other manifestations of zinc deficiency have been absent and serum zinc concentrations normal in other patients with nail changes, and the relationship, if any, of these effects to captopril-induced zinc deficiency has not been established.

Effects on Taste

Decrease in taste acuity, or alteration (persistent metallic or salty taste) or loss of taste perception is another common adverse effect of captopril, occurring in about 2-4% of patients (depending on renal function and dosage). Taste impairment usually occurs during the first 3 months of therapy; it is usually reversible within 2-3 months even when captopril therapy is continued. In some patients, taste impairment has been associated with subsequent weight loss. The mechanism of taste impairment has not been established. In patients not receiving captopril, alterations in taste perception have been associated with decreased plasma zinc concentrations, but normal plasma zinc concentrations have been reported in a few patients with captopril-induced taste impairment and these patients did not respond to oral zinc supplements.

Cardiovascular Effects

Excessive hypotension occurs rarely in hypertensive patients receiving captopril. Transient decreases in mean blood pressure greater than 20% may occur in about half of patients with heart failure treated with captopril. Hypotension has required discontinuance of therapy in about 3-5% of patients with heart failure receiving captopril.

Captopril-induced hypotension may occasionally be alleviated by initial dosage reduction (i.e., 6.25 or 12.5 mg 3 times daily), but hypotension has also occurred after low doses (i.e., a single 6.25-mg dose) of the drug. Orthostatic hypotension appears to occur more frequently during initiation of therapy and in patients with sodium depletion, hypovolemia, markedly elevated plasma renin or angiotensin II concentration, or overdosage. Transient hypotension in patients with heart failure or with hypertension may occur after any of the first several doses and usually is well tolerated, producing no symptoms or occasionally associated with brief, mild lightheadedness or dizziness, blurred vision, syncope, and, rarely, bradycardia or conduction defects. One patient with congestive heart failure who had markedly elevated PRA developed fatal refractory ventricular fibrillation, associated with hypotension, following two 6.25-mg doses of captopril. 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 of blood pressure within the first 3 hours after the initial dose of captopril. Symptomatic hypotension that occurs later in a course of captopril 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).

Enalapril, another ACE inhibitor, has produced severe hypotension in patients with severe heart failure with or without renal insufficiency, which was occasionally associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure, myocardial ischemia, and/or death. Captopril, which has a shorter duration of action than enalapril, may have a decreased risk associated with these adverse effects. Because of the risk of developing severe hypotension and potential compromise of the patient's hemodynamic status, patients with heart failure should be monitored closely for 2 weeks after initiation of captopril therapy and whenever dosage of captopril and/or a concomitantly administered diuretic is increased.

The possibility of severe hypotension may be minimized by withholding diuretic therapy and/or increasing sodium intake approximately 3-7 days prior to initiating captopril therapy. If hypotension occurs in patients receiving captopril, the patient should be placed in the supine or Trendelenburg's position; if hypotension is severe, 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 captopril, and therapy with the drug can be cautiously reinstated after blood pressure has been stabilized (e.g., with volume expansion). Asymptomatic hypotension often does not require specific therapy and may be well tolerated with continued captopril therapy; however, severe hypotension occasionally may require discontinuance of captopril therapy. In patients with heart failure, the reduction in blood pressure stabilizes within 1-2 weeks after starting captopril therapy, and blood pressure generally returns to pretreatment levels within 2 months without a decrease in therapeutic efficacy. Hypotension may also occur in captopril-treated patients during major surgery or during anesthesia with agents that produce hypotension. This hypotensive effect results from inhibition by captopril of the angiotensin II formation that occurs subsequent to compensatory renin release, and, if it is thought to be caused by captopril, can generally be corrected with fluid volume expansion.

Tachycardia, chest pain, and palpitations have each occurred in about 1% of patients receiving captopril. Flushing, pallor, angina pectoris, myocardial infarction, Raynaud's phenomenon, and heart failure have been reported rarely. Captopril has also produced hyperkinetic circulation (tachycardia, greatly increased cardiac output, and decreased mean blood transit time) in at least one patient with congestive heart failure. Although a causal relationship has not been established, other adverse cardiovascular effects that have been reported in patients receiving captopril include cardiac arrest, cerebrovascular accident and/or insufficiency, rhythm disturbances, and syncope.

Effects on Potassium

Although small increases in serum potassium concentration occur frequently in patients receiving captopril without a thiazide diuretic, hyperkalemia has occurred rarely. Patients with 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 captopril therapy, especially those with diabetes mellitus; serum potassium concentration should be monitored carefully in these patients, and potassium intake should be controlled and therapy with drugs that can increase serum potassium modified or discontinued as necessary. In a clinical trial in patients with type 1 diabetes mellitus who were receiving captopril for proteinuria, the drug was discontinued in about 2% of patients secondary to hyperkalemia. However, hyperkalemia was not reported in another trial in normotensive patients with type 1 diabetes mellitus who were receiving captopril for microalbuminuria.

Respiratory Effects

Cough has been reported in about 0.5-2% of patients receiving captopril. However, 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 and reversible following discontinuance of the drug. It has been suggested that accumulation of kinins in the respiratory tract secondary to ACE inhibition may in part be responsible for this cough. 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. Dyspnea and bronchospasm have been reported rarely during captopril therapy. Angioedema has occurred in 0.1% of patients receiving captopril, and, if associated with laryngeal edema or angioedema of the tongue or glottis, airway obstruction may occur, and angioedema may be fatal.(See Cautions: Precautions and Contraindications.)

Hepatic Effects

Hepatitis (including rare cases of hepatic necrosis), cholestasis, jaundice, and elevations in serum concentrations of hepatic enzymes, alkaline phosphatase, and bilirubin have been reported occasionally but have not been directly attributed to the drug, and rare cases of cholestatic jaundice and of hepatocellular injury (with or without secondary cholestasis) have been associated with captopril therapy.

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.

Other Adverse Effects

Hyponatremia (which may be symptomatic) has been reported occasionally in patients receiving captopril; some of these patients had heart failure or were receiving a low-sodium diet or concomitant diuretics. In at least one patient, gynecomastia occurred while receiving captopril, which was reversible following discontinuance of the drug.

Although a causal relationship has not been established, other adverse effects that have occurred rarely in patients receiving captopril include dry mouth, aphthous ulcers, ulceration of the tongue, reversible lymphadenopathy, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, dyspepsia, gastric irritation, peptic ulcer, pancreatitis, glossitis, headache, dizziness, paresthesia, malaise, asthenia, myalgia, myasthenia, ataxia, confusion, depression, nervousness, somnolence, blurred vision, impotence, and insomnia.

Precautions and Contraindications

Captopril may cause serious adverse effects (e.g., neutropenia) and must be used under close supervision, particularly in patients with renal impairment (especially those with collagen vascular disease). When the drug is used, the risk of neutropenia and agranulocytosis must be considered. When captopril is used as a fixed combination that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with captopril.

Because cough has been associated with the use of many ACE inhibitors, including captopril, it should be considered in the differential diagnosis of patients who develop cough during captopril therapy.

The possibility that proteinuria can develop and may progress to nephrotic syndrome in patients receiving captopril should be considered, particularly in those with preexisting renal disease or receiving captopril dosages exceeding 150 mg daily.(See Cautions: Renal Effects.)

Renal function should be evaluated prior to initiation of captopril therapy, and the drug should be used with caution in patients with renal impairment, particularly those with known or suspected renovascular disease. Reduction of captopril 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 captopril therapy; it may be impossible to reduce blood pressure to normal levels and maintain adequate renal perfusion. Because of an increased risk of reducing renal perfusion to a critically low level, captopril 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 in 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 Hypersensitivity Reactions.)

In patients with collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma) or in those receiving other drugs known to affect leukocytes or immune response, particularly those with coexisting impaired renal function, captopril should be used only after an assessment of the benefits and risks, and then with caution. If captopril is administered to patients with any of these conditions and/or with impaired renal function, complete and differential leukocyte counts should be performed prior to initiation of therapy, at approximately 2-week intervals for the first 3 months of therapy, and periodically thereafter. In other patients receiving captopril, complete leukocyte counts may be performed at approximately 2-week intervals for the first 3 months of therapy and periodically thereafter; differential leukocyte counts should be performed if the complete leukocyte count is less than 4000/mm or half of the pretreatment count. If the neutrophil count is less than 1000/mm, captopril should be discontinued and the patient closely monitored. Patients should be instructed to notify their clinician if any signs or symptoms of infection such as fever or sore throat occur. If infection is suspected, blood cell counts should be performed immediately.

Because rare cases of cholestatic jaundice and fulminant hepatic necrosis (sometimes fatal) have occurred in patients receiving ACE inhibitors, including captopril, the drug should be discontinued and patients monitored appropriately if jaundice or marked elevations in hepatic enzymes occur during therapy. (See Cautions: Hepatic Effects.)

Captopril 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). 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 treatment with an ACE inhibitor be initiated at low doses and gradually titrated upward as tolerated. Patients with heart failure should be closely monitored for the first 2 weeks of therapy and whenever the dosage of captopril and/or the diuretic is increased. Patients receiving captopril 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. The possibility that patients with aortic stenosis might be at risk of decreased coronary perfusion when treated with captopril should be considered.

Patients receiving captopril should be warned not to interrupt or discontinue therapy unless instructed by their clinician. Patients with heart failure receiving captopril should be cautioned against rapid increases in physical activity.

Although captopril and penicillamine are not pharmacologically related, many adverse effects (e.g., rash, taste impairment, proteinuria) of these drugs are similar. Because captopril and penicillamine contain sulfhydryl groups and are structurally related, it has been suggested that the common toxicities may in part result from the chemical and structural characteristics of the drugs; however, such a relationship has not been clearly determined. Since therapy with ACE inhibitors has been associated with development of a rare syndrome that usually is manifested initially by cholestatic jaundice that may progress to fulminant hepatic necrosis and occasionally may be fatal, patients receiving an ACE inhibitor, including captopril, 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 in patients receiving an ACE inhibitor (e.g., captopril), and, if associated with laryngeal edema, may be fatal. If swelling is confined to the extremities, face, lips, and mucous membranes of the mouth, the condition usually responds without treatment. Swelling of the tongue, glottis, or larynx may cause airway obstruction, and appropriate therapy (e.g., epinephrine) should be initiated immediately. Patients should be informed that swelling of the face, eyes, lips, tongue, larynx, or extremities or difficulty in breathing or in swallowing may be signs and symptoms of angioedema, and that they should discontinue captopril 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.

Captopril is contraindicated in patients with known hypersensitivity to the drug or to another ACE inhibitor (e.g., those who experienced angioedema during therapy with another ACE inhibitor).

Pediatric Precautions

Although there is limited clinical experience with captopril in children, safety and efficacy of the drug in children have not been established; however, pediatric dosage was reported to be comparable or less than dosage used in adults when calculated on the basis of body weight. Infants, especially neonates, may have increased susceptibility to captopril-induced adverse hemodynamic effects. Excessive, prolonged, and unpredictable decreases in blood pressure and associated complications (e.g., oliguria, seizures) have been reported in children receiving the drug. The manufacturer states that captopril should be used in children only when other measures for controlling blood pressure have not been effective. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

Mutagenicity and Carcinogenicity

Mutagenicity studies with captopril in fixed combination with hydrochlorothiazide (Capozide) have not been conducted, but the effects of the individual components in a 2:1 ratio have been studied. Captopril/hydrochlorothiazide did not exhibit mutagenic or clastogenic potential in vitro with or without metabolic activation in a bacterial reverse mutation (Ames) assays using Salmonella, a forward mutation assay in Saccharomyces pombe, a gene conversion assay using Saccharomyces cerevisiae, and a sister chromatid exchange test in human lymphocytes. In a cytogenetics assay in human lymphocytes exposed to captopril/hydrochlorothiazide concentrations of 5, 25, and 50 mcg/mL (total concentration of both drugs) with metabolic activation, chromosomal abnormalities were not observed consistently. When such aberrations were observed, no concentration response was noted. Captopril and hydrochlorothiazide in a 2:1 ratio were not genotoxic in the in vivo mouse micronucleus test at an oral dose of 2,500 mg/kg (total concentration of both drugs).

No evidence of carcinogenesis was observed in rats or mice receiving captopril dosages of 50-1350 mg/kg daily for 2 years.

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 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, and/or death were reported in neonates whose mothers had received ACE inhibitors during the second and third trimesters of pregnancy. 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 if 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 captopril therapy as soon as possible in any woman who becomes pregnant while receiving the drug, 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, captopril 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. Although captopril may be removed by hemodialysis in adults, it is not known if the drug is removed from circulation of neonates or older children by hemodialysis. Peritoneal dialysis is not effective in enhancing the elimination of captopril, and it is not known whether the drug may be removed by exchange transfusion.

Reproduction studies in hamsters and rats using 150 and 625 times the maximum human dosage, respectively, of captopril have not revealed evidence of teratogenic effects. However, the drug was associated with a low incidence of craniofacial malformations in rabbits when given at dosages 0.8-70 times the maximum human dosage. Reduction in neonatal survival occurred in the offspring of rats receiving captopril dosages 400 times the usual human dosage continuously during gestation and lactation, and an increased incidence of stillbirths has reportedly occurred in ewes.

Fertility

Reproduction studies in rats using captopril have not revealed evidence of impaired fertility.

Lactation

Captopril is distributed into milk in concentrations about 1% of those in maternal blood. Because of the potential for serious adverse reactions to captopril in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Hypotensive Agents and Diuretics

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

Captopril 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.) In addition, the duration of hypotensive effect is extended by concomitant diuretic therapy. The hypotensive effects of captopril and β-adrenergic blocking agents (β-blockers) (e.g., propranolol) are less than additive. Hypotensive drugs that cause release of renin (e.g., diuretics) will increase the hypotensive effect of captopril. Reduction of captopril 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 captopril 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 3-7 days prior to initiating captopril therapy.

While captopril may have pharmacodynamic interactions in patients receiving diuretics, use of furosemide concurrently with captopril in patients with renal impairment and hypertension does not alter the pharmacokinetics of captopril.

Hypotensive drugs that affect sympathetic nervous system activity such as ganglionic blocking agents (e.g., trimethaphan camsylate [no longer commercially available in the US]) or adrenergic neuron blocking agents (e.g., guanethidine sulfate) should be used with caution in patients receiving captopril, since the sympathetic nervous system may be especially important in maintaining blood pressure in patients treated with captopril.

Vasodilating Agents

Data on the effect of concomitant use of captopril and other vasodilators in the management of heart failure are not currently available. Pending accumulation of clinical data on such concomitant use, nitroglycerin or other nitrates or other drugs with vasodilating activity (e.g., hydralazine, prazosin) should be discontinued if possible before starting captopril; if such agents are resumed during captopril therapy, they should be administered with caution and possibly at lower dosage.

Drugs Increasing Serum Potassium Concentration

Since captopril decreases aldosterone secretion, small increases in serum potassium concentration frequently occur, especially in patients with impaired renal function; hyperkalemia has occurred rarely. Potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes should be used with caution in patients receiving captopril and only if hypokalemia is documented, since hyperkalemia may occur; serum potassium should be monitored carefully. Dosage of the potassium-sparing diuretic and/or potassium supplement should be reduced or the diuretic and/or supplement discontinued as necessary. Patients with renal impairment may be at increased risk of hyperkalemia. If the patient has received spironolactone at any time up to several months before captopril is administered, serum potassium concentration should be determined frequently when captopril is administered since the potassium-sparing effect of spironolactone may persist. However, angiotensin-converting enzyme (ACE) inhibitors have been administered with low-dosage spironolactone therapy and hyperkalemia was reported rarely.(See Uses: Heart Failure.)

Cardiac Glycosides

A study in healthy men revealed no evidence of a pharmacokinetic interaction between captopril and digoxin. However, studies in patients with heart failure indicate that serum digoxin concentrations may increase by about 15-30% when captopril and digoxin are used concomitantly. Such increases may result from decreased renal clearance (probably both glomerular filtration and tubular secretion) of digoxin and, possibly, displacement of the glycoside from tissue-binding sites by captopril-induced increases in serum potassium. Captopril has been administered concomitantly with digoxin in patients with heart failure without unusual adverse effects or apparent increased risk of cardiac glycoside toxicity. It has been postulated that captopril-induced increases in serum potassium may offset the potential toxic effects of increased serum digoxin concentrations. Reduction in digoxin dosage does not appear to be necessary when captopril is initiated; however, serum digoxin concentrations should be monitored and the patient observed for signs of glycoside toxicity when the drugs are used concomitantly. Further studies are needed to determine the clinical importance of this potential interaction.

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 captopril. 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 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]), many 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.

Antacids

Concomitant oral administration of captopril and antacids may decrease the rate and extent of GI absorption of captopril. Oral administration of a single, 50-mg dose of captopril 15 minutes after an oral dose of an antacid containing magnesium carbonate and aluminum and magnesium hydroxides resulted in a 40-45% decrease in captopril bioavailability, and a delay and decrease in peak serum concentrations of the drug. However, there is some evidence that this potential interaction may not be clinically important, but additional study is necessary.

Probenecid

Concomitant administration of probenecid may increase blood concentrations of captopril and its metabolites, probably through decreased tubular secretion of captopril and subsequently increased metabolism of the drug (the latter effect probably occurring indirectly as a result of decreased renal clearance of the drug). Prolongation of ACE inhibition by captopril and possible subsequent potentiation of clinical and toxic effects of the drug may occur during concomitant therapy, but the potential for such interaction has not been fully elucidated.

Other Drugs

Neuropathy reportedly developed in 2 patients receiving captopril and cimetidine; however, further documentation of this potential interaction is necessary.

Initiation of captopril therapy has been associated with unexplained hypoglycemia in several diabetic patients whose diabetes had been controlled with insulin or oral antidiabetic agents. Testing in these patients indicated that captopril may increase insulin sensitivity; the mechanism of this effect is not known. The risk of precipitating hypoglycemia should be considered when captopril therapy is initiated in diabetic patients.

Lithium and an ACE inhibitor (e.g., captopril) should be used concomitantly with caution and serum lithium concentrations should be monitored frequently since elevated serum lithium concentrations and lithium toxicity have occurred following concomitant therapy with the drugs. The risk of lithium toxicity in patients receiving captopril may be increased in patients who are also receiving diuretic therapy.

Pharmacokinetics

Absorption

Approximately 60-75% of an oral dose of captopril is rapidly absorbed from the GI tract in fasting healthy individuals or hypertensive patients. Food may decrease absorption of captopril by up to 25-40%, although there is some evidence that this effect is not clinically important. Following oral administration of a single 100-mg dose of captopril in fasting healthy individuals in one study, average peak blood drug concentrations of 800 ng/mL were attained in 1 hour.

The hypotensive effect of a single dose of orally administered captopril may be apparent within 15 minutes and is usually maximal in 1-2 hours. The duration of action is generally 2-6 hours but appears to increase with increasing doses and has been prolonged up to 12 hours in some patients receiving high doses. The reduction in blood pressure may be gradual, and several weeks of therapy may be required before the full effect of the drug is achieved. The reduction in blood pressure observed with the initial dose of captopril has been reported by some clinicians to be positively correlated with the reduction in blood pressure achieved by long-term therapy with the drug. Some clinicians have observed a triphasic hypotensive effect during the first 1-2 weeks of therapy: the initial blood pressure reduction in the first few days is followed by a period lasting 3-9 days during which blood pressure increases toward pretreatment levels or remains stable, and then, a further reduction in blood pressure occurs. Because of the apparent resistance that may occur, increases in captopril dosage are usually avoided in the first 1-2 weeks of therapy since the eventual reduction in blood pressure does not reflect the response observed during this period. After withdrawal of the drug, blood pressure gradually returns to pretreatment levels within 1-7 days; rebound hypertension has not been reported to date.

Distribution

Animal studies indicate that captopril is rapidly distributed into most body tissues, except the CNS. Captopril crosses the placenta in humans and is distributed into milk in concentrations about 1% of maternal blood concentrations.

Captopril is approximately 25-30% bound to plasma proteins, mainly albumin.

Elimination

The elimination half-life of unchanged captopril appears to be less than 2 hours in patients with normal renal function. The elimination half-life of captopril and its metabolites is correlated with creatinine clearance and increases to about 20-40 hours in patients with creatinine clearances less than 20 mL/minute and as long as 6.5 days in anuric patients.

About half the absorbed dose of captopril is rapidly metabolized, mainly to captopril-cysteine disulfide and the disulfide dimer of captopril. In vitro studies suggest that captopril and its metabolites may undergo reversible interconversions. It has been suggested that the drug may be more extensively metabolized in patients with renal impairment than in patients with normal renal function.

Captopril and its metabolites are excreted in urine. Renal excretion of unchanged captopril occurs principally via tubular secretion. In patients with normal renal function, more than 95% of an absorbed dose is excreted in urine in 24 hours; about 40-50% of the drug excreted in urine is unchanged captopril and the remainder is mainly the disulfide dimer of captopril and captopril-cysteine disulfide. In one study in healthy individuals, about 20% of a single dose of captopril was recovered in feces in 5 days, apparently representing unabsorbed drug. Captopril is removed by hemodialysis.

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