lisinopril 2.5 mg tablet generic zestril

Uses

Lisinopril is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. Lisinopril also is used in conjunction with other agents such as β-adrenergic blocking agents (β-blockers), cardiac glycosides, and diuretics in the management of heart failure. In addition, lisinopril may be used in conjunction with thrombolytic agents, aspirin, and/or β-blockers to improve survival in patients with acute myocardial infarction (MI) who are hemodynamically stable.

Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects, (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease) or in patients receiving immunosuppressive therapy, the possibility that similar adverse effects may occur with lisinopril should be considered since current evidence is insufficient to rule out such risk.

Hypertension

Lisinopril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. ACE inhibitors are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease, or cerebrovascular disease or following MI. ( and in .)

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors. Although ACE inhibitors have lowered blood pressure in all races studied, monotherapy with an ACE inhibitor has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension; however, this population difference in response does not appear to occur during combined therapy with an ACE inhibitor and a thiazide diuretic or calcium-channel blocker. In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied. (See ALLHAT study below and also and .)

The ALLHAT study, a large (33,357 patients), multicenter, randomized, active-control study in hypertensive patients 55 years of age or older with at least one other coronary heart disease risk factor, compared the cardiovascular benefit of therapy with an ACE inhibitor (lisinopril 10-40 mg daily) or a dihydropyridine-derivative calcium-channel blocker (amlodipine 2.5-10 mg daily) relative to therapy with a thiazide diuretic (chlorthalidone 12.5-25 mg daily). After a mean follow-up of 4.9 years, an intent-to-treat analysis revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI among the treatments.

Compared with chlorthalidone, the relative risks for the primary outcome were 0.99 for lisinopril and 0.98 for amlodipine. In addition, all-cause mortality, a secondary outcome, did not differ among the treatments. Although each drug decreased blood pressure substantially, the extent of reduction was not equivalent. Five-year systolic blood pressures were significantly higher in the lisinopril (2 mm Hg) and amlodipine (0.8 mm Hg) groups relative to that achieved with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg) relative to the thiazide. Control of hypertension (systolic and diastolic blood pressures less than 140 and 90 mm Hg, respectively) was achieved in approximately two-thirds of patients by 5 years of follow-up (61, 66, or 68% of patients treated with lisinopril, amlodipine, lisinopril, or chlorthalidone, respectively).

Subgroup analysis of the ALLHAT study for race-related effects revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI among the treatments in both black and nonblack patients. However, substantial race-related effects were observed in the incidence of secondary outcomes (e.g., stroke, combined cardiovascular disease events, heart failure). Compared with chlorthalidone, the relative risk for lisinopril was 1.4 or 1 (in black or nonblack patients, respectively) for stroke and 1.19 or 1.06 (in black or nonblack patients, respectively) for combined cardiovascular disease events. When amlodipine was compared with chlorthalidone, the only race-related difference observed was in the incidence of heart failure; the relative risk was 1.46 or 1.32 (in black or nonblack patients, respectively). The relative risk for heart failure in black versus nonblack patients receiving lisinopril was not considered to be statistically significant, and the overall relative risk for both groups was 1.19. In addition, after 4 years, in each treatment group, blood pressure reductions were greater in nonblack than in black patients; about 68 or 60% of nonblack or black patients, respectively, achieved a systolic/diastolic blood pressure of less than 140/90 mmHg. In nonblack patients receiving chlorthalidone, amlodipine, or lisinopril 69, 69, or 67% achieved the mentioned blood pressure, respectively, while in black patients receiving chlorthalidone, amlodipine, or lisinopril 63, 60, or 54% achieved such blood pressure, respectively.

Although the ALLHAT study provides strong evidence that these classes of antihypertensive agents (ACE inhibitors, dihydropyridine-derivative calcium-channel blockers, thiazide diuretics) are comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. Thiazide diuretic therapy was superior to ACE inhibitor therapy in preventing aggregate cardiovascular events, principally stroke, heart failure, angina, and the need for coronary revascularization. Thiazide therapy also was better tolerated than ACE inhibitor therapy (e.g., angioedema, which was more likely in blacks than nonblacks).

Post hoc analysis of the ALLHAT study directly comparing cardiovascular and other outcomes in patients receiving amlodipine or lisinopril revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI between patients receiving the ACE inhibitor and those receiving the calcium-channel blocking agent. However, patients receiving lisinopril were at higher risk for stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving amlodipine were at higher risk of developing heart failure. ALLHAT investigators suggested that the observed differences in cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of amlodipine compared with that of lisinopril, especially in women and black patients.

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

Heart Failure

Lisinopril is used as adjunctive therapy in the management of heart failure in patients who do not respond adequately to diuretics and a cardiac glycoside.

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. If ACE inhibitors are not tolerated, then an angiotensin II receptor antagonist is recommended as alternative therapy. In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization 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. For additional information on the use of ACE inhibitors in the management of heart failure, and

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.

Many patients with heart failure respond to lisinopril with improvement in cardiac function indexes, symptomatic (e.g., dyspnea, fatigue) relief, improved functional capacity, and increased exercise tolerance. In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 3 months. Although additional studies are needed to determine the specific role of lisinopril in the management of heart failure and its long-term efficacy, the efficacy of the drug appears to be similar to that of captopril and enalapril. However, like enalapril, lisinopril has a relatively long duration of action compared with captopril; therefore, the drug may produce more prolonged hypotensive effects, particularly at high doses, which potentially could result in adverse cerebral and renal effects. In addition, because the renin-angiotensin system appears to contribute substantially to preservation of glomerular filtration in patients with heart failure in whom renal function is severely compromised, therapy with an ACE inhibitor may adversely affect renal function. ( and in .)

Mortality Reduction After Acute Myocardial Infarction

Lisinopril is used in conjunction with standard therapies (e.g., thrombolytic agents, aspirin, β-blockers) to improve survival in hemodynamically stable patients with acute MI. Results of a multicenter, controlled, randomized, clinical study indicate that patients who received lisinopril or lisinopril concomitantly with nitrates within 24 hours of MI in addition to conventional therapy (thrombolytic agents, aspirin, β-blockers) had an 11% lower risk of death (6 weeks after infarction) compared with patients receiving conventional therapy only; mortality rates were 6.4 or 7.2% in patients receiving lisinopril and conventional therapy or conventional therapy alone, respectively.

Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI. The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia). In addition to their effects on mortality, ACE inhibitors also are used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular ''remodeling'') following acute MI. 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. However, the preponderance of evidence has shown a benefit of early oral therapy with ACE inhibitors, even in patients with no baseline dysfunction.

Current expert guidelines recommend the use of an ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction). While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction. ACE inhibitor therapy generally should be continued indefinitely in all patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, chronic kidney disease). The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.

Diabetic Nephropathy

Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed. For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see

Dosage and Administration

Administration

Lisinopril is administered orally. The manufacturers state that the absorption of lisinopril is not affected by the presence of food in the GI tract.

For pediatric patients and patients unable to swallow tablets, lisinopril may be administered orally as an extemporaneously prepared suspension. An extemporaneous suspension containing lisinopril 1 mg/mL can be prepared in the following manner. First, 10 mL of purified water is added to a polyethylene terephthalate (PET) bottle containing ten 20-mg tablets of lisinopril, and the contents are shaken for at least 1 minute. The concentrated suspension of lisinopril should be diluted with 30 mL of sodium citrate dihydrate (Bicitra) and 160 mL of syrup (Ora-Sweet), and the container then shaken gently for several seconds to disperse the ingredients. The suspension should be shaken before dispensing of each dose. The extemporaneous suspension is stable for 4 weeks when stored at or below 25°C.

Dosage

Dosage of lisinopril must be adjusted according to patient tolerance and response. Because of the risk of inducing hypotension, initiation of lisinopril therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. If therapy is initiated in a patient already receiving a diuretic, symptomatic hypotension may occur following the initial dose of the angiotensin-converting enzyme (ACE) inhibitor. The possibility of hypotension may be minimized by discontinuing the diuretic, reducing the diuretic dosage, or cautiously increasing salt intake prior to initiation of lisinopril therapy. If diuretic therapy cannot be discontinued, lisinopril should be initiated in adults at a dosage of 5 mg daily under close medical supervision until blood pressure has stabilized.(See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.) For additional information on initiating lisinopril in patients receiving diuretic therapy, see the disease-specific dosage sections in Dosage and Administration.

Hypertension

Lisinopril 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 lisinopril dosage of 10 mg once daily and a target dosage of 40 mg once daily are recommended. Target dosages generally can be achieved within 2-4 weeks, but it may take up to several months.

The manufacturer states that for the management of uncomplicated hypertension in adults not receiving a diuretic, the usual initial dosage of lisinopril is 10 mg once daily. In patients currently receiving diuretic therapy, it is recommended that the diuretic be discontinued, if possible, 2-3 days before initiating lisinopril. If blood pressure is not adequately controlled with the ACE inhibitor alone, diuretic therapy may be resumed cautiously. If diuretic therapy cannot be discontinued, lisinopril should be initiated in adults at a reduced dosage of 5 mg daily under close medical supervision for at least 2 hours and until blood pressure has stabilized for at least an additional hour.

Dosage of lisinopril should be adjusted according to blood pressure response. If the blood pressure response diminishes toward the end of the dosing interval during once-daily administration, which may be particularly likely with a dosage of 10 mg or less daily, consideration should be given to increasing the dosage. The manufacturer states that the usual maintenance dosage of lisinopril in adults is 20-40 mg daily, given as a single dose. Dosages up to 80 mg daily have been used, but do not appear to give a greater effect. If blood pressure is not controlled with lisinopril alone, a second antihypertensive agent (e.g., low dose of a diuretic) may be added.

For the management of hypertension in children 6 years of age and older, the usual initial dosage of lisinopril is 0.07 mg/kg (up to 5 mg) once daily. Dosage may be adjusted until the desired blood pressure goal is achieved. The safety and efficacy of doses exceeding 0.61 mg/kg or in excess of 40 mg have not been established.

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with lisinopril 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 lisinopril, dosage reduction should be considered; if adverse effects worsen or fail to resolve, discontinuance of the ACE inhibitor and initiation of another class of antihypertensive agent may be necessary.

Lisinopril/Hydrochlorothiazide Fixed-combination Therapy

The manufacturer states that therapy with the commercially available preparations containing lisinopril in fixed combination with hydrochlorothiazide should only be initiated in adults after an adequate response is not achieved with lisinopril or hydrochlorothiazide monotherapy. Alternatively, the fixed combination containing lisinopril with hydrochlorothiazide may be used in patients who have been receiving the drugs separately and in whom dosage of the individual drugs has been adjusted to the ratio in a commercial combination preparation. Such fixed combinations also may be used to prevent hydrochlorothiazide-induced potassium loss. Volume and/or salt depletion should be corrected before initiating therapy with lisinopril in fixed combination with hydrochlorothiazide. Patients whose blood pressure is not adequately controlled with lisinopril or hydrochlorothiazide monotherapy may receive the fixed combination containing 10 mg of lisinopril and 12.5 mg of hydrochlorothiazide or, alternatively, the preparation containing 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide. Further increases of either or both drugs depend on clinical response; however, dosage of hydrochlorothiazide generally should not be increased for about 2-3 weeks after initiation of therapy. Patients whose blood pressure has been adequately controlled with a hydrochlorothiazide dosage of 25 mg daily, but who experienced potassium loss, may achieve a similar response if they are switched to therapy with the fixed-combination preparation containing 10 mg of lisinopril and 12.5 mg of hydrochlorothiazide. The dosages of lisinopril and hydrochlorothiazide should not exceed 80 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 lisinopril 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.

Heart Failure

Because of the risk of severe hypotension, lisinopril therapy for heart failure should be initiated under very close medical supervision (e.g., in a hospital setting), especially in patients with low blood pressure (i.e., systolic blood pressure less than 80-100 mm Hg), with consideration given to recent diuretic therapy and the possibility of severe sodium and/or fluid depletion. Experts suggest that ACE inhibitor therapy also be initiated with caution in patients with markedly increased serum concentrations of creatinine (exceeding 3 mg/dL), bilateral renal artery stenosis, or elevated concentrations of serum potassium (exceeding 5 mEq/L).

For the management of heart failure, the usual initial dosage of lisinopril in adults with normal renal function and serum sodium concentration is 2.5-5 mg once daily. The usual effective dosage of lisinopril in adults with heart failure is 5-40 mg once daily.

Lisinopril often is administered in conjunction with other agents such as a cardiac glycoside, a diuretic, and a β-adrenergic blocking agent (β-blocker). After the initial dose, the patient should be monitored closely (especially those with systolic blood pressure less than 100 mg Hg) until blood pressure has stabilized. The mean peak blood pressure lowering usually occurs 6-8 hours after administration of a dose. Hypotension occurring after the initial dose does not preclude the administration of subsequent doses of the drug, provided due caution is exercised and the hypotension has been managed effectively. Evidence from a large clinical trial in patients with heart failure suggests that hypotension with lisinopril is dose-related. To minimize the likelihood of hypotension, the dosage of any diuretic given concomitantly with lisinopril should be reduced, if possible.

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, some experts recommend that dosages generally be titrated to a prespecified target (i.e., 20-40 mg of lisinopril daily) or highest tolerated dosage rather than according to response. However, one manufacturer states that dosage adjustment of lisinopril should be based on the clinical response of individual patients. Patients with severe heart failure, with or without renal impairment, should be monitored closely for the first 2 weeks of lisinopril therapy and periodically thereafter (e.g., whenever dosage of the drug and/or concomitantly administered diuretic is increased), especially those taking potassium supplements or those with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia.

Mortality Reduction After Acute Myocardial Infarction

Because of the risk of persistent hypotension (i.e., systolic blood pressure of less than 90 mm Hg lasting for more that 1 hour), lisinopril therapy should not be initiated in patients with myocardial infarction (MI) who are at risk of further severe hemodynamic deterioration (i.e., systolic blood pressure of 100 mm Hg or less after receiving therapy with a vasodilator) or who are in cardiogenic shock. In addition, because severe hypotension in patients with MI may result in MI or cerebrovascular accident, lisinopril therapy should be initiated under very close medical supervision in such patients, with close monitoring for the first 2 weeks of therapy and whenever dosage of the drug and/or concomitantly administered diuretic is increased.(See Hypotension under Warnings/Precautions: Warnings, in Cautions.)

To improve survival after acute MI in hemodynamically stable patients, the manufacturers state a 5-mg dose of lisinopril should be given within 24 hours of onset of symptoms of MI followed by a 5- and 10-mg dose 24 and 48 hours later, respectively; the drug should be administered in conjunction with standard therapies such as thrombolytic agents, aspirin, and/or β-blockers as appropriate. Thereafter, a maintenance dosage of 10 mg daily of lisinopril should be used and continued for 6 weeks. Patients who have low blood pressure (i.e., systolic pressure of 120 mm Hg or less) when lisinopril therapy is initiated or during the first 3 days after MI should be given a lower dose (i.e., 2.5 mg) of lisinopril; in addition, if hypotension (i.e., systolic pressure less than 100 mm Hg) occurs, the maintenance dosage should be reduced to 5 mg daily, which may be temporarily reduced further to 2.5 mg daily if needed. If prolonged hypotension occurs (i.e., systolic pressure less than 90 mm Hg lasting for more than 1 hour), lisinopril should be discontinued. Alternatively, experts recommend an initial lisinopril dosage of 2.5-5 mg daily (initiated within 24 hours of MI) titrated upward to 10 mg daily or higher as tolerated in patients with MI. For patients who develop symptoms of heart failure, the dosage indicated for heart failure should be administered.(See Dosage and Administration: Heart Failure).

Special Populations

The manufacturers state that modification of the usual initial dosage (10 mg once daily) of lisinopril is not necessary in hypertensive adults with creatinine clearances exceeding 30 mL/minute per 1.73 m. If the drug is used in hypertensive adults with more than mildly impaired renal function, dosage must be modified in response to the degree of renal impairment, and as with other ACE inhibitors, the theoretical risk of neutropenia must be considered. Hypertensive adults with creatinine clearances of 10-30 mL/minute can receive an initial lisinopril dosage of 5 mg once daily and those with creatinine clearances less than 10 mL/minute (usually on hemodialysis) can receive an initial dosage of 2.5 mg once daily. Subsequent dosage should be titrated according to individual tolerance and blood pressure response up to a maximum of 40 mg once daily. The manufacturers state that use of lisinopril in hypertensive pediatric patients with creatinine clearances less than 30 mL/minute per 1.73 m is not recommended.

The manufacturers state that adults with heart failure and hyponatremia (serum sodium concentration less than 130 mEq/L) or moderate to severe renal impairment (i.e., creatinine clearance of 30 mL/minute or less or serum creatinine exceeding 3 mg/dL) should receive an initial lisinopril dosage of 2.5 mg daily under close monitoring.(See Dosage and Administration: Dosage.)

The manufacturers state that lisinopril should be initiated with caution in patients with MI and renal impairment (serum creatinine concentrations exceeding 2 mg/dL). The manufacturers also state that dosage adjustments in patients with MI and severe renal impairment have not been evaluated. If renal impairment (serum creatinine concentrations exceeding 3 mg/dL) develops or if baseline serum creatinine concentrations are increased by 100% during lisinopril therapy, discontinuance of the drug should be considered.

When combination therapy with lisinopril 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. Dosages of the drugs should be titrated carefully by increasing slowly the dosage of each drug separately in small increments and the patient should be monitored closely. After careful titration of each drug separately, a fixed combination preparation can be substituted. 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 lisinopril in fixed combination with hydrochlorothiazide is not recommended for patients with severe renal impairment.

Cautions

Contraindications

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

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

Concomitant use of lisinopril and aliskiren in patients with diabetes mellitus.(See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Warnings/Precautions

Warnings

When hydrochlorothiazide is used in fixed combination with lisinopril, the usual cautions, precautions, and contraindications associated with hydrochlorothiazide must be considered in addition to those associated with lisinopril.

Hypotension

Symptomatic hypotension may occur, sometimes associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death. Patients at particular risk include those with heart failure with systolic blood pressure less than 100 mm Hg, hyponatremia, high-dose or recent intensive diuretic therapy, recent increase in diuretic dose, dialysis, or severe volume and/or salt depletion of any etiology. In such patients, it may be advisable to discontinue the diuretic (except in patients with heart failure), reduce the diuretic dosage, or cautiously increase salt intake, if possible, prior to initiating lisinopril therapy. Treatment with lisinopril must not be initiated in patients with acute myocardial infarction (MI) at risk of further serious hemodynamic deterioration following treatment with a vasodilator (e.g., systolic blood pressure of 100 mm Hg or lower) or in those with cardiogenic shock. Marked hypotension may result in MI or stroke in those with acute MI or ischemic cardiovascular or cerebrovascular disease.

Hematologic Effects

Neutropenia/agranulocytosis, particularly in patients with renal impairment (especially those with concomitant collagen vascular disease), reported with captopril. Data insufficient to rule out similar incidence of agranulocytosis with lisinopril in patients without prior reactions with other ACE inhibitors. Hemolytic anemia reported rarely; causal relationship to lisinopril cannot be ruled out. Myelosuppression, leukopenia/neutropenia, and thrombocytopenia reported rarely.

Hepatic Effects

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

Fetal/Neonatal Morbidity and Mortality

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

Sensitivity Reactions

Sensitivity reactions, including anaphylactoid reactions and angioedema (including laryngeal edema, tongue edema), are potentially fatal. Patients with head and neck angioedema involving the tongue, glottis, or larynx are likely to experience airway obstruction, especially in those with a history of airway surgery. If laryngeal stridor or angioedema of the face, lips, tongue, or glottis occurs, lisinopril should be discontinued and appropriate therapy (e.g., epinephrine) should be initiated immediately. Antihistamines and corticosteroids may not provide sufficient relief of symptoms even in patients experiencing only swelling of the tongue; prolonged observation may be necessary. Caution in patients with history of angioedema unrelated to ACE inhibitor therapy.

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.

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization with hymenoptera venom. Such reactions did not occur when ACE inhibitors were temporarily discontinued before desensitization but did recur following inadvertent rechallenge. Sudden and potentially life-threatening anaphylactoid reactions also have been reported in patients receiving ACE inhibitors while undergoing hemodialysis using high-flux membranes. In such patients, dialysis should be discontinued immediately, and aggressive therapy for anaphylactic reactions should be initiated. Antihistamines have not been effective for relieving symptoms in these patients; use of a different type of dialysis membrane or a different class of antihypertensive agent should be considered. In addition, anaphylactoid reactions have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption.

General Precautions

Aortic Stenosis/Hypertrophic Cardiomyopathy

Like other vasodilators, lisinopril should be administered with caution in patients with obstruction in the outflow tract of the left ventricle (e.g., aortic stenosis, hypertrophic cardiomyopathy).

Renal Effects

Inhibition of the renin-angiotensin-aldosterone (RAA) system may cause renal impairment and rarely renal failure and/or death in susceptible patients (e.g., those whose renal function depends on the activity of the RAA system such as patients with severe heart failure).

Deterioration of renal function, usually reversible upon discontinuance of the drug, manifested as minor and transient increases in BUN and serum creatinine concentrations, may occur following administration of ACE inhibitor therapy, particularly in hypertensive patients with unilateral or bilateral renal artery stenosis, preexisting renal impairment, or concomitant diuretic therapy. Renal function should be monitored during the first few weeks of therapy in such patients; dosage reduction and/or discontinuance of lisinopril and/or the diuretic may be required.

Renal artery stenosis, preexisting renal impairment, and concomitant diuretic therapy also are risk factors for renal impairment during ACE inhibitor therapy. In patients with acute MI who have evidence of renal dysfunction (i.e., serum creatinine concentration exceeding 2 mg/dL), consider discontinuance of lisinopril if serum creatinine exceeds 3 mg/dL or doubles from pretreatment value.

Hyperkalemia

Hyperkalemia can develop, especially in those with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes). Hyperkalemia can result in serious, potentially fatal, cardiac arrhythmias.

Cough

Persistent and nonproductive cough reported with all ACE inhibitors; resolves after drug discontinuance.

Surgery/Anesthesia

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension.

Specific Populations

Pregnancy

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

Lactation

Lisinopril is distributed into milk (as determined by presence of radioactivity following administration of radiolabeled drug) in rats; not known whether the drug is distributed into milk in humans. Hydrochlorothiazide is distributed into human milk. Because of the potential for serious adverse reactions to ACE inhibitors (e.g., lisinopril) in nursing infants, a decision should be made whether to discontinue nursing or lisinopril (either alone or in fixed combination with hydrochlorothiazide), taking into account the importance of the drug(s) to the woman.

Pediatric Use

Safety and efficacy not established in children less than 6 years of age and in pediatric patients with creatinine clearances less than 30 mL/minute per 1.73 m.

Geriatric Use

Clinical studies of lisinopril alone or in fixed combination with hydrochlorothiazide did not include sufficient numbers of patients (with hypertension and heart failure) 65 years of age and older to determine whether geriatric patients respond differently than younger patients, but other clinical experience has not revealed age-related differences. In pharmacokinetic studies, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of lisinopril were increased in geriatric individuals compared with younger individuals. Drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Renal Impairment

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

Black Patients

ACE inhibitors not as effective for decreasing blood pressure. Increased incidence of angioedema.(See Uses: Hypertension.)

Common Adverse Effects

Adverse effects reported in greater than 1% of patients receiving lisinopril or lisinopril in fixed combination with hydrochlorothiazide for the management of hypertension and more frequently than with placebo include headache, dizziness, cough, fatigue, diarrhea, upper respiratory tract infection, nausea, asthenia, rash, orthostatic effects, hypotension, vomiting, hyperkalemia, or minor increases in BUN and serum creatinine concentrations. Additional adverse effects reported in 1% or more of patients receiving lisinopril in fixed combination with hydrochlorothiazide include dyspepsia, muscle cramps, paresthesia, decreased libido, vertigo, nasal congestion, influenza, or impotence.

Adverse effects reported in greater than 1% of patients receiving lisinopril for the management of heart failure and more frequently than with placebo include dizziness, hypotension, headache, diarrhea, chest pain, nausea, abdominal pain, rash, and upper respiratory tract infection.

In a large trial in patients with acute MI, hypotension and renal dysfunction occurred more frequently in patients receiving lisinopril than in those not receiving the drug.

Drug Interactions

Drugs that Block the Renin-Angiotensin System

Increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (e.g., acute renal failure) with concomitant use of other drugs that block the renin-angiotensin system (e.g., aliskiren, angiotensin II receptor antagonists); when lisinopril is used concomitantly with such drugs, blood pressure, renal function, and serum electrolyte concentrations should be monitored closely. Concomitant use of lisinopril and aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m).

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (additive hyperkalemic effect). Includes potassium-sparing diuretics, potassium supplements, and other drugs that can increase serum potassium. The manufacturer states that lisinopril should be used cautiously (with frequent monitoring of serum potassium), if at all, with potassium supplements or salt substitutes containing potassium.

Antidiabetic Agents

Potential pharmacologic interaction (increased hypoglycemic effect), especially during initial weeks of combined treatment and in patients with renal impairment.

Digoxin

Clinically important adverse interaction not observed.

Diuretics

Potential pharmacokinetic and pharmacologic interaction (hypotensive effect).

Gold Compounds

Rare reports of nitritoid reactions (manifested by facial flushing, nausea, vomiting, and hypotension) in patients receiving parenteral aurothioglucose and gold sodium thiomalate concomitantly with ACE inhibitors, including lisinopril.

Lithium

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

Nonsteroidal Anti-inflammatory Agents

Potential pharmacologic interaction (decreased antihypertensive effect) when lisinopril is used concomitantly concurrently with nonsteroidal anti-inflammatory agents (NSAIAs). Potential pharmacologic interaction (decreased renal function) when lisinopril is used concomitantly with NSAIAs in patients with impaired renal function.

Propranolol

Clinically important pharmacokinetic interaction not observed.