VA Class:CV800

AHFS Class:

• Angiotensin-Converting Enzyme Inhibitors 24:32.04

Generic Name(s):

• Fosinopril Sodium

• Fosinoprilat

Molecular Formula:

• C₃₀H₄₆NO₇P

Fosinopril is an angiotensin-converting enzyme (ACE) inhibitor.1,2,3

Fosinopril is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.1,2,3,1200 Fosinopril also may be used in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers) in the management of heart failure.1,15,524,800

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)1 or in patients receiving immunosuppressive therapy,5,6 the possibility that similar adverse effects may occur with fosinopril should be considered since current evidence is insufficient to rule out such risk.1 (See Cautions: Hematologic Effects, in Captopril 24:32.04.)

Hypertension

Fosinopril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1,2,3,1200 ACE inhibitors are considered one of several preferred antihypertensive drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics.501,502,503,504,1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 (See Uses: Hypertension, in Captopril 24:32.04.) 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 (CKD), or cerebrovascular disease or following myocardial infarction.501,502,504,523,524,525,526,527,534,535,536,543,1200,1214,1215 (See Uses: Hypertension, in Captopril 24:32.04 and in Enalapril/Enalaprilat 24:32.04.)

In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1218 However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200,1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors.44,45,60,61,501,504,1200 Although ACE inhibitors have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension.44,45 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races.1,45,1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Captopril 24:32.04 and Enalapril/Enalaprilat 24:32.04.)

For additional information on the role of ACE inhibitors in the management of hypertension, see Uses in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Heart Failure

Fosinopril is used in the management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers.1,15,524,800

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.524,701,703,800 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.524,800 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.524,800 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.800 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,524 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.702,800 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.800 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.800 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.800 For additional information on the use of ACE inhibitors in the management of heart failure, see Uses: Heart Failure, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04. For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.

Many patients with heart failure respond to fosinopril with improvement in cardiac function indexes (e.g., LVEF), symptomatic (e.g., dyspnea, fatigue) relief, improved functional capacity, and increased exercise tolerance.1,15 In some patients, beneficial effects have been sustained for up to 2 years.1 Additional studies are needed to determine the specific role of fosinopril in the management of heart failure and its long-term effects on mortality associated with heart failure.1 Fosinopril, like enalapril, has a relatively long duration of action compared with captopril;14 therefore, the drug may produce more excessive hypotensive effects, particularly at high doses, which potentially could result in adverse renal effects.1 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.1,34 (See Cautions: Renal Effects in Captopril 24:32.04 and in Enalapril 24:32.04.)

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†53,54,55,56,57,1232 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.535,536,1232 The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.49 For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see Diabetic Nephropathy under Uses: Nephropathy, in Captopril 24:32.04.

Administration

Fosinopril sodium is administered orally.1,2 The rate but not the extent of GI absorption of the drug may be reduced by concomitant administration with food.1,2

Dosage

Dosage of fosinopril sodium must be adjusted according to patient tolerance and response.1 Because of the risk of inducing hypotension, initiation of fosinopril sodium therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances.1 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.1,3 The possibility of hypotension may be minimized by discontinuing the diuretic, reducing the diuretic dosage, or increasing salt intake prior to initiating fosinopril therapy; if such changes are not possible, the initial dosage of fosinopril sodium should be reduced and the patient observed closely for several hours until blood pressure has stabilized.600 (See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.) For additional information on initiating fosinopril in patients receiving diuretic therapy, see the disease-specific dosage sections in Dosage and Administration.

Hypertension

Fosinopril Therapy

For the management of hypertension in adults not receiving a diuretic, the usual initial dosage of fosinopril sodium is 10 mg once daily.600 In patients currently receiving a diuretic, it is recommended that the diuretic be discontinued, if possible, 2-3 days before initiating fosinopril.3,600 If blood pressure is not controlled adequately with the ACE inhibitor alone, diuretic therapy may be resumed.600 While the manufacturers of fosinopril sodium also recommend a dosage of 10 mg once daily for initiating therapy in patients receiving a diuretic, the risk of an exaggerated reduction in blood pressure following initiation of an ACE inhibitor and the desirability of initiating the ACE inhibitor at reduced dosage to minimize this risk should be considered for such patients.600 If fosinopril sodium is initiated at the usual dose of 10 mg in patients receiving a diuretic, the initial dose of the drug should be administered under close medical supervision for several hours until blood pressure has stabilized.600

Dosage of fosinopril sodium should be adjusted according to the patient's blood pressure response at times corresponding to peak (2-6 hours after dosing) and trough (about 24 hours after dosing) serum fosinopril concentrations.600 If the blood pressure response diminishes toward the end of the dosing interval during once-daily administration, increasing the dosage or giving the drug in divided doses daily should be considered.25,600 The manufacturer states that the usual maintenance dosage of fosinopril sodium in adults is 20-40 mg daily.600 Some experts state that the usual dosage range is 10-40 mg once daily.1200 Higher dosages (e.g., 80 mg daily) reportedly have resulted in increased response in some patients.600 If blood pressure is not adequately controlled with fosinopril sodium alone, a second antihypertensive agent (e.g., a diuretic1,39,40,41,42 ) may be added.

For the management of hypertension in children 6 years of age or older who weigh more than 50 kg, the usual initial dosage of fosinopril sodium is 5-10 mg once daily.1,1150 In children 6 years of age or older who weigh less than 50 kg, some experts recommend an initial dosage of 0.1 mg/kg (up to 5 mg) daily.1150 However, the manufacturer states that a dosage form suitable for providing an appropriate dosage for children weighing less than 50 kg is not commercially available in the US.1 Some experts state that the drug should be initiated at the low end of the dosage range and that the dosage should be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150 The safety and efficacy of dosages exceeding 40 mg daily have not been established.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Fosinopril/Hydrochlorothiazide Fixed-combination Therapy

When combination therapy is required for the management of hypertension, the manufacturers recommend that commercially available preparations containing fosinopril sodium in fixed combination with hydrochlorothiazide should not be used for initial therapy.43 The manufacturers also state that therapy can be initiated with the commercially available fixed-combination preparations in patients whose blood pressure is not adequately controlled with fosinopril or hydrochlorothiazide monotherapy.43 On average, the combination of 10 mg of fosinopril sodium and 12.5 mg of hydrochlorothiazide produces an antihypertensive effect similar to that produced by either 40 mg of fosinopril sodium or 37.5 mg of hydrochlorothiazide.43 Over the dosage range of hydrochlorothiazide 5-37.5 mg and fosinopril sodium 2.5-40 mg once daily, the antihypertensive effects of the fixed combination increase with increasing doses of either component.43

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with ACE inhibitor monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with fosinopril, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 a 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Heart Failure

Because of the risk of severe hypotension (including postural hypotension), fosinopril therapy for heart failure should be initiated under close medical supervision, with consideration given to recent diuretic therapy and the possibility of severe sodium and/or fluid depletion.1,524 Patients with heart failure, with or without renal impairment, should be monitored closely for the first 2 weeks of fosinopril therapy and whenever dosage of the drug and/or concomitantly administered diuretic is increased.1 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 creatinine concentrations (exceeding 3 mg/dL), bilateral renal artery stenosis, or elevated serum potassium concentrations (exceeding 5 mEq/L).524 Experts recommend that patients receiving an ACE inhibitor be monitored (i.e., renal function and serum potassium) within 1-2 weeks of initiation of therapy and periodically thereafter, especially patients with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia, or those taking potassium supplements.524

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.34 In addition, such therapy may reduce the risk of disease progression even if symptomatic improvement is not evident.34 Therefore, dosages generally should be titrated to a prespecified target or highest tolerated dosage (maximum dosage 40 mg once daily) rather than according to response.524

For the management of symptomatic heart failure, fosinopril often is administered in conjunction with other agents such as a cardiac glycoside, a diuretic, and a β-adrenergic blocking agent (β-blocker).1,524,800 The usual initial fosinopril sodium dosage for the management of heart failure in adults with normal renal function is 10 mg daily.1 In patients who have been vigorously treated with diuretics, an initial dose of 5 mg is recommended.1 After the initial dose, the patient should be monitored closely for at least 2 hours or until blood pressure has stabilized.1 Hypotension or azotemia occurring after the initial dose does not preclude the administration of subsequent doses of the drug, provided caution is exercised and the hypotension has been managed effectively.1 To minimize the likelihood of hypotension, the dosage of any diuretic given concomitantly with fosinopril should be reduced, if possible.1 Dosage is increased gradually according to the patient's tolerance and response.1 The usual effective dosage of fosinopril sodium in adults is 20-40 mg daily, given as a single dose; the maximum dosage is 40 mg daily.1

Special Populations

When initiating therapy, modification of fosinopril sodium dosage generally is not necessary in patients with renal impairment since the total body clearance of fosinoprilat, the active metabolite, does not appear to change appreciably with any degree of renal insufficiency;1,2,11 however, the manufacturers state that an initial dose of 5 mg is preferred in patients with heart failure and moderate to severe renal impairment.1 As with other ACE inhibitors, the theoretical risk of neutropenia in patients with renal impairment must be considered.1

Because of the greater frequency of decreased renal function in geriatric patients, dosage of fosinopril sodium should be selected carefully and monitoring of renal function may be useful in such patients.1

Contraindications

History of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor treatment.1

Known hypersensitivity to fosinopril, other ACE inhibitors, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

When hydrochlorothiazide is used in fixed combination with fosinopril, the usual cautions, precautions, and contraindications associated with hydrochlorothiazide must be considered in addition to those associated with fosinopril.43 (See Cautions, in the Thiazides General Statement 40:28.20.)

Cardiovascular Effects

Like other ACE inhibitors, fosinopril rarely is associated with hypotension in patients with uncomplicated hypertension.1 Symptomatic hypotension may occur; patients at particular risk include those with severe volume and/or salt depletion secondary to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.1 Volume and/or salt depletion should be corrected before starting fosinopril therapy.1

Marked hypotension may occur in patients with heart failure (with or without associated renal impairment), which may be associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.1 In patients with heart failure, fosinopril therapy should be started under close medical supervision, with close monitoring for the first 2 weeks of treatment and whenever the dosage of fosinopril sodium or diuretic is increased.1 In patients with heart failure who have normal or low blood pressure and who have been receiving intensive diuretic therapy or who are hyponatremic, consideration should be given to reduction of diuretic dosage.1

If hypotension occurs in patients receiving fosinopril-containing therapy, the patient should be placed in the supine position, and if necessary, an IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered.1 Fosinopril therapy usually may be continued following restoration of blood pressure and volume.1

Hematologic Effects

Neutropenia/agranulocytosis reported with captopril, particularly in patients with renal impairment (especially those with concomitant collagen vascular disease [e.g., systemic lupus erythematosus, scleroderma]).1 Data insufficient to rule out similar incidence of agranulocytosis with fosinopril in patients without prior reactions with other ACE inhibitors.1 Monitoring of leukocytes in patients with collagen vascular disease, especially if renal impairment exists, should be considered.1,43

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.1,26,27,28,29,30,31,32,33 ACE inhibitors also increase the risk of major congenital malformations when administered during the first trimester of pregnancy.4,62,63 Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.1,63 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.31,33 For additional information on the risk of ACE inhibitors during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.

Hepatic Effects

Rare ACE inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur; may progress to fulminant hepatic necrosis and is potentially fatal.1 Patients receiving an ACE inhibitor, including fosinopril, who develop jaundice or marked elevations of hepatic enzymes should discontinue the drug and receive appropriate monitoring.1

Sensitivity Reactions

Sensitivity reactions, including anaphylactoid reactions and angioedema (including laryngeal angioedema, tongue edema) are potentially fatal.1,43 Head and neck angioedema involving the tongue, glottis, or larynx may cause airway obstruction.1 If laryngeal stridor or angioedema of the face, lips, tongue, or glottis occurs, fosinopril should be discontinued and appropriate therapy (e.g., epinephrine) should be initiated immediately.1,43

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.1,43 Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery;1,43 symptoms usually have resolved after discontinuance of the ACE inhibitor.1,43 Intestinal angioedema should be considered in the differential diagnosis of patients who develop abdominal pain during therapy with an ACE inhibitor.1,43

Life-threatening anaphylactoid reactions have been reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.1,43 When ACE inhibitors were temporarily discontinued before desensitization with the venom, anaphylactoid reactions did not recur; however, such reactions recurred after inadvertent rechallenge.1,43 Anaphylactoid reactions have been reported following initiation of hemodialysis that used a high-flux membrane in patients receiving an ACE inhibitor.1,43 In addition, anaphylactoid reactions also have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption.1,43

General Precautions

Renal Effects

Inhibition of the renin-angiotensin-aldosterone (RAA) system may cause renal impairment and, rarely, renal failure and/or death in susceptible patients (e.g., those whose renal function depends on the activity of the RAA system such as patients with severe heart failure).1

Deterioration of renal function, manifested as transient increases in BUN and serum creatinine concentrations, may occur following administration of ACE inhibitor therapy, particularly in hypertensive patients with unilateral or bilateral renal artery stenosis, preexisting renal impairment, or concomitant diuretic therapy.1 This effect usually was reversible following discontinuance of ACE inhibitor and/or diuretic therapy.1 Renal function should be monitored closely during the first few weeks of therapy and periodically thereafter in such patients.1 Dosage reduction of fosinopril and/or discontinuance of diuretic therapy may be required.1,4

Effects on Potassium

Hyperkalemia can develop, especially in those with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).1

Cough

Persistent and nonproductive; resolves after drug discontinuance.1

Surgery/Anesthesia

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension.1 Hypotension in such patients may be corrected by volume expansion.1

Specific Populations

Pregnancy

Category C (first trimester); Category D (second and third trimesters).1 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Fosinoprilat is distributed into milk in humans.1 Because of the potential for serious adverse reactions from fosinopril in nursing infants, the manufacturer states that the drug should not be used in nursing women.1

Pediatric Use

Safety and efficacy not established in children younger than 6 years of age.1 The long-term effects of fosinopril on growth and development in children have not been studied.1 Safety profile of the drug in pediatric patients is similar to that in adults with hypertension.1 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Use

Experience in those 65 years of age or older insufficient to determine whether they respond differently from younger adults.1 Dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.1 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.1

Renal Impairment

Renal function may decrease with ACE inhibitor therapy in susceptible patients.1 Use with caution in those with renal impairment.1 (See Dosage and Administration: Special Populations and also see Renal Effects under Warnings/Precautions: General Precautions, in Cautions.)

Hepatic Impairment

Because fosinopril is primarily metabolized by hepatic and intestinal esterases to its active metabolite, fosinoprilat, patients with hepatic impairment may develop increased plasma concentrations of unchanged fosinopril.1,4 Decreased clearance of fosinoprilat has been reported in patients with alcoholic or biliary cirrhosis.1,64

Black Patients

ACE inhibitors generally are not as effective in black patients compared with other races.1 (See Uses: Hypertension.)

Common Adverse Effects

Adverse effects reported in greater than 1% of patients receiving fosinopril include cough,1 dizziness,1 nausea/vomiting,1 headache,1 diarrhea,1 fatigue,1 hypotension,1 orthostatic hypotension,1 musculoskeletal pain,1 chest pain (not cardiac),1 upper respiratory infection,1 subjective cardiac rhythm disturbance,1 weakness,1 and sexual dysfunction.1 Adverse effects reported in 2% or more of patients receiving fosinopril in fixed combination with hydrochlorothiazide include headache,43 cough,43 fatigue,43 dizziness,43 upper respiratory infection,43 and musculoskeletal pain.43

Diuretics

Potential pharmacokinetic and pharmacologic interaction (hypotensive effect).1

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (additive hyperkalemic effect).1 Includes potassium-sparing diuretics, potassium supplements, and other drugs that can increase serum potassium.1

Lithium

Potential pharmacokinetic interaction (increased lithium concentrations and clinical toxicity).1

Antacids

Potential pharmacokinetic interaction (decreased serum concentrations and decreased urinary excretion of fosinoprilat).1 If use of an antacid is indicated in patients receiving fosinopril therapy, administration of the antacid should be avoided within 2 hours of a fosinopril dose.1

Description

Fosinopril, a phosphinic acid derivative, is an angiotensin-converting enzyme (ACE, bradykininase, kininase II) inhibitor.1,2,3 Unlike captopril or lisinopril, but similar to benazepril, enalapril, moexipril, perindopril, quinapril, ramipril, and trandolapril, fosinopril, the propylester of fosinoprilat, is a prodrug and has little pharmacologic activity until hydrolyzed to fosinoprilat.1,2,3 Like benazepril, enalapril, lisinopril, moexipril, quinapril, and ramipril but unlike captopril, fosinopril does not contain a sulfhydryl group.3 In addition, fosinopril differs from these other ACE inhibitors by the presence of a phosphinic acid group.2,3,4 Renal and hepatobiliary excretion contribute about equally to the elimination of fosinoprilat.1

Advice to Patients

Risk of angioedema, anaphylactoid, and other sensitivity reactions; importance of reporting suggestive manifestation (e.g., edema of face, eyes, extremities, lips, tongue, larynx, mucous membranes; hoarseness; swallowing or breathing with difficulty).1

Risk of hypotension (e.g., lightheadedness, syncope), especially during initial therapy or with volume depletion secondary to excessive perspiration, vomiting, or diarrhea.1 Importance of adequate fluid intake.1 Importance of discontinuing drug and contacting clinician if symptoms of syncope occur.1

Importance of contacting a clinician promptly if manifestations of infection (e.g., sore throat, fever) develop.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Importance of advising patients to avoid taking antacids within 2 hours of fosinopril administration.1 Risk of hyperkalemia.1 Importance of avoiding the use of potassium supplements or salt substitutes containing potassium without consultation with a clinician.1

Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1,63 Risk of use during first, second, and third trimesters of pregnancy.1,62,63

Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturers' labelings should be consulted. It is essential that the manufacturers' labelings be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Bristol-Myers Squibb. Monopril^® (fosinopril sodium) tablets prescribing information. Princeton, NJ; 2003 Jul.

2. Murdoch D, McTavish D. Fosinopril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in essential hypertension. Drugs . 1992; 43:123-40. [PubMed 1372856]

3. McAreavey D, Robertson JIS. Angiotensin converting enzyme inhibitors and moderate hypertension. Drugs . 1990; 40:326-45. [PubMed 2226219]

4. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

5. Squibb. Capoten (captopril) tablets prescribing information. In: Physician's desk reference. 47th ed. Montvale, NJ: Medical Economics Company Inc; 1993:2356-62.

6. Reviewers's comments in enalapril/enalaprilat (personal observations).

8. Anon. Drugs for hypertension. Med Lett Drugs Ther . 1984; 26:107-12. [PubMed 6150424]

10. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull . 1992; 22:2.

11. Sica DA, Cutler RE, Parmer RJ et al. Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency. Clin Pharmacokinet . 1991; 20:420-7. [PubMed 1652404]

13. Oster JR, Materson BL. Renal and electrolyte complications of congestive heart faiulure and effects of therapy with angiotensin-converting enzyme inhibitors. Arch Intern Med . 1992; 152:704-10. [PubMed 1558426]

14. Leonetti G. Cuspidi C. Choosing the right ACE inhibitor: a guide to selection. Drugs . 1995; 49:516-35. [PubMed 7789286]

15. Brown EJ Jr, Chew PH, MacLean A et al for the Fosinopril Heart Failure Study Group. Effects of fosinopril on exercise tolerance and clinical deterioration in patients with chronic congestive heart failure not taking digitalis. Am J Cardiol . 1995; 75:596-600. [PubMed 7887385]

16. Mason N. Angiotensin-converting enzyme inhibitors and renal function. DICP . 1990; 24:496-505. [PubMed 2188438]

17. Baker DW, Konstam MA, Bottorff M. Management of heart failure. JAMA . 1994; 272:1361-6. [PubMed 7933398]

18. Packer M, Lee WH, Yushak M. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med . 1986; 315:847-53. [PubMed 3018566]

19. Zannad F, van den Broek SA, Bory M. Comparison of treatment with lisinopril versus enalapril for congestive heart failure. Am J Cardiol . 1992; 70:78-83C. [PubMed 1377441]

20. Young JB. Angiotensin-converting enzyme inhibitors in heart failure: new strategies justified by recent clinical trials. Int J Cardiol . 1994; 43:151-63. [PubMed 8181869]

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