Fosinopril

— THERAPEUTIC DISORDERS TREATED —
  • CHF and arrhythmias
  • Hypertension
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Fosinopril Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Fosinopril sodium 10mg+, 20mg, 40mg; tabs; +scored.

    Pharmacological Class

    ACE inhibitor.

    How Supplied

    Contact supplier.

    Manufacturer

    Various generic manufacturers

    Fosinopril Indications

    Indications

    Adjunct to diuretics in heart failure, with or without digitalis.

    Fosinopril Dosage and Administration

    Adult

    Initially 10mg once daily. Moderate to severe renal failure or volume depleted: initially 5mg once daily. Maintenance: 20–40mg once daily.

    Children

    Contact manufacturer.

    Renal Impairment

    • In patients with severe CHF whose renal function may depend on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including fosinopril sodium, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

    • In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in BUN and serum creatinine may occur. In these patients, monitor renal function during the first few weeks of therapy.

    Hepatic Impairment

    • Discontinue ACE inhibitor if patients develop jaundice or marked elevations of hepatic enzymes and administer appropriate medical follow-up.

    Fosinopril Contraindications

    Contraindications

    Hypersensitivity to fosinopril or any other ACE inhibitor (eg, angioedema). Concomitant use with aliskiren in patients with diabetes.

    Fosinopril Boxed Warnings

    Not Applicable

    Fosinopril Warnings/Precautions

    Warnings/Precautions

    Salt/volume depletion. Renal or hepatic impairment. Monitor WBCs in renal or collagen vascular disease. CHF. Dialysis (esp. high-flux membrane). Renal artery stenosis. Monitor for hyperkalemia in diabetics. Discontinue if angioedema, laryngeal edema, jaundice, or markedly elevated liver enzymes occurs. Surgery. Pregnancy (Cat.C in 1st trimester). Nursing mothers: not recommended.

    Warnings/Precautions

    Anaphylactoid and Possibly Related Reactions

    • Discontinue and institute appropriate therapy immediately if laryngeal stridor or angioedema of the face, lips, mucous membranes, tongue, glottis, or extremities occur.

    • If there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, promptly administer appropriate therapy with subcutaneous epinephrine solution 1:1000 (0.3mL or 0.5mL).

    • Increased risk for angioedema in patients taking concomitant mTOR inhibitor (eg, temsirolimus).

    Hypotension

    • May cause symptomatic hypotension.

    • Increased risk for symptomatic hypotension in patients who have been volume- and/or salt-depleted due to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

    • Correct volume- and/or salt-depletion prior to initiating treatment.

    • In patients with heart failure, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely with acute renal failure and death. In these patients, initiate fosinopril under close medical supervision and follow closely for the first 2 weeks of treatment.

    • If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

    Neutropenia/Agranulocytosis

    • Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

    Fetal Toxicity (Pregnancy Category D)

    • Drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

    • Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

    • Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

    • Discontinue fosinopril as soon as possible when pregnancy is detected.

    • Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue fosinopril unless it is considered lifesaving for the mother.

    Hepatic Failure

    • Discontinue ACE inhibitor if patients develop jaundice or marked elevations of hepatic enzymes and administer appropriate medical follow-up.

    Impaired Renal Function

    • In patients with severe CHF whose renal function may depend on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including fosinopril sodium, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

    • In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in BUN and serum creatinine may occur. In these patients, monitor renal function during the first few weeks of therapy.

    Hyperkalemia

    • Hyperkalemia may occur, particularly in patients with renal insufficiency, diabetes mellitus, and the concomitant use with potassium-sparing diuretics, potassium supplments, and/or potassium-containing salt substitutes; these products should be used cautiously (if at all) with fosinopril sodium.

    Surgery/Anesthesia

    • In patients undergoing surgery or during anesthesia with agents that produce hypotension, fosinopril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

    • Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (eg, AN69) in patients receiving ACE inhibitors as medication. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. 

    Pregnancy Considerations

    Fetal Toxicity (Pregnancy Category D)

    • Drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

    • Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

    • Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

    • Discontinue fosinopril as soon as possible when pregnancy is detected.

    • Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue fosinopril unless it is considered lifesaving for the mother.

    Nursing Mother Considerations

    • Do not administer to nursing mothers.

    Pediatric Considerations

    • Neonates with a history of in utero exposure to fosinopril sodium tablets: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. 

    Geriatric Considerations

    • Clinical studies did not include sufficient numbers of patients 65 years of age and older to determine if they respond differently from younger patients.

    • In general, use caution for dose selection in elderly patients, usually starting at the low end of the dose range.

    Renal Impairment Considerations

    • In patients with severe CHF whose renal function may depend on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including fosinopril sodium, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

    • In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in BUN and serum creatinine may occur. In these patients, monitor renal function during the first few weeks of therapy.

    Hepatic Impairment Considerations

    • Discontinue ACE inhibitor if patients develop jaundice or marked elevations of hepatic enzymes and administer appropriate medical follow-up.

    Fosinopril Pharmacokinetics

    Absorption

    Following oral administration, fosinopril (the prodrug) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine (duodenum/jejunum). While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected.

    Distribution

    Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs) and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours.

    Metabolism

    After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20% to 30% as a glucuronide conjugate of fosinoprilat, and 1% to 5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.

    Elimination

    After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective half-life for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective half-life was 14 hours.

    Fosinopril Interactions

    Interactions

    Potentiated by diuretics. Potassium or K+-sparing diuretics may cause hyperkalemia. May increase lithium levels. Separate antacid dosing by 2hrs. May cause false low serum digoxin measurements.

    Fosinopril Adverse Reactions

    Adverse Reactions

    Angina, orthostatic hypotension, dizziness, cough, GI upset, pain, hyperkalemia, upper respiratory infection, arrhythmias, asthenia; angioneurotic edema (discontinue if occurs).

    Fosinopril Clinical Trials

    Clinical Trials

    Randomized, double-blind, placebo-controlled trial

    • The trial included 179 patients with heart failure. Patients (all receiving diuretics and some receiving digoxin) were administered single doses of 10 mg, 20 mg, or 40 mg of fosinopril sodium or placebo.

    • Treatment with fosinopril 20 mg and 40 mg resulted in acute decreases in pulmonary capillary wedge pressure (preload) and mean arterial blood pressure and systemic vascular resistance (afterload). 

    • 155 of these patients were re-randomized to receive once daily doses of fosinopril 10 mg, 20 mg, or 40 mg for an additional 10 weeks. Hemodynamic measurements showed continued reduction in pulmonary capillary wedge pressure, mean arterial blood pressure, right atrial pressure and an increase in cardiac index and stroke volume for the 20 mg and 40 mg dose groups.

    3 double-blind, placebo-controlled trials

    • The trials evaluated fosinopril sodium 10–40 mg daily in 734 patients with heart failure. In 2 of the 3 trials, patients received concomitant diuretics and digitalis. In the third trial, patients were receiving only diuretics.

    • Results from all trials showed statistically significant benefits of fosinopril sodium therapy compared with placebo, in 1 or more of the following: exercise tolerance (one study), symptoms of dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification (2 studies), hospitalization for heart failure (2 studies), study withdrawals for worsening heart failure (2 studies), and/or need for supplemental diuretics (2 studies). 

    • Favorable effects were maintained for up to 2 years.

    Fosinopril Note

    Notes

    Formerly known under the brand name Monopril.

    Fosinopril Patient Counseling

    Patient Counseling

    Angioedema

    • Advise to immediately report any signs or symptoms suggesting angioedema (eg, swelling of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy.

    Symptomatic Hypotension

    • Advise that lightheadedness may occur, especially during the first days of therapy.

    • Discontinue if syncope occurs until physician has been consulted.

    • Caution patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure.

    Hyperkalemia

    • Do not use potassium supplements or salt substitutes containing potassium without consulting a physician.

    Neutropenia

    • Promptly report any indication of infection (eg, sore throat, fever).

    Pregnancy

    • Advise females of childbearing age about the consequences of exposure to fosinopril during pregnancy. Discuss treatment options with women planning to become pregnant.

    • Report pregnancies to their physicians as soon as possible.

    Fosinopril Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Fosinopril sodium 10mg+, 20mg, 40mg; tabs; +scored.

    Pharmacological Class

    ACE inhibitor.

    How Supplied

    Contact supplier.

    Manufacturer

    Various generic manufacturers

    Fosinopril Indications

    Indications

    Hypertension.

    Fosinopril Dosage and Administration

    Adult

    Initially 10mg once daily. Usual maintenance: 20–40mg daily in single or 2 divided doses; max 80mg/day. If on diuretic: suspend diuretic for 2–3 days before starting if possible; resume diuretic if pressure not controlled with fosinopril alone. If diuretic cannot be discontinued: give 10mg and monitor carefully.

    Children

    <6yrs (≤50kg): not recommended. ≥6yrs (>50kg): 5–10mg once daily.

    Renal Impairment

    • In patients with severe CHF whose renal function may depend on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including fosinopril sodium, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

    • In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in BUN and serum creatinine may occur. In these patients, monitor renal function during the first few weeks of therapy.

    Hepatic Impairment

    • Discontinue ACE inhibitor if patients develop jaundice or marked elevations of hepatic enzymes and administer appropriate medical follow-up.

    Fosinopril Contraindications

    Contraindications

    Hypersensitivity to fosinopril or any other ACE inhibitor (eg, angioedema). Concomitant use with aliskiren in patients with diabetes.

    Fosinopril Boxed Warnings

    Not Applicable

    Fosinopril Warnings/Precautions

    Warnings/Precautions

    Salt/volume depletion. Renal or hepatic impairment. Monitor WBCs in renal or collagen vascular disease. CHF. Dialysis (esp. high-flux membrane). Renal artery stenosis. Monitor for hyperkalemia in diabetics. Discontinue if angioedema, laryngeal edema, jaundice, or markedly elevated liver enzymes occurs. Surgery. Pregnancy (Cat.C in 1st trimester). Nursing mothers: not recommended.

    Warnings/Precautions

    Anaphylactoid and Possibly Related Reactions

    • Discontinue and institute appropriate therapy immediately if laryngeal stridor or angioedema of the face, lips, mucous membranes, tongue, glottis, or extremities occur.

    • If there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, promptly administer appropriate therapy with subcutaneous epinephrine solution 1:1000 (0.3mL or 0.5mL).

    • Increased risk for angioedema in patients taking concomitant mTOR inhibitor (eg, temsirolimus).

    Hypotension

    • May cause symptomatic hypotension.

    • Increased risk for symptomatic hypotension in patients who have been volume- and/or salt-depleted due to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

    • Correct volume- and/or salt-depletion prior to initiating treatment.

    • In patients with heart failure, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely with acute renal failure and death. In these patients, initiate fosinopril under close medical supervision and follow closely for the first 2 weeks of treatment.

    • If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

    Neutropenia/Agranulocytosis

    • Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

    Fetal Toxicity (Pregnancy Category D)

    • Drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

    • Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

    • Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

    • Discontinue fosinopril as soon as possible when pregnancy is detected.

    • Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue fosinopril unless it is considered lifesaving for the mother.

    Hepatic Failure

    • Discontinue ACE inhibitor if patients develop jaundice or marked elevations of hepatic enzymes and administer appropriate medical follow-up.

    Impaired Renal Function

    • In patients with severe CHF whose renal function may depend on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including fosinopril sodium, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

    • In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in BUN and serum creatinine may occur. In these patients, monitor renal function during the first few weeks of therapy.

    Hyperkalemia

    • Hyperkalemia may occur, particularly in patients with renal insufficiency, diabetes mellitus, and the concomitant use with potassium-sparing diuretics, potassium supplments, and/or potassium-containing salt substitutes; these products should be used cautiously (if at all) with fosinopril sodium.

    Surgery/Anesthesia

    • In patients undergoing surgery or during anesthesia with agents that produce hypotension, fosinopril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

    • Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (eg, AN69) in patients receiving ACE inhibitors as medication. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. 

    Pregnancy Considerations

    Fetal Toxicity (Pregnancy Category D)

    • Drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

    • Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

    • Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

    • Discontinue fosinopril as soon as possible when pregnancy is detected.

    • Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue fosinopril unless it is considered lifesaving for the mother.

    Nursing Mother Considerations

    • Do not administer to nursing mothers.

    Pediatric Considerations

    • Neonates with a history of in utero exposure to fosinopril sodium tablets: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. 

    Geriatric Considerations

    • Clinical studies did not include sufficient numbers of patients 65 years of age and older to determine if they respond differently from younger patients.

    • In general, use caution for dose selection in elderly patients, usually starting at the low end of the dose range.

    Renal Impairment Considerations

    • In patients with severe CHF whose renal function may depend on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including fosinopril sodium, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

    • In hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, increases in BUN and serum creatinine may occur. In these patients, monitor renal function during the first few weeks of therapy.

    Hepatic Impairment Considerations

    • Discontinue ACE inhibitor if patients develop jaundice or marked elevations of hepatic enzymes and administer appropriate medical follow-up.

    Fosinopril Pharmacokinetics

    Absorption

    Following oral administration, fosinopril (the prodrug) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine (duodenum/jejunum). While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected.

    Distribution

    Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs) and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours.

    Metabolism

    After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20% to 30% as a glucuronide conjugate of fosinoprilat, and 1% to 5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.

    Elimination

    After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective half-life for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective half-life was 14 hours.

    Fosinopril Interactions

    Interactions

    Potentiated by diuretics. Potassium or K+-sparing diuretics may cause hyperkalemia. May increase lithium levels. Separate antacid dosing by 2hrs. May cause false low serum digoxin measurements.

    Fosinopril Adverse Reactions

    Adverse Reactions

    Headache, cough, dizziness, GI upset, hyperkalemia, orthostatic hypotension, angioneurotic edema (discontinue if occurs).

    Fosinopril Clinical Trials

    Clinical Trials

    Adults

    • Following four weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of fosinopril 20 mg to 80 mg lowered supine or seated systolic and diastolic blood pressures 24 hours after dosing by an average of 8 to 9/6 to 7 mmHg more than placebo. The trough effect was about 50% to 60% of the peak diastolic response and about 80% of the peak systolic response.

    • In most trials, fosinopril sodium showed an increased antihypertensive effect during the first several weeks of repeated measurements. The antihypertensive effect was found to continue during long-term therapy for at least 2 years.

    Pediatric

    • The efficacy of fosinopril was evaluated in a randomized, double-blind study of 252 pediatric patients 6 to 16 years of age with hypertension or high-normal blood pressure. Patients were titrated to target doses of low (0.1 mg/kg), medium (0.3 mg/kg), and high (0.6 mg/kg) after one week and a total duration of 4 weeks.

    • The mean reductions from baseline to week 4 in trough systolic blood pressure were similar in all 3 dose groups.

    • Withdrawal of fosinopril resulted in an increase in blood pressure towards baseline over a 2 week period.

    Fosinopril Note

    Notes

    Formerly known under the brand name Monopril.

    Fosinopril Patient Counseling

    Patient Counseling

    Angioedema

    • Advise to immediately report any signs or symptoms suggesting angioedema (eg, swelling of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy.

    Symptomatic Hypotension

    • Advise that lightheadedness may occur, especially during the first days of therapy.

    • Discontinue if syncope occurs until physician has been consulted.

    • Caution patients that inadequate fluid intake or excessive persiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure.

    Hyperkalemia

    • Do not use potassium supplements or salt substitutes containing potassium without consulting a physician.

    Neutropenia

    • Promptly report any indication of infection (eg, sore throat, fever).

    Pregnancy

    • Advise females of childbearing age about the consequences of exposure to fosinopril during pregnancy. Discuss treatment options with women planning to become pregnant.

    • Report pregnancies to their physicians as soon as possible.

     

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