Fosinopril

Fosinopril
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
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	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

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Overview

Fosinopril is a Angiontensin converting enzyme inhibitor that is FDA approved for the {{{indicationType}}} of hypertension. Common adverse reactions include hypotension, hyperkalemia, nausea and vomiting, dizziness, cough.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Dosing Information

Recommeded initial dosage: 10 mg PO qd
Maintaining Dosage: 20-40 mg PO qd

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

Developed by: (Organization)

Class of Recommendation: (Class) (Link)

Strength of Evidence: (Category A/B/C) (Link)

Dosing Information/Recommendation

(Dosage)

Non–Guideline-Supported Use

Condition 1

Dosing Information

There is limited information about Off-Label Non–Guideline-Supported Use of Fosinopril in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

Dosing Information

(Dosage)

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

Developed by: (Organization)

Class of Recommendation: (Class) (Link)

Strength of Evidence: (Category A/B/C) (Link)

Dosing Information/Recommendation

(Dosage)

Non–Guideline-Supported Use

Condition 1

Dosing Information

There is limited information about Off-Label Non–Guideline-Supported Use of Fosinopril in pediatric patients.

Contraindications

Fosinopril sodium tablets are contraindicated in patients who are hypersensitive to this product or to any other angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema with any other ACE inhibitor therapy).

Warnings

Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including fosinopril sodium) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema

Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors. If Angioedema involves the tongue, glottis, or larynx, airway obstruction may occur and be fatal. If laryngeal stridor or Angioedema of the face, lips, mucous membranes, tongue, glottis, or extremities occurs, treatment with fosinopril sodium should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see Warnings and Precautions, Information for Patients and Adverse Reactions).

Intestinal Angioedema

Intestinal Angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial Angioedema and C-1 esterase levels were normal. The Angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal Angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

hypotension

Fosinopril sodium can cause symptomatic hypotension. Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril sodium. In patients with heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In such patients, fosinopril sodium therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased. Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic. If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Fosinopril sodium treatment usually can be continued following restoration of blood pressure and volume.

Neutropenia/agranulocytosis

Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of fosinopril are insufficient to show that fosinopril does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

Fetal/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of fosinopril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, fosinopril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Fosinopril is poorly dialyzed from the circulation of adults by hemodialysis and peritoneal dialysis. There is no experience with any procedure for removing fosinopril from the neonatal circulation. When fosinopril was given to pregnant rats at doses about 80 to 250 times (on a mg/kg basis) the maximum recommended human dose, three similar orofacial malformations and one fetus with situs inversus were observed among the offspring. No teratogenic effects of fosinopril were seen in studies in pregnant rabbits at doses up to 25 times (on a mg/kg basis) the maximum recommended human dose.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

PRECAUTIONS

General

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including fosinopril sodium tablets, 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 blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when fosinopril sodium has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of fosinopril sodium and/or discontinuation of the diuretic may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function (see Dosage and Administration). Impaired renal function decreases total clearance of fosinoprilat and approximately doubles AUC. In general, no adjustment of dosing is needed. However, patients with heart failure and severely reduced renal function may be more sensitive to the hemodynamic effects (e.g., hypotension) of ACE inhibition (see CLINICAL PHARMACOLOGY).

Hyperkalemia

In clinical trials, hyperkalemia (serum potassium greater than 10% above the upper limit of normal) has occurred in approximately 2.6% of hypertensive patients receiving fosinopril sodium. In most cases, these were isolated values which resolved despite continued therapy. In clinical trials, 0.1% of patients (2 patients) were discontinued from therapy due to an elevated serum potassium. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with fosinopril sodium tablets (seeWarnings and Precautions, Drug Interaction).

Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Impaired Liver Function

Since fosinopril is primarily metabolized by hepatic and gut wall esterases to its active moiety, fosinoprilat, patients with impaired liver function could develop elevated plasma levels of unchanged fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the extent of hydrolysis was unaffected, although the rate was slowed. In these patients, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled.

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.

Hemodialysis

Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., 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 (see Warnings and Precautions, Anaphylactoid Reactions During Membrane Exposure).

Adverse Reactions

Clinical Trials Experience

Fosinopril sodium tablets have been evaluated for safety in more than 2100 individuals in hypertension and heart failure trials, including approximately 530 patients treated for a year or more. Generally adverse events were mild and transient, and their frequency was not prominently related to dose within the recommended daily dosage range.

Hypertension

In placebo-controlled clinical trials (688 fosinopril sodium-treated patients), the usual duration of therapy was 2 to 3 months. Discontinuations due to any clinical or laboratory adverse event were 4.1% and 1.1% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reasons (0.4 to 0.9%) were headache, elevated transaminases, fatigue, cough (see PRECAUTIONS, General, Cough), diarrhea, and nausea and vomiting. During clinical trials with any fosinopril sodium regimen, the incidence of adverse events in the elderly (≥ 65 years old) was similar to that seen in younger patients. Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium alone and at least as frequent on fosinopril sodium as on placebo in placebo-controlled clinical trials are shown in the table below.

The following events were also seen at > 1% on fosinopril sodium but occurred in the placebo group at a greater rate: headache, diarrhea, fatigue, and sexual dysfunction. Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.2 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled or uncontrolled clinical trials (N = 1479) and less frequent, clinically significant events include (listed by body system): General: Chest pain, edema, weakness, excessive sweating. Cardiovascular: Angina/myocardial infarction, cerebrovascular accident, hypertensive crisis, rhythm disturbances, palpitations, hypotension, syncope, flushing, claudication. Orthostatic hypotension occurred in 1.4% of patients treated with fosinopril monotherapy. Hypotension or orthostatic hypotension was a cause for discontinuation of therapy in 0.1% of patients. Dermatologic: Urticaria, rash, photosensitivity, pruritus. Endocrine/Metabolic: Gout, decreased libido. Gastrointestinal: Pancreatitis, hepatitis, dysphagia, abdominal distention, abdominal pain, flatulence, constipation, heartburn, appetite/weight change, dry mouth. Hematologic: Lymphadenopathy. Immunologic: Angioedema (see WARNINGS, Head and Neck Angioedema and Intestinal Angioedema). Musculoskeletal: Arthralgia, musculoskeletal pain, myalgia/muscle cramp. Nervous/Psychiatric: Memory disturbance, tremor, confusion, mood change, paresthesia, sleep disturbance, drowsiness, vertigo. Respiratory: Bronchospasm, pharyngitis, sinusitis/rhinitis, laryngitis/hoarseness, epistaxis. A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril. Special Senses: Tinnitus, vision disturbance, taste disturbance, eye irritation. Urogenital: Renal insufficiency, urinary frequency. Heart Failure In placebo-controlled clinical trials (361 fosinopril sodium-treated patients), the usual duration of therapy was 3 to 6 months. Discontinuations due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of fosinopril sodium was angina pectoris (1.1%). Significant hypotension after the first dose of fosinopril sodium occurred in 14/590 (2.4%) of patients; 5/590 (0.8%) patients discontinued due to first dose hypotension. Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium and at least as common as the placebo group, in placebo-controlled trials are shown in the table below.

The following events also occurred at a rate of 1% or more on fosinopril sodium tablets but occurred on placebo more often: fatigue, dyspnea, headache, rash, abdominal pain, muscle cramp, angina pectoris, edema, and insomnia. The incidence of adverse events in the elderly (≥ 65 years old) was similar to that seen in younger patients. Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.4 to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled clinical trials (N = 516) and less frequent, clinically significant events include (listed by body system): General: Fever, influenza, weight gain, hyperhidrosis, sensation of cold, fall, pain. Cardiovascular: Sudden death, cardiorespiratory arrest, shock (0.2%), atrial rhythm disturbance, cardiac rhythm disturbances, non-anginal chest pain, edema lower extremity, hypertension, syncope, conduction disorder, bradycardia, tachycardia. Dermatologic: Pruritus. Endocrine/Metabolic: Gout, sexual dysfunction. Gastrointestinal: Hepatomegaly, abdominal distention, decreased appetite, dry mouth, constipation, flatulence. Immunologic: Angioedema (0.2%). Musculoskeletal: Muscle ache, swelling of an extremity, weakness of an extremity. Nervous/Psychiatric: Cerebral infarction, TIA, depression, numbness, paresthesia, vertigo, behavior change, tremor. Respiratory: Abnormal vocalization, rhinitis, sinus abnormality, tracheobronchitis, abnormal breathing, pleuritic chest pain. Special Senses: Vision disturbance, taste disturbance. Urogenital: Abnormal urination, kidney pain. Fetal/Neonatal Morbidity and Mortality See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Potential Adverse Effects Reported With ACE Inhibitors Body as a whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions and PRECAUTIONS, Hemodialysis). Other medically important adverse effects reported with ACE inhibitors include: Cardiac arrest; eosinophilic pneumonitis; neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia; acute renal failure; hepatic failure, jaundice (hepatocellular or cholestatic); symptomatic hyponatremia; bullous pemphigus, exfoliative dermatitis; a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia, or an elevated ESR. Laboratory Test Abnormalities Serum Electrolytes Hyperkalemia, (see PRECAUTIONS); hyponatremia, (see PRECAUTIONS, Drug Interactions, Diuretics). BUN/Serum Creatinine Elevations, usually transient and minor, of BUN or serum creatinine have been observed. In placebo-controlled clinical trials, there were no significant differences in the number of patients experiencing increases in serum creatinine (outside the normal range or 1.33 times the pre-treatment value) between the fosinopril and placebo treatment groups. Rapid reduction of longstanding or markedly elevated blood pressure by any antihypertensive therapy can result in decreases in the glomerular filtration rate, and in turn, lead to increases in BUN or serum creatinine (see PRECAUTIONS, General). Hematology In controlled trials, a mean hemoglobin decrease of 0.1 g/dL was observed in fosinopril-treated patients. In individual patients decreases in hemoglobin or hematocrit were usually transient, small, and not associated with symptoms. No patient was discontinued from therapy due to the development of anemia. Other: Neutropenia (see WARNINGS), leukopenia and eosinophilia. Liver Function Tests Elevations of transaminases, LDH, alkaline phosphatase, and serum bilirubin have been reported. Fosinopril therapy was discontinued because of serum transaminase elevations in 0.7% of patients. In the majority of cases, the abnormalities were either present at baseline or were associated with other etiologic factors. In those cases which were possibly related to fosinopril therapy, the elevations were generally mild and transient and resolved after discontinuation of therapy. Pediatric Patients The adverse experience profile for pediatric patients is similar to that seen in adult patients with hypertension. The long-term effects of fosinopril sodium on growth and development have not been studied.