Monopril (Fosinopril Sodium)

MONOPRIL™

Bristol-Myers Squibb

Fosinopril Sodium

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Fosinopril is an angiotensin converting enzyme (ACE) inhibitor which is used in the treatment of mild to moderate essential hypertension and in the management of symptomatic congestive heart failure.

Following oral administration, fosinopril is rapidly hydrolyzed to fosinoprilat, its principal active metabolite.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE activity leads to decreased levels of angiotensin II thereby resulting in decreased vasoconstriction and decreased aldosterone secretion. The latter decrease may result in a small increase in serum potassium. Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion results in increases in plasma renin activity.

ACE is identical to kininase II. Thus, fosinopril may interfere with the degradation of bradykinin, a potent peptide vasodilator. However, it is not known whether this contributes to the therapeutic effects of fosinopril.

While the mechanism through which fosinopril lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, fosinopril has an antihypertensive effect even in patients with low-renin hypertension.

The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in nonblacks.

Pharmacokinetics: 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. The bioavailability of fosinoprilat is reduced by about 20%.

Hydrolysis of fosinopril to the active fosinoprilat is rapid and complete. This biotransformation probably occurs in the gastrointestinal mucosa and liver.

After an oral dose of radiolabeled fosinopril to healthy subjects, 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. In urine, 75% of the drug excreted was fosinoprilat, the remainder consisted primarily of the glucuronide conjugate of fosinoprilat. In rats, the para-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate of fosinoprilat is devoid of ACE inhibitor activity.

After single and repeated doses, areas under serum concentration-time curves (AUCs) and peak concentrations (Cmax) were directly proportional to the dose of fosinopril. The time to reach peak concentrations (Tmax) was independent of dose and achieved in approximately 3 hours. In patients with congestive heart failure, the effective half-life was about 14 hours.

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, while in patients with heart failure, the effective half-life was 14 hours. Fosinoprilat is highly protein-bound (95%), has a relatively small volume of distribution, and negligible binding to cellular components in blood.

After i.v. administration, elimination of fosinoprilat was shared equally by the liver and kidney. After an oral dose of radiolabeled fosinopril, approximately half of the absorbed dose was excreted in urine and the remainder was excreted in the feces. In normal subjects, the mean body clearance of i.v. fosinoprilat was between 26 and 39 mL/min.

In patients with renal insufficiency, pharmacokinetic parameters (including absorption, bioavailability, protein binding, and biotransformation/metabolism) were not appreciably altered by reduced renal function. The total body clearance of fosinoprilat in patients with impaired renal function.

Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.

In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the extent of absorption was not affected. In single and multiple dose pharmacokinetic studies, the mean AUC for fosinoprilat were markedly increased (50 to 100%) as compared to those of patients with normal liver functions. The extent of hydrolysis of fosinopril was not appreciably reduced although the rate may be slowed. Patients with hepatic insufficiency could develop elevated plasma levels of unchanged fosinopril.

In elderly (male) subjects (65 to 74 years old) with clinically normal renal and hepatic function, there were no significant differences in the pharmacokinetic parameters of fosinoprilat as compared to those in younger subjects (20 to 35 years old).

Fosinoprilat was found to cross the placenta of pregnant animals.

Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier.

Pharmacodynamics: Administration of fosinopril to patients with mild to moderate essential hypertension has reduced both supine and standing blood pressures with minimal effect on heart rate. Following administration of a single dose, the onset of an antihypertensive effect is seen within 1 hour with peak blood pressure reduction usually achieved by 3 to 6 hours after dosing. Achievement of maximum blood pressure lowering effect may require several weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients. The effectiveness of fosinopril appears to be similar in the elderly (over 65 years of age) and younger adult patients given the same daily dosages.

The antihypertensive effect of fosinopril and thiazide diuretics used concurrently is greater than that seen with either agent alone.

Abrupt withdrawal of fosinopril has not resulted in rapid increase in blood pressure.

In hemodynamic study involving patients with mild to moderate hypertension, after 3 months of therapy, responses (changes in blood pressure, heart rate, cardiac index and peripheral vascular resistance) to various stimuli (e.g., isometric exercise, 45 degree head-up tilt and mental challenge) were unchanged compared to baseline, suggesting that fosinopril does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate.

Administration of fosinopril to patients with congestive heart failure reduces afterload and preload of the heart, resulting in an increase in cardiac output, without reflex tachycardia. At the recommended doses, the hemodynamic effects are maintained throughout the 24-hour dosing interval in most patients.

Indications And Clinical Uses: In the treatment of mild to moderate essential hypertension. It may be used alone or in association with thiazide diuretics.

In using fosinopril consideration should be given to the risk of angioedema (see Warnings).

Fosinopril should normally be used in those patients in whom treatment with a diuretic or a beta-blocker was found ineffective or has been associated with unacceptable adverse effects.

Fosinopril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

The safety and efficacy of fosinopril in renovascular hypertension have not been established and therefore, its use in this condition is not recommended.

The safety and efficacy of concurrent use of fosinopril with antihypertensive agents other than thiazide diuretics have not been established.

In the management of symptomatic congestive heart failure as adjunctive treatment with diuretics, and where appropriate, digoxin. Treatment with fosinopril should be initiated under medical supervision.

Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected fosinopril should be discontinued as soon as possible (see Warnings, Pregnancy and Precautions, Information for the Patient).

Contra-Indications: Patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor.

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including fosinopril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, fosinopril should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of s.c. epinephrine solution 1:1 000) should be administered promptly (see Adverse Effects).

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in nonblack patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Hypotension: Symptomatic hypotension has occurred after administration of fosinopril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with fosinopril.

In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been associated with oliguria and/or progressive azotemia, and rarely, with acute renal failure and/or death. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects). Because of the potential fall in blood pressure in these patients, therapy with fosinopril should be started under close medical supervision. Such patients should be followed closely for the first 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, receive an i.v. infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. However, lower doses of fosinopril and/or reduced concomitant diuretic therapy should be considered.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Current experience with fosinopril shows the incidence to be rare and a causal relationship to the administration of fosinopril has not been established. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, fosinopril should be discontinued as soon as possible.

In rare cases (probably less than once in every thousand of pregnancies) in which no alternative to ACE inhibitors therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, fosinopril should be discontinued unless it is considered life-saving for the mother. A nonstress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with a history 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 impaired renal function, however, limited experience with those procedures has not been associated with significant clinical benefit. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively of urea clearance.

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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 and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

Animal Data: In pregnant rabbits, maternal toxicity was evident at doses ranging from 2.5 to 40 mg/kg/day (approximately 3 to 50 times the maximum human dose). Fosinopril was embryocidal in rabbits at 10 and 40 mg/kg/day (approximately 12 and 50 times the maximum human dose). These effects were probably due to marked decreases in blood pressure caused by ACE inhibition in this species. There were no teratogenic effects in rabbits at any dose level tested.

In pregnant rats, there was evidence of maternal toxicity at all dose levels tested, i.e. 25 to 400 mg/kg/day (about 30 to 500 times the maximum human dose). Slight reductions in placental weights and degree of skeletal ossification were observed at all dose levels, and fetal body weights were reduced in the high-dose group. Three similar orofacial malformations and one fetus with situs inversus occurred in fosinopril-treated animals. The association of these anomalies with treatment is uncertain.

Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of fosinopril should include appropriate assessment of renal function.

Surgery/Anesthesia: ACE inhibitors may augment the hypotensive effects of anesthetics and analgesics. 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.

Hyperkalemia and Potassium-Sparing Diuretics: In clinical trials, elevated serum potassium (greater than 5.5 mEq/L) was observed in approximately 2.6% of hypertensive patients receiving fosinopril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in less than 0.1% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (e.g., heparin) (see Precautions, Drug Interactions and Adverse Effects).

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile (PAN) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Anaphylactoid Reactions During Desensitization: There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Patients with Impaired Liver Function: Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors including fosinopril, in patients with or without pre-existing liver abnormalities (see Adverse Effects). Fosinopril therapy was discontinued because of serum transaminase elevations in 0.7% of patients. In most cases the changes were reversed on discontinuation of the drug.

Should the patients receiving fosinopril experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of fosinopril should be considered when appropriate.

Fosinopril should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Cough: Cough has been reported with the use of fosinopril. Characteristically, ACE-inhibitor induced cough is non productive, persistent and resolves after discontinuation of therapy or lowering of the dose. Fosinopril induced cough should be considered as part of the differential diagnosis of the cough.

Lactation: Ingestion of 20 mg daily for 3 days resulted in detectable levels of fosinoprilat in breast milk. Fosinopril should not be administered to nursing mothers.

Children: The safety and effectiveness of fosinopril in children have not been established; therefore, its use in this age group is not recommended.

Geriatrics: Although clinical experience has not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Drug Interactions: Concomitant Diuretic Therapy: Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of fosinopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with fosinopril. If it is not possible to discontinue the diuretic, the starting dose can be reduced, and the patient should be closely observed for several hours following an initial dose and until blood pressure has stabilized (see Warnings and Dosage).

Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients on concomitant diuretics than in those treated with fosinopril alone (see Adverse Effects, Laboratory Test Abnormalities).

Agents Increasing Serum Potassium: Since fosinopril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium, since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of fosinopril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

With Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.

With Antacids: In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administered alone, suggesting that antacids may impair absorption of fosinopril. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours.

With ASA: In a study with concomitant administration of ASA and fosinopril the bioavailability of unbound fosinoprilat was not altered. Since it is believed that it is free fosinoprilat that inhibits ACE, the reduced bioavailability (30 to 40%) of bound fosinoprilat would not be expected to have a significant effect on the antihypertensive effects of fosinopril.

With Digoxin: In a study with concomitant administration of digoxin and fosinopril, the bioavailability of fosinoprilat was not altered. The bioavailability of digoxin (i.e. AUC and Cmax) appeared to be reduced slightly in the presence of fosinopril. This reduction, of less than 20%, is considered to have little or no clinical relevance.

With Furosemide: In a steady-state pharmacokinetic study, coadministration of furosemide with fosinopril increased the AUC of fosinoprilat by 26% and Cmax by 25%. Furosemide levels were decreased.

With Warfarin: In a pharmacokinetic interaction study with warfarin, bioavailability parameters, the degree of protein binding and the anticoagulant effect (measured by prothrombin time) of warfarin were not significantly changed. The bioavailability of fosinoprilat was not altered by coadministration of fosinopril with warfarin.

Other: In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide and propantheline, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.

Drug/Laboratory Test Interactions : Fosinopril may cause a false low measurement of serum digoxin levels with the Digi-Tab RIA kit for digoxin. Other kits such as the Coat-A-Count RIA kit may be used.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of fosinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, tongue, difficulty in swallowing or breathing); they should immediately stop taking fosinopril and consult with their physician (see Warnings).

Hypotension: Patients should be cautioned to report light-headedness, especially during the first few days of fosinopril therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Neutropenia: Patients should be advised to report promptly any signs or symptoms of infection (e.g., pharyngitis, fever) since these may be an early indicator of neutropenia (see Warnings and Adverse Effects).

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be advised not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Precautions and Adverse Effects).

Pregnancy: Since the use of fosinopril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Adverse Reactions: Fosinopril has been evaluated for safety in hypertension trials in 1 548 patients. Of these, 1 479 patients including 1 048 who were treated with fosinopril monotherapy. In heart failure trials, 516 patients were treated with fosinopril including 316 who participated in placebo-controlled trials. Fosinopril has been evaluated for long-term safety in approximately 519 patients treated for 1 year or more.

Severe adverse reactions occurring in hypertensive patients treated with fosinopril were: angioedema (1 case) and orthostatic hypotension (2.7%). Myocardial infarction (2 cases) and cerebrovascular accident (4 cases) occurred, possibly secondary to excessive hypotension in high risk patients (see Warnings). In 516 heart failure patients, the severe adverse reaction occurring with the highest frequency was angina pectoris (1.6%).

In placebo-controlled hypertensive trials, the most frequent adverse experiences were: nausea/vomiting, diarrhea, fatigue, musculoskeletal pain, headache, dizziness and cough. Discontinuation of therapy due to adverse events was required in 4.1% of the 688 patients. Cough was the cause for discontinuation of therapy in 0.4% of these patients.

In placebo-controlled heart failure trials, the most frequent adverse reactions were: dizziness, cough, headache and fatigue. Significant hypotension after the first dose of fosinopril occurred in 2.4% of patients, while 0.8% discontinued due to first dose hypotension (see Warnings, Hypotension). Discontinuation of therapy due to adverse events was required in 7.8% of the 361 patients. Cough was the cause for discontinuation of therapy in 0.8% of these patients.

Clinical adverse reactions occurring in less than 1% of the 1 479 hypertensive patients and 516 heart failure patients treated with fosinopril in controlled clinical trials are listed below by body system:

Cardiovascular: angina/myocardial infarction, cerebrovascular accidents, palpitations, syncope, edema, tachycardia, flushing, cardiac chest pain, hypertension, rhythm disturbances, heart failure, peripheral vascular disease of arteries, cardiac tamponade, coronary artery disease, hypertensive crisis, sudden death, cardiorespiratory arrest, shock, atrial rhythm disturbance, nonanginal chest pain, edema lower extremity, conduction disorder and bradycardia.

Dermatologic: pemphigus, Stevens-Johnson syndrome pruritus, dermatitis, skin induration, skin dryness, urticaria, skin eschar, photosensitivity, pruritic rash and nail abnormality.

Endocrine/Metabolic: gout, libido change, breast disorder and menstrual disorder.

Gastrointestinal: upper abdominal pain, abdominal distention, appetite change, constipation, flatulence, dysphagia, pancreatitis, hepatitis, tongue lesion and hepatomegaly.

General: chest pain, excess sweating, change in weight, volume depletion, influenza, fever, hyperhidrosis and sensation of cold.

Hematologic: lymphadenopathy, leukopenia, neutropenia (see Warnings), eosinophilia and hemolytic anemia.

Immunology/Sensitivity Disorders: angioedema.

Musculoskeletal/Connective Tissue: arthralgia, muscle/ache, swelling extremity, and weakness extremity.

Nervous System: sleep disturbance, stress, paresthesia, mood change, equilibrium disturbance, drowsiness, tremor, cerebrovascular accident, mental activity disorder, memory disturbance, cranial nerve disorder, confusion, vertigo, cerebral infarction, transient ischemic attack, depression, numbness and behavior change.

Renal/Genitourinary: renal insufficiency, change in urinary frequency, abnormal urination and kidney pain.

Respiratory: sinus abnormality, pharyngitis, rhinitis, epistaxis, hoarseness, laryngitis, breathing abnormality, asthma, bronchospasm, sinusitis, abnormal vocalization, tracheobronchitis and pleuritic chest pain. A symptom-complex of cough, bronchospasm and eosinophilia has been observed in 2 hypertensive patients treated with fosinopril.

Special Senses: eye irritation, vision disturbance, tinnitus, taste disturbance, ear pain, abnormal visual field and abnormal intraocular pressure.

As with other ACE inhibitors, a syndrome has been reported which includes: fever, myalgia, arthralgia, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Findings have usually resolved with discontinuation of treatment.

Laboratory Test Findings: Serum Electrolytes: hyperkalemia (see Precautions), hyponatremia (see Precautions, Drug Interactions-with 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 pretreatment value) between the fosinopril and placebo treatment groups.

Urinary Albumin: In placebo-controlled trials, a urinary albumin (2 consecutive dip-stick values greater than 3+ or 2 times the pretreatment value) unassociated with a rise in serum creatinine was seen in 0.4% of fosinopril-treatment patients without pre-existing renal disease. Increases in urinary albumin usually developed in patients with pre-existing proteinuria or diabetes mellitus. In the majority of these patients, values returned to baseline despite continuation of therapy.

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.

Liver Function Tests: Elevations of transaminases, LDH, alkaline phosphatase and serum bilirubin have been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No data are available regarding overdosage of fosinopril in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by i.v. volume expansion with 0.9% sodium chloride. Hemodialysis and peritoneal dialysis have little effect on the elimination of fosinoprilat.

Dosage And Administration: Dosage must be individualized.

Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with fosinopril may need to be adjusted.

Monotherapy: The recommended initial dose is 10 mg once daily. Dosage should be adjusted according to blood pressure response, generally, at intervals of at least 2 weeks. The usual maintenance dose is 20 mg daily administered in a single daily dose. No additional blood pressure lowering effects were achieved with doses greater than 40 mg daily. A dose of 40 mg daily should not be exceeded.

In most patients, the antihypertensive effect of fosinopril is maintained with a once daily dosage regimen. In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with fosinopril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of fosinopril.

Concomitant Diuretic Therapy: Symptomatic hypotension occasionally may occur following the initial dose of fosinopril and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2 to 3 days before beginning therapy with fosinopril to reduce the likelihood of hypotension (see Warnings). If the diuretic cannot be discontinued, an initial dose of 10 mg fosinopril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of fosinopril should subsequently be titrated to the optimal response.

Heart Failure: Fosinopril is generally used in conjunction with a diuretic, with or without digoxin. Blood pressure and renal function should be monitored, both before and during treatment with fosinopril, because severe hypotension, and more rarely renal failure, have been reported (see Warnings, Hypotension and Precautions, Renal Impairment).

Initiation of therapy requires consideration of recent diuretic therapy, and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment to reduce the likelihood of hypotension (see Precautions, Drug Interactions).

In patients with heart failure, the recommended initial dose is 10 mg once daily, initiated under close medical supervision. If the initial dose is well tolerated, the dose should be titrated over 1 to 3 weeks to 20 to 40 mg once daily. The occurrence of hypotension after the initial dose may not preclude careful dose titration following effective management of hypotension.

In patients with severe congestive heart failure with or without renal insufficiency, therapy should be initiated with caution (see Warnings, Hypotension). A lower starting dose should be considered.

Renal Impairment: In hypertensive patients with renal impairment and normal liver function no dosage adjustment is necessary. The recommended initial dose is 10 mg once daily. Depending on the response, the dose should then be titrated, to achieve the optimal response (see Pharmacology, Pharmacokinetics and Precautions, Hemodialysis Patients). In such patients with heart failure, therapy should be initiated with caution.

Hepatic Impairment: In hypertensive patients with hepatic impairment and normal renal function no dosage adjustment is necessary. The recommended initial dose is 10 mg once daily. Depending on the response, the dose should then be titrated to achieve the optimal response (see Pharmacology, Pharmacokinetics). In such patients with heart failure, therapy should be initiated with caution.

Availability And Storage: 10 mg: Each white to off-white, flat end diamond-shaped, compressed tablet, with a partial bisect bar engraved with BMS on one side and MONOPRIL 10 on the other, contains: fosinopril sodium 10 mg. Nonmedicinal ingredients: crospovidone, lactose, microcrystalline cellulose, povidone and sodium stearyl fumarate. Bottles of 100.

20 mg: Each white to off-white, oval-shaped, compressed tablet, engraved with BMS on one side and MONOPRIL 20 on the other, contains: fosinopril sodium 20 mg. Nonmedicinal ingredients: crospovidone, lactose, microcrystalline cellulose, povidone and sodium stearyl fumarate. Bottles of 100.

Store at room temperature (15 to 30°C). Keep container tightly closed. Protect from high humidity. (Shown in Product Recognition Section)

MONOPRIL™ Bristol-Myers Squibb Fosinopril Sodium Angiotensin Converting Enzyme Inhibitor

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