Monopril

Overdose

Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality. Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril overdosage is likely to be hypotension.

Laboratory determinations of serum levels of fosinoprilat and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of fosinopril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites. Fosinoprilat is poorly removed from the body by both hemodialysis and peritoneal dialysis.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution.

No adverse clinical events were reported in 23 pediatric patients, age 6 months to 6 years, given a single 0.3 mg/kg oral dose of fosinopril.

There is a published report of a 20-month-old female, weighing 12 kg, who ingested approximately 200 mg MONOPRIL (fosinopril sodium). After receiving gastric lavage and activated charcoal within 1 hour of the ingestion, she made an uneventful recovery.

Monopril price

Contraindications

MONOPRIL (fosinopril sodium) (fosinopril sodium tablets) is 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).

Undesirable effects

MONOPRIL (fosinopril sodium) has 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.

In placebo-controlled clinical trials (688 MONOPRIL (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 MONOPRIL (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 MONOPRIL (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 MONOPRIL (fosinopril sodium) alone and at least as frequent on MONOPRIL (fosinopril sodium) as on placebo in placebo-controlled clinical trials are shown in the table below.

Clinical Adverse Events in Placebo-Controlled Trails (Hypertension)

The following events were also seen at > 1% on MONOPRIL (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 MONOPRIL (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.

In placebo-controlled clinical trials (361 MONOPRIL (fosinopril sodium) -treated patients), the usual duration of therapy was 3-6 months. Discontinuations due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in MONOPRIL (fosinopril sodium) -treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of MONOPRIL (fosinopril sodium) was angina pectoris (1.1%). Significant hypotension after the first dose of MONOPRIL (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 MONOPRIL (fosinopril sodium) and at least as common as the placebo group, in placebo-controlled trials are shown in the table below.

Clinical Adverse Events in Placebo-Controlled Trails (Heart Failure)

The following events also occurred at a rate of 1% or more on MONOPRIL (fosinopril sodium) (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 MONOPRIL (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.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

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.

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.

The adverse experience profile for pediatric patients is similar to that seen in adult patients with hypertension. The long-term effects of MONOPRIL (fosinopril sodium) on growth and development have not been studied.

Therapeutic indications

MONOPRIL (fosinopril sodium) (fosinopril sodium tablets) is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.

MONOPRIL (fosinopril sodium) is indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics with or without digitalis (see DOSAGE AND ADMINISTRATION).

In using MONOPRIL (fosinopril sodium) , consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that MONOPRIL does not have a similar risk (see WARNINGS).

In considering use of MONOPRIL (fosinopril sodium) , it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema).

Fertility, pregnancy and lactation

See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Qualitative and quantitative composition

10 mg tablets: White to off-white, biconvex flat-end diamond-shaped, compressed partially scored tablets with “BMS” on one side and “MONOPRIL (fosinopril sodium) 10” on the other. They are supplied in bottles of 90 (NDC 0087-0158-46) and 1000 (NDC 0087-0158-85). Bottles contain a desiccant canister.

20 mg tablets: White to off-white, oval-shaped, compressed tablets with “BMS” on one side and “MONOPRIL (fosinopril sodium) 20” on the other. They are supplied in bottles of 90 (NDC 0087-0609-42) and 1000 (NDC 0087-0609-85). Bottles contain a desiccant canister.

40 mg tablets: White to off-white, biconvex hexagonal-shaped, compressed tablets with “BMS” on one side and “MONOPRIL (fosinopril sodium) 40” on the other. They are supplied in bottles of 90 (NDC 0087-1202-13). Bottles contain a desiccant canister.

Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). Protect from moisture by keeping bottle tightly closed.

Bristol-Myers Squibb Company Princeton, NJ 08543 USA. Rev July 2008.

Special warnings and precautions for use

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including MONOPRIL (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 MONOPRIL (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 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.

MONOPRIL (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 MONOPRIL (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, MONOPRIL (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. MONOPRIL (fosinopril sodium) treatment usually can be continued following restoration of blood pressure and volume.

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.

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.

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.

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 MONOPRIL (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 MONOPRIL (fosinopril sodium) has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of MONOPRIL (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 MONOPRIL (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 MONOPRIL (fosinopril sodium tablets) (see PRECAUTIONS: DRUG INTERACTIONS).

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.

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: Anaphylactoid reactions during membrane exposure.)

No evidence of a carcinogenic effect was found when fosinopril was given in the diet to mice and rats for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose in mice and rats is about 250 times the maximum human dose of 80 mg, assuming a 50 kg subject. On a body surface area basis, in mice, this dose is 20 times the maximum human dose; in rats, this dose is 40 times the maximum human dose. Male rats given the highest dose level had a slightly higher incidence of mesentery/omentum lipomas.

Neither fosinopril nor the active fosinoprilat was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo.

In the Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation.

There were no adverse reproductive effects in male and female rats treated with 15 or 60 mg/kg daily. On a body weight basis, the high dose of 60 mg/kg is about 38 times the maximum recommended human dose. On a body surface area basis, this dose is 6 times the maximum recommended human dose. There was no effect on pairing time prior to mating in rats until a daily dose of 240 mg/kg, a toxic dose, was given; at this dose, a slight increase in pairing time was observed. On a body weight basis, this dose is 150 times the maximum recommended human dose. On a body surface area basis, this dose is 24 times the maximum recommended human dose.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Ingestion of 20 mg daily for 3 days resulted in detectable levels of fosinoprilat in breast milk. MONOPRIL (fosinopril sodium) should not be administered to nursing mothers.

Clinical studies of MONOPRIL (fosinopril sodium) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The antihypertensive effects of fosinopril have been evaluated in a double-blind study in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Hypertension). The pharmacokinetics of fosinopril have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism). Fosinopril was generally well tolerated and adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients).

Dosage (Posology) and method of administration

The recommended initial dose of MONOPRIL (fosinopril sodium tablets) is 10 mg once a day, both as monotherapy and when the drug is added to a diuretic. Dosage should then be adjusted according to blood pressure response at peak (2-6 hours) and trough (about 24 hours after dosing) blood levels. The usual dosage range needed to maintain a response at trough is 20-40 mg but some patients appear to have a further response to 80 mg. In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval. If trough response is inadequate, dividing the daily dose should be considered. If blood pressure is not adequately controlled with MONOPRIL (fosinopril sodium) alone, a diuretic may be added.

Concomitant administration of MONOPRIL (fosinopril sodium) with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS).

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of MONOPRIL (fosinopril sodium). To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with MONOPRIL (see WARNINGS). Then, if blood pressure is not controlled with MONOPRIL (fosinopril sodium) alone, diuretic therapy should be resumed. If diuretic therapy cannot be discontinued, an initial dose of 10 mg of MONOPRIL (fosinopril sodium) should be used with careful medical supervision for several hours and until blood pressure has stabilized. (See WARNINGS and PRECAUTIONS: Information for Patients and DRUG INTERACTIONS.)

Since concomitant administration of MONOPRIL (fosinopril sodium) with potassium supplements, or potassium-containing salt substitutes or potassium-sparing diuretics may lead to increases in serum potassium, they should be used with caution (see PRECAUTIONS).

In children, doses of MONOPRIL (fosinopril sodium) between 0.1 and 0.6 mg/kg have been studied and shown to reduce blood pressure to a similar extent (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects). Based on this, the recommended dose of

MONOPRIL (fosinopril sodium) in children weighing more than 50 kg is 5 to 10 mg once per day as monotherapy. An appropriate dosage strength is not available for children weighing less than 50 kg.

Digitalis is not required for MONOPRIL (fosinopril sodium) to manifest improvements in exercise tolerance and symptoms. Most placebo-controlled clinical trial experience has been with both digitalis and diuretics present as background therapy.

The usual starting dose of MONOPRIL (fosinopril sodium) should be 10 mg once daily. Following the initial dose of MONOPRIL (fosinopril sodium) , the patient should be observed under medical supervision for at least 2 hours for the presence of hypotension or orthostasis, and if present, until blood pressure stabilizes. An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed.

Dosage should be increased, over a several week period, to a dose that is maximal and tolerated but not exceeding 40 mg once daily. The usual effective dosage range is 20 to 40 mg once daily.

The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretic.

For Hypertensive or Heart Failure Patients With Renal Impairment: In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function. Since hepatobiliary elimination partially compensates for diminished renal elimination, the total body clearance of fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances < 80 mL/min/1.73 m2), including end-stage renal failure (creatinine clearance < 10 mL/min/1.73 m2). This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment. (See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis.)

Interaction with other medicinal products and other forms of interaction

Since concomitant administration of MONOPRIL (fosinopril sodium) with potassium supplements, or potassium-containing salt substitutes or potassium-sparing diuretics may lead to increases in serum potassium, they should be used with caution (see PRECAUTIONS).

In children, doses of MONOPRIL (fosinopril sodium) between 0.1 and 0.6 mg/kg have been studied and shown to reduce blood pressure to a similar extent (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects). Based on this, the recommended dose of

MONOPRIL (fosinopril sodium) in children weighing more than 50 kg is 5 to 10 mg once per day as monotherapy. An appropriate dosage strength is not available for children weighing less than 50 kg.

Digitalis is not required for MONOPRIL (fosinopril sodium) to manifest improvements in exercise tolerance and symptoms. Most placebo-controlled clinical trial experience has been with both digitalis and diuretics present as background therapy.

The usual starting dose of MONOPRIL (fosinopril sodium) should be 10 mg once daily. Following the initial dose of MONOPRIL (fosinopril sodium) , the patient should be observed under medical supervision for at least 2 hours for the presence of hypotension or orthostasis, and if present, until blood pressure stabilizes. An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed.

Dosage should be increased, over a several week period, to a dose that is maximal and tolerated but not exceeding 40 mg once daily. The usual effective dosage range is 20 to 40 mg once daily.

The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretic.

For Hypertensive or Heart Failure Patients With Renal Impairment: In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function. Since hepatobiliary elimination partially compensates for diminished renal elimination, the total body clearance of fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances < 80 mL/min/1.73 m2), including end-stage renal failure (creatinine clearance < 10 mL/min/1.73 m2). This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment. (See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis.)

10 mg tablets: White to off-white, biconvex flat-end diamond-shaped, compressed partially scored tablets with “BMS” on one side and “MONOPRIL (fosinopril sodium) 10” on the other. They are supplied in bottles of 90 (NDC 0087-0158-46) and 1000 (NDC 0087-0158-85). Bottles contain a desiccant canister.

20 mg tablets: White to off-white, oval-shaped, compressed tablets with “BMS” on one side and “MONOPRIL (fosinopril sodium) 20” on the other. They are supplied in bottles of 90 (NDC 0087-0609-42) and 1000 (NDC 0087-0609-85). Bottles contain a desiccant canister.

40 mg tablets: White to off-white, biconvex hexagonal-shaped, compressed tablets with “BMS” on one side and “MONOPRIL (fosinopril sodium) 40” on the other. They are supplied in bottles of 90 (NDC 0087-1202-13). Bottles contain a desiccant canister.

Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). Protect from moisture by keeping bottle tightly closed.

Bristol-Myers Squibb Company Princeton, NJ 08543 USA. Rev July 2008.

MONOPRIL (fosinopril sodium) has 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.

In placebo-controlled clinical trials (688 MONOPRIL (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 MONOPRIL (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 MONOPRIL (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 MONOPRIL (fosinopril sodium) alone and at least as frequent on MONOPRIL (fosinopril sodium) as on placebo in placebo-controlled clinical trials are shown in the table below.

Clinical Adverse Events in Placebo-Controlled Trails (Hypertension)

The following events were also seen at > 1% on MONOPRIL (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 MONOPRIL (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.

In placebo-controlled clinical trials (361 MONOPRIL (fosinopril sodium) -treated patients), the usual duration of therapy was 3-6 months. Discontinuations due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in MONOPRIL (fosinopril sodium) -treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of MONOPRIL (fosinopril sodium) was angina pectoris (1.1%). Significant hypotension after the first dose of MONOPRIL (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 MONOPRIL (fosinopril sodium) and at least as common as the placebo group, in placebo-controlled trials are shown in the table below.

Clinical Adverse Events in Placebo-Controlled Trails (Heart Failure)

The following events also occurred at a rate of 1% or more on MONOPRIL (fosinopril sodium) (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 MONOPRIL (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.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

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.

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.

The adverse experience profile for pediatric patients is similar to that seen in adult patients with hypertension. The long-term effects of MONOPRIL (fosinopril sodium) on growth and development have not been studied.

Diuretics: Patients on diuretics, especially those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with MONOPRIL (fosinopril sodium tablets). The possibility of hypotensive effects with MONOPRIL (fosinopril sodium) can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with MONOPRIL (fosinopril sodium). If this is not possible, the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized (see DOSAGE AND ADMINISTRATION).

Potassium supplements and potassium-sparing diuretics: MONOPRIL (fosinopril sodium) can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

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

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 administrated 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.

Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including MONOPRIL (fosinopril sodium).

Other: Neither MONOPRIL (fosinopril sodium) nor its metabolites have been found to interact with food. In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs. In a study with concomitant administration of aspirin and MONOPRIL (fosinopril sodium) , the bioavailability of unbound fosinoprilat was not altered.

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.

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.