Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1096
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MONOPRIL (Tablet)
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Hypertension:<br/>Adults: 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 alone, a diuretic
may be added. Concomitant administration of MONOPRIL
with potassium supplements, potassium salt substitutes, or potassium-sparing
diuretics can lead to increases of serum potassium . In
patients who are currently being treated with a diuretic, symptomatic hypotension
occasionally can occur following the initial dose of MONOPRIL. To reduce the
likelihood of hypotension, the diuretic should, if possible, be discontinued
2 to 3 days prior to beginning therapy with MONOPRIL .
Then, if blood pressure is not controlled with MONOPRIL alone, diuretic therapy
should be resumed. If diuretic therapy cannot be discontinued, an initial
dose of 10 mg of MONOPRIL 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 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 .<br/>Pediatrics: In children, doses of MONOPRIL 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 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.<br/>Heart Failure: Digitalis is not required for MONOPRIL
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
should be 10 mg once daily. Following the initial dose of MONOPRIL, 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 m),
including end-stage renal failure (creatinine clearance<10 mL/min/1.73
m). 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.
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MONOPRIL (fosinopril
sodium tablets) is the sodium salt of fosinopril, the ester prodrug of an
angiotensin-converting enzyme (ACE) inhibitor, fosinoprilat. It contains a
phosphinate group capable of specific binding to the active site of angiotensin-convertingenzyme. Fosinopril sodium is designated chemically as: L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-,
sodium salt, trans-. Fosinopril sodium
is a white to off-white crystalline powder. It is soluble in water (100 mg/mL),
methanol, and ethanol and slightly soluble in hexane. Its
structural formula is: Its empirical formula is CHNNaOP,
and its molecular weight is 585.65. MONOPRIL is available
for oral administration as 10 mg, 20 mg, and 40 mg tablets. Inactive ingredients
include: lactose, microcrystalline cellulose, crospovidone, povidone, and
sodium stearyl fumarate.
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Mechanism of Action: In animals and humans, fosinopril sodium is hydrolyzed by esterases
to the pharmacologically active form, fosinoprilat, a specific competitive
inhibitor angiotensin-converting enzyme (ACE). 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 results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease
may result in a small increase of serum potassium. In 647 hypertensive patients treated with fosinopril alone for
an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were
observed. Similar increases were observed among all patients treated with
fosinopril, including those receiving concomitant diuretic therapy. Removal
of angiotensin II negative feedback on renin secretion leads to increased
plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin.
Whether increased levels of bradykinin, a potent vasodepressor peptide, play
a role in the therapeutic effects of MONOPRIL remains to be elucidated. While the mechanism through which MONOPRIL lowers blood pressure
is believed to be primarily suppression of the renin-angiotensin-aldosterone
system, MONOPRIL has an antihypertensive effect even in patients with low-renin
hypertension. Although MONOPRIL was antihypertensive in all races studied,
black hypertensive patients (usually a low-renin hypertensive population)
had a smaller average response to ACE inhibitor monotherapy than non-black
patients. In patients with heart failure, the beneficial effects of MONOPRIL
are thought to result primarily from suppression of the renin-angiotensin-aldosterone
system; inhibition of the angiotensin-converting enzyme produces decreases
in both preload and afterload.<br/>Pharmacokinetics and Metabolism: 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. Fosinoprilat
is highly protein-bound (approximately 99.4%), has a relatively small volume
of distribution, and has negligible binding to cellular components in blood.
After single and multiple oral doses, plasma levels, areas under plasma concentration-time
curves (AUCs), and peak concentrations (C) are
directly proportional to the dose of fosinopril. Times to peak concentrations
are independent of dose and are achieved in approximately 3 hours. After
an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was
present as active fosinoprilat, 20-30% as a glucuronide conjugate of fosinoprilat,
and 1-5% as a p-hydroxy metabolite of fosinoprilat. Since
fosinoprilat is not biotransformed after intravenous administration, fosinopril,
not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy
metabolites. In rats, the p-hydroxy metabolite of fosinoprilat
is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate
is devoid of ACE inhibitory activity. After intravenous
administration, fosinoprilat was eliminated approximately equally by the liver
and kidney. After oral administration of radiolabeled fosinopril, approximately
half of the absorbed dose is excreted in the urine and the remainder is excreted
in the feces. In two studies involving healthy subjects, the mean body clearance
of intravenous fosinoprilat was between 26 and 39 mL/min. In
healthy subjects, the terminal elimination half-life (t)
of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours.
In hypertensive patients with normal renal and hepatic function, who received
repeated doses of fosinopril, the effective tfor
accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure,
the effective twas 14 hours. In
patients with mild to severe renal insufficiency (creatinine clearance
10-80 mL/min/1.73 m), the clearance of fosinoprilat
does not differ appreciably from normal, because of the large contribution
of hepatobiliary elimination. In patients with end-stage renal disease (creatinine
clearance<10 mL/min/1.73 m), the total body
clearance of fosinoprilat is approximately one-half of that in patients with
normal renal function. Fosinopril
is not well dialyzed. 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 hydrolysis of fosinopril is not appreciably reduced, although
the rate of hydrolysis may be slowed; the apparent total body clearance of
fosinoprilat is approximately one-half of that in patients with normal hepatic
function. In elderly (male) subjects
(65-74 years old) with clinically normal renal and hepatic function, there
appear to be no significant differences in pharmacokinetic parameters for
fosinoprilat compared to those of younger subjects (20-35 years old). In
pediatric patients, (N=20) age 6 to 16 years, with glomerular filtration
rate���25 mL/min, given a single dose of fosinopril (0.3 mg/kg given as solution),
the mean AUC and Cvalues of fosinoprilat (the active
form of fosinopril) were similar to those seen in healthy adults receiving
20 mg (about 0.3 mg/kg for a 70 kg adult) of fosinopril as a solution. The
terminal elimination half-life of fosinoprilat in pediatric patients was 11-13
hours, also similar to that observed in adults. 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.<br/>Pharmacodynamics and Clinical Effects: Serum ACE activity was inhibited by���90% at 2 to 12 hours after
single doses of 10 to 40 mg of fosinopril. At 24 hours, serum ACE activity
remained suppressed by 85%, 93%, and 93% in the 10, 20, and 40 mg dose groups,
respectively.<br/>Hypertension:<br/>Adult: Administration of MONOPRIL (fosinopril
sodium tablets) to patients with mild to moderate hypertension results in
a reduction of both supine and standing blood pressure to about the same extent
with no compensatory tachycardia. Symptomatic postural hypotension is infrequent,
although it can occur in patients who are salt- and/or volume-depleted . Use of MONOPRIL in combination with thiazide
diuretics gives a blood pressure-lowering effect greater than that seen with
either agent alone. Following oral administration of
single doses of 10-40 mg, MONOPRIL lowered blood pressure within 1 hour, with
peak reductions achieved 2-6 hours after dosing. The antihypertensive effect
of a single dose persisted for 24 hours. Following 4 weeks of monotherapy
in placebo-controlled trials in patients with mild to moderate hypertension,
once daily doses of 20-80 mg lowered supine or seated systolic and diastolic
blood pressures 24 hours after dosing by an average of 8-9/6-7 mmHg more than
placebo. The trough effect was about 50-60% of the peak diastolic response
and about 80% of the peak systolic response. In most
trials, the antihypertensive effect of MONOPRIL increased during the first
several weeks of repeated measurements. The antihypertensive effect of MONOPRIL
has been shown to continue during long-term therapy for at least 2 years.
Abrupt withdrawal of MONOPRIL has not resulted in a rapid increase in blood
pressure. Limited experience in controlled and uncontrolled
trials combining fosinopril with a calcium channel blocker or a loop diuretic
has indicated no unusual drug-drug interactions. Other ACE inhibitors have
had less than additive effects with beta-adrenergic blockers, presumably because
both drugs lower blood pressure by inhibiting parts of the renin-angiotensin
system. ACE inhibitors are generally less effective
in blacks than in non-blacks. The effectiveness of MONOPRIL was not influenced
by age, sex, or weight. In hemodynamic studies in hypertensive
patients, after 3 months of therapy, responses (changes in BP, heart rate,
cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45��head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting
that MONOPRIL 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.<br/>Pediatric: Reduction of blood pressure with low
(0.1 mg/kg), medium (0.3 mg/kg) and high (0.6 mg/kg) target doses of once-daily
fosinopril was evaluated in a randomized, double-blind study of 252 pediatric
patients 6 to 16 years of age with hypertension or high-normal blood pressure.
Fosinopril doses in the medium and high dose groups were titrated to target
doses after 1 week and the total duration of treatment was 4 weeks. The maximum
dose studied was 40 mg once daily. At the end of 4 weeks
of treatment, the mean reductions from baseline in trough systolic blood pressure
were similar in all three dose groups. Withdrawal of fosinopril treatment
resulted in an increase in blood pressure towards baseline over a 2-week period.
Fosinopril was generally well tolerated.<br/>Heart Failure: In a randomized, double-blind, placebo-controlled
trial, 179 patients with heart failure, all receiving diuretics and some receiving
digoxin, were administered single doses of 1, 20, or 40 mg
of MONOPRIL or placebo. Doses of 20 and 40 mg of MONOPRIL resulted in acute
decreases in pulmonary capillary wedge pressure (preload) and mean arterial
blood pressure and systemic vascular resistance (afterload). One hundred fifty-five
of these patients were re-randomized to once daily therapy with MONOPRIL (1,
20, or 40 mg) for an additional 10 weeks. Hemodynamic measurements made 24
hours after dosing showed (relative to baseline) continued reduction in pulmonary
capillary wedge pressure, mean arterial blood pressure, right atrial pressure
and an increase in cardiac index and stroke volume for the 20 and 40 mg dose
groups. No tachyphylaxis was seen. MONOPRIL was studied
in 3 double-blind, placebo-controlled, 12-24 week trials including a total
of 734 patients with heart failure, with MONOPRIL doses from 10 to 40 mg daily.
Concomitant therapy in 2 of these 3 trials included diuretics and digitalis;
in the third trial patients were receiving only diuretics. All 3trials showed
statistically significant benefits of MONOPRIL therapy, compared to placebo,
in one or more of the following: exercise tolerance (1 study), symptoms of
dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification
(2 studies), hospitalization for heart failure (2 studies), study withdrawals
for worsening heart failure (2 studies), and/or need for supplemental diuretics
(2 studies). Favorable effects were maintained for up to 2 years. Effects
of MONOPRIL on long-term mortality in heart failure have not been evaluated.
The once daily dosage for the treatment of congestive heart failure was the
only dosage regimen used during clinical trial development and was determined
by the measurement of hemodynamic responses.
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MONOPRIL (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).
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MONOPRIL (fosinopril
sodium tablets) 10 mg tablets: White to
off-white, biconvex flat-end diamond-shaped, compressed partially scored tablets
with���BMS���on one side and���MONOPRIL 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
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 40���on the other. They are supplied
in bottles of 90 (NDC 0087-1202-13). Bottles contain a desiccant canister.<br/>STORAGE: Store
at 25��C (77��F); excursions permitted to 15��C - 30��C (59��F - 86��F) [see USP
Controlled Room Temperature]. Protect from moisture by keeping bottle tightly
closed.
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USE IN PREGNANCY: When used in pregnancy during the
second and third trimesters, ACE inhibitors can cause injury and even death
to the developing fetus. When pregnancy is detected, MONOPRIL should
be discontinued as soon as possible. See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.
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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 MONOPRIL (fosinopril sodium tablets), may be
associated with oliguria and/or progressive azotemia and (rarely) with acute
renal failureand/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 has been given concomitantly with a diuretic. This is more likely
to occur in patients with preexisting renal impairment. Dosage reduction of
MONOPRIL and/or discontinuation of the diuretic may be required. Evaluation
of patients with hypertension or heart failure should always include assessment
of renal function . 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 . 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. 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 thedevelopment 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) . 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.<br/>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:
Anaphylactoid reactions during membrane exposure.)<br/>Information for Patients: Angioedema: Angioedema,
including laryngeal edema, can occur with treatment with ACE inhibitors, especially
following the first dose. Patients should be advised to immediately report
to their physician any signs or symptoms suggesting angioedema (e.g., swelling
of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty
in swallowing or breathing; hoarseness) and to discontinue therapy. (See WARNINGS: Head and Neck Angioedema and Intestinal Angioedema and ADVERSE
REACTIONS.) Symptomatic Hypotension: Patients
should be cautioned that lightheadedness can occur, especially during the
first days of therapy, and it should be reported to a physician. Patients
should be told that if syncope occurs, MONOPRIL should be discontinued until
the physician has been consulted. All patients should
be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure, with the same
consequences of lightheadedness and possible syncope. Hyperkalemia: Patients
should be told not to use potassium supplements or salt substitutes containing
potassium without consulting the physician. Neutropenia: Patients
should be told to promptly report any indication of infection (e.g., sore
throat, fever), which could be a sign of neutropenia. Pregnancy: Female patients
of childbearing age should be told about the consequences of second- and third-trimester
exposure to ACE inhibitors, and they should also be told that these consequences
do not appear to have resulted from intrauterine ACE-inhibitor exposure that
has been limited to the first trimester. These patients should be asked to
report pregnancies to their physicians as soon as possible.<br/>Drug Interactions: 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 can be minimized by either discontinuing the diuretic
or increasing salt intake prior to initiation of treatment with MONOPRIL.
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 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. Other: Neither MONOPRIL
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, 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.<br/>Drug/Laboratory Test Interaction: 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.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.<br/>Pregnancy:<br/>Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.<br/>Nursing Mothers: Ingestion of 20 mg daily for 3 days resulted
in detectable levels of fosinoprilat in breast milk. MONOPRIL should not be
administered to nursing mothers.<br/>Geriatric Use: Clinical studies of MONOPRIL 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 thegreater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.<br/>Pediatric Use: 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).
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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. After receiving gastric lavage and activated
charcoal within 1 hour of the ingestion, she made an uneventful recovery.
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FOSINOPRIL SODIUM
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MONOPRIL (Tablet)
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MONOPRIL 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.<br/>Hypertension: In placebo-controlled clinical trials
(688 MONOPRIL-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-treated and placebo-treated patients, respectively.
The most frequent reasons (0.4 to 0.9%) were headache, elevated transaminases,
fatigue, cough , diarrhea, and nausea and vomiting. During
clinical trials with any MONOPRIL 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 alone
and at least as frequent on MONOPRIL as on placebo in placebo-controlled clinical
trials are shown in the table below. The following events were also seen at>1% on MONOPRIL
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 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.<br/>Heart Failure: In placebo-controlled clinical trials
(361 MONOPRIL-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-treated and placebo-treated
patients, respectively. The most frequent reason for discontinuation of MONOPRIL
was angina pectoris (1.1%). Significant hypotension after the first dose of
MONOPRIL 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 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 MONOPRIL (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 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.<br/>Fetal/Neonatal Morbidity and Mortality: See WARNINGS: Fetal/Neonatal Morbidity
and Mortality.<br/>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.<br/>Laboratory Test Abnormalities: Serum Electrolytes: Hyperkalemia,
; hyponatremia, . 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. 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
, 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.<br/>Pediatric Patients: The adverse experience profile for pediatric patients is similar
to that seen in adult patients with hypertension. The long-term effects of
MONOPRIL on growth and development have not been studied.
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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 MONOPRIL) 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 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.<br/>Hypotension: MONOPRIL
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. 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 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
treatment usually can be continued following restoration of blood pressure
and volume.<br/>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.<br/>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.<br/>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.
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| dailymed-instance:indicatio... |
MONOPRIL (fosinopril sodium tablets)
is indicated for the treatment of hypertension. It may be used alone or in
combination with thiazide diuretics. MONOPRIL 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,
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 . In
considering use of MONOPRIL, 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).
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MONOPRIL
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