Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3827
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MONOPRIL-HCT (Tablet)
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Fosinopril is an effective treatment
of hypertension in once-daily doses of 10���80 mg, while hydrochlorothiazide
is effective in doses of 12.5���50 mg per day. In clinical trials of fosinopril/hydrochlorothiazide
combination therapy using fosinopril doses of 2.5���40 mg and hydrochlorothiazide
doses at 5���37.5 mg, the antihypertensive effects increased with increasing
dose of either component. The hazards of fosinopril are generally rare and apparently
independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent
phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis),
the former much more common than the latter. Therapy with any combination
of fosinopril and hydrochlorothiazide will be associated with both sets of
dose-independent hazards. To minimize dose-independent hazards, it is usually
appropriate to begin combination therapy only after a patient has failed to
achieve the desired effect with monotherapy.<br/>Dose Titration by Clinical Effect: A patient whose blood pressure is not
adequately controlled with fosinopril or hydrochlorothiazide monotherapy may
be switched to combination therapy with MONOPRIL-HCT. Dosage must be guided
by clinical response; controlled clinical trials showed that the addition
of 12.5 mg of hydrochlorothiazide to 10���20 mg of fosinopril will typically
be associated with additional reduction in seated diastolic blood pressure
at 24 hours after dosing. On average, the effect of the combination of 10
mg of fosinopril with 12.5 mg of hydrochlorothiazide was similar to the effect
seen with monotherapy using either 40 mg of fosinopril or 37.5 mg of hydrochlorothiazide.<br/>Use in Renal Impairment: In patients with severe renal impairment
(creatinine clearance is<30 mL/min/1.73 m,
serum creatine roughly���3 mg/dL or 265��mol/L), loop diuretics are preferred
to thiazides, so MONOPRIL-HCT is not recommended. In patients with lesser
degrees of renal impairment, MONOPRIL-HCT may be used with no change in dosage.
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Fosinopril
sodium is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol, and slightly soluble in hexane. Fosinopril
sodium is designated chemically as L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-,
sodium salt, trans-; its structural formula is: Its empirical formula is CHNNaOP,
and its molecular weight is 585.65. Fosinoprilat, the
active metabolite of fosinopril, is a non-sulfhydryl angiotensin-converting
enzyme inhibitor. Fosinopril is converted to fosinoprilat by hepatic cleavage
of the ester group. Hydrochlorothiazide, USP is a white,
or practically white, practically odorless, crystalline powder. It is slightly
soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine,
and in dimethylformamide; sparingly soluble in methanol; and insoluble in
ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is
designated chemically as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide
1,1-dioxide; its structural formula is: Its
empirical formula is CHClNOS, and its molecular weight is 297.73. Hydrochlorothiazide is a thiazide diuretic. MONOPRIL-HCT
(fosinopril sodium-hydrochlorothiazide tablets) is a combination of fosinopril
sodium and hydrochlorothiazide, USP. It is available for oral use in two tablet
strengths: MONOPRIL-HCT 10/12.5, containing 10 mg of fosinopril sodium and
12.5 mg of hydrochlorothiazide, USP; and MONOPRIL-HCT 20/12.5, containing
20 mg of fosinopril sodium and 12.5 mg of hydrochlorothiazide, USP. The inactive
ingredients of the tablets include lactose, croscarmellose sodium, povidone,
sodium stearyl fumarate, and iron oxide.
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Mechanism of Action: Fosinopril and fosinoprilat inhibit
angiotensin-converting enzyme (ACE) in human subjects and in animals. 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. Hypertensive patients treated with fosinopril
alone for an average of 8 weeks had elevations of serum potassium of approximately
0.1 mEq/L. Similar patients treated with hydrochlorothiazide alone had a mean
reduction in serum potassium of 0.15 mEq/L, while patients who received combined
treatment with 10/12.5 mg or 20/12.5 mg of fosinopril and
hydrochlorothiazide had reductions of 0.07 and 0.03 mEq/L,
respectively. 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-HCT (fosinopril sodium-hydrochlorothiazide tablets) remains to be
elucidated. While the mechanism through which fosinopril
lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone
system, fosinopril has an antihypertensive effect even in patients with low-renin
hypertension. Hydrochlorothiazide is a thiazide diuretic.
Thiazides affect the renal tubular mechanisms of electrolyte reabsorption,
directly increasing excretion of sodium and chloride in approximately equivalent
amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in aldosterone
secretion, increases in urinary potassium loss, and decreases in serum potassium.
The renin-aldosterone link is mediated by angiotensin, so coadministration
of an ACE inhibitor tends to reverse the potassium loss associated with these
diuretics. The mechanism of the antihypertensive effect
of thiazides is unknown.<br/>Pharmacokinetics and Metabolism: The absolute absorption of fosinopril
averages 36% of an oral dose. The primary site of absorption is the proximal
small intestine. 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. Following oral administration
of hydrochlorothiazide, peak plasma concentrations are achieved in 1���2.5 hours,
and the extent of absorption is 50���80%. The reported studies of food effects
on hydrochlorothiazide absorption have been inconclusive. The absorption of
hydrochlorothiazide is increased by agents that reduce gastrointestinal motility.
It is reported to be decreased by 50% in patients with congestive heart failure. Cleavage
of the ester group (primarily in the liver) converts fosinopril to its active
metabolite, fosinoprilat. The time to peak plasma concentrations of fosinoprilat
is about 3 hours, independent of the administered dose of fosinopril. In patients
with hepatic dysfunction due to cirrhosis, conversion of fosinopril to fosinoprilat
may be slowed, but the extent of this conversion is unchanged. Fosinoprilat
is highly protein bound (95%), but has negligible binding to cellular components
of blood. The peak serum concentration and the area under the concentration-time
curve of fosinoprilat is directly proportional to the administered dose of
fosinopril. 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. Studies in animals indicate
that fosinopril and fosinoprilat do not cross the blood-brain barrier, but
fosinoprilat does cross the placenta of pregnant animals. In humans, hydrochlorothiazide
crosses the placenta freely, and levels in umbilical-cord blood are similar
to those in the maternal circulation. Hydrochlorothiazide
is not metabolized. Its apparent volume of distribution is 3.6���7.8 L/kg,
and its measured plasma protein binding is 67.9%. The drug also accumulates
in red blood cells, so that whole blood levels are 1.6���1.8 times those measured
in plasma. After intravenous administration, fosinoprilat
is 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 hypertensive patients
with normal renal and hepatic function, the effective half-life of accumulation
of fosinoprilat following multiple dosing of fosinopril sodium is 11.5 hours.
Thus, steady-state concentrations of fosinoprilat should be reached after
2 or 3 doses of MONOPRIL-HCT given once daily. In
patients with renal insufficiency (creatinine clearance<80 mL/min/1.73
m), the total body clearance of fosinoprilat is
approximately one half of that in patients with normal renal function, while
absorption, bioavailability, and protein binding are not appreciably altered.
The clearance of fosinoprilat does not differ appreciably with the degree
of renal insufficiency, because the diminished renal elimination is offset
by increased hepatobiliary elimination. A modest increase in plasma AUC levels
(less than two times that in normals) was observed in patients with various
degrees of renal insufficiency, including end-stage renal failure (creatinine
clearance<10 mL/min/1.73 m). 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 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). Thiazide diuretics are
eliminated by the kidney, with a terminal half-life of 5���15 hours. In a study
of patients with impaired renal function (mean creatinine clearance of 19
mL/min), the half-life of hydrochlorothiazide elimination was lengthened to
21 hours. When fosinopril and hydrochlorothiazide are
administered concomitantly, the pharmacokinetics of hydrochlorothiazide are
essentially unaffected. Serum levels of fosinoprilat are increased after several
weeks of coadministration of hydrochlorothiazide and fosinopril, but the increase
is not sufficient to warrant any change in dosing.<br/>Pharmacodynamics: After single doses of 10���40 mg of fosinopril,
serum ACE activity was inhibited by at least 90% from 2���12 hours after dosing.
At 24 hours, serum ACE activity remains suppressed by 85���93%. Administration
of fosinopril 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. In studies in hypertensive patients after
three months of fosinopril monotherapy, hemodynamic responses to various stimuli
(isometric exercise, 45��head-up tilt, mental challenges) were unchanged compared
to baseline, suggesting that fosinopril did not affect the activity of the
sympathetic nervous system. Instead, fosinopril-induced reduction in blood
pressure appears to be mediated by a reduction in peripheral vascular resistance
without reflex cardiac effects. In similar studies, renal, splanchnic, cerebral,
and skeletal-muscle blood flows were all unchanged compared to baseline, as
was glomerular filtration rate. Symptomatic postural hypotension is infrequent,
although it can occur in patients who are salt- and/or volume-depleted . Following oral
administration of single doses of 10���40 mg, fosinopril lowered blood pressure
within one hour, with peak reductions achieved 2���6 hours after dosing. The
antihypertensive effect of a single dose persisted for 24 hours. Following
four 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
blood pressures (systolic/diastolic) 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
clinical studies of various combinations that included 0���40 mg of fosinopril
and 0���37.5 mg of hydrochlorothiazide, the antihypertensive effects were increased
with increasing dose of either component. Peak blood pressure reductions were
achieved 2���6 hours after dosing. The mean reductions in seated blood pressure
(systolic/diastolic) associated with MONOPRIL-HCT (fosinopril sodium-hydrochlorothiazide
tablets) 10/12.5 after 24 hours were 9���18/5���7 mmHg greater than those associated
with placebo; those associated with MONOPRIL-HCT 20/12.5 after 24 hours were
12���17/8���10 mmHg greater than those associated with placebo. These trough effects
were 60���90% of the corresponding peak effects. Although
hydrochlorothiazide tends to be more effective in low-renin hypertensive patients
(mainly blacks), and fosinopril���like other ACE inhibitors���tends to be more
effective in high-renin patients (mainly non-blacks), the effectiveness of
MONOPRIL-HCT is independent of race, age, and gender.
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MONOPRIL-HCT is contraindicated in patients
who are anuric. MONOPRIL-HCT is also contraindicated in patients who are hypersensitive
to fosinopril, to any other ACE inhibitor, to hydrochlorothiazide, or other
sulfonamide-derived drugs, or any other ingredient or component in the formulation.
Hypersensitivity reactions are more likely to occur in patients with a history
of allergy or bronchial asthma.
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MONOPRIL-HCT
(fosinopril sodium-hydrochlorothiazide tablets) is available in two different
strengths. Dosage strengths of both components, tablet characteristics, and
available quantities/packaging are identified below.<br/>Storage: Store
at 25��C (77��F); excursions permitted to 15�����30��C (59�����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-HCT
should be discontinued as soon as possible. See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.
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General: Derangements of Serum Electrolytes: In
clinical trials of fosinopril monotherapy, hyperkalemia (serum potassium at
least 10% greater than the upper limit of normal) occurred in approximately
2.6% of hypertensive patients receiving fosinopril. In most cases, these were
isolated values which resolved despite continued therapy. Risk factors for
the development of hyperkalemia included renal insufficiency, diabetes mellitus,
and the concomitant use of potassium-sparing diuretics, potassium supplements,
and/or potassium-containing salt substitutes. Conversely,
treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia,
and hypochloremic alkalosis. These disturbances have sometimes been manifest
as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness,
restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, nausea, and vomiting. Hypokalemia can also sensitize or exaggerate
the response of the heart to the toxic effects of digitalis. The risk of hypokalemia
is greatest in patients with cirrhosis of the liver, in patients experiencing
a brisk diuresis, in patients who are receiving inadequate oral intake of
electrolytes, and in patients receiving concomitant therapy with corticosteroids
or ACTH. The opposite effects of fosinopril and hydrochlorothiazide
on serum potassium will approximately balance each other in many patients,
so that no net effect upon serum potassium will be seen. In other patients,
one or the other effect may be dominant. Initial and periodic determinations
of serum electrolytes to detect possible electrolyte imbalance should be performed
at appropriate intervals. Chloride deficits are generally
mild and require specific treatment only under extraordinary circumstances
(e.g., in liver disease or renal disease). Dilutional hyponatremia may occur
in edematous patients; appropriate therapy is water restriction rather than
administration of salt, except in rare instances when the hyponatremia is
life-threatening. In actual salt depletion, appropriate replacement is the
therapy of choice. Calcium excretion is decreased by
thiazides. In a few patients on prolonged thiazide therapy, pathological changes
in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia.
More serious complications of hyperparathyroidism (renal lithiasis, bone resorption,
and peptic ulceration) have not been seen. Thiazides
increase the urinary excretion of magnesium, and hypomagnesemia may result. Other Metabolic Disturbances: Thiazidediuretics tend to reduce glucose tolerance and to raise serum levels of cholesterol,
triglycerides, and uric acid. These effects are usually minor, but frank gout
or overt diabetes may be precipitated in susceptible patients. 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. 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/>Information for Patients: Angioedema: Angioedema,
including laryngeal edema, can occur with treatment with ACE inhibitors, especially
following the first dose. A patient receiving MONOPRIL-HCT should be told
to report immediately any signs or symptoms suggesting angioedema (swelling
of face, eyes, lips, or tongue, or difficulty in breathing) and to take no
more drug until after consulting with the prescribing physician. 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. Symptomatic Hypotension: A
patient receiving MONOPRIL-HCT (fosinopril sodium-hydrochlorothiazide tablets)
should be cautioned that lightheadedness can occur, especially during the
first days of therapy, and that it should be reported to the prescribing physician.
The patients should be told that if syncope occurs, MONOPRIL-HCT should be
discontinued until the physician has been consulted. All
patients should be cautioned that inadequate fluid intake, excessive perspiration,
diarrhea, or vomiting can lead to an excessive fall in blood pressure, with
the same consequences of lightheadedness and possible syncope. Hyperkalemia: A patient
receiving MONOPRIL-HCT should be told not to use potassium supplements or
salt substitutes containing potassium without consulting the prescribing 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.<br/>Laboratory Tests: Therapy with MONOPRIL-HCT should be interrupted
for a few days before carrying out tests of parathyroid function. Fosinopril
may cause false low measurement of serum digoxin levels when the Digi-Tab (Nuclear
Medical) RIA Kit is used. The accuracy of the Coat-A-Count (Diagnostic
Products Corporation) kit is not affected.<br/>Drug Interactions: Potassium
supplements and potassium-sparing diuretics: As noted above (���Derangements
of Serum Electrolytes���), the net effect of MONOPRIL-HCT may be to elevate
a patient's serum potassium, to reduce it, or to leave it unchanged. Potassium-sparing
diuretics (spironolactone, amiloride, triamterene, and others) or potassium
supplements can increase the risk of hyperkalemia. 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. Because renal
clearance of lithium is reduced by thiazides, the risk of lithium toxicity
is presumably raised further when, as in therapy with MONOPRIL-HCT (fosinopril
sodium-hydrochlorothiazide tablets), a thiazide diuretic is coadministered
with the ACE inhibitor. MONOPRIL-HCT and lithium should be coadministered
with caution, and frequent monitoring of serum lithium levels is recommended. Antacids: In
a clinical pharmacology study, serum levels and urinary excretion of fosinoprilat
were reduced when fosinopril was coadministered with an antacid (aluminum
hydroxide, magnesium hydroxide, and simethicone) suggesting that antacids
may impair absorption of fosinopril. 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-HCT. Other: The
bioavailability of unbound fosinoprilat is not altered by coadministration
of fosinopril with aspirin, chlorthalidone, cimetidine, digoxin, metoclopramide, nifedipine, propranolol, propantheline, or
warfarin. Other ACE inhibitors have had less than additive effects
with beta-adrenergic blockers, presumably because drugs of both
classes lower blood pressure by inhibiting parts of the renin-angiotensin
system. Interaction studies with warfarin have
failed to identify any clinically important effects of fosinopril on the serum
concentration or clinical effects of the anticoagulant. Insulin
requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides
may decrease arterial responsiveness to norepinephrine, but not
enough to preclude effectiveness of the pressor agent for therapeutic use. Thiazides
may increase the responsiveness to tubocurarine. The
diuretic, natriuretic, and antihypertensive effects of thiazide diuretics
may be reduced by concurrent administration of nonsteroidal anti-inflammatory
agents; the effects (if any) of these agents on the antihypertensive
effect of MONOPRIL-HCT have not been studied. By alkalinizing
the urine, hydrochlorothiazide may decrease the effectiveness of methenamine. Cholestyramine
and colestipol resins: Absorption of hydrochlorothiazide is impaired
in the presence of anionic exchange resins. Single doses of either cholestyramine
or colestipol resins bind the hydrochlorothiazide and reduce its absorption
from the gastrointestinal tract by up to 85% and 43%, respectively.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Fosinopril-Hydrochlorothiazide: Reproductive
studies and long-term carcinogenicity studies with MONOPRIL-HCT have not been
conducted. The combination of fosinopril and hydrochlorothiazide was not mutagenic
in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay,
or the Chinese hamster ovary cell cytogenetic assay. The combination was also
not genotoxic in a mouse micronucleus test in vivo. Fosinopril Sodium: No evidence
of a carcinogenicity was found when fosinopril was given in the diet to rats
and mice for up to 24 months at doses up to 400 mg/kg/day. On a body weight
basis, the highest dose was about 250 times the maximum human dose of 80 mg,
given to a 50 kg subject. On a body surface area basis, this
dose is 20 (mice) to 40 (rats) times the maximum human dose. Neither
fosinopril nor the fosinoprilat moiety 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 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 up to 60 mg/kg daily. At doses
4 times higher, slight increases in pairing time were seen. This higher dose
is about 125 (body surface area basis) or 600 (body weight basis) times greater
than the dose received by a 50 kg human receiving 20 mg a day. Hydrochlorothiazide: Under
the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide
for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body
weight basis, these highest doses were about 2400 times (mice) or 400 times
(rats) the MONOPRIL-HCT dose of 12.5 mg, given to a 50 kg subject. On a body
surface area basis, these doses are 226 times (mice) and 82 times (rats) the
MONOPRIL-HCT dose. These studies uncovered no evidence of carcinogenicity
in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity
in male mice. Hydrochlorothiazide was not genotoxic
in in vitro assays using strains TA 98, TA 100, TA 1535,
TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay);
in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in
vivo assays using mouse germinal cell chromosomes; Chinese Hamster
bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait
gene.Using concentrations of hydrochlorothiazide of 43���1300 mg/mL,
positive test results were obtained in the in vitro CHO Sister
Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity)
assays. Using an unspecified concentration of hydrochlorothiazide, positive
test results were also obtained in the Aspergillus nidulans nondisjunction
assay. No adverse effects upon fertility were seen
when rats and mice received dietary hydrochlorothiazide prior to mating and
throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These
doses are from 3.2 (body surface area basis in rats) to 400 (weight basis
in mice) times greater than the dose received by a 50 kg human receiving 12.5
mg a day.<br/>Pregnancy:<br/>Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.<br/>Nursing Mothers: Both fosinopril and hydrochlorothiazide
are excreted in human milk. Because of the potential for serious adverse reactions
in nursing infants, a decision should be made whether to discontinue nursing
or to discontinue MONOPRIL-HCT, taking into account the importance of the
drug to the mother.<br/>Geriatric Use: Clinical studies of fosinopril sodium-hydrochlorothiazide
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 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.<br/>Pediatric Use: Safety and effectiveness in pediatric
patients have not been established.
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To
obtain up-to-date information about the treatment of overdose, a good resource
is a certified Regional Poison Control Center. Telephone numbers of certified
poison control centers are listed in the Physicians' Desk Reference (PDR).
In managing overdose, consider the possibilities of multiple-drug overdoses,
drug-drug interactions, and unusual drug kinetics in your patient. No
specific information is available on the treatment of overdosage with MONOPRIL-HCT
(fosinopril sodium-hydrochlorothiazide tablets); treatment should be symptomatic
and supportive. Therapy with MONOPRIL-HCT should be discontinued, and the
patient should be observed. Dehydration, electrolyte imbalance, and hypotension
should be treated by established procedures. In rats,
single oral doses of 2600 mg/kg of fosinopril were associated with significant
lethality. In single-dose studies of hydrochlorothiazide, most rats survived
doses of up to 2750 mg/kg. Both doses are more than 6000 times (on a mg/kg
basis) the maximum recommended daily dose of either fosinopril or hydrochlorothiazide
in MONOPRIL-HCT. Data from human overdoses of fosinopril
are scanty, but the most common manifestation of human fosinopril overdosage
is likely to be hypotension. In human hydrochlorothiazide overdose, the most
common signs and symptoms observed have been those of dehydration and electrolyte
depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also
been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory
determinations of serum levels of fosinopril 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 removedfrom the body by hemodialysis or 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.
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FOSINOPRIL SODIUM and HYDROCHLOROTHIAZIDE
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MONOPRIL-HCT (Tablet)
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MONOPRIL-HCT (fosinopril sodium-hydrochlorothiazide
tablets) has been evaluated for safety in over 660 patients with hypertension;
approximately 137 of these patients were treated for more than one year. The
observed adverse events were generally mild, transient, and similar to those
seen with fosinopril and hydrochlorothiazide taken separately. There was no
relationship between the incidence of side effects and age. In
placebo-controlled clinical trials of MONOPRIL-HCT, the usual duration of
therapy was two months. Adverse clinical or laboratory events led to discontinuation
of therapy by 4.3% of 368 placebo-treated patients and by 3.5% of 660 MONOPRIL-HCT-treated
patients. The most common reasons for discontinuation
of therapy with MONOPRIL-HCT in U.S. studies were headache (0.3%), cough (0.3%;
see PRECAUTIONS), and fatigue (0.2%). The
side effects considered probably or possibly related to study drug that occurred
in placebo-controlled trials in more than 2% of patients treated with MONOPRIL-HCT
are shown in the table below. Other side effects considered possibly or probably related
to study drug that occurred in controlled trials in 0.5% to<2.0% of patients
treated with MONOPRIL-HCT, and rarer but clinically significant events regardless
of causal relationship were: General: Chest
pain, weakness, fever, viral infection. Cardiovascular: Orthostatic
hypotension (seen in 1.8% of MONOPRIL-HCT patients and 0.3% of placebo patients;
no patients discontinued therapy due to orthostatic hypotension), edema, flushing,
rhythm disturbance, syncope. Dermatologic: Pruritus,
rash. Endocrine/Metabolic: Sexual
dysfunction, change in libido, breast mass. Gastrointestinal: Nausea/vomiting,
diarrhea, dyspepsia/heartburn, abdominal pain, gastritis/esophagitis. Immunologic: Angioedema
(see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema). Musculoskeletal: Myalgia/muscle
cramps. Neurologic/Psychiatric: Somnolence,
depression, numbness/paresthesia. Respiratory: Sinus
congestion, pharyngitis, rhinitis. Special
Senses: Tinnitus. Urogenital: Urinary
tract infection, urinary frequency, dysuria. Laboratory
Test Abnormalities: Serum electrolytes, uric acid, glucose, magnesium,
cholesterol, triglycerides, and calcium .
Neutropenia.<br/>Fetal/Neonatal Morbidity and Mortality: See WARNINGS: Fetal/Neonatal
Morbidity and Mortality. Antihypertensive monotherapy with fosinopril
has been evaluated for safety in more than 1500 patients, of whom approximately
450 patients were treated for a year or more. The observed adverse events
included events similar to those seen with MONOPRIL-HCT; in addition, the
following others have also been reported with fosinopril: Cardiovascular: Angina,
myocardial infarction, cerebrovascular accident, hypertensive crisis, hypotension,
claudication. Dermatologic: Urticaria,
photosensitivity. Endocrine/Metabolic: Gout. Gastrointestinal: Pancreatitis,
hepatitis, dysphagia, abdominal distention, flatulence, appetite/weight change,
dry mouth. Hematologic: Lymphadenopathy. Musculoskeletal: Arthralgia. Neurologic/Psychiatric: Memory disturbance,
tremor, confusion, mood change, sleep disturbance. Respiratory: Bronchospasm,
laryngitis/hoarseness, epistaxis, and (in two patients) a symptom-complex
of cough, bronchospasm, and eosinophilia. Special
Senses: Vision disturbance, taste disturbance, eye irritation. Urogenital: Renal
insufficiency. Laboratory Test Abnormalities: Elevations
(usually transient and minor) of BUN and creatinine have been observed, but
these have not been more frequent than in parallel patients treated with placebo.
The hemoglobin in fosinopril-treated patients generally decreases by an average
of 0.1 g/dL, but this nonprogressive change has never been
symptomatic. Leukopenia and eosinophilia have also been reported. Serum
levels of liver function tests (transaminases, LDH, alkaline phosphatase and
serum bilirubin) have occasionally been found to be elevated, and these elevations
have lead to discontinuation of therapy in 0.7% of patients. Other risk factors
for liver dysfunction have often been present in these cases; in any event
the elevations generally have resolved after discontinuation of therapy with
fosinopril.<br/>Other Adverse Events Reported with ACE Inhibitors: Other adverse effects reported with ACE
inhibitors include cardiac arrest; pancytopenia, hemolytic anemia; aplastic
anemia; thrombocytopenia; bullous pemphigus, exfoliative dermatitis; and a
syndrome that may include one or more of arthralgia/arthritis, vasculitis,
serositis, myalgia, fever, rash or other dermopathy, positive ANA titer, leukocytosis,
eosinophilia, and elevated ESR. Hydrochlorothiazide
has now been extensively prescribed for many years, but there has not been
enough systematic collection of data to support an estimate of the frequency
of the observed adverse reactions. Within organ-system groups, the reported
reactions are listed here in decreasing order of severity, without regard
to frequency. Cardiovascular: Orthostatic
hypotension (may be potentiated by alcohol, barbiturates, or narcotics). Gastrointestinal: Pancreatitis,
jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping,
nausea, gastric irritation, constipation, and anorexia. Hematologic: Aplastic
anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia. Immunologic: Necrotizing
angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis
and pulmonary edema), anaphylactic reactions, purpura, urticaria, rash, and
photosensitivity. Metabolic: Hyperglycemia,
glycosuria, and hyperuricemia. Musculoskeletal: Muscle
spasm. Neurologic: Vertigo, lightheadedness,
transient blurred vision, headache, paresthesia, xanthopsia, weakness, and
restlessness.
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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-HCT)
may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema
of the face, extremities, lips, tongue, glottis, and larynx has
been reported in patients treated with angiotensin-converting enzyme inhibitors.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor
or angioedema of the face, tongue, or glottis occurs, treatment with MONOPRIL-HCT
should be discontinued and appropriate therapy instituted immediately. When
involvement of the tongue, glottis, or larynx appears likely to cause airway
obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection
1:1000 (0.3���0.5 mL) should be promptly administered (see PRECAUTIONS 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-HCT
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-HCT. MONOPRIL-HCT
(fosinopril sodium-hydrochlorothiazide tablets) should be used cautiously
in patients receiving concomitant therapy with other antihypertensives. The
thiazide component of MONOPRIL-HCT may potentiate the action of other antihypertensive
drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The
antihypertensive effects of the thiazide component may also be enhanced in
the post-sympathectomy patient. In patients with congestive
heart failure, with or without associated renal insufficiency, ACE inhibitor
therapy may cause excessive hypotension, which may be associated with oliguria,
azotemia, and (rarely) with acute renal failure and death. In such patients,
MONOPRIL-HCT 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. If
hypotension occurs, the patient should be placed in a supine position, and,
if necessary, treated with intravenous infusion of physiological saline. MONOPRIL-HCT
treatment usually can be continued following restoration of blood pressure
and volume.<br/>Impaired Renal Function: MONOPRIL-HCT should be used with caution
in patients with severe renal disease. Thiazides may precipitate azotemia
in such patients, and the effects of repeated dosing may be cumulative. When
the renin-angiotensin-aldosterone system is inhibited by ACE inhibitors, changes
in renal function may be anticipated in susceptible individuals. In patients
with severe congestive heart failure, whose renal function may
depend on the activity of the renin-angiotensin-aldosterone system, treatment
with angiotensin-converting enzyme inhibitors (including fosinopril) may be
associated with oliguria and/or progressive azotemia and (rarely) with acute
renal failure and/or death. In some studies of hypertensive
patients with unilateral or bilateral renal artery stenosis,
treatment with ACE inhibitors has been associated with increases in blood
urea nitrogen and serum creatinine; these increases were reversible upon discontinuation
of ACE inhibitor therapy, concomitant diuretic therapy, or both. When such
patients are treated with MONOPRIL-HCT, renal function should be monitored
during the first few weeks of therapy. Some ACE-inhibitor-treated
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 the ACE inhibitor has been given concomitantly
with a diuretic. Dosage reduction of MONOPRIL-HCT may be required. Evaluation
of the hypertensive patient should always include assessment of renal function
.<br/>Neutropenia/Agranulocytosis: Another angiotensin-converting enzyme
inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow
depression, rarely in uncomplicated patients (incidence probably less than
once per 10,000 exposures), but more frequently (incidence possibly as great
as once per 1,000 exposures) in patients with renal impairment, especially
those who 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. Neutropenia/agranulocytosis
has also been associated with thiazide diuretics.<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, MONOPRIL-HCT
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 peritoneal 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, and indeed there is no experience with any
procedure for removing fosinopril from the neonatal circulation, but limited
experience with other ACE inhibitors has not shown that such removal is central
to the treatment of these infants. When fosinopril
is 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. In pregnant rabbits, no teratogenic effects of fosinopril were
seen in studies at doses up to 25 times (on a mg/kg basis) the maximum recommended
human dose.<br/>Impaired Hepatic Function: Rarely, ACE inhibitors have been associated
with a syndrome that begins with cholestatic jaundice and progresses to fulminant
hepatic necrosis and (sometimes) death. The mechanism of this syndrome is
not understood. A patient receiving MONOPRIL-HCT who develops jaundice or
marked elevation of hepatic enzymes should discontinue MONOPRIL-HCT (fosinopril
sodium-hydrochlorothiazide tablets) and receive appropriate medical follow-up. MONOPRIL-HCT
should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte
balance may precipitate hepatic coma. Also, since the metabolism of fosinopril
to fosinoprilat is normally dependent upon hepatic esterases, patients with
impaired liver function could develop elevated plasma levels of fosinopril.
In a study of patients with alcoholic or biliary cirrhosis the rate (but not
the extent) of hydrolysis to fosinoprilat was reduced. In these patients the
clearance of fosinoprilat was reduced, and the area under the fosinoprilat-time
curve was approximately doubled.<br/>Systemic Lupus Erythematosus: Thiazide diuretics have been reported
to cause exacerbation or activation of systemic lupus erythematosus.
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MONOPRIL-HCT (fosinopril sodium-hydrochlorothiazide
tablets) is indicated for the treatment of hypertension. These
fixed dose combinations are not indicated for initial therapy. In
using MONOPRIL-HCT, 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 fosinopril does not have a similar
risk . 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-HCT
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