A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Univasc Warnings, Precautions, Pregnancy, Nursing, Abuse - Moexipril
Univasc Warnings, Precautions, Pregnancy, Nursing, Abuse - Moexipril
WARNINGS
Anaphylactoid and Possibly Related REACTIONS
Presumably because angiotensin-converting enzyme
inhibitors affect the
metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE
inhibitors, including UNIVASC®, may be subject
to a variety of adverse
reactions, some of them serious.
Angioedema:
Angioedema involving the face, extremities, lips, tongue, glottis,
and/or larynx has been
reported in patients treated with ACE
inhibitors, including UNIVASC®. Symptoms suggestive
of angioedema or
facial edema occurred
in <0.5% of moexipril-treated patients in placebo-controlled
trials. None of the cases were considered life-threatening and all
resolved either without treatment
or with medication
(antihistamines or glucocorticoids). One patient
treated with hydrochlorothiazide
alone experienced laryngeal edema. no
instances of angioedema
were reported in placebo-treated patients. In cases of angioedema,
treatment should be
promptly discontinued and the patient carefully observed until the
swelling disappears.
In instances where swelling
has been confined to the face
and lips, the condition
has generally resolved without treatement, although antihistamines
have been useful in relieving symptoms.
Angioedema associated with involvement of the tongue, glottis,
or larynx, may be fatal
due to airway obstruction.
Appropriate therapy,
e.g., subcutaneous epinephrine solution
1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway,
should be promptly provided (see ADVERSE
REACTIONS)
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 did not occur when ACE
inhibitors were temporarily withheld, but they reappeared when the
ACE inhibitors were inadvertently
readministered.
Anaphylactoid Reactions During Membrane Exposure:
Anaphylactoid reactions have been reported in patients dialyzed
with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients
undergoing low-density lipoprotein apheresis with dextran
sulfate absorption.
Hypotension
UNIVASC® can cause
symptomatic hypotension,
although, as with other ACE
inhibitors, this is unusual in uncomplicated hypertensive patients
treated with UNIVASC® alone. Symptomatic hypotension
was seen in 0.5% of patients given moexipril and led to discontinuation
of therapy in about
0.25%. Symptomatic hypotension
is most likely to occur in patients who have been salt- and volume-depleted
as a result of prolonged diuretic therapy,
dietary salt
restriction, dialysis,
diarrhea, or vomiting.
Volume- and salt-depletion should be corrected and
in general, diuretics stopped, before initiating therapy
with UNIVASC® (see PRECAUTIONS
,
Drug Interactions, and ADVERSE
REACTIONS).
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
or progressive azotemia,
and rarely, with acute
renal failure
and death. In these patients,
UNIVASC® therapy should be started under close medical
supervision, and patients should be followed closely for the first
two weeks of treatment
and whenever the dose of
moexipril or an accompanying diuretic
is increased. Care in avoiding hypotension
should also be taken in patients with ischemic heart disease, aortic
stenosis, or cerebrovascular
disease, in whom an
excessive decrease in blood
pressure could result
in a myocardial infarction
or a cerebrovascular accident. If hypotension
occurs, the patient
should be placed in a supine
position and
if necessary, treated with an intravenous infusion of normal
saline. UNIVASC® treatment
usually can be continued following restoration
of blood pressure
and volume.
Neutropenia/Agranulocytosis
Another ACE inhibitor,
captopril, has been shown to cause
agranulocytosis and bone
marrow depression,
rarely in patients with uncomplicated hypertension, but more frequently
in hypertensive
patients with renal impairment,
especially if they also have a collagen-vascular disease
such as systemic
lupus erythematosus or
scleroderma. Although there were no
instances of severe neutropenia (absolute neutrophil
count <500/mm3) among
patients given UNIVASC®, as with other ace inhibitors,
monitoring of white blood
cell counts should be considered
for patients who have collagen-vascular disease,
especially if the disease
is associated with impaired renal
function. Available data from clinical
trials of UNIVASC® are insufficient to show that
UNIVASC® does not cause
agranulocytosis
at rates similar to captopril.
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 were caused by the ACE
inhibitor exposure.
Fetal and neonatal
morbidity do not appear
to have resulted from intrauterine ACE inhibitor
exposure limited to
the first trimester. Mothers who have used ACE
inhibitors only during the first trimester
should be informed of this. Nonetheless, when patients become pregnant,
physicians should make every effort
to discontinue the use of moexipril 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, moexipril 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 be detected 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 means of reversing hypotension
and/or substituting for disordered renal function.
Theoretically, the ACE
inhibitor could be
removed from the neonatal circulation by exchange
transfusion, but no experience
with this procedure has been reported.
No embryotoxic, fetotoxic, or teratogenic
effects were seen in rats or in rabbits treated with up to 90.9
and 0.7 times, respectively, the Maximum Recommended Human Dose
(MRHD) on a mg/m2 basis.
Hepatic Failure
Rarely, ACE inhibitors
have been associated with a syndrome
that starts with cholestatic jaundice
and progresses to fulminant
hepatic necrosis and
sometimes death. The mechanism
of this syndrome is
not understood. Patients receiving ACE
inhibitors who develop jaundice
or marked elevations of hepatic
enzymes should discontinue the ACE
inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function: As
a consequence of
inhibition of the renin-angiotensin-aldosterone system, changes
in renal function may
be anticipated in susceptible
individuals. There is no
clinical experience
of UNIVASC® in the treatment
of hypertension
in patients with renal
failure. 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 UNIVASC® has been given concomitantly
with a thiazide diuretic. This is more likely to occur in patients
with preexisting renal
impairment. There may be a need for dose
adjustment of UNIVASC®
and/or the discontinuation of the thiazide diuretic.
Evaluation of hypertensive
patients should always include assessment of renal
function (see DOSAGE
AND ADMINISTRATION).
Hypertensive Patients With Congestive Heart Failure:
In hypertensive patients with severe congestive heart
failure, whose renal function may depend on the activity
of the renin-angiotensin-aldosterone system, treatment
with ACE inhibitors, including
UNIVASC®, may be associated with oliguria
and/or progressive
azotemia and
rarely, acute renal failure
and/or death.
Hypertensive Patients With Renal Artery Stenosis:
In hypertensive patients
with unilateral or
bilateral renal
artery stenosis,
increases in blood urea
nitrogen and serum
creatinine have been
observed in some patients following ACE
inhibitor therapy.
These increases were almost always reversible upon discontinuation
of the ACE inhibitor
and/or diuretic therapy.
In such patients, renal
function should be
monitored during the first few weeks of therapy.
Hyperkalemia: In
clinical trials, persistent
hyperkalemia (serum potassium
above 5.4 mEq/L) occurred in approximately 1.3% of hypertensive
patients receiving UNIVASC®. Risk factors for the
development of hyperkalemia
with ACE inhibitors 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 UNIVASC®
(see DRUG INTERACTIONS).
Surgery/Anesthesia: In
patients undergoing major surgery or during anesthesia
with agents that produce hypotension,
moexipril may block the effects of compensatory renin
release. If hypotension
occurs in this setting and is considered to be due to this mechanism,
it can be corrected by volume
expansion.
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. In controlled
trials with moexipril, cough
was present in 6.1%
of moexipril patients and 2.2% of patients given placebo.
Information for Patients
See PATIENT INFORMATION.
Drug Interactions
See ADVERSE REACTIONS , DRUG
INTERACTIONS,and DOSAGE AND
ADMINISTRATION
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity
was detected in long-term studies in mice and rats at doses up to
14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a
mg/m2 basis.
No mutagenicity was detected in the Ames test
and microbial reverse mutation assay, with and without metabolic
activation, or in an in vivo nucleus anomaly test. However,
increased chromosomal aberration
frequency in Chinese
hamster ovary cells was
detected under metabolic activation
conditions at a 20-hour harvest
time.
Reproduction studies have been performed in rabbits at oral
doses up to 0.7 times the MRHD on a mg/m2 basis, and
in rats up to 90.9 times the MRHD on a mg/m2 basis. No
indication of impaired
fertility, reproductive toxicity,
or teratogenicity was observed.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and
third trimesters). See WARNINGS
,
Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether UNIVASC® is excreted in
human milk. Because many drugs are excreted in human
milk, caution should be exercised when UNIVASC® is
given to a nursing mother.
Geriatric Use
Of the patients who received UNIVASC® in controlled
clinical studies, 33% were 65 years of age
or older. No overall differences
in effectiveness or safety were observed between these patients
and younger patients. In elderly patients receiving UNIVASC®,
plasma levels of drug
are slightly higher and renal
clearance is reduced
when compared to younger patients, but this did not have detectable
consequences.
Pediatric Use
Safety and effectiveness
of UNIVASC® in pediatric
patients have not been established.
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