WARNINGS
Anaphylactoid and Possibly Related REACTIONS
Presumably because angiotensin-converting inhibitors
affect the metabolism of eicosanoids and polypeptides,
including endogenous bradykinin, patients receiving ACE
inhibitors (including benazepril HCl) may be subject to
a variety of adverse reactions, some of them serious.
Angioedema: Angioedema of the face,
extremities, lips, tongue, glottis, and larynx has been
reported in patients treated with angiotensin-converting
enzyme inhibitors. In U.S. clinical trials, symptoms consistent
with angioedema were seen in none of the subjects who
received placebo and in about 0.5% of the subjects who
received benazepril HCl. Angioedema associated with laryngeal
edema can be fatal. If laryngeal stridor or angioedema
of the face, tongue, or glottis occurs, treatment with
benazepril HCl 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 injection 1:1000 (0.3 ml to 0.5
ml) should be promptly administered (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
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
(a procedure dependent upon devices not approved in the
United States).
Hypotension
Benazepril HCl can cause symptomatic hypotension. Like
other ACE inhibitors, benazepril 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 benazepril HCl.
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 azotemia and, rarely, with acute renal
failure and death. In such patients, benazepril HCl 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 benazepril 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. benazepril HCl treatment
usually can be continued following restoration of blood
pressure and volume.
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 or benazepril are insufficient
to show that benazepril 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.
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 benazepril 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, benazepril should be
discontinued unless it is considered lifesaving for the
mother. Contraction stress testing (CST), a nonstress
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 means of reversing hypotension and/or substituting
for disordered renal function. Benazepril, which crosses
the placenta, can theoretically be removed from the neonatal
circulation by these means; there are occasional reports
of benefit from these maneuvers with another ACE inhibitor,
but experience is limited.
No teratogenic effects of benazepril were seen in studies
of pregnant rats, mice, and rabbits. On a mg/m2 basis,
the doses used in these studies were 60 times (in rats),
9 times (in mice), and more than 0.8 times (in rabbits)
the maximum recommended human dose (assuming a 50 kg woman).
On a mg/kg basis these multiples are 300 times (in rats),
90 times (in mice) and more than 3 times (in rabbits)
the maximum recommended human dose.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome
that starts with cholestatic jaundice and progresses to
fulminent 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 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
benazepril HCl, may be associated with oliguria and/or
progressive azotemia and (rarely) with acute renal failure
and/or death. In a small study of hypertensive patients
with renal artery stenosis in a solitary kidney or bilateral
renal artery stenosis, treatment with benazepril HCl was
associated with increases in blood urea nitrogen and serum
creatinine; these increases were reversible upon discontinuation
of benazepril HCl or diuretic therapy, or both. When such
patients are treated with ACE inhibitors, 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 benazepril HCl has been given
concomitantly with a diuretic. This is more likely to
occur in patients with preexisting renal impairment. Dosage
reduction of benazepril HCl and/or discontinuation of
the diuretic may be required. Evaluation of the hypertensive
patient should always include assessment of renal function
(see DOSAGE AND ADMINISTRATION).
Hemodialysis Patients: Anaphylactoid
reactions have been reported in patients dialyzed with
high-flux membranes and treated concomitantly with an
ACE inhibitor. In these patients, consideration should
be given to using a different type of dialysis membrane
or a different class of antihypertensive agent.
Hyperkalemia: In clinical trials, hyperkalemia
(serum potassium at least 0.5 mEq/L greater than the upper
limit of normal) occurred in approximately 1% of hypertensive
patients receiving benazepril HCl. In most cases, these
were isolated values which resolved despite continued
therapy. Risk factors for the development of hyperkalemia
include renal insufficiency, diabetes mellitus, and the
concomitant use of potassium-sparing diuretics, potassium
supplements, and/or potassium-containing salt substitutes,
which should be used cautiously, if at all, with benazepril
HCl (see DRUG INTERACTIONS).
Cough: Cough has been reported with
the use of ACE inhibitors. Characteristically, the cough
is nonproductive, persistent, and resolves after discontinuation
of therapy. ACE inhibitor-induced cough should be considered
as part of the differential diagnosis of cough.
Impaired Liver Function: In patients
with hepatic dysfunction due to cirrhosis, levels of benazeprilat
are essentially unaltered.
Surgery/Anesthesia: In patients undergoing
surgery or during anesthesia with agents that produce
hypotension, benazepril 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.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
No evidence of carcinogenicity was found when benazepril
was administered to rats and mice for up to two years
at doses of up to 150 mg/kg/day. When compared on the
basis of body weights, this dose is 110 times the maximum
recommended human dose; When compared on the basis to
body surface areas, this dose is 18 and 9 times (rats
and mice, respectively) the maximum recommended human
dose (calculations assume a patient weight of 60 kg).
No mutagenic activity was detected in the Ames test in
bacteria (with or without metabolic activation), in an
in vitro test for forward mutations in cultured mammalian
cells, or in a nucleus anomaly test. In doses of 50-500
mg/kg/day (6-60 times the maximum recommended human dose
based on mg/m2 comparison and 37-375 times the maximum
recommended human dose based on a mg/kg comparison). Benazepril
HCl had no adverse effect on the reproductive performance
of male and female rats.
Pregnancy Categories C (first trimester) and
D (second and third trimesters): See
WARNINGS
, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Minimal amounts of unchanged benazepril and of benazeprilat
are excreted into the breast milk of lactating women treated
with benazepril. A newborn child ingesting entirely breast
milk would receive less than 0.1% of the mg/kg maternal
dose of benazepril and benazeprilat.
Geriatric Use
Of the total number of patients who received benazepril
in U.S. clinical studies of benazepril HCl, 18% were 65
or older while 2% were 75 or older. No overall differences
in effectiveness or safety were observed between these
patients and younger patients, and other reported clinical
experience has not identified differences in responses
between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled
out.
Pediatric Use
Safety and effectiveness in children have not been established.
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