BENAZEPRIL HCL
DESCRIPTION:
PRESCRIBING INFORMATION
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, BENACE should be discontinued
as soon as possible. See WARNINGS,
FETAL/NEONATAL MORBIDITY AND MORTALITY.
Benazepril hydrochloride is a white to off-white crystalline powder, soluble
(>100 mg/mL) in water, in ethanol, and in methanol. Benazepril's chemical name
is 3-((1-(ethoxy- carbonyl)-3-phenyl- (1S)-propyl)amino)-2,3,4,5-tetrahydro-2-
oxo-1H- 1-(3S)-benzazepine-1-acetic acid monohydrochloride.
C24H28N2O5.HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl
angiotensin- converting enzyme inhibitor. Benazepril is converted to
benazeprilat by hepatic cleavage of the ester group.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Benazepril and benazeprilat inhibit angiotensin- converting enzyme (ACE) in
human subjects and 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 BENACE alone for up to 52 weeks had elevations of serum
potassium of up to 0.2 mEq/L. Similar patients treated with BENACE and
hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum
potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to
increased plasma renin activity. In animal studies, benazepril had no inhibitory
effect on the vasopressor response to angiotensin II and did not interfere with
the hemodynamic effects of the autonomic neurotransmitters acetylcholine,
epinephrine, and norepinephrine.
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 BENACE remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed
to be primarily suppression of the renin-angiotensin-aldosterone system,
benazepril has an antihypertensive effect even in patients with low-renin
hypertension. (see INDICATIONS AND USAGE).
PHARMACOKINETICS AND METABOLISM
Following oral administration of BENACE, peak plasma concentrations of
benazepril are reached within 0.5-1.0 hours. The extent of absorption is at
least 37% as determined by urinary recovery and is not significantly influenced
by the presence of food in the GI tract.
Cleavage of the ester group (primarily in the liver) converts benazepril to its
active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are
reached 1-2 hours after drug intake in the fasting state and 2-4 hours after
drug intake in the nonfasting state. The serum protein binding of benazepril is
about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium
dialysis; on the basis of in vitro studies, the degree of protein binding should
be unaffected by age, hepatic dysfunction, or concentration (over the
concentration range of 0.24-23.6 micromol/L).
Benazepril is almost completely metabolized to benazeprilat, which has much
greater ACE inhibitory activity than benazepril, and to the glucuronide
conjugates of benazepril and benazeprilat. Only trace amounts of an administered
dose of BENACE can be recovered in the urine as unchanged benazepril, while
about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide,
and 8% as benazeprilat glucuronide.
The kinetics of benazepril are approximately dose-proportional within the dosage
range of 10-80 mg.
The effective half-life of accumulation of benazeprilat following multiple
dosing of benazepril hydrochloride is 10-11 hours. Thus, steady-state
concentrations of benazeprilat should be reached after 2 or 3 doses of
benazepril hydrochloride given once daily.
The kinetics did not change, and there was no significant accumulation during
chronic administration (28 days) of once-daily doses between 5 mg and 20 mg.
Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19
and 1.27, respectively.
When dialysis was started two hours after ingestion of 10 mg of benazepril,
approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent
compound, benazepril, was not detected in the dialysate.
The disposition of benazepril and benazeprilat in patients with mild-to-moderate
renal insufficiency (creatinine clearance >30 mL/min) is similar to that in
patients with normal renal function. In patients with creatinine clearance =30
mL/min, peak benazeprilat levels and the initial (alpha phase) half-life
increase, and time to steady state may be delayed (see DOSAGE AND
ADMINISTRATION).
Benazepril and benazeprilat are cleared predominantly by renal excretion in
healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion
accounts for approximately 11%-12% of benazeprilat excretion in healthy
subjects. In patients with renal failure, biliary clearance may compensate to an
extent for deficient renal clearance.
In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat
are essentially unaltered. The pharmacokinetics of benazepril and benazeprilat
do not appear to be influenced by age.
In studies in rats given 14C-benazepril, benazepril and its metabolites crossed
the blood- brain barrier only to an extremely low extent. Multiple doses of
benazepril did not result in accumulation in any tissue except the lung, where,
as with other ACE inhibitors in similar studies, there was a slight increase in
concentration due to slow elimination in that organ.
Some placental passage occurred when the drug was administered to pregnant rats.
PHARMACODYNAMICS
Single and multiple doses of 10 mg or more of BENACE cause inhibition of
plasma ACE activity by at least 80%-90% for at least 24 hours after dosing.
Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4
hours post-dose) at the 10-mg dose.
Administration of BENACE 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 (see WARNINGS).
In single-dose studies, BENACE lowered blood pressure within 1 hour, with peak
reductions achieved 2-4 hours after dosing. The antihypertensive effect of a
single dose persisted for 24 hours. In multiple-dose studies, once-daily doses
of 20-80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing
by about 6-12/4-7 mmHg. The trough values represent reductions of about 50% of
that seen at peak.
Four dose-response studies using once-daily dosing were conducted in 470 mild-
to-moderate hypertensive patients not using diuretics. The minimal effective
once-daily dose of BENACE was 10 mg; but further falls in blood pressure,
especially at morning trough, were seen with higher doses in the studied dosing
range (10-80 mg). In studies comparing the same daily dose of BENACE given as
a single morning dose or as a twice-daily dose, blood pressure reductions at the
time of morning trough blood levels were greater with the divided regimen.
During chronic therapy, the maximum reduction in blood pressure with any dose is
generally achieved after 1-2 weeks. The antihypertensive effects of BENACE
have continued during therapy for at least two years. Abrupt withdrawal of
BENACE has not been associated with a rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, BENACE 10-20 mg was similar in
effectiveness to captopril, hydrochlorothiazide, nifedipine SR, and propranolol.
The antihypertensive effects of BENACE were not appreciably different in
patients receiving high- or low-sodium diets.
In hemodynamic studies in dogs, blood pressure reduction was accompanied by a
reduction in peripheral arterial resistance, with an increase in cardiac output
and renal blood flow and little or no change in heart rate. In normal human
volunteers, single doses of benazepril caused an increase in renal blood flow
but had no effect on glomerular filtration rate.
Use of BENACE in combination with thiazide diuretics gives a blood-pressure-
lowering effect greater than that seen with either agent alone. By blocking the
renin-angiotensin-aldosterone axis, administration of BENACE tends to reduce
the potassium loss associated with the diuretic.
INDICATIONS AND USAGE:
BENACE is indicated for the treatment of hypertension. It may be used alone or
in combination with thiazide diuretics.
In using BENACE, 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 BENACE does not have a similar
risk (see WARNINGS).
Black patients receiving ACE-inhibitor monotherapy have been reported to have a
higher incidence of angioedema compared to nonblacks. It should also be noted
that in controlled clinical trials ACE inhibitors have an effect on blood
pressure that is less in black patients than in nonblacks.
CONTRAINDICATIONS:
BENACE is contraindicated in patients who are hypersensitive to this product
or to any other ACE inhibitor.
WARNINGS:
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, BENACE should be discontinued
as soon as possible. See WARNINGS,
FETAL/NEONATAL MORBIDITY AND MORTALITY.
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 BENACE) 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 BENACE. Angioedema associated with laryngeal edema can
be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis
occurs, treatment with BENACE 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
BENACE 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
BENACE.
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, BENACE 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.
BENACE 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 of 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 life- saving 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 BENACE were seen in studies of pregnant rats, mice,
and rabbits. On amg/M(squared) 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 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 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 BENACE, 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 BENACE was associated with increases in blood urea nitrogen and
serum creatinine; these increases were reversible upon discontinuation of
BENACE 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 BENACE has been given
concomitantly with a diuretic. This is more likely to occur in patients with
preexisting renal impairment. Dosage reduction of BENACE 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).
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 BENACE. 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 BENACE (see Drug Interactions).
COUGH: Presumably due to the inhibition of the degradation of endogenous
bradykinin, persistent nonproductive cough has been reported with all ACE
inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-
induced cough should be considered in the differential diagnosis of cough.
IMPAIRED LIVER FUNCTION: In patients with hepatic dysfunction due to cirrhosis,
levels of benazeprilat are essentially unaltered (see WARNINGS, Hepatic
Failure).
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.
INFORMATION FOR PATIENTS
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.
ANGIOEDEMA: Angioedema, including laryngeal edema, can occur at any time with
treatment with ACE inhibitors. Patients should be so advised and 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 they
have consulted with the prescribing physician.
SYMPTOMATIC HYPOTENSION: Patients should be cautioned that lightheadedness can
occur, especially during the first days of therapy, and it should be reported to
the prescribing physician. Patients should be told that if syncope occurs,
BENACE should be discontinued until the prescribing 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 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.
DRUG INTERACTIONS
DIURETICS: Patients on diuretics, especially those in whom diuretic therapy was
recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with BENACE. The possibility of
hypotensive effects with BENACE can be minimized by either discontinuing the
diuretic or increasing the salt intake prior to initiation of treatment with
BENACE. If this is not possible, the starting dose should be reduced (see
DOSAGE AND ADMINISTRATION).
POTASSIUM SUPPLEMENTS AND POTASSIUM-SPARING DIURETICS: BENACE 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.
ORAL ANTICOAGULANTS: Interaction studies with warfarin and acenocoumarol failed
to identify any clinically important effects on the serum concentrations or
clinical effects of these anticoagulants.
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.
OTHER: No clinically important pharmacokinetic interactions occurred when
BENACE was administered concomitantly with hydrochlorothiazide,
chlorthalidone, furosemide, digoxin, propranolol, atenolol, naproxen, or
cimetidine.
BENACE has been used concomitantly with beta- adrenergic-blocking agents,
calcium-channel- blocking agents, diuretics, digoxin, and hydralazine, without
evidence of clinically important adverse interactions. Benazepril, like other
ACE inhibitors, has had less than additive effects with beta-adrenergic
blockers, presumably because both drugs lower blood pressure by inhibiting parts
of the renin-angiotensin system.
CARCINOGENESIS, MUTAGENESIS, 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 of 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/M(squared) comparison and 37-375 times the
maximum recommended human dose based on a mg/kg comparison), BENACE 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 BENACE, 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 pediatric patients have not been established.
DRUG INTERACTIONS:
DIURETICS: Patients on diuretics, especially those in whom diuretic therapy was
recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with BENACE. The possibility of
hypotensive effects with BENACE can be minimized by either discontinuing the
diuretic or increasing the salt intake prior to initiation of treatment with
BENACE. If this is not possible, the starting dose should be reduced (see
DOSAGE AND ADMINISTRATION).
POTASSIUM SUPPLEMENTS AND POTASSIUM-SPARING DIURETICS: BENACE 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.
ORAL ANTICOAGULANTS: Interaction studies with warfarin and acenocoumarol failed
to identify any clinically important effects on the serum concentrations or
clinical effects of these anticoagulants.
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.
OTHER: No clinically important pharmacokinetic interactions occurred when
BENACE was administered concomitantly with hydrochlorothiazide,
chlorthalidone, furosemide, digoxin, propranolol, atenolol, naproxen, or
cimetidine.
BENACE has been used concomitantly with beta- adrenergic-blocking agents,
calcium-channel- blocking agents, diuretics, digoxin, and hydralazine, without
evidence of clinically important adverse interactions. Benazepril, like other
ACE inhibitors, has had less than additive effects with beta-adrenergic
blockers, presumably because both drugs lower blood pressure by inhibiting parts
of the renin-angiotensin system.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
BENACE has been evaluated for safety in over 6000 patients with hypertension;
over 700 of these patients were treated for at least one year. The overall
incidence of reported adverse events was comparable in BENACE and placebo
patients.
The reported side effects were generally mild and transient, and there was no
relation between side effects and age, duration of therapy, or total dosage
within the range of 2 to 80 mg. Discontinuation of therapy because of a side
effect was required in approximately 5% of U.S. patients treated with BENACE
and in 3% of patients treated with placebo.
The most common reasons for discontinuation were headache (0.6%) and cough
(0.5%) (see PRECAUTIONS, Cough).
The side effects considered possibly or probably related to study drug that
occurred in U.S. placebo-controlled trials in more than 1% of patients treated
with BENACE are shown below.
PATIENTS IN U.S. PLACEBO-CONTROLLED STUDIES
BENACE PLACEBO
(N=964) (N=496)
N % N %
Headache 60 6.2 21 4.2
Dizziness 35 3.6 12 2.4
Fatigue 23 2.4 11 2.2
Somnolence 15 1.6 2 0.4
Postural Dizziness 14 1.5 1 0.2
Nausea 13 1.3 5 1.0
Cough 12 1.2 5 1.0
Other adverse experiences reported in controlled clinical trials (in less than
1% of benazepril patients), and rarer events seen in postmarketing experience,
include the following (in some, a causal relationship to drug use is uncertain):
CARDIOVASCULAR: Symptomatic hypotension was seen in 0.3% of patients, postural
hypotension in 0.4%, and syncope in 0.1%; these reactions led to discontinuation
of therapy in 4 patients who had received benazepril monotherapy and in 9
patients who had received benazepril with hydrochlorothiazide (see PRECAUTIONS
and WARNINGS). Other reports include angina pectoris, palpitations, and
peripheral edema.
RENAL: Of hypertensive patients with no apparent preexisting renal disease,
about 2% have sustained increases in serum creatinine to at least 150% of their
baseline values while receiving BENACE, but most of these increases have
disappeared despite continuing treatment. A much smaller fraction of these
patients (less than 0.1%) developed simultaneous (usually transient) increases
in blood urea nitrogen and serum creatinine.
FETAL/NEONATAL MORBIDITY AND MORTALITY: See WARNINGS, Fetal/Neonatal Morbidity
and Mortality.
ANGIOEDEMA: Angioedema has been reported in patients receiving ACE inhibitors.
During clinical trials in hypertensive patients with benazepril, 0.5% of
patients experienced edema of the lips or face without other manifestations of
angioedema. Angioedema associated with laryngeal edema and/or shock may be
fatal. If angioedema of the face, extremities, lips, tongue, or glottis and/or
larynx occurs, treatment with BENACE should be discontinued and appropriate
therapy instituted immediately (see WARNINGS).
DERMATOLOGIC: Stevens-Johnson syndrome, apparent hypersensitivity reactions
(manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.
There have been rare reports of pemphigus in patients receiving ACE inhibitors.
GASTROINTESTINAL: Pancreatitis, constipation, gastritis, vomiting, and melena.
HEMATOLOGIC: Thrombocytopenia. There have been rare reports of hemolytic anemia
in patients receiving ACE inhibitors.
NEUROLOGIC AND PSYCHIATRIC: Anxiety, decreased libido, hypertonia, insomnia,
nervousness, and paresthesia.
OTHER: Arthralgia, arthritis, asthenia, asthma, bronchitis, dyspnea, impotence,
infection, myalgia, sinusitis, sweating, and urinary tract infection.
CLINICAL LABORATORY TEST FINDINGS
CREATININE AND BLOOD UREA NITROGEN: Of hypertensive patients with no apparent
preexisting renal disease, about 2% have sustained increases in serum creatinine
to at least 150% of their baseline values while receiving BENACE, but most of
these increases have disappeared despite continuing treatment. A much smaller
fraction of these patients (less than 0.1%) developed simultaneous (usually
transient) increases in blood urea nitrogen and serum creatinine. None of these
increases required discontinuation of treatment. Increases in these laboratory
values are more likely to occur in patients with renal insufficiency or those
pretreated with a diuretic and, based on experience with other ACE inhibitors,
would be expected to be especially likely in patients with renal artery stenosis
(see PRECAUTIONS, General).
POTASSIUM: Since benazepril decreases aldosterone secretion, elevation of serum
potassium can occur. Potassium supplements and potassium-sparing diuretics
should be given with caution, and the patient's serum potassium should be
monitored frequently (see PRECAUTIONS).
HEMOGLOBIN: Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were
rare, occurring in only 1 of 2014 patients receiving BENACE alone and in 1 of
1357 patients receiving BENACE plus a diuretic. No U.S. patients discontinued
treatment because of decreases in hemoglobin.
OTHER (CAUSAL RELATIONSHIPS UNKNOWN): Clinically important changes in standard
laboratory tests were rarely associated with BENACE administration. Elevations
of uric acid, blood glucose, serum bilirubin, and liver enzymes (see WARNINGS)
have been reported, as have scattered incidents of hyponatremia,
electrocardiographic changes, leukopenia, eosinophilia, and proteinuria. In U.S.
trials, less than 0.5% of patients discontinued treatment because of laboratory
abnormalities.
OVERDOSAGE:
Single oral doses of 3 g/kg benazepril were associated with significant
lethality in mice. Rats, however, tolerated single oral doses of up to 6 g/kg.
Reduced activity was seen at 1 g/kg in mice and at 5 g/kg in rats. Human
overdoses of benazepril have not been reported, but the most common
manifestation of human benazepril overdosage is likely to be hypotension.
Laboratory determinations of serum levels of benazepril and its metabolites are
not widely available, and such determinations have, in any event, no established
role in the management of benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to
change the pH of the urine) that might accelerate elimination of benazepril and
its metabolites. Benazepril is only slightly dialyzable, but dialysis might be
considered in overdosed patients with severely impaired renal function (see
WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the
setting of benazepril overdose, but angiotensin II is essentially unavailable
outside of scattered research facilities. Because the hypotensive effect of
benazepril is achieved through vasodilation and effective hypovolemia, it is
reasonable to treat benazepril overdose by infusion of normal saline solution.
DOSAGE AND ADMINISTRATION:
The recommended initial dose for patients not receiving a diuretic is 10 mg
once-a-day. The usual maintenance dosage range is 20-40 mg per day administered
as a single dose or in two equally divided doses. A dose of 80 mg gives an
increased response, but experience with this dose is limited. The divided
regimen was more effective in controlling trough (pre-dosing) blood pressure
than the same dose given as a once-daily regimen. Dosage adjustment should be
based on measurement of peak (2-6 hours after dosing) and trough responses. If a
once-daily regimen does not give adequate trough response, an increase in dosage
or divided administration should be considered. If blood pressure is not
controlled with BENACE alone, a diuretic can be added.
Total daily doses above 80 mg have not been evaluated.
Concomitant administration of BENACE with potassium supplements, potassium
salt substitutes, or potassium-sparing diuretics can lead to increases of serum
potassium (see PRECAUTIONS).
In patients who are currently being treated with a diuretic, symptomatic
hypotension occasionally can occur following the initial dose of BENACE. To
reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued two to three days prior to beginning therapy with BENACE (see
WARNINGS). Then, if blood pressure is not controlled with BENACE alone,
diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg BENACE should
be used to avoid excessive hypotension.
DOSAGE ADJUSTMENT IN RENAL IMPAIRMENT
For patients with a creatinine clearance <30 mL/min/1.73 M(squared) (serum
creatinine >3 mg/dL), the recommended initial dose is 5 mg BENACE once daily.
Dosage may be titrated upward until blood pressure is controlled or to a maximum
total daily dose of 40 mg (see WARNINGS).
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