BENAZEPRIL HYDROCHLORIDE  - benazepril hydrochloride tablet, film coated 
International Labs, Inc.

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Benazepril Hydrochloride Tablets - PACKAGE LABELS

Benazepril Hydrochloride Tablets 20 mg

LB0063 - Benazepril Hydrochloride Tablets, 20 mg

Shellpak® Label

Benazepril Hydrochloride Tablets, 40 mg


LB0065 - Benazepril Hydrochloride Tablets, 40 mg

Shellpak® Label

USE IN PREGNANCY

When used in pregnancy, ACE inhibitors can cause injury and even death to
the developing fetus. When pregnancy is detected, benazepril hydrochloride tablets
should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal
Morbidity and Mortality

DESCRIPTION

Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol and in methanol. Its 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; its structural formula is:Chemical Structure of Benazepril HCl
Its moloecular formula is C24H28N2O5.HCI 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.Benazepril hydrochloride is supplied as tablets containing 5 mg, 10 mg, 20 mg and 40 mg of benazepril hydrochloride for oral administration. The inactive ingredients are lactose monohydrate, microcrystalline cellulose, pregelatinized starch, hydrogenated castor oil, crospovidone, colloidal silicon dioxide, zinc stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80.The 5mg and 10 mg tablets also contain D and C yellow No. 10 and FD and C yellow NO.6. The 20 mg tablets also contain FD and C red No. 40 and FD and C yellow NO.6. The 40 mg tablets also contain FD and C red No. 40.

CLINICAL PHARMACOLOGY SECTION

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 benazepril hydrochloride alone for up to 52 weeks had elevations of serum
potassium of up to 0.2 mEq/L. Similar patients treated with benazepril hydrochloride
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 benazepril hydrochloride 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 benazepril hydrochloride, peak plasma concentrations of
benazepril are reached within 0.5 to 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 Gl 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 to
2 hours after drug intake in the fasting state and 2 to 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 mcmol/L to 23.6 mcmol/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 benazepril hydrochloride
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 mg to 80 mg.
In adults, the effective half-life of accumulation of benazeprilat following multiple dosing
of benazepril hydrochloride is 10 to 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.
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% to 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 renal insufficiency, 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).
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.
In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of
benazeprilat are essentially unaltered. The pharmacokinetics of benazepril and
benazeprilat do not appear to be influenced by age.

In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily
doses of benazepril hydrochloride tablets (0.1 mg/kg to 0.5 mg/kg), the clearance of
benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of
healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was
0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of
benazeprilat in pediatric patients was around 5 hours, one- third that observed in adults.
Pharmacodynamics
Single and multiple doses of 10 mg or more of benazepril hydrochloride cause inhibition
of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. Pressor
responses to exogenous angiotensin I were inhibited by 60% to 90% (up to 4 hours
post-dose) at the 10 mg dose.
Hypertension
Adult: Administration of benazepril hydrochloride 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, benazepril hydrochloride lowered blood pressure within 1 hour,
with peak reductions achieved 2 to 4 hours after dosing. The antihypertensive effect of
a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20
mg to 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 mildto-
moderate hypertensive patients not using diuretics. The minimal effective oncedaily
dose of benazepril hydrochloride was 10 mg; but further falls in blood pressure,
especially at morning trough, were seen with higher doses in the studied dosing range
(10 mg to 80 mg). In studies comparing the same daily dose of benazepril hydrochloride
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 to 2 weeks. The antihypertensive effects of benazepril
hydrochloride have continued during therapy for at least two years. Abrupt withdrawal
of benazepril hydrochloride has not been associated with a rapid increase in blood
pressure.
In patients with mild-to-moderate hypertension, benazepril hydrochloride 10 mg to 20 mg
was similar in effectiveness to captopril, hydrochlorothiazide, nifedipine SR and propranolol.
The antihypertensive effects of benazepril hydrochloride 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 benazepril hydrochloride in combination with thiazide diuretics gives a bloodpressure-
lowering effect greater than that seen with either agent alone. By blocking the
renin-angiotensin-aldosterone axis, administration of benazepril hydrochloride tends to
reduce the potassium loss associated with the diuretic.
Pediatric: In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either
systolic or diastolic pressure above the 95th percentile, patients were given 0.1 mg/kg
or 0.2 mg/kg then titrated up to 0.3 mg/kg or 0.6 mg/kg with a maximum dose of 40
mg once daily. After four weeks of treatment, the 85 patients whose blood pressure
was reduced on therapy were then randomized to either placebo or benazepril and were
followed up for an additional two weeks. At the end of two weeks, blood pressure (both
systolic and diastolic) in children withdrawn to placebo rose by 4 mmHg to 6 mmHg more
than in children on benazepril. No dose-response was observed for the three doses.

INDICATIONS AND USAGE SECTION

Benazepril hydrochloride tablets are indicated for the treatment of hypertension. They
may be used alone or in combination with thiazide diuretics.
In using benazepril hydrochloride tablets, 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 benazepril hydrochloride does not have a similar risk
(see WARNINGS).
Black patients receiving ACE inhibitors 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

Benazepril hydrochloride tablets are contraindicated in patients who are hypersensitive
to this product or to any other ACE inhibitor.

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 benazepril hydrochloride) 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. 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 hydrochloride. Angioedema associated with laryngeal edema can be
fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment
with benazepril hydrochloride 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 1:1,000 (0.3 mL to 0.5 mL) should be promptly administered
(see
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 (a
procedure dependent upon devices not approved in the United States).
Hypotension
Benazepril hydrochloride 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 hydrochloride.
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 hydrochloride 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 hydrochloride
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 collagenvascular
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, benazepril hydrochIoride should be discontinued as soon as
possible and monitoring of the fetal development should be performed on a regular basis.
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.
In addition, use of ACE inhibitors during the first trimester of pregnancy has been
associated with a potentially increased risk of birth defects. In women planning to
become pregnant, ACE inhibitors (including benazepril hydrochloride) should not be
used. Women of child-bearing age should be made aware of the potential risk and
ACE inhibitors (including benazepril hydrochloride) should only be given after careful
counseling and consideration of individual risks and benefits.
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 benazepril hydrochloride 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 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-angiotensinaldosterone
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 hydrochloride, 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 hydrochloride
was associated with increases in blood urea nitrogen and serum creatinine; these
increases were reversible upon discontinuation of benazepril hydrochloride 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 hydrochloride has been given concomitantly with a diuretic. This is more likely
to occur in patients with preexisting renal impairment. Dosage reduction of benazepril
hydrochloride 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 percent of hypertensive
patients receiving benazepril hydrochloride. 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 hydrochloride (see
PRECAUTIONS, 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 exposure to ACE inhibitors. Discuss other treatment options with women planning to
become pregnant. 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, benazepril
hydrochloride tablets 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 benazepril hydrochloride. The possibility of hypotensive effects
with benazepril hydrochloride can be minimized by either discontinuing the diuretic or
increasing the salt intake prior to initiation of treatment with benazepril hydrochloride.
If this is not possible, the starting dose should be reduced (see DOSAGE AND
ADMINISTRATION
).
Potassium Supplements and Potassium-Sparing Diuretics: Benazepril hydrochloride
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 (including benazepril) 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.
Anti-diabetics: In rare cases, diabetic patients receiving an ACE inhibitor (including
benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia.
Such patients should therefore be advised about the possibility of hypoglycemic
reactions and should be monitored accordingly.
Other: No clinically important pharmacokinetic interactions occurred when benazepril
hydrochloride was administered concomitantly with hydrochlorothiazide, chlorthalidone,
furosemide, digoxin, propranolol, atenolol, naproxen or cimetidine.
Benazepril hydrochloride 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 mg/kg/day to 500
mg/kg/day (6 to 60 times the maximum recommended human dose based on mg/m2
comparison and 37 to 375 times the maximum recommended human dose based on a
mg/kg comparison), benazepril hydrochloride had no adverse effect on the reproductive
performance of male and female rats.
Pregnancy Category D
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 0.1percent 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 hydrochloride, 18 percent were 65 or older while 2 percent 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.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly
patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
Pediatric Use
The antihypertensive effects of benazepril hydrochloride have been evaluated
in a double-blind study in pediatric patients 7 to 16 years of age (see CLINICAL
PHARMACOLOGY, Pharmacodynamics and Hypertension
). The pharmacokinetics of
benazepril hydrochloride have been evaluated in pediatric patients 6 to 16 years of age
(see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). Benazepril
hydrochloride was generally well tolerated and adverse effects were similar to those
described in adults. (See ADVERSE REACTIONS, Pediatric Patients).
Treatment with benazepril hydrochloride is not recommended in pediatric patients
less than 6 years of age (see ADVERSE REACTIONS), and in children with glomerular
filtration rate less than 30 mL/min as there are insufficient data available to support a dosing
recommendation in these groups. (See CLINICAL PHARMACOLOGY, Pharmacokinetics
and Metabolism
, In pediatric patients and DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS

Benazepril hydrochloride has been evaluated for safety in over 6,000 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 benazepril hydrochloride 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 mg to 80 mg. Discontinuation of therapy because of a side effect was required in
approximately 5% of U.S. patients treated with benazepril hydrochloride 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 benazepril
hydrochloride are shown below.

Picture of Placebo-controlled study table


Other adverse experiences reported in controlled clinical trials (in less than 1% of
benazepril patients), and rarer events seen in post-marketing 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 included 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 benazepril hydrochloride, 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
benazepril hydrochloride should be discontinued and appropriate therapy instituted
immediately (see WARNINGS).
Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity
reactions (manifested by dermatitis, pruritus or rash), photosensitivity and flushing.
Gastrointestinal: Pancreatitis, constipation, gastritis, vomiting and melena.
Hematologic: Thrombocytopenia and hemolytic anemia.
Neurologic and Psychiatric: Anxiety, decreased libido, hypertonia, insomnia,
nervousness and paresthesia.
Other: Asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination,
infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia and sweating.
Another potentially important adverse experience, eosinophilic pneumonitis, has been
attributed to other ACE inhibitors.
The following adverse events of unknown frequency have been reported during postmarketing
use of benazepril: small bowel angioedema, anaphylactoid reactions,
hyperkalemia, agranulocytosis and neutropenia.
Pediatric Patients: The adverse experience profile for pediatric patients appears to be
similar to that seen in adult patients. Infants below the age of 1 year should not be given
ACE inhibitors due to concerns over possible effects on kidney development.
The long-term effects of benazepril on growth and development have not been studied.
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 benazepril hydrochloride, 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 2,014 patients receiving benazepril hydrochloride alone and
in 1 of 1,357 patients receiving benazepril hydrochloride 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 benazepril hydrochloride 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

Hypertension
Adults: The recommended initial dose for patients not receiving a diuretic is 10 mg once
a day. The usual maintenance dosage range is 20 mg to 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 to 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 benazepril hydrochloride alone, a
diuretic can be added.
Total daily doses above 80 mg have not been evaluated.
Concomitant administration of benazepril hydrochloride 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 benazepril hydrochloride. To reduce
the likelihood of hypotension, the diuretic should, if possible, be discontinued two to
three days prior to beginning therapy with benazepril hydrochloride (see WARNINGS).
Then, if blood pressure is not controlled with benazepril hydrochloride alone, diuretic
therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg
benazepril hydrochloride should be used to avoid excessive hypotension.
Pediatrics: In children, doses of benazepril hydrochloride between 0.1 mg/kg and 0.6
mg/kg once daily have been studied, and doses greater than 0.1 mg/kg were shown to
reduce blood pressure (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Based
on this, the recommended starting dose of benazepril hydrochloride is 0.2 mg/kg once
per day as monotherapy. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not
been studied in pediatric patients.
For pediatric patients who cannot swallow tablets, or for whom the calculated
dosage (mg/kg) does not correspond to the available tablet strengths for benazepril
hydrochloride, follow the suspension preparation instructions to administer benazepril
hydrochloride as a suspension.
Treatment with benazepril hydrochloride is not advised for children below the age of
6 years (see PRECAUTIONS, Pediatric Use) and in pediatric patients with glomerular
filtration rate less than 30 mL, as there are insufficient data available to support a dosing
recommendation in these groups.
For Hypertensive Patients with Renal Impairment: For patients with a creatinine
clearance less than 30 mL/min/1.73 m2 (serum creatinine greater than 3 mg/dL), the recommended initial
dose is 5 mg benazepril hydrochloride once daily. Dosage may be titrated upward until
blood pressure is controlled or to a maximum total daily dose of 40 mg (see WARNINGS).

HOW SUPPLIED

HOW SUPPLIED

Picture of How supplied table


BENAZEPRIL HYDROCHLORIDE 
benazepril hydrochloride   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)54458-956 (0185-0048)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
BENAZEPRIL HYDROCHLORIDE (BENAZEPRIL) BENAZEPRIL HYDROCHLORIDE40 mg
Inactive Ingredients
Ingredient NameStrength
No Inactive Ingredients Found
Product Characteristics
ColorredScore no score
ShapeROUND (bi-convex) Size8mm
FlavorImprint Code E;48
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
154458-956-1030 TABLET In 1 BLISTER PACKNone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07640203/01/2009

BENAZEPRIL HYDROCHLORIDE 
benazepril hydrochloride   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)54458-957 (0185-0820)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
BENAZEPRIL HYDROCHLORIDE (BENAZEPRIL) BENAZEPRIL HYDROCHLORIDE20 mg
Inactive Ingredients
Ingredient NameStrength
No Inactive Ingredients Found
Product Characteristics
ColorpinkScore no score
ShapeROUND (bi-convex) Size8mm
FlavorImprint Code E;82
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
154458-957-1030 TABLET In 1 BLISTER PACKNone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07640203/01/2009

Labeler - International Labs, Inc. (023569924)
Registrant - International Labs, Inc. (023569924)
Establishment
NameAddressID/FEIOperations
International Labs, Inc.023569924manufacture, relabel, repack
Establishment
NameAddressID/FEIOperations
Sandoz Inc.614842560manufacture
Revised: 02/2010International Labs, Inc.