BENAZEPRIL HYDROCHLORIDE
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benazepril hydrochloride tablet, film coated
International Labs, Inc.
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Benazepril Hydrochloride Tablets - PACKAGE LABELSLB0063 - Benazepril Hydrochloride Tablets, 20 mg
LB0065 - Benazepril Hydrochloride Tablets, 40 mg
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
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:
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.
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.
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.
Benazepril hydrochloride tablets are contraindicated in patients who are hypersensitive
to this product or to any other ACE inhibitor.
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.
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).
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.
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).
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.
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
BENAZEPRIL HYDROCHLORIDE
benazepril hydrochloride tablet, film coated |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA076402 | 03/01/2009 |
BENAZEPRIL HYDROCHLORIDE
benazepril hydrochloride tablet, film coated |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA076402 | 03/01/2009 |
Labeler - International Labs, Inc. (023569924) |
Registrant - International Labs, Inc. (023569924) |
Establishment | |||
Name | Address | ID/FEI | Operations |
International Labs, Inc. | 023569924 | manufacture, relabel, repack |
Establishment | |||
Name | Address | ID/FEI | Operations |
Sandoz Inc. | 614842560 | manufacture |