BENAZEPRIL HYDROCHLORIDE tablet, coated

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Active ingredient:
BENAZEPRIL HYDROCHLORIDE (UNII: N1SN99T69T) (BENAZEPRILAT - UNII:JRM708L703)
Available from:
RPK Pharmaceuticals, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Benazepril hydrochloride tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from
Product summary:
Product: 53002-1233 NDC: 53002-1233-0 100 TABLET, COATED in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
53002-1233-0

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BENAZEPRIL HYDROCHLORIDE- benazepril hydrochloride tablet, coated

RPK Pharmaceuticals, Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BENAZEPRIL HYDROCHLORIDE

TABLETS safely and effectively. See full prescribing information for use BENAZEPRIL HYDROCHLORIDE

TABLETS.

BENAZEPRIL HYDROCHLORIDE tablets, film coated for oral use

Initial U.S. Approval: 1991

WARNING-FETAL TOXICITY

See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue benazepril hydrochloride tablets as soon as possible. (5.1)

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing

fetus. (5.1)

INDICATIONS AND USAGE

Benazepril hydrochloride is an angiotensin-converting enzyme (ACE) inhibitor indicated for the treatment of hypertension,

to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily

strokes and myocardial infarctions. (1)

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

The most common adverse reactions leading to discontinuation were headache (0.6%) and cough (0.5%) (6)

To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Adult Patients: Initiate with 10 mg once daily (or 5 mg if patient is on diuretic). Titrate to 40 mg daily based on blood

pressure response. (2.1)

Pediatric patients age 6 years and above with glomerular filtration rate (GFR) >30 mL/min/1.73 m : Initiate with 0.2

mg/kg once daily. Maximum dose is 0.6 mg/kg once daily.

Renal Impairment: Initiate with 5 mg once daily in patients with GFR <30 mL/min/1.73 m (serum creatinine >3

mg/dL) (2.2)

Tablets: 5 mg, 10 mg, 20 mg, 40 mg

Angioedema or history of hereditary or idiopathic angioedema (4)

Hypersensitivity (4)

Co-administration with aliskiren in patients with diabetes (4)

Angioedema: Discontinue benazepril hydrochloride and treat appropriately. (5.2)

Monitor renal function periodically. (5.3)

Monitor blood pressure after initiation. (5.4)

Hyperkalemia: Monitor serum potassium periodically. (5.5)

Hepatic toxicity: Monitor for jaundice or signs of liver failure. (5.6)

Diuretics: Excessive drop in blood pressure (7.1)

Antidiabetics: Increased risk of hypoglycaemia (7.2)

NSAIDS: Increased risk of renal impairment and loss of antihypertensive efficacy (7.3)

Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

2.2 Dose Adjustment for Renal Impairment

2.3 Preparation of Suspension (for 150 mL of a 2 mg/mL Suspension)

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

5.2 Angioedema and Anaphylactoid Reactions

5.3 Impaired Renal Function

5.4 Hypotension

5.5 Hyperkalemia

5.6 Hepatic Failure

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

7.1 Diuretics

7.2 Antidiabetics

7.3 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors

(COX-2 Inhibitors)

7.4 Dual Blockade of the Renin-Angiotensin System (RAS)

7.5 Mammalian Target of Rapamycin (mTOR) Inhibitors

7.6 Lithium

7.7 Neprilysin Inhibitor

7.8 Gold

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Pediatric Use

8.4 Geriatric Use

8.5 Race

8.6 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia

(7.4)

Lithium: Symptoms of lithium toxicity (7.6)

Neprilysin Inhibitor: Increased risk of angioedema (7.7)

Gold: Nitritoid reactions (7.8)

Pediatrics: Safety and effectiveness have not been established in patients < 6 years of age or with GFR < 30

mL/min/1.73 m2 (8.3)

Race: Less antihypertensive effect in Blacks as monotherapy (8.5)

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue benazepril hydrochloride tablets as soon as

possible. (5.1)

Drugs that act directly on the renin-angiotensin system can cause injury and death to the

developing fetus [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Benazepril hydrochloride tablets are indicated for the treatment of hypertension, to lower blood

pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events,

primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of

antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this

drug principally belongs.

Control of high blood pressure should be part of comprehensive cardiovascular risk management,

including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,

exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood

pressure goals. For specific advice on goals and management, see published guidelines, such as those

of the National High Blood Pressure Education Program’s Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different

mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular

morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other

pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions

in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk

increase per mm Hg is greater at higher blood pressures, so that even modest reductions of severe

hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is

similar across populations with varying absolute risk, so the absolute benefit is greater in patients who

are at higher risk independent of their hypertension (for example, patients with diabetes or

hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a

lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients,

and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart

failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Sections or subsections omitted from the full prescribing information are not listed.

It may be used alone or in combination with thiazide diuretics.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

ADULTS

The recommended initial dose for patients not receiving a diuretic is 10 mg once a day. The usual

maintenance dosage range is 20 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.

Use with diuretics in adults

The recommended starting dose of benazepril hydrochloride tablets in a patient on a diuretic is 5 mg

once daily. If blood pressure is not controlled with benazepril hydrochloride alone, a low dose of

diuretic may be added.

PEDIATRIC PATIENTS 6 YEARS OF AGE AND OLDER

The recommended starting dose for pediatric patients is 0.2 mg/kg once per day. Titrate as needed to

0.6 mg/kg once per day. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in

pediatric patients.

Benazepril hydrochloride tablets are not recommended in pediatric patients less than 6 years of age or

in pediatric patients with GFR less than 30 mL/min/1.73 m [see Use in Specific Populations (8.3)].

2.2 Dose Adjustment for Renal Impairment

For adults with a GFR < 30 mL/min/1.73 m (serum creatinine > 3 mg/dL), the recommended initial dose

is 5 mg benazepril hydrochloride tablets once daily. Dosage may be titrated upward until blood

pressure is controlled or to a maximum total daily dose of 40 mg. Benazepril hydrochloride tablets can

also worsen renal function [see Warnings and Precautions (5.3)].

2.3 Preparation of Suspension (for 150 mL of a 2 mg/mL Suspension)

Add 75 mL of Ora-Plus®* oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle

containing fifteen benazepril hydrochloride 20 mg tablets, and shake for at least two minutes. Allow the

suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a

minimum of one additional minute. Add 75 mL of Ora-Sweet®* oral syrup vehicle to the bottle and

shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2°to8°C

(36°to46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap

closure. Shake the suspension before each use.

*Ora-Plus® and Ora-Sweet® are registered trademarks of Paddock Laboratories, Inc. Ora Plus®

contains carrageenan, citric acid, methylparaben, microcrystalline cellulose, carboxymethylcellulose

sodium, potassium sorbate, simethicone, sodium phosphate monobasic, xanthan gum, and water. Ora-

Sweet® contains citric acid, berry citrus flavorant, glycerin, methylparaben, potassium sorbate, sodium

phosphate monobasic, sorbitol, sucrose, and water.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 5 mg, 10 mg, 20 mg, and 40 mg

Each 5 mg tablet is white with “S” on one side and “341” on the other

Each 10 mg tablet is red with “S” on one side and “342” on the other

4 CONTRAINDICATIONS

Benazepril hydrochloride tablets are contraindicated in patients:

Benazepril hydrochloride tablets are contraindicated in combination with a neprilysin inhibitor (e.g.,

sacubitril). Do not administer benazepril hydrochloride tablets within 36 hours of switching to or from

sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions (5.2)].

Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors; including benazepril

hydrochloride tablets in patients with diabetes [see Drug Interactions (7.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

PREGNANCY CATEGORY D

Benazepril hydrochloride tablets can cause fetal harm when administered to a pregnant woman. Use of

drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy

reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting

oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential

neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When

pregnancy is detected, discontinue benazepril hydrochloride tablets as soon as possible [see Use in

Specific Populations (8.1)].

5.2 Angioedema and Anaphylactoid Reactions

Angioedema

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx including some fatal reactions,

have occured in patients treated with benazepril hydrochloride. Patients with involvement of the tongue,

glottis or larynx are likely to experience airway obstruction, especially those with a history of airway

surgery. Benazepril hydrochloride should be promptly discontinued and appropriate therapy and

monitoring should be provided until complete and sustained resolution of signs and symptoms of

angioedema has occurred.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of

angioedema while receiving an ACE inhibitor [see Contraindications (4)]. ACE inhibitors have been

associated with a higher rate of angioedema in Black than in non-Black patients.

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin)

inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased

risk for angioedema [see Drug Interactions (7.7)].

Intestinal Angioedema

Intestinal angioedema has occurred 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. In some cases, the angioedema was diagnosed

by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after

Each 20 mg tablet is grey with “S” on one side and “343” on the other

Each 40 mg tablet is blue with “S” on one side and “344” on the other

who are hypersensitive to benazepril or to any other ACE inhibitor

with a history of angioedema with or without previous ACE inhibitor treatment

stopping the ACE inhibitor.

Anaphylactoid Reactions

Anaphylactoid Reactions During Desensitization

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE

inhibitors sustained life-threatening anaphylactoid reactions.

Anaphylactoid Reactions During Dialysis

Sudden and potentially life threatening anaphylactoid reactions have occurred in some patients dialyzed

with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis

must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated.

Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration

should be given to using a different type of dialysis membrane or a different class of antihypertensive

agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein

apheresis with dextran sulfate absorption.

5.3 Impaired Renal Function

Monitor renal function periodically in patients treated with benazepril hydrochloride. Changes in renal

function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin sytem.

Patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients

with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial

infarction, or volume depletion) may be at particular risk of developing acute renal failure on benazepril

hydrochloride. Consider withholding or discontinuing therapy in patients who develop a clinically

significant decrease in renal function on benazepril hydrochloride.

5.4 Hypotension

Benazepril hydrochloride can cause symptomatic hypotension, sometimes complicated by oliguria,

progressive azotemia, acute renal failure, or death. Patients at risk of excessive hypotension include

those with the following conditions or characteristics: heart failure with systolic blood pressure below

100 mm Hg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy,

renal dialysis, or severe volume and/or salt depletion of any etiology.

In such patients, follow closely for the first 2 weeks of treatment and whenever the dose of benazepril

or diuretic is increased. Avoid use of benazepril hydrochloride in patients who are hemodynamically

unstable after acute MI.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension,

benazepril hydrochloride may block angiotensin II formation secondary to compensatory renin release.

If hypotension occurs, correct by volume expansion.

5.5 Hyperkalemia

Serum potassium should be monitored periodically in patients receiving benazepril hydrochloride.

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. 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 [see

Drug Interactions (7.1)].

5.6 Hepatic Failure

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.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another

drug and may not reflect the rates observed in practice.

Benazepril hydrochloride 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 similar 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 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%).

Adverse reactions seen in at least 1% greater frequency in patients treated with benazepril

hydrochloride than placebo were headache (6% vs. 4%), dizziness (4% vs. 2%), somnolence (2% vs.

0%) and postural dizziness (2% vs. 0%).

Adverse reactions reported in controlled clinical trials (less than 1% more on benazepril than on

placebo), and rarer events seen in post-marketing experience, include the following (in some, a causal

relationship to drug use is uncertain):

Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested

by dermatitis, pruritus, or rash), photosensitivity, and flushing.

Gastrointestinal: Nausea, pancreatitis, constipation, gastritis, vomiting, and melena.

Hematologic: Thrombocytopenia and hemolytic anemia.

Neurologic/Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia.

Other: Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination,

infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating.

Laboratory Abnormalities:

Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes [see Adverse Reactions S (5)]

have been reported, as have incidents of hyponatremia, electrocardiographic changes, eosinophilia, and

proteinuria.

7 DRUG INTERACTIONS

7.1 Diuretics

Hypotension

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 or decreasing the dose of diuretic prior to initiation of treatment with

benazepril hydrochloride [see Dosage and Administration (2.1)].

Hyperkalemia

Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the risk of

hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum

potassium frequently. Benazepril hydrochloride attenuates potassium loss caused by thiazide-type

diuretics.

7.2 Antidiabetics

Concomitant administration of benazepril hydrochloride and antidiabetic medicines (insulins, oral

hypoglycemic agents) may increase the risk of hypoglycemia.

7.3 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors

(COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised

renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors,

including benazepril, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible. Monitor renal function periodically in patients receiving

benazepril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.

7.4 Dual Blockade of the Renin-Angiotensin System (RAS)

Dual Blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is

associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including

acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS

inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use

of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on

benazepril hydrochloride and other agents that affect the RAS.

Do not coadminister aliskiren with benazepril hydrochloride in patients with diabetes. Avoid use of

aliskiren with benazepril hydrochloride in patients with renal impairment (GFR < 60 ml/min).

7.5 Mammalian Target of Rapamycin (mTOR) Inhibitors

Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus,

everolimus) therapy may be at increased risk for angioedema. Monitor for signs of angioedema [see

Warnings and Precautions (5.2)].

7.6 Lithium

Lithium toxicity has been reported in patients receiving lithium concomitantly with benazepril

hydrochloride. Lithium toxicity was usually reversible upon discontinuation of lithium or benazepril

hydrochloride. Monitor serum lithium levels during concurrent use.

7.7 Neprilysin Inhibitor

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema [see Warnings

and Precautions].

7.8 Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been

reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE

inhibitor therapy.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Benazepril hydrochloride can cause fetal harm when administered to a pregnant woman. Use of drugs

that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces

fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies

examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not

distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When

pregnancy is detected, discontinue benazepril hydrochloride as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population are

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the general U.S. population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes,

premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum

hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine

death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second

and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to

anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia,

hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs

affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to

the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be

appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that

oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe

infants with histories of in utero exposure to benazepril hydrochloride for hypotension, oliguria, and

hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to

benazepril hydrochloride, support blood pressure and renal perfusion. Exchange transfusions or

dialysis may be required as a means of reversing hypotension and substituting for disordered renal

function.

8.2 Lactation

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.

8.3 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 (12.3)]. The pharmacokinetics of

benazepril hydrochloride have been evaluated in pediatric patients 6 to 16 years of age [see Clinical

Pharmacology (12.3)].

Infants below the age of 1 year should not be given benazepril hydrochloride because of the risk of

effects on kidney development.

Safety and effectiveness of benazepril hydrochloride have not been established in pediatric patients less

than 6 years of age or in children with glomerular filtration rate < 30 mL/min/1.73m² [see Dosage and

Administration (2.1) and Clinical Pharmacology 12.3)].

8.4 Geriatric Use

Of the total number of patients who received benazepril in U.S. clinical studies of benazepril

hydrochloride, 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.

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 [see Dosage and Administration (2.2)].

8.5 Race

ACE inhibitors, including benazepril hydrochloride, as monotherapy, have an effect on blood pressure

that is less in Black patients than in non-Blacks.

8.6 Renal Impairment

Dose adjustment of benazepril hydrochloride is required in patients undergoing hemodialysis or whose

creatinine clearance is ≤ 30 mL/min. No dose adjustment of benazepril hydrochloride is required in

patients with creatinine clearance > 30 mL/min [see Dosage and Administration (2.2) and Clinical

Pharmacology (12.3)].

10 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, for which the usual treatment would be

intravenous infusion of normal saline solution. Hypotension can be associated with electrolyte

disturbances and renal failure.

Benazepril is only slightly dialyzable, but consider dialysis to support patients with severely impaired

renal function [see Warnings and Precautions (5.3)].

If ingestion is recent, consider activated charcoal. Consider gastric decontamination (e.g., vomiting,

gastric lavage) in the early period after ingestion.

Monitor for blood pressure and clinical symptoms. Supportive management should be employed to

ensure adequate hydration and to maintain systemic blood pressure.

In the case of marked hypotension, infuse physiological saline solution; as needed, consider

vasopressors (e.g., catecholamines i.v.).

11 DESCRIPTION

Benazepril hydrochloride, USP is a white to off-white crystalline powder, soluble (> 100 mg/mL) in

water, in ethanol, and in methanol. Its chemical name is benazepril 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

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