BENAZEPRIL HYDROCHLORIDE

Main information

  • Trade name:
  • BENAZEPRIL HYDROCHLORIDE- benazepril hydrochloride tablet
  • Composition:
  • BENAZEPRIL HYDROCHLORIDE 40 mg
  • Administration route:
  • ORAL
  • Prescription type:
  • PRESCRIPTION DRUG
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BENAZEPRIL HYDROCHLORIDE- benazepril hydrochloride tablet
    United States
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • Benazepril HCl tablets, USP 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 va
  • Product summary:
  • Benazepril HCl tablets, USP, 40 mg , are supplied as white, biconvex, round, uncoated tablets, debossed with “54” on one side and “A” on the other side. They are available as follows: Bottles of 30:                NDC 68788-8968-3 Bottles of 60:                NDC 68788-8968-6 Bottles of 90:                NDC 68788-8968-9 Bottles of 100:               NDC 68788-8968-1 Bottles of 120:               NDC 68788-8968-8 Storage: Store at 20º to 25°C (68° to 77ºF); excursions permitted between 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container as defined in the USP.

Status

  • Source:
  • DailyMed - NLM - National Library of Medicine
  • Authorization status:
  • Abbreviated New Drug Application
  • Authorization number:
  • 68788-8968-1, 68788-8968-3, 68788-8968-6, 68788-8968-8, 68788-8968-9
  • Last update:
  • 26-05-2019

Summary of Product characteristics: dosage, interactions, side effects

BENAZEPRIL HYDROCHLORIDE- benazepril hydrochloride tablet

Preferred Pharmaceuticals Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BENAZEPRIL HCl TABLETS safely and

effectively. See full prescribing information for BENAZEPRIL HCl TABLETS.

BENAZEPRIL HCl tablets, USP 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 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 HCl tablets, USP 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 Amneal Pharmaceuticals at 1-877-835-5472 or

www.amneal.com 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 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 hypoglycemia (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

(7.4)

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 3/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: FETAL TOXICITY

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 Nursing Mothers

8.3 Pediatric Use

8.4 Geriatric Use

8.5 Race

8.6 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

(7.4)

Lithium: Symptoms of lithium toxicity (7.6)

Neprilysin Inhibitor: Increased risk of angioedema (7.7)

Gold: Nitritoid reactions (7.8)

Pregnancy: Discontinue drug if pregnancy is detected (5.1, 8.1)

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

mL/min/1.73 m (8.3)

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

12.1 Mechanism of Action

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 HCl as soon as possible.

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 HCl tablets, USP 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 mmHg 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 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.

Use with diuretics in adults

The recommended starting dose of benazepril HCl tablets, USP in a patient on a diuretic is 5 mg once

daily. If blood pressure is not controlled with benazepril HCl tablets, USP 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 HCl tablets, USP is not recommended in pediatric patients less than 6 years of age or in

pediatric patients with GFR less than 30 mL/min/1.73 m² [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 HCl tablets, USP once daily. Dosage may be titrated upward until blood pressure is

controlled or to a maximum total daily dose of 40 mg. Benazepril HCl tablets, USP 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 HCl tablets, USP 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° to 8°C

(36° to 46°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, biconvex, round, uncoated tablets, debossed with “51” on one side and

“A” on the other

Each 10 mg tablet is white, biconvex, round, uncoated tablets, debossed with “52” on one side and

4 CONTRAINDICATIONS

Benazepril HCl tablets, USP are contraindicated in patients:

Benazepril HCl is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not

administer benazepril HCl within 36 hours of switching to or from sacubitril/valsartan, a neprilysin

inhibitor [see Warnings and Precautions (5.2)].

Do not co-administer aliskiren with angiotensin receptor blockers, ACE inhibitors, including benazepril

HCl tablets, USP in patients with diabetes [see Drug Interactions (7.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Pregnancy Category D

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 HCl 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 occurred in patients treated with benazepril HCl. Patients with involvement of the tongue, glottis or

larynx are likely to experience airway obstruction, especially those with a history of airway surgery.

Benazepril HCl 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 co-administration 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

“A” on the other

Each 20 mg tablet is white, biconvex, round, uncoated tablets, debossed with “53” on one side and

“A” on the other

Each 40 mg tablet is white, biconvex, round, uncoated tablets, debossed with “54” on one side and

“A” on the other

who are hypersensitive to benazapril 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 HCl. Changes in renal function,

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

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease

in renal function on benazepril HCl.

5.4 Hypotension

Benazepril HCl 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 mmHg,

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 HCl 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 HCl 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 HCl. 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 HCl 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 HCl 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 HCl 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 HCl 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 Warnings and

Precautions (5)] have been reported, as have incidents of hyponatremia, electrocardiographic changes,

eosinophilia, and proteinuria.

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472

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

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 HCl. The possibility of hypotensive effects with benazepril HCl can be minimized by either

discontinuing or decreasing the dose of diuretic prior to initiation of treatment with benazepril HCl [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 HCl attenuates potassium loss caused by thiazide-type diuretics.

7.2 Antidiabetics

Concomitant administration of benazepril HCl 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, co-administration 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 HCl and other agents that affect the RAS.

Do not co-administer aliskiren with benazepril HCl in patients with diabetes. Avoid use of aliskiren with

benazepril HCl in patients with renal impairment (GFR <60 mL/min).

7.5 Mammalian Target of Rapamycin (mTOR) Inhibitors

Patients receiving co-administration 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 HCl.

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

Pregnancy Category D

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 HCl as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third

trimester of pregnancy. 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. Appropriate management of maternal hypertension during

pregnancy is important to optimize outcomes for both mother and fetus. 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. If oligohydramnios is observed, discontinue benazepril HCl,

unless it is considered lifesaving for the mother. 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 HCl for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations

(8.3)].

8.2 Nursing Mothers

Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of

lactating women treated with benazepril. A newborn child ingesting entirely breast milk would receive

less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.

8.3 Pediatric Use

The antihypertensive effects of benazepril HCl 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

HCl 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 HCl because of the risk of effects on

kidney development.

Safety and effectiveness of benazepril HCl have not been established in pediatric patients less than 6

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

Administration (2.1) and Clinical Pharmacology (12.3)].

Neonates with a history of in utero exposure to benazepril HCl:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a 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.

8.4 Geriatric Use

Of the total number of patients who received benazepril in U.S. clinical studies of benazepril HCl, 18%

were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were

observed between these patients and younger patients, and other reported clinical experience has not

identified differences in responses between the elderly and younger patients, but greater sensitivity of

some older individuals cannot be ruled out.

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 HCl, 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 HCl is required in patients undergoing hemodialysis or whose creatinine

clearance is ≤30 mL/min. No dose adjustment of benazepril HCl 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 HCl, 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:

Its empirical formula is C

H N O HCl, and its molecular weight is 460.96.

Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme

inhibitor.

Benazepril HCl tablets, USP are supplied as white, round, biconvex tablets containing either 5 mg, 10

mg, 20 mg, and 40 mg of benazepril HCl, USP for oral administration. The inactive ingredients are

crospovidone, lactose anhydrous, magnesium stearate, microcrystalline cellulose, pregelatinized corn

starch and talc.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals.

Benazeprilat has much greater ACE inhibitory activity than does benazepril. 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.

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 HCl

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.

12.2 Pharmacodynamics

Single and multiple doses of 10 mg or more of benazepril HCl 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.

Drug interactions

Benazepril HCl 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

12.3 Pharmacokinetics

The pharmacokinetics of benazepril are approximately dose-proportional within the dosage range of 10

to 80 mg.

Following oral administration of benazepril HCl, peak plasma concentrations of benazepril, and its

active metabolite benazeprilat are reached within 0.5 to 1 hours and 1 to 2 hours, respectively. While

the bioavailability of benazepril is not affected by food, time to peak plasma concentrations of

benazeprilat is delayed to 2 to 4 hours.

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 to

23.6 μmol/L).

Benazepril is almost completely metabolized to benazeprilat by cleavage of the ester group (primarily

in liver). Both benazepril and benazeprilat undergo glucuronidation.

Benazepril and benazeprilat are cleared predominantly by renal excretion. About 37% of an orally

administered dose was recovered in urine as benazeprilat (20%), benazeprilat glucuronide (8%),

benazepril glucuronide (4%) and as trace amounts of benazepril. Nonrenal (i.e., biliary) excretion

accounts for approximately 11% to 12% of benazeprilat excretion. The effective half-life of

benazeprilat following once daily repeat oral administration 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.

Accumulation ratio based on AUC of benazeprilat was 1.19 following once daily administration.

Specific Populations

Renal impairment

The pharmacokinetics of systemic exposure to 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

(2)].

When dialysis was started 2 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.

Hepatic impairment

In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are

essentially unaltered.

Drug Interactions

The pharmacokinetics of benazepril are not affected by the following drugs: hydrochlorothiazide,

furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen,

acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially

affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).

Pediatrics

The pharmacokinetics of benazaprilat, evaluated in pediatric patients with hypertension following oral

administration of a single dose is presented in table below.

Age group

(ng/mL)

(ng/mL*h)

CL/F/wt

(L/h/Kg)

>1 to ≤ 24

months

(192, 391)

(0.6, 2)

1328

(773, 2117)

0.26

(0.18, 0.4)

(4, 5.8)

>2 to ≤ 6 years

(168, 244)

(1.4, 2.4)

(842, 1152)

0.36

(0.31, 0.42)

(4.7, 6.5)

>6 to ≤ 12 years

(194, 258)

(1.2, 2.2)

1041

(855, 1313)

0.25

(0.21, 0.31)

(4.7, 6.5)

>12 to ≤ 17

years

(217, 420)

(1.3, 2.3)

1794

(1478, 2340)

0.16

(0.13, 0.21)

(4.2, 5.7)

13 NONCLINICAL TOXICOLOGY

13.1 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,

0-inf

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 to 500 mg/kg/day (6 to 60 times the

maximum recommended human dose based on mg/m comparison and 37 to 375 times the maximum

recommended human dose based on a mg/kg comparison), benazepril HCl had no adverse effect on the

reproductive performance of male and female rats.

14 CLINICAL STUDIES

Hypertension

Adult Patients

In single-dose studies, benazepril HCl lowered blood pressure within 1 hour, with peak reductions

achieved between 2 and 4 hours after dosing. The antihypertensive effect of a single dose persisted for

24 hours. In multiple-dose studies, once-daily doses of between 20 mg and 80 mg decreased seated

pressure 24 hours after dosing by about 6 to 12 mmHg systolic and 4 to 7 mmHg diastolic. The trough

values represent reductions of about 50% of that seen at peak.

Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate

hypertensive patients not using diuretics. The minimal effective once-daily dose of benazepril HCl was

10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in

the studied dosing range (10 to 80 mg). In studies comparing the same daily dose of benazepril HCl

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.

The antihypertensive effects of benazepril HCl were not appreciably different in patients receiving

high- or low-sodium diets.

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 HCl in combination with thiazide diuretics gives a blood-pressure-lowering effect

greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone axis,

administration of benazepril HCl tends to reduce the potassium loss associated with the diuretic.

Pediatric Patients

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 or 0.2 mg/kg then titrated up to 0.3 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 to 6 mmHg more than in children on benazepril.

No dose-response was observed.

16 HOW SUPPLIED/STORAGE AND HANDLING

Benazepril HCl tablets, USP, 40 mg, are supplied as white, biconvex, round, uncoated tablets, debossed

with “54” on one side and “A” on the other side.

They are available as follows:

Bottles of 30: NDC 68788-8968-3

Bottles of 60: NDC 68788-8968-6

Bottles of 90: NDC 68788-8968-9

Bottles of 100: NDC 68788-8968-1

Bottles of 120: NDC 68788-8968-8

Storage: Store at 20º to 25°C (68° to 77ºF); excursions permitted between 15º to 30ºC (59º to 86ºF)

[see USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

Pregnancy: Tell female patients of childbearing age about the consequences of exposure to benazepril

HCl during pregnancy. Discuss treatment options with women planning to become pregnant. Instruct

patients 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. Tell patients 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: Tell patients to report light-headedness especially during the first few

days of therapy. If actual syncope occurs, tell the patient to discontinue the drug until they have

consulted with the prescribing physician.

Tell patients that excessive perspiration and dehydration may lead to an excessive fall in blood pressure

because of a reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea

may also lead to a fall in blood pressure; advise patients accordingly.

Hyperkalemia: Tell patients not to use potassium supplements or salt substitutes containing potassium

without consulting the prescribing physician.

Hypoglycemia: Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE

inhibitor to monitor for hypoglycemia closely, especially during the first month of combined use.

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 08-2017-02

Repackaged By: Preferred Pharmaceuticals Inc.

PRINCIPAL DISPLAY PANEL

Preferred Pharmaceuticals Inc.

BENAZEPRIL HYDROCHLORIDE

benazepril hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code (Source )

NDC:6 8 78 8 -8 9 6 8 (NDC:6 516 2-754)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

BENAZEPRIL HYDRO CHLO RIDE (UNII: N1SN9 9 T6 9 T) (BENAZEPRILAT -

UNII:JRM70 8 L70 3)

BENAZEPRIL

HYDROCHLORIDE

40 mg

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND (Bico nvex)

S iz e

9 mm

Flavor

Imprint Code

54;A

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 78 8 -8 9 6 8 -3

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/11/20 16

2

NDC:6 8 78 8 -8 9 6 8 -6

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/11/20 16

3

NDC:6 8 78 8 -8 9 6 8 -9

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/11/20 16

4

NDC:6 8 78 8 -8 9 6 8 -1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/11/20 16

5

NDC:6 8 78 8 -8 9 6 8 -8

120 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/11/20 16

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 8 20

0 1/11/20 16

Labeler -

Preferred Pharmaceuticals Inc. (791119022)

Registrant -

Preferred Pharmaceuticals Inc. (791119022)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Preferred Pharmaceuticals Inc.

79 1119 0 22

REPACK(6 8 78 8 -8 9 6 8 )

Revised: 3/2018