Benazepril hydrochloride 10 MG Oral Tablet
Generic Name: BENAZEPRIL HYDROCHLORIDE
Brand Name: Benazepril Hydrochloride
- Substance Name(s):
- BENAZEPRIL HYDROCHLORIDE
DRUG INTERACTIONS
7 •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 ( 7.4) •Lithium: Symptoms of lithium toxicity ( 7.5) 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 otassium-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, 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 hydrochloride and other agents that affect the RAS.
Do not co-administer 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 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.
OVERDOSAGE
10 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.).
DESCRIPTION
11 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 benazepril 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is Its empirical formula is C 24H 28N 2O 5•HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor.
Benazepril hydrochloride is supplied as film-coated tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration.
The inactive ingredients are carnauba wax, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, titanium dioxide, and triacetin.
The 10 mg tablet also contains FD&C Red No.
40 aluminum lake.
The 20 mg tablet also contains black iron oxide and yellow iron oxide.
The 40 mg tablet also contains FD&C Blue No.
2 aluminum lake.
Benazepril hydrochloride tablets USP, 5 mg, 10 mg, 20 mg and 40 mg meet USP Dissolution Test 2.
Structure
CLINICAL STUDIES
14 Hypertension Adult Patients In single-dose studies, benazepril hydrochloride 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 12mmHg 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 hydrochloride was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10-80 mg).
In studies comparing the same daily dose of benazepril hydrochloride given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.
The antihypertensive effects of benazepril hydrochloride 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 hydrochloride 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 hydrochloride 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.
HOW SUPPLIED
16 /STORAGE AND HANDLING Benazepril hydrochloride tablets, USP, 10 mg, are round, red, film-coated tablets, debossed “S” on one side and “342” on the other side, packaged as follows: Bottle of 30 – 68788-9327-3 Bottle of 60 – 68788-9327-6 Bottle of 90 – 68788-9327-9 Bottle of 100 – 68788-9327-100 Benazepril hydrochloride tablets, USP, 20 mg, are round, grey, film-coated tablets, debossed “S” on one side and “343” on the other side, packaged as follows: Bottle of 30 – 68788-9313-3 Bottle of 60 – 68788-9313-6 Bottle of 90 – 68788-9313-9 Bottle of 100 – 68788-9313-100 Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature].
Protect from moisture.
Dispense in tight container (USP).
Distributed by: Solco Healthcare US, LLC Cranbury, NJ 08512, USA Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd.
Xunqiao, Linhai, Zhejiang 317024, China Revised: 12/2015 07713-04 Repackaged by Preferred Pharmaceuticals, Inc.
DOSAGE FORMS AND STRENGTHS
3 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 •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 •Tablets: 5 mg, 10 mg, 20 mg, 40 mg
INDICATIONS AND USAGE
1 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 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.
It may be used alone or in combination with thiazide diuretics.
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)
BOXED WARNING
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)] 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)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS •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) 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 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 may be at increased risk for angioedema.
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 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 occured 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 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 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Pregnancy: Tell female patients of childbearing age about the consequences of exposure to benazepril hydrochloride 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.
DOSAGE AND ADMINISTRATION
2 •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 2: 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 3 mg/dL) ( 2.3) 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 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 2 [see Use in Specific Populations ( 8.4)].
2.2 Dose Adjustment for Renal Impairment For adults with a GFR 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 2-8°C (36-46°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.