Benazepril

Mechanism of Action

Angiotensin converting enzyme (ACE) inhibitors dilate arteries and veins by competively inhibiting the conversion of angiotensin I to angiotensin II (a potent endogenous vasoconstrictor) and by inhibiting bradykinin metabolism; these actions result in preload and afterload reductions on the heart

ACE inhibitors also promote sodium and water excretion by inhibiting angiotensin-II induced aldosterone secretion; elevation in potassium may also be observed

ACE inhibitors also elicit renoprotective effects through vasodilation of renal arterioles

ACE inhibitors reduce cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction

Absorption

Bioavailability: 37%

Onset: 1-2 hr (peak effect with 2-20 mg dose)

Duration: 24 hr (with 5-20 mg dose)

Peak plasma time: 0.5-1 hr (parent drug)

Distribution

Protein bound: 95-97%

Vd: 8.7 L

Metabolism

Metabolite: Benazeprilat (active)

Elimination

Half-life: 10-11 hr

Dialyzable: Minimal

Excretion: Urine (primarily); bile (11-12%)

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-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is

Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.

Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.

Lotensin is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.

Lotensin is 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.

The most common benazepril side effects are:

• headache
• dizziness
• tiredness
• drowsiness
• nausea
• cough

Tell your doctor if any of these symptoms are severe or do not go away.

Less common, but more serious benazepril side effects are:

• swelling of the face, legs, feet, ankles, arms, lips, tongue, and throat 
• swelling of the intestines (intestinal angioedema)
• serious allergic reactions
• rash
• decreased kidney function
• pancreatitis
• asthma
• difficulty breathing
• increased levels of potassium in the blood (hyperkalemia)
• anemia
• increased risk of infections
• liver failure

This is not a complete list of benazepril side effects. Ask your doctor or pharmacist for more information. Tell your doctor if you develop any side effects.

You should not use this medicine if you are allergic to benazepril or to any other ACE inhibitor, such as captopril, fosinopril, enalapril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

If you have diabetes, do not use benazepril together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo).

You may also need to avoid taking benazepril with aliskiren if you have kidney disease.

To make sure benazepril is safe for you, tell your doctor if you have:

• kidney disease (or if you are on dialysis);

• liver disease;

• diabetes;

• any history of heart disease; or

• if you have had an organ transplant.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Benazepril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

Benazepril can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using benazepril.

Benazepril is not approved for use by anyone younger than 6 years old.

It is very important that your doctor check your progress at regular visits to make sure benazepril is working properly. Blood tests may be needed to check for unwanted effects.

Using benazepril while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using benazepril, tell your doctor right away.

benazepril may cause serious types of allergic reactions. These reactions can be life-threatening and require immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your face, arms, legs, eyes, lips, tongue, or throat while you are using benazepril.

Call your doctor right away if you have severe stomach pain (with or without nausea or vomiting). This could be a symptom of intestinal angioedema.

Dizziness, lightheadedness, or fainting may also occur, especially when you get up from a lying or sitting position or if you have been taking a diuretic (water pill). Make sure you know how you react to the medicine before you drive, use machines, or do other things that could be dangerous if you are dizzy or not alert. If you feel dizzy, lie down so you do not faint. Then sit for a few moments before standing to prevent the dizziness from returning. If you faint, stop using benazepril and call your doctor right away.

Check with your doctor right away if you become sick while taking benazepril, especially with severe or continuing nausea, vomiting, or diarrhea. These conditions may cause you to lose too much water or salt and may lead to low blood pressure. You can also lose water by sweating, so drink plenty of water during exercise or in hot weather.

Check with your doctor if you have a fever, chills, or sore throat. These may be symptoms of an infection caused by low white blood cells.

Hyperkalemia (high potassium in the blood) may occur while you are using benazepril. Check with your doctor right away if you have the following symptoms: abdominal or stomach pain, confusion, difficulty breathing, irregular heartbeat, nausea or vomiting, nervousness, numbness or tingling in the hands, feet, or lips, shortness of breath, or weakness or heaviness of the legs. Do not use medicines, supplements, or salt substitutes containing potassium without first checking with your doctor.

Check with your doctor right away if you have upper stomach pain, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Make sure any doctor or dentist who treats you knows that you are using benazepril. You may need to stop using benazepril several days before having surgery or medical tests.

benazepril may be less effective in black patients. Black patients also have an increased risk of swelling of the hands, arms, face, mouth, or throat.

Do not take other medicines unless they have been discussed with your doctor. This especially includes over-the-counter (nonprescription) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, since they may tend to increase your blood pressure.

For all patients taking this medicine:

• If you have an allergy to benazepril or any other part of benazepril.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have ever had a very bad or life-threatening reaction called angioedema. Signs may be swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; unusual hoarseness.
• If you have kidney disease.
• If you are taking a drug that has aliskiren in it and you also have high blood sugar (diabetes) or kidney problems. Check with your doctor or pharmacist if you are not sure if a drug you take has aliskiren in it.
• If you have taken a drug that has sacubitril in it in the last 36 hours.

Children:

• If your child is younger than 6 years of age. Do not give this medicine to a child younger than 6 years of age.

This is not a list of all drugs or health problems that interact with benazepril.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use benazepril as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Take this medicine at the same time of day.
• Keep taking benazepril as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.
• A liquid (suspension) can be made if you cannot swallow pills. Talk with your doctor or pharmacist.
• If a liquid (suspension) is made, shake well before use.
• Measure liquid doses carefully. Use the measuring device that comes with this medicine. If there is none, ask the pharmacist for a device to measure benazepril.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of a high potassium level like a heartbeat that does not feel normal; change in thinking clearly and with logic; feeling weak, lightheaded, or dizzy; feel like passing out; numbness or tingling; or shortness of breath.
• Very bad dizziness or passing out.
• Cough that does not go away.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Very bad belly pain.
• Very upset stomach or throwing up.
• Liver problems have happened with drugs like this one. Sometimes, this has been deadly. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

• Store at room temperature.
• Protect from heat.
• Store in a dry place. Do not store in a bathroom.
• If a liquid (suspension) is made from the tablets, store in a refrigerator. Do not freeze. Throw away any part not used after 30 days.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Pregnancy

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 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 hydrochloride, 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 hydrochloride for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.3)].

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.

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)].

Neonates with a history of in utero exposure to Benazepril hydrochloride:

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.

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)].

Race

ACE inhibitors, including Benazepril hydrochloride, as monotherapy, have an effect on blood pressure that is less in Black patients than in non-Blacks.

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)].

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.).

Benazepril Hydrochloride Tablets USP 5 mg 100s Label Text

NDC 0093-5124-01

Benazepril
Hydrochloride
Tablets USP
5 mg

Rx only

100 TABLETS

TEVA

Competitive inhibition of angiotensin I being converted to angiotensin II, a potent vasoconstrictor, through the angiotensin I-converting enzyme (ACE) activity, with resultant lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion

Absorption

Rapid (37%); food does not alter significantly; metabolite (benazeprilat) itself unsuitable for oral administration due to poor absorption

Distribution

Vd: ~8.7 L (Balfour 1991)

Metabolism

Rapidly and extensively hepatic to its active metabolite, benazeprilat, via enzymatic hydrolysis; extensive first-pass effect

Excretion

Urine (trace amounts as benazepril; 20% as benazeprilat; 12% as other metabolites)

Clearance: Nonrenal clearance (ie, biliary, metabolic) appears to contribute to the elimination of benazeprilat (11% to 12%), particularly patients with severe renal impairment; hepatic clearance is the main elimination route of unchanged benazepril

Dialysis: ~6% of metabolite removed within 4 hours of dialysis following 10 mg of benazepril administered 2 hours prior to procedure; parent compound not found in dialysate

Store at ≤30°C (86°F). Protect from moisture.

Initial dose: With a diuretic: 5 mg orally once a day; without a diuretic: 10 mg orally once a day
Maintenance dose: 20 to 40 mg/day orally as a single dose or in two equally divided doses
Maximum dose: 80 mg/day

Comments:
-The divided dose regimen was more effective in controlling pre-dosing blood pressure.
-If discontinuing a diuretic prior to initiating this drug to reduce the likelihood of hypotension, conclude diuretic therapy 2 to 3 days prior to starting this drug.

Mild to moderate renal dysfunction (CrCl 30 mL/min/1.73 m2 or greater): No adjustment recommended

Severe renal dysfunction (CrCl less than 30 mL/min/1.73 m2):
-Pediatrics: Not recommended
-Adults: Initial dose: 5 mg orally once a day; Maximum dose: 40 mg/day

• Benazepril is used in the treatment of high blood pressure (hypertension), to lower blood pressure.
• Effective alone or in combination with other treatments for high blood pressure.

• Peak concentrations of benazepril are reached within half an hour to one hour of oral administration. Benazepril is metabolized to an active metabolite, benazeprilat, which also lowers blood pressure.
• Blood pressure lowering effects are seen within an hour of oral administration with peak effects achieved between two and four hours after dosing. Blood pressure lowering effects are maintained for at least 24 hours, although in some patients these effects may diminish towards the end of the 24 hour period. It may take several weeks before optimal blood pressure lowering effects are achieved.
• Abrupt withdrawal of benazepril has not resulted in an abrupt increase in blood pressure; however, as with most antihypertensive drugs, it is best to discontinue benazepril slowly.

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Summary of Use during Lactation

Because of the low levels of benazepril in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.

Drug Levels

Benazapril is an inactive drug that is metabolized to the active metabolite benazaprilat. Benazaprilat is poorly absorbed orally.

Maternal Levels. In 9 women (time postpartum not stated) given an oral dose of 20 mg of benazepril daily for 3 days, peak milk levels of 0.9 mcg/L of benazepril at 1 hour after the dose and 2 mcg/L of its active metabolite benazeprilat at 1.5 hours after the dose were detected. The authors estimated that the infant would receive a dose less than 0.14% of the mother's weight-adjusted dose of benazepril, mostly as benazeprilat.[1]

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Captopril, Enalapril, Quinapril

References

1. Kaiser G, Ackerman R, Dieterle W et al. Benazepril and benazeprilat in human plasma and breast milk. Eur J Clin Pharmacol. 1989;36(suppl):A303. Abstract.