Data from FDA - Curated by Toby Galbraith - Last updated 28 July 2017

Indication(s)

1 INDICATIONS AND USAGE Benazepril hydrochloride 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. It may be used alone or in combination with thiazide diuretics. Benazepril hydrochloride tablets USP are 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)

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Advisory information

contraindications
4 CONTRAINDICATIONS Benazepril hydrochloride tablets are contraindicated in patients: who are hypersensitive to benazepril or to any other ACE inhibitor with a history of angioedema with or without previous ACE inhibitor treatment Do not coadminister aliskiren with benazepril hydrochloride tablets in patients with diabetes [see Drug Interactions (7.4)]. Angioedema or history of hereditary or idiopathic angioedema (4) Hypersensitivity (4) Coadministration with aliskiren in patients with diabetes (4)
Adverse reactions
6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Benazepril hydrochloride has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in benazepril hydrochloride and placebo patients. The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with benazepril hydrochloride and in 3% of patients treated with placebo. The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) Adverse reactions seen in at least 1% greater frequency in patients treated with benazepril hydrochloride than placebo were headache (6% vs 4%), dizziness (4% vs 2%), somnolence (2% vs 0%) and postural dizziness (2% vs 0%). Adverse reactions reported in controlled clinical trials (less than 1% more on benazepril than on placebo), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain): Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing. Gastrointestinal: Nausea, pancreatitis, constipation, gastritis, vomiting, and melena. Hematologic: Thrombocytopenia and hemolytic anemia. Neurologic/Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia Other: Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating. Laboratory Abnormalities: Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes [see Warnings and Precautions (6.5)] have been reported, as have incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria The most common adverse reactions leading to discontinuation were headache (0.6%) (5.6) and cough (5.7) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 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 m2 : 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 m2 (serum creatinine > 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 tablets 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/1.73m2 [see Use in Specific Populations (8.4)]. 2.2. Dose Adjustment for Renal Impairment For adults with a GFR < 30 mL/min/1.73 m2 (serum creatinine > 3 mg/dL), the recommended initial dose is 5 mg Benazepril hydrochloride tablets once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg. Benazepril hydrochloride tablets can also worsen renal function [see Warnings and Precautions (5.3)]. 2.3. Preparation of Suspension (for 150 mL of a 2 mg/mL Suspension) Add 75 mL of Ora-Plus®* oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen benazepril hydrochloride 20 mg tablets, and shake for at least two minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of one additional minute. Add 75 mL of Ora-Sweet®* oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 28°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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 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/1.73m2 (8.4) Race: Less antihypertensive effect in blacks as monotherapy (8.6) 8.1 Pregnancy Teratogenic Effects 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 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 (8.4)]. 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. 8.4 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. 8.5 Geriatric Use Of the total number of patients who received benazepril in U.S. clinical studies of benazepril hydrochloride, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.2)]. 8.6 Race ACE inhibitors, including benazepril hydrochloride, as monotherapy, have an effect on blood pressure that is less in black patients than in non-blacks. 8.7 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)].
Pregnancy and lactation
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.

Interactions

7 DRUG INTERACTIONS 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) Lithium: Symptoms of lithium toxicity (7.6) 7.1 Diuretics Hypotension Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with benazepril hydrochloride. The possibility of hypotensive effects with benazepril hydrochloride can be minimized by either discontinuing or decreasing the dose of diuretic prior to initiation of treatment with benazepril hydrochloride [see Dosage and Administration (2.1)]. Hyperkalemia Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently. Benazepril hydrochloride attenuates potassium loss caused by thiazide-type diuretics. 7.2 Antidiabetics Concomitant administration of benazepril hydrochloride and antidiabetic medicines (insulins, oral hypoglycemic agents) may increase the risk of hypoglycemia. 7.3 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs. 7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual Blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on benazepril hydrochloride and other agents that affect the RAS. Do not coadminister aliskiren with benazepril hydrochloride in patients with diabetes. Avoid use of aliskiren with benazepril hydrochloride in patients with renal impairment (GFR < 60 mL/min). 7.5 Mammalian Target of Rapamycin (mTOR) Inhibitors Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Monitor for signs of angioedema [see Warnings and Precautions (5.2)]. 7.6 Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with benazepril hydrochloride. Lithium toxicity was usually reversible upon discontinuation of lithium or benazepril hydrochloride. Monitor serum lithium levels during concurrent use. 7.7 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.

More information

Category Value
Authorisation number ANDA076211
Agency product number N1SN99T69T
Orphan designation No
Product NDC 54458-893
Date Last Revised 09-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 898719
Marketing authorisation holder International Laboratories, LLC
Warnings WARNING: FETAL TOXICITY When pregnancy is detected, discontinue benazepril hydrochloride tablets 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)]. 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)