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Benazepril Hydrochloride (Tablet)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/167

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Benazepril Hydrochloride (Tablet)
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Hypertension:<br/>Adults: The recommended initial dose for patients not receiving a diuretic is 10 mg once-a-day. The usual maintenance dosage range is 20 to 40 mg per day administered as a single dose or in two equally divided doses. A dose of 80 mg gives an increased response, but experience with this dose is limited. The divided regimen was more effective in controlling trough(pre-dosing) blood pressure than the same dose given as a once-daily regimen. Dosage adjustment should be based on measurement of peak (2 to 6 hours after dosing) and trough responses. If a once-daily regimen does not give adequate trough response, an increase in dosage or divided administration should be considered. If blood pressure is not controlled with benazepril hydrochloride alone, a diuretic can be added. Total daily doses above 80 mg have not been evaluated. Concomitant administration of benazepril hydrochloride with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium . In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of benazepril hydrochloride. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapywith benazepril hydrochloride . Then, if blood pressure is not controlled with benazepril hydrochloride alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg benazepril hydrochloride should be used to avoid excessive hypotension.<br/>Pediatrics: In children, doses of benazepril hydrochloride between 0.1 and 0.6 mg/kg once daily have been studied, and doses greater than 0.1 mg/kg were shown to reduce blood pressure (see Pharmacodynamics). Based on this, the recommended starting dose of benazepril hydrochloride is 0.2 mg/kg once per day as monotherapy. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in pediatric patients. For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for benazepril hydrochloride, follow the suspension preparation instructions below to administer benazepril hydrochloride as a suspension. Treatment with benazepril hydrochloride is not advised for children below the age of 6 years and in pediatric patients with glomerular filtration rate<30 mL, as there are insufficient data available to support a dosing recommendation in these groups.<br/>For Hypertensive Patients with Renal Impairment: For patients with a creatinine clearance<30 mL/min/1.73 m(serum creatinine>3 mg/dL), the recommended initial dose is 5 mg benazepril hydrochloride once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg .<br/>Preparation of Suspension (for 150 mL of a 2 mg/mL suspension): Add 75 mL of Ora-Plusoral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen benazepril hydrochloride 20 mg tablets, and shake for at least 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 75 mL of Ora-Sweetoral 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.
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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 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 CHNO���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. Benazepril hydrochloride is supplied as tablets containing 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration. The inactive ingredients are microcrystalline cellulose, lactose monohydrate, pregelatinised starch, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400, polysorbate 80, iron oxide yellow (10 mg) and iron oxide red (20 mg and 40 mg).
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Mechanism of Action: Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. 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. Hypertensive patients treated with benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their 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 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 .<br/>Pharmacokinetics and Metabolism: Following oral administration of benazepril, peak plasma concentrations of benazepril are reached within 0.5 to 1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract. Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1 to 2 hours after drug intake in the fasting state and 2 to 4 hours after drug intake in the nonfasting state. 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��mol/L). Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and benazeprilat. Only trace amounts of an administered dose of benazepril can be recovered in the urine as unchanged benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide. The kinetics of benazepril are approximately dose-proportional within the dosage range of 10 to 80 mg. In adults, the effective half-life of accumulation of benazeprilat following multiple dosing 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. The effective half-life of accumulation of benazeprilat following multiple dosing 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. The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively. Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11% to 12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance. In patients with renal insufficiency, the disposition of 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 . 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. In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are essentially unaltered. The pharmacokinetics of benazepril and benazeprilat do not appear to be influenced by age. In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of benazepril (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults.<br/>Pharmacodynamics: Single and multiple doses of 10 mg or more of benazepril 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.<br/>Hypertension: Adult Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted . In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2 to 4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20 to 80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6 to 12 /4 to 7 mmHg. 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 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 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. During chronic therapy, the maximum reduction in blood pressure with any dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of benazepril have continued during therapy for at least two years. Abrupt withdrawal of benazepril has not been associated with a rapid increase in blood pressure. In patients with mild-to-moderate hypertension, benazepril 10 to 20 mg was similar in effectiveness to captopril, hydrochlorothiazide, nifedipine SR, and propranolol. The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets. In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or no change in heart rate. In normal human volunteers, single doses of benazepril caused an increase in renal blood flow buthad no effect on glomerular filtration rate. Use of benazepril 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 tends to reduce the potassium loss associated with the diuretic. Pediatric 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. Nodose-response was observed for the three doses.
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Benazepril hydrochloride tablets are contraindicated in patients who are hypersensitive to this product or to any other ACE inhibitor.
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Benazepril Hydrochloride Tablets USP, 10 mg are dark yellow, circular, biconvex, beveled edge film-coated tablets debossed with���E' on one side and���15' on the other side. Bottles of 90 NDC 65862-116-90 Benazepril Hydrochloride Tablets USP, 20 mg are pink, circular, biconvex, beveled edge film- coated tablets debossed with���E' on one side and���16' on the other side. Bottles of 90 NDC 65862-117-90 Benazepril Hydrochloride Tablets USP, 40 mg are dark pink, circular, biconvex, beveled edge film-coated tablets debossed with���E' on one side and���17' on the other side. Bottles of 90 NDC 65862-118-90 Store at 20��to 25��C (68��to 77��F); excursions permitted to 15��to 30��C (59��to 86��F) [see USP Controlled Room Temperature]. Protect from moisture. Manufactured for: Aurobindo Pharma USA, Inc. 2400 Route 130 North Dayton, NJ 08810 Manufactured by: Aurobindo Pharma Limited Hyderabad���500 072, India
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BOXED WARNING:
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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. Laboratory determinations of serum levels of benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of benazepril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of benazepril and its metabolites. Benazepril is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function . Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable totreat benazepril overdose by infusion of normal saline solution.
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Benazepril Hydrochloride
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Benazepril Hydrochloride (Tablet)
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Benazepril 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 comparable in benazepril 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 and in 3% of patients treated with placebo. The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) . The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with benazepril are shown below.<br/>Cardiovascular: Symptomatic hypotension was seen in 0.3% of patients, postural hypotension in 0.4%, and syncope in 0.1%; these reactions led to discontinuation of therapy in 4 patients who had received benazepril monotherapy and in 9 patients who had received benazepril with hydrochlorothiazide . Other reports included angina pectoris, palpitations, and peripheral edema.<br/>Renal: Of hypertensive patients with no apparent preexisting renal disease, about 2% have sustained increases in serum creatinine to at least 150% of their baseline values while receiving benazepril, but most of these increases have disappeared despite continuing treatment. A much smaller fraction of these patients (less than 0.1%) developed simultaneous (usually transient) increases in blood urea nitrogen and serum creatinine.<br/>Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.<br/>Angioedema: Angioedema has been reported in patients receiving ACE inhibitors. During clinical trials in hypertensive patients with benazepril, 0.5% of patients experienced edema of the lips or face without other manifestations of angioedema. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema of the face, extremities, lips, tongue, or glottis and/or larynx occurs, treatment with benazepril should be discontinued and appropriate therapy instituted immediately .<br/>Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.<br/>Gastrointestinal: Pancreatitis, constipation, gastritis, vomiting, and melena.<br/>Hematologic: Thrombocytopenia and hemolytic anemia.<br/>Neurologic and Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia.<br/>Other: Asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, and sweating. Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors. The following adverse events of unknown frequency have been reported during post-marketing use of benazepril: small bowel angioedema, anaphylactoid reactions, hyperkalemia, agranulocytosis, and neutropenia.<br/>Pediatric Patients: The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. Infants below the age of 1 year should not be given ACE inhibitors due to concerns over possible effects on kidney development. The long-term effects of benazepril on growth and development have not been studied.<br/>Clinical Laboratory Test Findings:<br/>Creatinine and Blood Urea Nitrogen: Of hypertensive patients with no apparent preexisting renal disease, about 2% have sustained increases in serum creatinine to at least 150% of their baseline values while receiving benazepril, but most of these increases have disappeared despite continuing treatment. A much smaller fraction of these patients (less than 0.1%) developed simultaneous (usually transient) increases in blood urea nitrogen and serum creatinine. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis .<br/>Potassium: Since benazepril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and the patient's serum potassium should be monitored frequently .<br/>Hemoglobin: Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving benazepril alone and in 1 of 1,357 patients receiving benazepril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin.<br/>Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with benazepril administration. Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, leukopenia, eosinophilia, and proteinuria. In U.S. trials, less than 0.5% of patients discontinued treatment because of laboratory abnormalities.
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Benazepril hydrochloride tablets are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using benazepril, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that benazepril does not have a similar risk . Black patients receiving ACE-inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks. It should also be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in nonblacks.
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Benazepril Hydrochloride