BENAZEPRIL HYDROCHLORIDE

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-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is Its empirical formula is C 24 H 28 N 2 O 5 •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, USP 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. Image of Structural Formula

Benazepril hydrochloride tablets, USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.

Hypertension Adults The recommended initial dose for patients not receiving a diuretic is 10 mg once a day. The usual maintenance dosage range is 20-40 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 (2-6 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 tablets alone, a diuretic can be added. Total daily doses above 80 mg have not been evaluated. Concomitant administration of benazepril hydrochloride tablets with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS ). In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of benazepril hydrochloride tablets. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with benazepril hydrochloride tablets (see WARNINGS ). Then, if blood pressure is not controlled with benazepril hydrochloride tablets alone, diuretic therapy should be resumed. If the diuretic cannot be discontinued, an initial dose of 5 mg benazepril should be used to avoid excessive hypotension. 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 tablets, follow the suspension preparation instructions below to administer benazepril hydrochloride tablets as a suspension. Treatment with benazepril hydrochloride tablets is not advised for children below the age of 6 years (see PRECAUTIONS , Pediatric Use ) and in pediatric patients with glomerular filtration rate <30 mL, as there are insufficient data available to support a dosing recommendation in these groups. For Hypertensive Patients with Renal Impairment For patients with a creatinine clearance <30 mL/min/1.73 m 2 (serum creatinine >3 mg/dL), the recommended initial dose is 5 mg benazepril hydrochloride tablet once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see WARNINGS ). 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 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-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.

Benazepril hydrochloride tablets are contraindicated in patients who are hypersensitive to benazepril or to any other ACE inhibitor. Benazepril hydrochloride tablets are also contraindicated in patients with a history of angioedema with or without previous ACE inhibitor treatment. Do not co-administer aliskiren with angiotensin receptor blockers, ACE inhibitors, including benazepril hydrochloride in patients with diabetes.

Benazepril hydrochloride tablets have 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 hydrochloride tablets 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 tablets and in 3% of patients treated with placebo. The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) (see PRECAUTIONS , Cough ). 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 hydrochloride tablets are shown below. Patients in U.S. Placebo-Controlled Studies Benazepril Hydrochloride Tablets (N=964) Placebo (N=496) N % N % Headache 60 6.2 21 4.2 Dizziness 35 3.6 12 2.4 Somnolence 15 1.6 2 0.4 Postural Dizziness 14 1.5 1 0.2 Other adverse experiences reported in controlled clinical trials (in less than 1% of benazepril patients or with less than 1% difference in incidence between benazepril or placebo treatment), 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 and 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, and sweating. Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors. Pediatric Patients: The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. Clinical Laboratory Test Findings 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 hydrochloride tablets alone and in 1 of 1,357 patients receiving benazepril hydrochloride tablets plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin. Other (causal relationships unknown): Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes (see WARNINGS ) have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, leukopenia, eosinophilia, and proteinuria.

Diuretics: 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 tablets. The possibility of hypotensive effects with benazepril hydrochloride tablets can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with benazepril hydrochloride tablets. If this is not possible, the starting dose should be reduced (see DOSAGE AND ADMINISTRATION ). Potassium Supplements and Potassium-Sparing Diuretics: Concomitant use with benazepril hydrochloride tablets may effect potassium levels. Monitor potassium periodically. Oral Anticoagulants: Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including benazepril) during therapy with lithium. Monitor lithium levels when used concomitantly with benazepril hydrochloride tablets. 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. Anti-diabetics: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 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. 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. Closely monitor blood pressure, renal function and electrolytes in patients on benazepril hydrochloride and other agents that block 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). Other: Benazepril hydrochloride tablets have 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. 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).