Benazepril Hydrochloride (Page 2 of 5)

5.3 Impaired Renal Function

Monitor renal function periodically in patients treated with benazepril. Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin system. 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. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on benazepril.

5.4 Hypotension

Benazepril 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 mm Hg, 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 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 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. 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.

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 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 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%).

Adverse reactions seen in at least 1% greater frequency in patients treated with benazepril 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 (5)] have been reported, as have incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria.

7 DRUG INTERACTIONS

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. The possibility of hypotensive effects with benazepril can be minimized by either discontinuing or decreasing the dose of diuretic prior to initiation of treatment with benazepril [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 attenuates potassium loss caused by thiazide-type diuretics.

7.2 Antidiabetics

Concomitant administration of benazepril 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 and other agents that affect the RAS.

Do not coadminister aliskiren with benazepril in patients with diabetes. Avoid use of aliskiren with benazepril 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. Lithium toxicity was usually reversible upon discontinuation of lithium or benazepril. Monitor serum lithium levels during concurrent use.

7.7 Neprilysin Inhibitor

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema [see Warnings and Precautions].

7.8 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.

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