What are the side effects of benazepril, an Angiotensin-Converting Enzyme (ACE) inhibitor?

Side Effects of Benazepril

Benazepril causes cough in approximately 5-10% of patients, hypotension and dizziness in nearly all patients to some degree, and carries risks of hyperkalemia and worsening renal function, particularly in patients with pre-existing renal disease, diabetes, or those taking potassium supplements. 1

Most Common Side Effects

The most frequently reported adverse effects are generally mild and transient:

• Headache occurs in 6% of patients (vs 4% with placebo), representing the most common non-pharmacologic side effect 1
• Dizziness affects 4% of patients (vs 2% with placebo) 1
• Cough is the most common reason for drug discontinuation, occurring in 5-10% of white patients and up to 50% in Chinese patients 2. The cough is typically dry with a tickling or scratching sensation in the throat 2. Onset ranges from hours after the first dose to months after initiation, and resolution typically occurs within 1-4 weeks of stopping the drug, though it may persist up to 3 months 2
• Somnolence occurs in 2% of patients (vs 0% with placebo) 1
• Postural dizziness affects 2% of patients (vs 0% with placebo) 1
• Fatigue is reported in approximately 7% of patients 3

Serious Adverse Effects Related to Angiotensin Suppression

Hypotension

• Blood pressure declines occur in nearly every patient, but symptomatic hypotension is the primary concern 2
• Hypotension is most frequent during the first few days of therapy or after dose increases, particularly in patients with hypovolemia, recent marked diuresis, or severe hyponatremia (sodium <130 mmol/L) 2, 3
• Symptomatic hypotension occurs in 15.9% of patients 3
• Management approach: Reduce diuretic doses, liberalize salt intake (if no fluid retention), or reduce/stagger other hypotensive agents to avoid peak effect overlap 2

Worsening Renal Function

• Glomerular filtration becomes critically dependent on angiotensin II-mediated efferent arteriolar vasoconstriction in states of reduced renal perfusion 2, 3
• Significant increases in serum creatinine (>0.3 mg/dL) occur in 15-30% of patients with severe heart failure, but only 5-15% with mild to moderate symptoms 2
• Risk is substantially greater with bilateral renal artery stenosis or concurrent NSAID use 2
• Management approach: Reduce diuretic doses when possible; mild to moderate azotemia may need to be tolerated to maintain ACE inhibitor therapy 2
• Monitor renal function before initiation, 1-2 weeks after each dose increment, and at 3-6 month intervals 3

Hyperkalemia

• Can be sufficiently severe to cause cardiac conduction disturbances 2
• Occurs most commonly in patients with deteriorating renal function, those taking potassium supplements, potassium-sparing diuretics, aldosterone antagonists, or patients with diabetes 2
• The absolute increase in hyperkalemia frequency is 2.3% compared to placebo 2

Serious Adverse Effects Related to Kinin Potentiation

Angioedema

• Occurs in <1% of patients but can be life-threatening 2
• Occurs more frequently in Black patients 2
• Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported, including fatal reactions 1
• Patients with tongue, glottis, or larynx involvement are at high risk for airway obstruction, especially those with prior airway surgery 1
• Intestinal angioedema presents with abdominal pain (with or without nausea/vomiting), sometimes without prior facial angioedema 1
• Absolute contraindication: History of angioedema with any ACE inhibitor 2, 3, 1
• Patients on concurrent mTOR inhibitors (temsirolimus, sirolimus, everolimus) are at increased risk 1

Less Common Adverse Effects

• Dermatologic: Stevens-Johnson syndrome, pemphigus, hypersensitivity reactions (dermatitis, pruritus, rash), photosensitivity, flushing 1
• Gastrointestinal: Nausea, pancreatitis, constipation, gastritis, vomiting, melena 1
• Hematologic: Thrombocytopenia, hemolytic anemia 1
• Neurologic/Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, paresthesia 1
• Other: Asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating 1
• Laboratory abnormalities: Elevations of uric acid, blood glucose, serum bilirubin, liver enzymes, hyponatremia, ECG changes, eosinophilia, proteinuria 1

Drug Discontinuation Rates

• Approximately 5% of patients discontinue benazepril due to adverse effects (vs 3% with placebo) 1
• Most common reasons for discontinuation are headache (0.6%) and cough (0.5%) 1
• In heart failure trials, ACE inhibitor discontinuation rates due to adverse events were 7.4% (vs 12.3% with placebo), showing no significant difference 2

Special Warnings and Contraindications

• Pregnancy Category D: Discontinue immediately when pregnancy is detected due to fetal toxicity, including oligohydramnios, fetal lung hypoplasia, skeletal deformations, skull hypoplasia, anuria, hypotension, renal failure, and death 1
• Bilateral renal artery stenosis: Absolute contraindication 3
• Anaphylactoid reactions: Can occur during desensitization therapy with hymenoptera venom or during dialysis with high-flux membranes 1
• Lithium toxicity: Monitor serum lithium levels during concurrent use 1
• Hypoglycemia risk: Increased when combined with antidiabetic medications 1

Important Drug Interactions

• NSAIDs/COX-2 inhibitors: May cause deterioration of renal function and attenuate antihypertensive effects 1
• Potassium-sparing diuretics: Markedly increase hyperkalemia risk 3, 1
• Dual RAS blockade (with ARBs or aliskiren): Associated with increased risks of hypotension, hyperkalemia, and renal dysfunction; avoid combination 1
• Aspirin: May attenuate hemodynamic benefits, though clinical significance remains controversial 3

Clinical Context

Despite these adverse effects, benazepril demonstrates a favorable benefit-risk profile. In heart failure trials, patients on ACE inhibitors actually experienced significantly lower rates of serious adverse events (57.3% vs 63.0% with placebo) 2, and the overall adverse event burden was only modestly higher (87.0% vs 82.0%, absolute difference +5%) 2. Most adverse effects are manageable with dose adjustments and careful monitoring 2, 1.