AMLODIPINE BESYLATE AND BENAZEPRIL HYDROCHLORIDE
Clinical safety rating: avoid
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Risk of angioedema can occur at any time discontinue immediately.
Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, causing peripheral vasodilation and reduction of peripheral vascular resistance. Benazepril is a prodrug that is hydrolyzed to benazeprilat, a competitive inhibitor of angiotensin-converting enzyme (ACE), preventing conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction, aldosterone secretion, and sodium and water retention.
| Metabolism | Amlodipine is extensively metabolized in the liver via CYP3A4 to inactive metabolites; benazepril is hydrolyzed rapidly to its active metabolite benazeprilat by hepatic esterases; benazeprilat undergoes further minimal metabolism via glucuronidation and renal excretion. |
| Excretion | Amlodipine: 60% renal (10% unchanged, rest as metabolites), 20-25% biliary/feces. Benazepril: 11-12% renal (as unchanged benazepril and benazeprilat), 85-90% biliary (as benazeprilat conjugates). |
| Half-life | Amlodipine terminal half-life 30-50 hours (allows once-daily dosing; steady state reached after 7-10 days). Benazeprilat effective half-life 10-11 hours (accumulation minimal). |
| Protein binding | Amlodipine ~93% bound (plasma proteins). Benazeprilat ~90% bound (mainly albumin). |
| Volume of Distribution | Amlodipine Vd ~21 L/kg (large, indicating extensive tissue distribution). Benazeprilat Vd ~0.12 L/kg (limited to extracellular fluid). |
| Bioavailability | Amlodipine oral bioavailability 64-90% (mean ~64%). Benazepril reaches steady state in 2-3 days; bioavailability not reported separately due to prodrug conversion (benazeprilat bioavailability ~28%). |
| Onset of Action | Oral: antihypertensive effect begins within 2-4 hours; peak effect at 6-8 hours. |
| Duration of Action | 24 hours (once-daily dosing maintains antihypertensive efficacy over 24 hours). Clinical note: may require 2 weeks for full therapeutic effect. |
| Molecular Weight | Amlodipine besylate: 567.05 Da; Benazepril hydrochloride: 460.95 Da |
Oral, one capsule daily. Initial: 2.5 mg/10 mg for patients not on either drug; up to 10 mg/40 mg daily.
| Dosage form | CAPSULE |
| Renal impairment | CrCl <30 mL/min: not recommended; CrCl 30-60 mL/min: monitor potassium and creatinine. Use lowest doses. |
| Liver impairment | Child-Pugh A or B: initial 2.5 mg/10 mg; Child-Pugh C: contraindicated due to benazepril accumulation. |
| Pediatric use | Not established; avoid use in children under 18 years. |
| Geriatric use | Initiate at 2.5 mg/10 mg; titrate slowly due to increased sensitivity and higher risk of hypotension and renal impairment. |
| 1st trimester | Risk of fetal toxicity; use only if benefit outweighs risk. Pregnancy Category D. |
| 2nd trimester | Risk of fetal and neonatal toxicity; use only if benefit outweighs risk. Pregnancy Category D. |
| 3rd trimester | Risk of fetal and neonatal toxicity; use only if benefit outweighs risk. Pregnancy Category D. |
Clinical note
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Risk of angioedema can occur at any time discontinue immediately.
| FDA category | Contraindicated |
| Placental transfer | Both amlodipine and benazeprilat (active metabolite of benazepril) cross the placenta. Benazepril is known to cause fetal and neonatal morbidity and death when administered to pregnant women. |
| Breastfeeding |
■ FDA Black Box Warning
None
| Common Effects | heart failure |
| Serious Effects |
History of angioedema related to previous ACE inhibitor therapyHereditary or idiopathic angioedemaHypersensitivity to amlodipine, benazepril, or any component of the formulationConcomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²)
| Precautions | Fetal toxicity: ACE inhibitors can cause injury and death to the developing fetus when used during the second and third trimesters; discontinue as soon as pregnancy is detected., Hypotension: Symptomatic hypotension may occur, especially in volume-depleted patients (e.g., those treated with diuretics)., Angioedema: Risk of angioedema (including laryngeal edema) with ACE inhibitors; higher risk in Black patients., Hyperkalemia: Monitor serum potassium, especially in patients with renal impairment, diabetes, or those taking potassium-sparing diuretics or potassium supplements., Renal impairment: Monitor renal function; may cause reversible increases in serum creatinine and BUN., Hepatic impairment: Caution in patients with hepatic impairment (amlodipine clearance decreased)., Aortic stenosis: Use caution in patients with severe aortic stenosis (amlodipine may increase risk of hypotension or syncope)., Cough: Dry, persistent cough is common with ACE inhibitors., Surgery/anesthesia: May cause hypotension in patients undergoing major surgery or anesthesia., Combination with ARBs or aliskiren: Avoid combination with aliskiren in patients with diabetes or renal impairment (creatinine clearance <60 mL/min). |
Loading safety data…
| Amlodipine and benazepril are excreted in human milk. Due to potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pregnancy Category D. First trimester: Teratogenic risk not established; however, ACE inhibitors (benazepril) are associated with fetal renal abnormalities, oligohydramnios, and skull ossification defects when used in second and third trimesters. Calcium channel blockers (amlodipine) have not shown teratogenicity in animal studies but human data limited. Second and third trimesters: ACE inhibitors cause fetal and neonatal morbidity and mortality, including renal failure, hypotension, and hyperkalemia. Amlodipine may cause fetal hypoxia due to maternal hypotension. Use is contraindicated in second and third trimesters. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function (serum creatinine, BUN), serum electrolytes (especially potassium), and urine protein. Fetal monitoring includes serial ultrasound assessments for oligohydramnios, fetal growth restriction, and fetal renal function during second and third trimesters. Consider fetal echocardiography due to risk of fetal cardiac defects. Monitor infant for hypotension, hyperkalemia, and renal dysfunction after delivery. |
| Fertility Effects | Amlodipine may reversibly decrease sperm motility and function in some men, potentially affecting male fertility. Benazepril has no reported direct effects on fertility; however, ACE inhibitors in general may impair fertility in some animal studies. Human data insufficient. Advise patients of potential reversible effects. |
| Food/Dietary | No specific food interactions with amlodipine; benazepril absorption may be decreased by food, but clinical significance is minimal; maintain consistent timing with or without meals. Avoid excessive alcohol intake. |
| Clinical Pearls | Avoid in pregnancy (ACE inhibitor risk); monitor serum potassium and renal function; caution in hepatic impairment (amlodipine metabolized by liver); start with lowest dose in elderly; may cause peripheral edema from amlodipine, which can be mitigated by evening dosing or using a diuretic; combination typically used when hypertension is not controlled on monotherapy. |
| Patient Advice | Do not take if pregnant or planning pregnancy; use effective contraception. · Take exactly as prescribed; do not stop suddenly. · Report swelling in ankles/feet, persistent cough, dizziness, or signs of angioedema (swelling of face/lips/tongue). · Avoid potassium supplements and salt substitutes containing potassium unless directed. |