Amlodipine Besilate + Benazepril Hydrochloride

Approved Indications:

• Hypertension (Primary Indication):
  Used for the treatment of hypertension in patients who are not adequately controlled on monotherapy with either Amlodipine or Benazepril alone. It helps reduce the risk of cardiovascular morbidity such as stroke and myocardial infarction.

Off-label / Clinically Accepted Uses:

• Hypertension with Left Ventricular Hypertrophy (LVH):
  Often used as combination therapy in hypertensive patients with evidence of LVH, where dual blockade improves cardiac remodeling.
• Proteinuric Chronic Kidney Disease (CKD), stage 1–3 (Non-Diabetic):
  In patients with hypertension and proteinuria, this combination may be beneficial to reduce protein excretion and slow disease progression.

Adults:

• Initial Dose:
  One capsule of Amlodipine 2.5 mg + Benazepril 10 mg once daily.
• Usual Maintenance Dose:
  Ranges from Amlodipine 2.5–10 mg / Benazepril 10–40 mg once daily.
• Maximum Dose:
  Amlodipine 10 mg + Benazepril 40 mg per day.

Elderly:

• Start with the lower end of the dosing range. Monitor for orthostatic hypotension and renal function.

Renal Impairment:

• Mild to Moderate (eGFR ≥30 mL/min/1.73 m²):
  Start with caution; monitor potassium and serum creatinine regularly.
• Severe Impairment (eGFR <30 mL/min/1.73 m²):
  Use not recommended due to risk of hyperkalemia and worsening renal function.

Hepatic Impairment:

• Start Amlodipine at the lowest possible dose (2.5 mg) due to reduced hepatic metabolism.

Pediatrics:

• Safety and efficacy not established.

Administration:

• Oral use, once daily, with or without food.
• Capsules should be swallowed whole and not opened or chewed.

This combination contains two antihypertensive agents with complementary mechanisms:

• Amlodipine, a dihydropyridine calcium channel blocker, inhibits calcium influx in vascular smooth muscle and cardiac muscle, leading to vasodilation and decreased peripheral resistance.
• Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, prevents the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction, aldosterone secretion, and sodium/water retention.

Together, they lower blood pressure more effectively while minimizing compensatory mechanisms (e.g., reflex tachycardia or renin-angiotensin activation).

Amlodipine:

• Absorption: ~64–90% bioavailability, unaffected by food.
• Onset of Action: Within 24 hours.
• Peak Plasma Time: 6–12 hours.
• Half-life: 30–50 hours.
• Metabolism: Hepatic (CYP3A4) to inactive metabolites.
• Excretion: 60% urine, 20–25% feces.

Benazepril:

• Absorption: ~37% bioavailability.
• Conversion: Prodrug, converted to active metabolite Benazeprilat in liver.
• Peak Plasma Time: 0.5–1 hour (Benazepril), 1–2 hours (Benazeprilat).
• Half-life: Benazeprilat ~10–11 hours.
• Excretion: Primarily renal (urine), minor in feces.

Pregnancy:

• FDA Category D (2nd and 3rd trimesters):
  Drugs affecting the renin-angiotensin system can cause fetal injury or death. Discontinue as soon as pregnancy is detected.

Lactation:

• Benazepril: Small amounts may be excreted in breast milk. Not recommended.
• Amlodipine: Limited data suggest minimal excretion into breast milk. Use only if clearly needed.

Recommendation: Avoid during pregnancy and breastfeeding unless the benefits outweigh the risks.

• Primary Class: Antihypertensive
• Subclasses:
• Amlodipine: Calcium Channel Blocker (Dihydropyridine type)
• Benazepril: ACE Inhibitor (Second-generation)

• Known hypersensitivity to Amlodipine, Benazepril, or any excipients
• History of angioedema related to ACE inhibitors
• Pregnancy (especially 2nd and 3rd trimester)
• Severe renal impairment with bilateral renal artery stenosis
• Co-administration with aliskiren in patients with diabetes or renal impairment (eGFR <60 mL/min/1.73 m²)

• Hypotension: Especially in volume-depleted or salt-depleted patients.
• Hyperkalemia: Monitor potassium in patients with renal impairment or those on potassium-sparing diuretics.
• Angioedema: Rare but potentially life-threatening; discontinue immediately if it occurs.
• Renal Function Decline: Monitor serum creatinine and eGFR periodically.
• Hepatic Impairment: Use cautiously due to altered metabolism of Amlodipine.
• Cough: ACE inhibitors may induce persistent dry cough.

Common:

• Cardiovascular: Peripheral edema, hypotension, palpitations
• Respiratory: Dry cough (Benazepril-related)
• Gastrointestinal: Nausea, abdominal pain
• Neurological: Headache, dizziness, fatigue

Serious/Rare:

• Angioedema
• Hyperkalemia
• Acute renal failure
• Hepatic dysfunction or jaundice
• Severe hypotension or syncope

Timing & Dose Dependence:

• Peripheral edema is dose-related (Amlodipine).
• Cough may develop within days to weeks after starting Benazepril.

• Potassium Supplements or Potassium-Sparing Diuretics: Risk of hyperkalemia
• NSAIDs: May reduce antihypertensive effect; increase risk of renal dysfunction
• Lithium: Risk of lithium toxicity increased with ACE inhibitors
• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): May increase plasma levels of Amlodipine
• Alcohol: May potentiate hypotensive effect
• Aliskiren: Contraindicated in diabetic or renally impaired patients

• FDA/EMA: Reinforced contraindications with Aliskiren in diabetic/renal impairment cases.
• ACC/AHA Hypertension Guidelines: Endorses combination therapy for stage 2 hypertension and those with BP ≥20/10 mmHg above target.
• KDIGO 2021: Recommends ACE inhibitor-based therapy in CKD with proteinuria, combination with CCB if monotherapy insufficient.

• Temperature: Store below 30°C (room temperature).
• Humidity: Store in a dry place.
• Light Protection: Protect from direct sunlight.
• Handling: Do not open capsules.
• Refrigeration: Not required.