Norvasc - Drug Monograph

Introduction

Norvasc (amlodipine besylate) is a widely prescribed calcium channel blocker belonging to the dihydropyridine class. It is primarily used in the management of hypertension and chronic stable angina. First approved by the FDA in 1992, Norvasc has become one of the most commonly prescribed antihypertensive medications worldwide due to its favorable safety profile and once-daily dosing convenience.

Mechanism of Action

Norvasc exerts its therapeutic effects by selectively inhibiting calcium influx through voltage-sensitive L-type calcium channels in vascular smooth muscle and cardiac muscle. This inhibition results in:

• Peripheral arterial vasodilation (reducing peripheral vascular resistance)
• Coronary vasodilation (increasing myocardial oxygen delivery)
• Reduced afterload without significantly affecting cardiac contractility or conduction

The drug's predominant effect on vascular smooth muscle over cardiac tissue makes it particularly effective for hypertension management with minimal negative inotropic effects.

Indications

FDA-approved indications:

• Hypertension (alone or in combination with other antihypertensive agents)
• Chronic stable angina
• Vasospastic angina (Prinzmetal's or variant angina)

Off-label uses (with supporting evidence):

• Raynaud's phenomenon
• Certain cases of systolic heart failure (as adjunct therapy)

Dosage and Administration

• Hypertension: 2.5-10 mg once daily
• Angina: 5-10 mg once daily

• Geriatric patients: Start with 2.5 mg daily
• Hepatic impairment: Start with 2.5 mg daily
• Renal impairment: No dosage adjustment required
• Pediatric patients: Safety and effectiveness not established

• May be taken with or without food
• Tablets should be swallowed whole
• Consistent timing daily recommended

Pharmacokinetics

• Oral bioavailability: 64-90%
• Peak plasma concentration: 6-12 hours post-dose
• Food does not significantly affect absorption

• Volume of distribution: 21 L/kg
• Protein binding: ~93%
• Steady state achieved after 7-8 days of continuous dosing

• Extensive hepatic metabolism via CYP3A4 isozyme
• No active metabolites

• Elimination half-life: 30-50 hours
• Excretion: primarily urine (60%) and feces (20-25%)
• Not significantly dialyzable

Contraindications

• Hypersensitivity to amlodipine or any component of the formulation
• Patients with severe hypotension (systolic BP <90 mmHg)
• Cardiogenic shock
• Concomitant use with strong CYP3A4 inhibitors in patients with hepatic impairment

Warnings and Precautions

• Hypotension: Symptomatic hypotension may occur, particularly in volume-depleted patients
• Worsening angina or acute MI: May occur at initiation or dosage increase
• Hepatic impairment: Use with caution; reduced clearance may occur
• Heart failure: Use cautiously in patients with heart failure
• Aortic stenosis: Use with caution in patients with severe obstruction

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole): May increase amlodipine levels
• Simvastatin: Amlodipine may increase simvastatin exposure
• Cyclosporine: May increase cyclosporine levels

• Other antihypertensives: Additive hypotensive effects
• Sildenafil and other PDE5 inhibitors: Enhanced hypotensive effects
• Lithium: May increase lithium toxicity risk

Adverse Effects

• Peripheral edema (dose-dependent)
• Headache
• Fatigue
• Dizziness
• Flushing
• Palpitations

• Severe hypotension
• Syncope
• Worsening angina
• Myocardial infarction
• Allergic reactions
• Hepatitis
• Gingival hyperplasia (long-term use)

Monitoring Parameters

• Blood pressure (sitting, standing)
• Heart rate
• Liver function tests
• Renal function
• ECG if cardiac disease suspected

• Blood pressure at each visit
• Signs/symptoms of peripheral edema
• Weight monitoring
• Angina symptoms (if applicable)
• Liver function (periodically)

• Elderly patients: Fall risk assessment
• Heart failure patients: Signs of worsening HF

Patient Education

• Take medication at the same time each day
• Do not stop abruptly; consult provider before discontinuing
• Rise slowly from sitting/lying position to prevent dizziness
• Report swelling in ankles/feet, dizziness, or rapid weight gain
• Avoid grapefruit juice (may increase drug levels)
• Regular blood pressure monitoring important
• Inform all healthcare providers about Norvasc use
• Store at room temperature away from moisture

• Maintain healthy diet low in sodium
• Regular physical activity as tolerated
• Limit alcohol consumption
• Smoking cessation recommended

References

1. FDA Prescribing Information: Norvasc (amlodipine besylate). 2019 2. Chrysant SG. Amlodipine: an overview of its pharmacodynamic and pharmacokinetic properties. Clin Cardiol. 1994;17(Suppl III):III3-III6 3. Messerli FH. Amlodipine in chronic stable angina: results of a multicenter clinical trial. Am J Cardiol. 1994;73:36A-40A 4. Epstein BJ, Vogel K, Palmer BF. Dihydropyridine calcium channel antagonists in the management of hypertension. Drugs. 2007;67(9):1309-1327 5. National Institute for Health and Care Excellence (NICE). Hypertension in adults: diagnosis and management. NICE guideline [NG136]. 2019 6. Williams B, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104 7. Micromedex Solutions. Amlodipine: Drug Information. Truven Health Analytics. 2023