What are the potential drug interactions with Norvasc (amlodipine)?

Norvasc (Amlodipine) Drug Interactions

Amlodipine has relatively few clinically significant drug interactions compared to other calcium channel blockers, but important interactions exist with CYP3A4 inhibitors, immunosuppressants, and simvastatin that require dose adjustments or monitoring. 1

CYP3A4-Mediated Interactions

Strong CYP3A4 Inhibitors

• Strong CYP3A4 inhibitors (itraconazole, clarithromycin) may substantially increase amlodipine plasma concentrations, requiring careful monitoring for hypotension and edema 1
• Diltiazem (180 mg daily) increased amlodipine systemic exposure by 60% in elderly hypertensive patients 1
• Erythromycin did not significantly change amlodipine exposure in healthy volunteers, suggesting moderate CYP3A4 inhibitors have less impact 1

No Interaction with Common Agents

• Cimetidine, antacids (magnesium/aluminum hydroxide), sildenafil, and grapefruit juice have no impact on amlodipine exposure 1

Amlodipine's Effect on Other Drugs

Simvastatin (Clinically Important)

• Amlodipine 10 mg increased simvastatin exposure by 77%, significantly raising myopathy risk 1
• Limit simvastatin dose when coadministered with amlodipine to reduce myopathy risk 2

Immunosuppressants (Critical Monitoring Required)

• Amlodipine increased cyclosporine trough levels by an average of 40% in renal transplant patients (N=11) 1
• Tacrolimus exposure increased 2.5- to 4-fold in CYP3A5 expressers when coadministered with amlodipine 1
• A 3-fold increase in tacrolimus exposure occurred even in a CYP3A5 non-expresser, indicating interaction risk exists regardless of genotype status 1
• Monitor immunosuppressant levels closely and adjust doses accordingly when initiating or discontinuing amlodipine 1

No Clinically Significant Interactions

• Amlodipine does not affect exposure to atorvastatin, digoxin, ethanol, or warfarin prothrombin time 1
• In vitro data confirm amlodipine has no effect on plasma protein binding of digoxin, phenytoin, warfarin, or indomethacin 1

Combination with Beta-Blockers

Additive Heart Rate Effects (Context-Specific)

• When amlodipine is combined with BOTH a beta-blocker AND another calcium channel blocker, additive effects on heart rate may occur 2
• Amlodipine administered with beta-blockers alone showed no adverse electrocardiographic effects in clinical studies of hypertension or angina patients 1
• Amlodipine does not change sinoatrial nodal function or atrioventricular conduction 1

Pharmacodynamic Interactions

Blood Pressure Lowering Effects

• NSAIDs (including COX-2 inhibitors) can attenuate the antihypertensive effects of amlodipine and should be used cautiously 3
• Sildenafil and amlodipine each independently exert blood pressure lowering effects when used together 1

Older Adults Considerations

• The 2019 AGS Beers Criteria does not specifically flag amlodipine for problematic drug-drug interactions in older adults, unlike non-dihydropyridine calcium channel blockers 2

Key Clinical Distinctions

Amlodipine vs. Other Calcium Channel Blockers

• Amlodipine is a weak CYP3A4 inhibitor, unlike diltiazem and verapamil which are potent CYP3A4 inhibitors responsible for the majority of significant calcium channel blocker drug interactions 4
• This makes amlodipine preferable when drug interaction risk is a concern 4

Dextromethorphan (Over-the-Counter Cough Medications)

• No clinically significant interaction exists between amlodipine and dextromethorphan 5
• Amlodipine does not significantly inhibit CYP2D6, the enzyme responsible for dextromethorphan metabolism 5
• No dose adjustment or additional monitoring is required when using over-the-counter dextromethorphan products with amlodipine 5

Special Populations

Renal Impairment

• Amlodipine pharmacokinetics are not significantly influenced by renal impairment, and patients with renal failure may receive the usual initial dose 1

Hepatic Impairment

• Elderly patients and those with hepatic insufficiency have 40-60% increased AUC due to decreased clearance, requiring lower initial doses 1

Heart Failure

• Patients with moderate to severe heart failure show similar increases in AUC (40-60%) 1

Common Pitfalls to Avoid

• Do not assume all calcium channel blockers have the same interaction profile—amlodipine has far fewer significant interactions than diltiazem or verapamil 4
• Always check immunosuppressant levels when starting or stopping amlodipine in transplant patients, regardless of CYP3A5 genotype 1
• Limit simvastatin dose when coadministered to avoid myopathy risk from the 77% increase in simvastatin exposure 1
• Monitor for hypotension and edema when strong CYP3A4 inhibitors are added to amlodipine therapy 1