What is the interaction between itraconazole and amitriptyline?

Interaction Between Itraconazole and Amitriptyline

Direct Answer

Itraconazole significantly increases amitriptyline plasma concentrations through potent CYP3A4 and CYP2C19 inhibition, creating substantial risk for tricyclic antidepressant toxicity including cardiac arrhythmias, QT prolongation, and potentially fatal torsades de pointes—this combination requires either avoidance or extreme caution with dose reduction and cardiac monitoring. 1, 2

Mechanism of Interaction

Pharmacokinetic Basis:

• Itraconazole is a potent inhibitor of the CYP3A4 enzyme system, which is a primary metabolic pathway for amitriptyline, reducing its metabolism and leading to 2-3 fold elevations in plasma concentrations 1, 3, 2
• Itraconazole also inhibits CYP2C19 enzymes, creating a dual inhibitory effect on amitriptyline metabolism, with high interpatient variability due to genetic CYP2C19 polymorphisms that may amplify the interaction 4
• The inhibition occurs through both hepatic CYP450 pathways and intestinal drug-metabolizing enzymes, with effects persisting for several days after itraconazole discontinuation due to its long half-life 3
• Itraconazole is additionally an inhibitor and substrate of P-glycoprotein, which may further contribute to elevated amitriptyline concentrations 1, 2

Clinical Consequences and Toxicity Risk

Cardiac Toxicity (Most Critical):

• Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when itraconazole is coadministered with drugs metabolized by CYP3A4 2, 5
• A documented case demonstrated itraconazole-induced torsades de pointes in a patient on methadone (another CYP3A4 substrate), presenting with chest discomfort, syncope, and prolonged QT interval requiring hospitalization 5
• Elevated tricyclic antidepressant levels increase risk of cardiac conduction abnormalities, arrhythmias, and sudden cardiac death 2

Other Toxicity Manifestations:

• Anticholinergic toxicity including confusion, urinary retention, dry mouth, blurred vision, and constipation 2
• Central nervous system effects including excessive sedation, ataxia, and altered mental status 2
• Orthostatic hypotension and symptomatic hypotension may occur with elevated amitriptyline concentrations 2

Management Algorithm

Step 1: Risk Assessment Before Initiating Combination

• Review complete medication list for all CYP3A4 substrates and other potential interactions that could compound the effect 6, 4
• Assess baseline liver function, as hepatic impairment increases risk of drug-drug interactions 4
• Obtain baseline ECG to evaluate QT interval and identify pre-existing cardiac conduction abnormalities 5
• Identify genetic polymorphisms affecting CYP3A4 and CYP2C19 if available, as poor metabolizers will experience more pronounced interactions 3, 4

Step 2: Consider Alternatives (Preferred Approach)

• Use alternative antifungal agents such as echinocandins (caspofungin, micafungin, anidulafungin) which lack significant CYP450 interactions 4
• Consider terbinafine as an alternative oral antifungal, which has no drug-drug contraindications and revealed no new interactions in postmarketing surveillance of 25,884 patients 7
• If azole therapy is required, fluconazole at lower doses may have fewer CYP3A4 interactions than itraconazole, though caution is still warranted 1, 7

Step 3: If Combination is Unavoidable

• Reduce amitriptyline dose by 50-66% when initiating itraconazole, anticipating a 2-3 fold increase in exposure 4, 2
• Use itraconazole oral solution instead of capsules in patients taking proton pump inhibitors or H2 blockers, as solution absorption is enhanced by gastric acid and should be taken without food 1, 6
• Itraconazole capsules should be administered with food for optimal absorption, but solution formulation provides more predictable pharmacokinetics 1

Step 4: Monitoring Protocol

• Obtain ECG at baseline, within 1 week of initiating combination, and weekly for the first month to monitor QT interval 4, 5
• Monitor hepatic enzyme levels at baseline, then at 1,2, and 4 weeks, and every 3 months during therapy as both drugs may be hepatotoxic 1, 6
• Implement therapeutic drug monitoring for itraconazole after 2 weeks to ensure levels are therapeutic (≥1.0 mg/mL) but not excessive (≤10.0 mg/mL) 1, 6
• Assess for anticholinergic toxicity signs including confusion, urinary retention, tachycardia, and altered mental status 2
• Monitor blood pressure for orthostatic hypotension and symptomatic changes 2, 8

Step 5: Patient Counseling

• Counsel patients about cardiac symptoms requiring immediate medical attention: chest pain, palpitations, syncope, or near-syncope 5
• Advise patients to report excessive sedation, confusion, dizziness, or falls 2
• Inform patients about anticholinergic side effects and when to seek medical attention 2
• Emphasize that the interaction persists for several days after discontinuing itraconazole due to its long half-life 3

Common Pitfalls to Avoid

Critical Errors:

• Failing to recognize the bidirectional nature of azole interactions and not anticipating the magnitude of plasma concentration increases (2-3 fold) 3, 4
• Inadequate cardiac monitoring, particularly ECG assessment for QT prolongation in the first weeks of combination therapy 5
• Not considering the duration of interaction, which persists for several days after itraconazole discontinuation 3
• Overlooking the cumulative effect when patients are on multiple CYP3A4 substrates simultaneously with itraconazole 3, 6

Dosing Errors:

• Using itraconazole capsules interchangeably with oral solution—drug exposure is greater with oral solution at the same dose, and capsule absorption is variable 1
• Failing to adjust amitriptyline dose downward when initiating itraconazole, leading to preventable toxicity 4, 2
• Not accounting for food effects: itraconazole solution should be taken without food, while capsules require food for absorption 1

Monitoring Failures:

• Not obtaining baseline ECG before initiating combination therapy 5
• Inadequate frequency of hepatic enzyme monitoring given dual hepatotoxicity risk 1, 6
• Failing to implement therapeutic drug monitoring for itraconazole to avoid excessive serum concentrations that amplify the interaction 1, 6