What are the potential drug interactions with itraconazole?

Itraconazole Drug Interactions

Itraconazole is a potent inhibitor of CYP3A4 enzymes and P-glycoprotein transporters, causing numerous significant drug interactions that can lead to potentially life-threatening adverse effects, including cardiac dysrhythmias, heart failure, and other serious toxicities. 1

Mechanism of Drug Interactions

Itraconazole's interactions occur through several mechanisms:

• CYP3A4 inhibition: Itraconazole and its active metabolites (hydroxy-itraconazole, keto-itraconazole, and N-desalkyl-itraconazole) are potent inhibitors of CYP3A4 enzymes 1, 2
• P-glycoprotein inhibition: Blocks this important drug transporter 1
• Non-competitive inhibition: Interacts with the heme moiety of CYP3A4, resulting in noncompetitive inhibition of oxidative metabolism 1
• Metabolite contribution: Metabolites account for approximately 50% of the total CYP3A4 inhibition, with their contribution increasing with time after dosing 3, 2

Major Drug Classes with Significant Interactions

1. Cardiovascular Medications

• Contraindicated drugs: Disopyramide, dofetilide, dronedarone, quinidine, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone 4
• Risk: QT prolongation, torsade de pointes, ventricular tachyarrhythmias, and sudden death 4

2. Opioid Analgesics

• Contraindicated: Methadone 4
• Not recommended: Fentanyl 4
• Require monitoring: Alfentanil, buprenorphine, oxycodone, sufentanil 4
• Risk: Increased opioid plasma concentrations leading to respiratory depression, excessive sedation, and potentially fatal outcomes 4

3. Chemotherapeutic Agents

• Serious interactions: Cyclophosphamide, vincristine, and other vinca alkaloids 1
• Risk: Enhanced toxicity requiring additional monitoring 1
• Management: Mold-active azoles should be stopped several days before administering these drugs 1

4. Immunosuppressants

• Affected drugs: Cyclosporine, tacrolimus, sirolimus 1
• Risk: Increased immunosuppressant levels leading to nephrotoxicity and other adverse effects 1
• Management: Therapeutic drug monitoring of both itraconazole and immunosuppressants is strongly recommended 1

5. Other Critical Interactions

• Contraindicated drugs: Cisapride, pimozide, ergot alkaloids, oral midazolam, triazolam, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin 4
• Risk: Various severe adverse effects including rhabdomyolysis with statins and ergotism with ergot alkaloids 4

Cardiac Considerations

• Negative inotropic effects: Itraconazole can cause negative inotropic effects and should not be used in patients with ventricular dysfunction 4
• Congestive heart failure: Risk factors include cardiac disease, significant pulmonary disease, renal failure, and edematous disorders 4
• Calcium channel blockers: Additive negative inotropic effects when combined with itraconazole 4

Monitoring and Management Strategies

Therapeutic Drug Monitoring (TDM)

• Strong recommendation: Obtain serum trough drug levels for itraconazole and potentially interacting drugs 1
• Timing: Once steady state has been reached 1
• Purpose: Enhance therapeutic efficacy, evaluate failures due to suboptimal drug exposure, and minimize toxicities 1

Clinical Management Approaches

1. Review all medications before initiating itraconazole therapy 1
2. Avoid contraindicated combinations completely 4
3. Adjust dosages of interacting drugs that cannot be avoided 1
4. Consider alternative antifungals with less interaction potential (echinocandins) when necessary 1
5. Monitor for signs of toxicity from increased levels of concomitant drugs 1

Special Populations and Considerations

• Renal impairment: Oral solution is preferred over IV formulation due to accumulation of cyclodextrin vehicle in renal impairment 1
• Cancer patients: Particularly careful monitoring needed due to multiple potential interactions with chemotherapeutic agents 1
• Transplant recipients: Close monitoring of immunosuppressant levels essential 1

Common Pitfalls and Caveats

• Formulation differences: Itraconazole capsules and oral solution should not be used interchangeably (solution has greater bioavailability) 1, 4
• Food effects: Absorption of itraconazole solution is enhanced by gastric acid (take without food); capsules should be taken with food 1
• Metabolite contribution: Underestimating the contribution of itraconazole's metabolites to drug interactions (they account for ~50% of inhibitory effect) 2, 5
• Delayed effects: Drug interactions may persist for up to 2 weeks after discontinuation due to long half-life 4

By understanding these complex interactions and implementing appropriate monitoring strategies, clinicians can minimize the risks associated with itraconazole therapy while maintaining its antifungal efficacy.