Rifampicin and Itraconazole: Contraindicated Combination
Rifampicin and itraconazole should not be administered concomitantly due to severe reduction in itraconazole concentrations that renders it subtherapeutic and clinically ineffective. 1
Mechanism of Interaction
Rifampicin is a potent inducer of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, which are the primary metabolic and transport pathways for itraconazole. 2, 3 This induction reaches maximum effect within approximately 1 week of starting rifampicin and persists for roughly 2 weeks after discontinuation. 3
Clinical Evidence of Interaction Severity
The magnitude of this interaction is profound and clinically unacceptable:
In healthy volunteers, coadministration of rifampicin with itraconazole resulted in undetectable itraconazole levels in all subjects except one, with an estimated minimum 88% decrease in itraconazole exposure (AUC). 4
In AIDS patients, the interaction caused an estimated minimum 64% decrease in itraconazole exposure. 4
The resulting itraconazole concentrations are insufficient to achieve therapeutic antifungal activity. 1
Clinical Outcomes and Treatment Failures
Patients receiving this combination experience treatment failures:
Multiple patients with systemic mycoses who received azoles (including itraconazole) with rifampin experienced substantial decreases in azole serum concentrations. 5
Two patients with coccidioidomycosis failed to respond to itraconazole when combined with rifampin. 5
Two patients with cryptococcosis suffered relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. 5
Management Recommendations
When both tuberculosis treatment and systemic antifungal therapy are required, use the following approach:
Option 1: Alternative Antifungal Agent (Preferred)
- Substitute fluconazole for itraconazole, as fluconazole can be used with rifamycins, though the fluconazole dose may need to be increased. 1
- Fluconazole experiences only a 22% decrease in AUC when combined with rifampicin, which is manageable with dose adjustment. 6
- Monitor clinical response and consider increasing fluconazole dose if needed. 6
Option 2: Alternative Rifamycin
- Consider rifabutin instead of rifampicin for tuberculosis treatment, as rifabutin has less potent enzyme-inducing effects. 1
- However, note that itraconazole concentrations may still be subtherapeutic with any rifamycin. 1
Option 3: Non-Rifamycin TB Regimen
- Use a tuberculosis regimen that omits rifampicin entirely and extend treatment duration to 18 months. 1
- This option should be reserved for situations where both itraconazole is essential and no alternative antifungal is suitable. 1
Critical Timing Considerations
If rifampicin must be discontinued to allow itraconazole use:
- Wait at least 2 weeks after stopping rifampicin before expecting full itraconazole efficacy, as enzyme induction effects persist during this period. 3
- Conversely, if itraconazole dose was increased during rifampicin coadministration, reduce the itraconazole dose within 2 weeks after discontinuing rifampicin to avoid toxicity. 1
Contraindications in Specific Populations
The combination is explicitly contraindicated in certain clinical scenarios:
- Concomitant use of dabigatran with itraconazole is contraindicated. 1
- Concomitant use of rivaroxaban with azole antimycotics (including itraconazole) is contraindicated due to combined CYP3A4 and P-gp inhibition. 1
- When treating chronic myelogenous leukemia with dasatinib, avoid itraconazole as it may increase dasatinib plasma concentrations. 1
Common Clinical Pitfall
The most critical error is attempting to overcome this interaction by increasing itraconazole dose. The magnitude of enzyme induction is so profound that therapeutic itraconazole concentrations cannot be reliably restored through dose escalation. 1 This approach leads to treatment failure and potential development of antifungal resistance.