Ritonavir × Voriconazole

Ritonavir is a strong CYP3A4 inhibitor, but it also induces CYP2C19 and CYP2C9, the main enzymes that clear voriconazole. Induction wins, and voriconazole exposure falls. With ritonavir 400 mg twice daily, voriconazole AUC drops by 82% and Cmax by 66%; with 100 mg twice daily, by 39% and 24% (Vfend SmPC, EMA). Voriconazole inhibits CYP3A4, but this barely affects ritonavir: its exposure is unchanged with the high dose and falls by 13% (AUC) with the low dose.

The main risk is loss of antifungal effect: invasive aspergillosis, candidiasis or another fungal infection treated with voriconazole fails to respond or progresses. The voriconazole and ritonavir labels (EMA and FDA) warn of a possible loss of effect. On the ritonavir side there is little to see: its concentration changes little, and the labels describe no added ritonavir toxicity.

Do not combine voriconazole with ritonavir at 400 mg twice daily or higher, the dose at which ritonavir is an antiretroviral in its own right: both labels list this as a contraindication (Vfend SmPC, EMA, section 4.3; Norvir SmPC, EMA, section 4.3; Vfend and Norvir prescribing information, FDA, sections 4 and 7). Also avoid voriconazole with ritonavir 100 mg twice daily, the booster dose for another protease inhibitor, unless an assessment of benefit and risk for the patient justifies voriconazole (Vfend SmPC, EMA, sections 4.4 and 4.5; Norvir SmPC, EMA, section 4.5). The labels give no voriconazole dose adjustment for this case. When keeping both drugs, expect voriconazole exposure to fall by about 39% (Vfend SmPC, EMA) and watch the response of the fungal infection. When ritonavir is used as a booster, look up the contraindications of the boosted protease inhibitor in its own label (Norvir SmPC, EMA, section 4.3).