Drug Interactions between Kaletra and voriconazole

CONTRAINDICATED: Coadministration with ritonavir may significantly decrease or increase the plasma concentrations of voriconazole. The proposed mechanism may involve ritonavir-mediated induction of voriconazole metabolism via the CYP450 isoenzymes 2C19 and 2C9. Voriconazole is primarily metabolized via CYP450 2C19, and to a lesser extent, by CYP450 2C9 and 3A4. In a randomized, placebo-controlled study in healthy adult male subjects (n=29), high-dose ritonavir (400 mg twice daily for 10 days) administered with oral voriconazole (400 mg twice daily for one day, then 200 mg twice daily for 9 days) decreased the mean steady-state voriconazole peak plasma concentration (Cmax) and systemic exposure (area under the concentration-time curve from 0 to 12 hours, or AUC (0-12)) by 68% and 83%, respectively. Low-dose ritonavir (100 mg every 12 hours for 10 days) administered with the same oral voriconazole regimen in healthy adult male subjects (n=17) decreased the mean steady-state Cmax and AUC (0-12) of voriconazole by 24% and 39%, respectively. However, the opposite effect may occur in patients who are poor metabolizers of CYP450 2C19. The net effect in these patients may be increased exposure to voriconazole via ritonavir-mediated inhibition of CYP450 3A4. In the high-dose ritonavir study above, one subject had an increased voriconazole exposure of 2.5-fold. In the low-dose ritonavir study, 4 subjects showed increased voriconazole exposure; three of these had slight increases (10% to 42%), but one subject had an approximately 3.5-fold increase in voriconazole exposure. Although voriconazole is also considered a strong inhibitor of CYP450 3A4 and an inhibitor of CYP450 2C19 and 2C9, the pharmacokinetics of high-dose ritonavir were not significantly affected by voriconazole; mean steady-state Cmax and AUC (0-12) of low-dose ritonavir decreased slightly by approximately 24% and 14%, respectively, during coadministration with oral voriconazole.

MANAGEMENT: The use of voriconazole in combination with high-dose ritonavir (400 mg or more every 12 hours) is considered contraindicated. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should also be avoided, unless the benefit justifies the risk.

GENERALLY AVOID: Lopinavir in combination with ritonavir may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a study of 39 healthy adults who were administered lopinavir-ritonavir at a therapeutic dosage of 400 mg-100 mg twice daily and a supratherapeutic dosage of 800 mg-200 mg twice daily, the maximum mean time-matched difference in QTcF interval from placebo (after baseline correction) was 5.3 msec for the lower dosage and 15.2 msec for the supratherapeutic dosage in the 12 hours post-dose on treatment day 3 when exposures were approximately 1.5 and 3-fold higher, respectively, than those observed with recommended once-daily or twice-daily dosages of lopinavir-ritonavir at steady state. No subject experienced an increase in QTcF greater than 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec. There have been cases of QT interval prolongation and torsade de pointes arrhythmia during postmarketing use of lopinavir-ritonavir, although causality could not be established. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of lopinavir-ritonavir with other drugs that can prolong the QT interval should generally be avoided. Patients treated with any medication that can cause QT prolongation should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.