Drug interactions between fluconazole and Kaletra

fluconazole ↔ lopinavir

Applies to:fluconazole and Kaletra (lopinavir/ritonavir)

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 postdose 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: The use of lopinavir-ritonavir in combination with other drugs that may prolong the QT interval should generally be avoided. Patients treated with any medication that can cause QT prolongation should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope.

fluconazole ↔ ritonavir

Applies to:fluconazole and Kaletra (lopinavir/ritonavir)

The coadministration with fluconazole may slightly increase the plasma concentrations of ritonavir. The proposed mechanism is fluconazole inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of ritonavir. In an open-label, randomized, crossover study consisting of eight healthy subjects, fluconazole (400 mg on day 1, 200 mg on days 2 to 5) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ritonavir (200 mg every 6 hours for 4 days) by approximately 15% and 12%, respectively, compared to when ritonavir was administered alone. In a study of 3 HIV-infected patients treated with ritonavir 600 mg orally twice a day, there were no detectable changes in the pharmacokinetics of ritonavir following addition of fluconazole. Other azole antifungal agents are expected to affect ritonavir in a similar fashion but possibly to a greater extent, since fluconazole is a relatively weak inhibitor of CYP450 3A4. No special precautions are necessary when fluconazole is given with ritonavir.