Drug Interactions between fluconazole and saquinavir

GENERALLY AVOID: Saquinavir 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 elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. 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).

Coadministration with fluconazole may increase the plasma concentrations of saquinavir. The proposed mechanism is fluconazole inhibition of CYP450 3A4-mediated first-pass metabolism of saquinavir in the intestine. Fluconazole may also inhibit P-glycoprotein, which is responsible for the active efflux of saquinavir and other drugs back into the intestinal lumen. In a study consisting of five HIV-infected subjects, the median increase in peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of saquinavir (administered as saquinavir mesylate 1200 mg orally three times a day) was 56% and 50%, respectively, following the addition of fluconazole (400 mg orally once, then 200 mg daily for 5 days). These alterations probably do not warrant an adjustment in saquinavir dosage. However, it may be appropriate to monitor patients for potentially excessive plasma levels and increased adverse effects of saquinavir such as diarrhea, nausea, abdominal discomfort, dyspepsia, dyslipidemia, and lipodystrophy. The interaction has not been studied using the saquinavir soft gel capsule (SGC) formulation.

MANAGEMENT: Ritonavir-boosted saquinavir should not be used with other drugs that may prolong the QT interval. 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, palpitations, or syncope.