Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 1A2 and/or 3A4 may increase the plasma concentrations of levobupivacaine, which is primarily metabolized by these isoenzymes. Although no clinical studies have been conducted, the possibility of prolonged and/or increased pharmacologic effects of levobupivacaine should be considered.

MANAGEMENT: Caution may be advisable if levobupivacaine is administered to patients receiving inhibitors of CYP450 1A2 (e.g., quinolones, deferasirox, mexiletine, propafenone, ticlopidine, zileuton) or CYP450 3A4 (e.g., azole antifungals, macrolide antibiotics, protease inhibitors, kinase inhibitors, aprepitant, conivaptan, cyclosporine, delavirdine, diltiazem, nefazodone, verapamil). Particular caution and dosage adjustment of levobupivacaine may be warranted during concomitant use of both a CYP450 1A2 inhibitor and a CYP450 3A4 inhibitor, or a drug that inhibits both isoenzymes (e.g., fluvoxamine). Patients should be monitored for early signs and symptoms of central nervous system toxicity such as dizziness, drowsiness, lightheadedness, anxiety, restlessness, incoherent speech, tremors, twitching, numbness and tingling of the mouth and lips, metallic taste, tinnitus, and blurred vision, as well as more serious reactions including convulsions, hypotension, arrhythmias, and cardiorespiratory depression.

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.