Drug Interaction Report

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of vemurafenib, which has been shown in vitro to be a substrate of the isoenzyme. Because vemurafenib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death. However, clinical and pharmacokinetic data are currently lacking. A reverse interaction may also occur, since many CYP450 3A4 inhibitors are also substrates of the isoenzyme and vemurafenib is an inducer. The possibility of diminished pharmacologic effects of these agents should be considered during coadministration with vemurafenib.

MANAGEMENT: Caution is advised if vemurafenib is prescribed in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored regularly, and treatment interrupted if QTc exceeds 500 ms. Any electrolyte abnormalities must then be corrected and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) under control prior to resuming treatment. Vemurafenib may be restarted once QTc decreases below 500 ms, but at a reduced dosage as described in the product labeling. Permanent discontinuation of treatment is recommended if, after correction of associated risk factors, both the QTc is greater than 500 ms and the QTc increase is greater than 60 ms from pretreatment values. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, irregular heartbeat, shortness of breath, or syncope. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should be monitored during coadministration with vemurafenib.

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.