Drug Interactions between Prezcobix and vemurafenib

MONITOR: Coadministration with drugs that are inducers of CYP450 3A4 may decrease the plasma concentrations of protease inhibitors (PIs), which are primarily metabolized by the isoenzyme.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, protease inhibitors should be used cautiously with agents that induce CYP450 3A4, particularly if only one PI is used in the antiretroviral regimen. Coadministration of atazanavir without ritonavir and carbamazepine, phenobarbital, or phenytoin is not recommended. Antiretroviral response should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary.

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.