Drug Interactions between givinostat and panobinostat

GENERALLY AVOID: Panobinostat can cause dose-dependent 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 premarketing multiple myeloma trial, QTc prolongation with values between 451 to 480 msec and between 481 to 500 msec occurred in 10.8% and 1.3% of patients receiving panobinostat, respectively. A maximum QTcF increase from baseline of 31 to 60 msec and greater than 60 msec was observed in 14.5% and 0.8% of panobinostat-treated patients, respectively. No episodes of QTcF prolongation exceeding 500 msec were reported with panobinostat given at a dose of 20 mg in combination with bortezomib and dexamethasone in the multiple myeloma trial. Pooled clinical data from over 500 patients treated with panobinostat monotherapy at different dose levels for various indications have shown that the incidence of CTC Grade 3 QTc prolongation (i.e., QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher. 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, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Concomitant use of panobinostat with other drugs that can prolong the QT interval should generally be avoided. Anti-emetic drugs with known QT prolonging risk such as dolasetron, granisetron, ondansetron, palonosetron, and tropisetron may be used with frequent ECG monitoring. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting panobinostat therapy and periodically during treatment as clinically indicated. In the premarketing trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles. Panobinostat should not be started if baseline QTc is greater than 450 msec. Likewise, treatment should be interrupted in patients who develop QTc prolongation of 480 msec or greater until recovery to less than or equal to Grade 1, then resumed at a reduced dose. In case of recurrence, therapy should be withheld until recovery to less than or equal to Grade 1, then resumed at a further reduced dose if necessary. Permanently discontinue panobinostat therapy if Grade 3 or 4 QTc prolongation does not resolve. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.