Drug Interactions between Akynzeo for Injection and quinine

MONITOR: Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The risk of an individual agent or a combination of these 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).

MANAGEMENT: Caution and clinical monitoring are recommended if multiple agents associated with QT interval prolongation are prescribed together. 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.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of quinine, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, administration of a single 600 mg oral dose of quinine sulfate in combination with the potent CYP450 3A4 inhibitor troleandomycin (500 mg orally every 8 hours for 48 hours) significantly increased the mean quinine peak plasma concentration (Cmax), systemic exposure (AUC) and terminal elimination half-life by 26%, 90% and 63%, respectively, and decreased the mean oral clearance (Cl/F) by 45% compared to administration of quinine alone. Troleandomycin also reduced the average Cmax, AUC and apparent formation clearance of the main metabolite, 3-hydroxyquinine, by 75%, 58% and 81%, respectively. Likewise, in a study of nine healthy volunteers, administration of a single 500 mg oral dose of quinine hydrochloride in combination with another potent CYP450 3A4 inhibitor ketoconazole (100 mg twice daily for 3 days) resulted in a 45% increase in mean quinine AUC and a 31% decrease in mean oral clearance compared to administration of quinine alone. Clinically, high plasma levels of quinine may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. Fatal torsade de pointes arrhythmia was reported in an elderly patient who received quinine in combination with erythromycin, a moderately potent CYP450 3A4 inhibitor, and dopamine. However, a causal relationship was not established in this case. The risk of other quinine toxicities such as cinchonism may also be increased.

MANAGEMENT: Caution is advised if quinine is used in combination with potent and moderate CYP450 3A4 inhibitors. Patients should be monitored closely for adverse reactions associated with quinine such as hematologic toxicities and cardiac arrhythmias including torsade de pointes and atrial fibrillation. Patients should be advised to contact their physician if they experience increased side effects such as headache, flushing, sweating, nausea, vomiting, diarrhea, abdominal pain, tinnitus, dizziness, vertigo, hearing impairment, blurred vision, vision impairment, and irregular heart rhythm.