Drug Interaction Report

MONITOR CLOSELY: Pasireotide can cause bradycardia and QT prolongation. 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 healthy study subjects given therapeutic (0.6 mg twice daily) and supratherapeutic (1.95 mg twice daily) dosages of pasireotide, the maximum mean placebo-subtracted QTcI change from baseline was 12.7 msec and 16.6 msec, respectively. Both dosages decreased heart rate, with a maximum mean placebo-subtracted change from baseline of -10.9 beats per minute (bpm) observed at 1.5 hours for the therapeutic dosage and -15.2 bpm at 0.5 hours for the supratherapeutic dosage. The mean steady-state peak plasma concentration (Cmax) produced by the supratherapeutic dosage was 3.3-fold that observed with the therapeutic dosage. In clinical studies of patients with Cushing's disease, two of 201 patients experienced single occurrences of QTcF exceeding 500 msec. Torsade des pointes arrhythmias were not observed in these or other studies. 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). 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 is recommended if pasireotide is used in combination with other drugs that can prolong the QT interval. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting pasireotide therapy and periodically during treatment in accordance with the product labeling. Hypokalemia and hypomagnesemia must be corrected prior to pasireotide administration. 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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pazopanib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of pazopanib. The mechanism of interaction is unknown. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in peak plasma concentration (Cmax) and systemic exposure (AUC).

MANAGEMENT: Patients treated with pazopanib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Pazopanib should be administered at least one hour before or two hours after a meal.