Drug Interactions between amitriptyline / perphenazine and pacritinib

GENERALLY AVOID: Pacritinib can cause 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 24-week study of 54 patients with myelofibrosis treated with pacritinib 200 mg twice daily, the largest mean (90% confidence interval [CI]) increase in QTcF was 11 msec (90% CI: 5 to 17 msec). In clinical trials, QTc prolongation >500 msec and QTc increase of at least 60 msec over baseline were higher in pacritinib-treated patients (1.4% and 1.9%, respectively) than in control arm patients (1% and 1%, respectively). In addition, QTc prolongation was reported for 3.8% of pacritinib-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported. 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 pacritinib with drugs that have significant potential for QTc prolongation should be avoided. An electrocardiogram should be obtained prior to initiating pacritinib therapy and as clinically indicated during treatment. Correct hypokalemia before and during treatment. In addition to electrolyte management, pacritinib treatment should be interrupted and the dosage reduced based on severity of QT prolongation in accordance with product labeling. 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: Pacritinib can cause 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 24-week study of 54 patients with myelofibrosis treated with pacritinib 200 mg twice daily, the largest mean (90% confidence interval [CI]) increase in QTcF was 11 msec (90% CI: 5 to 17 msec). In clinical trials, QTc prolongation >500 msec and QTc increase of at least 60 msec over baseline were higher in pacritinib-treated patients (1.4% and 1.9%, respectively) than in control arm patients (1% and 1%, respectively). In addition, QTc prolongation was reported for 3.8% of pacritinib-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported. 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 pacritinib with drugs that have significant potential for QTc prolongation should be avoided. An electrocardiogram should be obtained prior to initiating pacritinib therapy and as clinically indicated during treatment. Correct hypokalemia before and during treatment. In addition to electrolyte management, pacritinib treatment should be interrupted and the dosage reduced based on severity of QT prolongation in accordance with product labeling. 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 of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.