Drug Interactions between amitriptyline / perphenazine and fexinidazole

GENERALLY AVOID: Fexinidazole can cause concentration-dependent prolongation of the QT interval. 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. Based on the exposure-response relationship, treatment with fexinidazole is predicted to cause an average increase of 19 msec in the Fridericia-corrected QT interval (QTcF) at the recommended dosing regimen. In addition, drugs that are inducers of hepatic CYP450 enzymes, such as apalutamide and enzalutamide, may significantly increase the plasma concentration of fexinidazole's active metabolites, fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). The observed increase in QTcF appears to be associated with the sulfone (M2) metabolite of fexinidazole; therefore, an increase in the plasma concentration of the sulfone (M2) metabolite may increase the risk of QT prolongation. 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: The concurrent use of fexinidazole with other medications that can prolong the QT interval, block cardiac potassium channels, and/or induce bradycardia should generally be avoided. If coadministration is unavoidable, treatment with fexinidazole should not be initiated until the opposing drug is eliminated from the body (allow a washout period of 5 half-lives) or do not initiate treatment with the opposing drug until fexinidazole is eliminated from the body (allow a washout period of 7 days). All QT-prolonging drugs including fexinidazole should be interrupted in patients who develop clinically significant ventricular arrhythmia or a QTcF interval greater than 500 msec confirmed by repeat ECG. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope.

GENERALLY AVOID: Fexinidazole can cause concentration-dependent prolongation of the QT interval. 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. Based on the exposure-response relationship, treatment with fexinidazole is predicted to cause an average increase of 19 msec in the Fridericia-corrected QT interval (QTcF) at the recommended dosing regimen. In addition, drugs that are inducers of hepatic CYP450 enzymes, such as apalutamide and enzalutamide, may significantly increase the plasma concentration of fexinidazole's active metabolites, fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). The observed increase in QTcF appears to be associated with the sulfone (M2) metabolite of fexinidazole; therefore, an increase in the plasma concentration of the sulfone (M2) metabolite may increase the risk of QT prolongation. 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: The concurrent use of fexinidazole with other medications that can prolong the QT interval, block cardiac potassium channels, and/or induce bradycardia should generally be avoided. If coadministration is unavoidable, treatment with fexinidazole should not be initiated until the opposing drug is eliminated from the body (allow a washout period of 5 half-lives) or do not initiate treatment with the opposing drug until fexinidazole is eliminated from the body (allow a washout period of 7 days). All QT-prolonging drugs including fexinidazole should be interrupted in patients who develop clinically significant ventricular arrhythmia or a QTcF interval greater than 500 msec confirmed by repeat ECG. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, 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.