Drug Interactions between Etrafon Forte and Onmel

MONITOR: The coadministration with azole antifungal agents may increase the plasma concentrations of some tricyclic antidepressants (TCAs). Elevated TCA levels may result in CNS toxicity, anticholinergic symptoms, and QT interval prolongation. The mechanism is decreased TCA clearance due to azole-related inhibition of the CYP450 3A4 isoenzyme, which is partially responsible for the metabolism of TCAs like amitriptyline, clomipramine, imipramine, and possibly others. Fluconazole additionally inhibits CYP450 2C19, which is another secondary route of metabolism for several TCAs. The effect of a single dose of fluconazole on TCA pharmacokinetics has not been reported. In a pharmacokinetic study involving six healthy subjects, ketoconazole (200 mg/day for 14 days) increased the half-life and area under the plasma concentration-time curve (AUC) of a single dose of imipramine (100 mg) by 15% and 20%, respectively, but did not affect the pharmacokinetics of desipramine or its metabolite.

MANAGEMENT: During concomitant therapy with azole antifungal agents, patients stabilized on their TCA regimen should be observed for increased pharmacologic response to the TCA, and the dosage adjusted accordingly if necessary. Serum TCA levels should be monitored following initiation or discontinuation of azole antifungal therapy. Patients should be advised to notify their caregiver if they experience excessive dry mouth, visual disturbances, urinary retention, dizziness, syncope, fast or irregular heartbeat, constipation, or seizures.

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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.

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