Drug Interactions between Etrafon Forte and Paxil CR

GENERALLY AVOID: Coadministration with paroxetine may significantly increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is paroxetine inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of many antidepressant and psychotropic drugs. Several-fold increases in plasma levels and decreases in metabolic clearance have been reported for desipramine and nortriptyline, while smaller changes have been reported for amitriptyline and imipramine, presumably because other CYP450 isoenzymes are also involved in their metabolism. Pharmacodynamically, the combination of paroxetine (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors.

MANAGEMENT: In general, the use of paroxetine (or other SSRIs) with TCAs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Pharmacologic response and plasma TCA levels should be monitored more closely whenever paroxetine is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia).

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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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MONITOR: The coadministration with paroxetine may increase the plasma concentrations of phenothiazines. The mechanism is paroxetine inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of most, if not all, phenothiazines. The interaction has been studied specifically with perphenazine. In eight extensive metabolizers of CYP450 2D6, paroxetine treatment (20 mg/day orally for 10 days) resulted in a 2- to 21-fold decrease in 2D6 activity and a 2- to 13-fold increase in peak plasma concentrations of perphenazine (0.11 mg/kg single oral dose). These changes were associated with a significant increase in central nervous system side effects of perphenazine, including oversedation, extrapyramidal symptoms, and impairment of psychomotor performance and memory. Severe extrapyramidal adverse effects were also reported in a 29-year-old man treated with trifluoperazine following addition of paroxetine. The symptoms resolved after withdrawal of medication and did not recur following reinstitution of trifluoperazine.

MANAGEMENT: Caution is advised if phenothiazines must be used concomitantly with paroxetine. Pharmacologic response to the phenothiazine should be monitored more closely whenever paroxetine is added to or withdrawn from therapy, and the phenothiazine dosage adjusted as necessary. Patients should be monitored for the development of extrapyramidal symptoms (e.g., tremor, shuffling gait, drooling, mask-like face, tongue stiffness, muscle spasms or rigidity, involuntary movements) and changes in mental status.

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