Drug Interactions between Clozaril and darifenacin

MONITOR: Coadministration with darifenacin may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6, including many psychotherapeutic drugs such as tricyclic antidepressants, phenothiazines, and other neuroleptics. The mechanism is decreased clearance due to inhibition of the CYP450 2D6 isoenzyme by darifenacin. According to the product labeling, darifenacin (30 mg once daily) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of imipramine by 57% and 70%, respectively. These changes were accompanied by a 3.6-fold increase in the mean Cmax and AUC of desipramine, the active metabolite of imipramine. Pharmacodynamically, anticholinergic effects may also increase when darifenacin is used in combination with these drugs. Excessive parasympatholytic effects may result in mydriasis, blurred vision, flushed face, dry skin and mucous membranes, tachycardia, urinary retention, constipation, paralytic ileus, hyperthermia, and heat stroke.

MANAGEMENT: Caution is advised if darifenacin must be used concomitantly with tricyclic antidepressants, phenothiazines, or other neuroleptics. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever darifenacin is added to or withdrawn from therapy. Clinicians should also be alerted to the potential for additive anticholinergic effects during concomitant administration. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations.

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