Drug Interactions between Denzapine and Limbitrol

MONITOR CLOSELY: Coadministration with other psychotropic agents may potentiate the adverse effects of clozapine on cardiovascular function. Orthostatic hypotension with or without syncope, in rare cases accompanied by profound collapse and cardiorespiratory arrest, has occurred during initiation of clozapine treatment alone and in combination with other psychotropic agents, occasionally even on the first dose. The risk is greatest during initial titration in association with rapid dose escalation. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest. Other adverse effects that may be increased during use of clozapine with other psychotropic agents include CNS depression, tardive dyskinesia, blood dyscrasias (leukopenia, neutropenia, agranulocytosis), tachycardia, and ECG changes such as QT interval prolongation. Anticholinergic effects of these agents may also be additively increased. Excessive anticholinergic effects may 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: Caution is advised when clozapine is initiated in patients receiving other psychotropic drugs. Vital signs should be closely monitored. Patients who have had even a brief interval off clozapine (i.e. 2 or more days since the last dose) should be restarted with 12.5 mg once or twice daily. The potential for additive effects on the QT interval and increased risk of torsade de pointes arrhythmia should also be considered when clozapine is used in combination with phenothiazines, tricyclic antidepressants, some atypical antipsychotics (e.g., asenapine, quetiapine, iloperidone, iloperidone, paliperidone, risperidone, ziprasidone), or other psychotherapeutic agents that can prolong the QT interval such as amoxapine, haloperidol, maprotiline, mirtazapine, and trazodone. Serum electrolytes, including potassium, magnesium and calcium, should be measured at baseline and periodically during treatment, and any abnormalities corrected prior to initiating clozapine. Routine ECG assessment may detect QTc prolongation but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. 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. Ambulatory patients may want 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 CLOSELY: Benzodiazepines and clozapine may have additive effects on respiratory and cardiovascular function. Ataxia, excessive salivation, hypotension, collapse, respiratory depression, respiratory arrest, loss of consciousness, cardiac arrest, and sudden death have been reported. The mechanism is unknown and causality has not been clearly determined.

MANAGEMENT: Caution is advised if concurrent therapy is necessary. Vital signs should be closely monitored.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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