Potential for Other Drugs to Affect Clozapine
Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine tablets concomitantly with drugs that are inducers or inhibitors of these enzymes.
Concomitant use of clozapine tablets and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the clozapine tablets dose to one third of the original dose when clozapine tablets are coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The clozapine tablets dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration Clinical Pharmacology].
Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when clozapine tablets are coadministered with these inhibitors. Consider reducing the clozapine tablets dosage if necessary [see Dosage and Administration ].
CYP2D6 and CYP3A4 Inhibitors
Concomitant treatment with clozapine tablets and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology]. Use caution and monitor patients closely when using such inhibitors. Consider reducing the clozapine tablets dose [see Dosage and Administration ].
CYP1A2 and CYP3A4 Inducers
Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of clozapine tablets. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the clozapine tablets dose if used concomitantly with inducers of these enzymes. However, concomitant use of clozapine tablets and strong CYP3A4 inducers is not recommended [see Dosage and Administration].
Consider reducing the clozapine tablets dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration ].
Drugs that Cause QT Interval Prolongation
Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions].
Potential for Clozapine to Affect Other Drugs
Concomitant use of clozapine with other drugs metabolized by CYP2D6 can increase levels of these CYPD26 substrates. Use caution when coadministering clozapine with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).
The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.
Management of Overdosage
For the most up-to-date information on the management of clozapine overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®
, a registered trademark of Thomson PDR. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for clozapine.
In managing overdosage, consider the possibility of multiple-drug involvement.