The risks of using CLOZARIL in combination with other drugs have not been systematically evaluated.
Pharmacodynamic -Related Interactions
The mechanism of CLOZARIL-induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression warrants consideration. Therefore, CLOZARIL should not be used with other agents having a well-known potential to suppress bone marrow function.
Given the primary CNS effects of CLOZARIL, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.
Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately 1 case per 3,000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even CLOZARIL by itself. Although it has not been established that there is an interaction between CLOZARIL and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
CLOZARIL may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine -type drugs. The administration of epinephrine should be avoided in the treatment of drug -induced hypotension because of a possible reverse epinephrine effect.
Pharmacokinetic -Related Interactions
Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes.
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, nicotine, and rifampin may decrease CLOZARIL plasma levels, resulting in a decrease in effectiveness of a previously effective CLOZARIL dose.
Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, citalopram, ciprofloxacin, and erythromycin may increase plasma levels of CLOZARIL, potentially resulting in adverse effects. Although concomitant use of CLOZARIL and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in CLOZARIL plasma levels.
In a study of schizophrenic patients who received clozapine under steady-state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of coadministration, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about three-fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when CLOZARIL is combined with these drugs, particularly with fluvoxamine. A reduced CLOZARIL dose should be considered.
A subset (3%-10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.
Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, coadministration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.