indication

For use in patients with treatment-resistant schizophrenia.

pharmacology

Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT₂), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT₂ with similar receptor affinities may explain some of the other therapeutic and side effects of Clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.

mechanism of action

Clozapine's antipsychotic action is likely mediated through a combination of antogistic effects at D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms.

toxicity

Clozapine carries a black-box warning for agranulocytosis.

biotransformation

Hepatic

absorption

Rapid and almost complete

half life

8 hours (range 4-12 hours)

route of elimination

Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.

drug interactions

Alprazolam: Increased risk of toxicity

Bromazepam: Bromazepam may increase the adverse effects of clozapine. Consider alternate therapy or a reduction in the bromazepam dose. Monitor for respiratory depression and hypotension if concomitant therapy is initiated.

Caffeine: Caffeine increases the effect and toxicity of clozapine

Carbamazepine: Carbamazepine may decrease the serum concentration of clozapine by increasing its metabolism. Concomitant therapy should also be avoided due to increased risk of bone marrow suppression. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of clozapine if carbamazepine is initiated, discontinued or dose changed.

Chlordiazepoxide: Increased risk of toxicity

Cimetidine: Cimetidine may increase the serum concentratin of clozapine. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of clozapine if cimetidine is initiated, discontinued or dose changed.

Cinolazepam: Increased risk of toxicity

Ciprofloxacin: Ciprofloxacin may increase clozapine serum levels

Citalopram: The antidepressant increases the effect of clozapine

Clobazam: Increased risk of toxicity

Clonazepam: Increased risk of toxicity

Clorazepate: Increased risk of toxicity

Diazepam: Increased risk of toxicity

Donepezil: Possible antagonism of action

Erythromycin: Erythromycin increases the effect of clozapine

Estazolam: Increased risk of toxicity

Ethotoin: Hydantoin decreases the effect of clozapine

Flunitrazepam: Increased risk of toxicity

Fluoxetine: The antidepressant increases the effect of clozapine

Flurazepam: Increased risk of toxicity

Fluvoxamine: The antidepressant increases the effect of clozapine

Fosphenytoin: Hydantoin decreases the effect of clozapine

Galantamine: Possible antagonism of action

Halazepam: Increased risk of toxicity

Haloperidol: Clozapine, a moderate CYP2D6 inhibitor, may increase the serum concentration of haloperidol by decreasing its metabolism. Additive CNS despresant and anticholinergic effects may also occur. Monitor for changes in the therapeutic and adverse effects of haloperidol if clozapine is initiated, discontinued or dose changed. Also monitor for increased CNS depressant and anticholinergic effects during concomitant therapy.

Josamycin: Erythromycin increases the effect of clozapine

Ketazolam: Increased risk of toxicity

Lamotrigine: Lamotrigine increases the effect and toxicity of clozapine

Lorazepam: Increased risk of toxicity

Mephenytoin: Hydantoin decreases the effect of clozapine

Midazolam: Increased risk of toxicity

Modafinil: Modafinil increases the effect and toxicity of clozapine

Nitrazepam: Increased risk of toxicity

Norfloxacin: Ciprofloxacin may increase clozapine serum levels

Oxazepam: Increased risk of toxicity

Phenytoin: Phenytoin may decrease the effect of clozapine.

Prazepam: Increased risk of toxicity

Quazepam: Increased risk of toxicity

Rifabutin: Rifabutin decreases the effect of clozapine

Rifampin: Rifampin decreases the effect of clozapine

Ritonavir: Ritonavir increases the effect and toxicity of clozapine

Rivastigmine: Possible antagonism of action

Sertraline: The antidepressant increases the effect of clozapine

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Clozapine, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.

Tamoxifen: Clozapine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Clozapine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Clozapine is initiated, discontinued, or dose changed.

Temazepam: The benzodiazepine, Temazepam, may increase the adverse effects of Clozapine. Monitor for respiratory depression and hypotension if concomitant therapy is initiated.

Tetrabenazine: May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.

Thiabendazole: The strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Clozapine by decreasing Clozapine metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Clozapine if Thiabendazole is initiated, discontinued or dose changed.

Tramadol: Clozapine may decrease the effect of Tramadol by decreasing active metabolite production.

Triazolam: Increased risk of toxicity

Trimethobenzamide: Trimethobenzamide and Clozapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Triprolidine: Triprolidine and Clozapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Clozapine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Vilazodone: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of clozapine. If concurrent use of these agents is employed, monitor for increased toxic effects of clozapine if a selective serotonin reuptake inhibitor (SSRI) is initiated/dose increased, or decreased effects if a SSRI is discontinued/dose decreased.