Clozaril (clozapine) has complex pharmacology and interacts with many other medications, both prescription and over-the-counter. Some interactions increase clozapine levels which can lead to toxicity, while others reduce clozapine levels and effectiveness. Careful management of medication regimen is required to limit risks and ensure safety.
CYP450 Enzyme Inhibition
Clozapine is metabolized by CYP1A2, CYP2D6, and CYP3A4 enzymes in the liver. Medications that inhibit these enzymes will increase clozapine levels in the blood. Examples include:
- Fluvoxamine (antidepressant): Can increase clozapine levels up to 6-fold. Avoid combination if possible due to high toxicity risk. If essential, use lowest effective doses of both and monitor plasma clozapine levels closely.
- Ketoconazole (antifungal): Increases clozapine levels by up to 50-90% via CYP3A4 inhibition. Monitor for toxicity or adjust clozapine dose if used long-term. Single-dose antifungals are less likely to significantly alter clozapine metabolism.
- Ciprofloxacin (antibiotic): CYP1A2 inhibitor that can increase clozapine levels by up to 70%. Clozapine dose may need reduction if used concurrently to avoid toxicity. Plasma level monitoring is advisable.
- Hormonal contraceptives: Estrogen in oral contraceptives is a weak CYP1A2 inhibitor. Clozapine dose adjustments are usually unnecessary but females starting or stopping birth control require monitoring.
CYP450 Enzyme Induction
Substances that induce hepatic enzymes can significantly lower clozapine plasma concentrations. Examples include:
- Carbamazepine (mood stabilizer): Potent CYP1A2 inducer that reduces clozapine levels by up to 50-70%. May require up to doubling the clozapine dose to compensate but plasma level monitoring is essential due to variability between individuals.
- Phenytoin (anticonvulsant): Like carbamazepine, phenytoin induces CYP1A2 and can decrease clozapine levels enough to reduce effectiveness. Dose increases will depend on degree of induction and should be guided by drug level testing.
- St. John’s wort (herbal supplement): Also significantly lowers clozapine levels through CYP induction. Patients should avoid St. John’s wort due to risks of losing response to clozapine treatment.
- Smoking: Polycyclic aromatic hydrocarbons in cigarette smoke strongly induce CYP1A2 enzymes. Smoking cessation causes clozapine levels to rise, often sharply. Clozapine dose reduction of up to 50% may be required with monitoring of plasma drug concentrations. Gradual titration is needed if resuming smoking.
In summary, clinicians must closely consider a patient’s complete medication and supplement regimen when prescribing clozapine and make adjustments as needed based on potential for significant interactions. Similarly, patients and caregivers need to understand the importance of routinely reporting any changes to the clozapine treatment team. Ongoing vigilance and management of both induction and inhibition effects on clozapine metabolism are paramount to maximizing safety and effectiveness. Monitoring of plasma levels in complex or unstable cases provides an additional safeguard given the possibility of individual variability and unpredictable responses. While adding to the overall monitoring burden, medication reviews and dose titrations based on changes represent a key strategy for optimizing clozapine treatment and limiting risks in certain patient subgroups.