From the Guidelines
Clozapine levels can be significantly affected by smoking status, requiring careful monitoring and dose adjustments. Cigarette smoking induces CYP1A2 enzymes in the liver, which metabolize clozapine more rapidly, resulting in lower blood levels of the medication 1. When a patient who smokes starts clozapine, they typically need higher doses to achieve therapeutic blood levels compared to non-smokers. If a patient stops smoking while on clozapine, their blood levels can increase by 50-70% within 2-4 weeks, potentially leading to toxicity with symptoms like sedation, hypersalivation, seizures, or myocarditis. Conversely, if a patient starts smoking while on clozapine, blood levels may decrease, potentially causing symptom relapse.
Key Considerations
- Healthcare providers should monitor clozapine levels closely during changes in smoking status, with more frequent blood tests recommended.
- Dose reductions of approximately 30-50% are typically needed when a patient stops smoking, while dose increases may be necessary when a patient starts smoking.
- This interaction applies to tobacco smoking specifically, not nicotine replacement therapies or vaping, as it's the polycyclic aromatic hydrocarbons in tobacco smoke that affect the enzyme system.
Clinical Implications
- The American Psychiatric Association recommends monitoring patients with schizophrenia for tobacco use and other substance use as part of the initial assessment 1.
- Patients with schizophrenia who smoke may require closer monitoring and more frequent dose adjustments when taking clozapine.
- Healthcare providers should consider the potential effects of smoking on clozapine levels when developing a treatment plan for patients with schizophrenia.
From the FDA Drug Label
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. Tobacco smoke is a moderate inducer of CYP1A2. It may be necessary to increase the clozapine dose if used concomitantly with inducers of these enzymes.
The effect of smoking on Clozapine (Clozaril) therapy is that it may decrease the plasma concentration of clozapine, resulting in decreased effectiveness of the medication, as tobacco smoke is a moderate inducer of CYP1A2. It may be necessary to increase the clozapine dose in patients who smoke 2, 2.
From the Research
Effect of Smoking on Clozapine Therapy
- Smoking significantly impacts clozapine blood levels, with lower levels found in smokers compared to non-smokers 3
- The concentration to dose (C/D) ratios are also lower in smokers, indicating increased clearance of clozapine 3
- Smoking cessation can lead to increased clozapine plasma concentrations and severe side effects, with case reports documenting sedation, fatigue, and confusion 4, 5, 6
- The effect of smoking on clozapine dose and plasma concentrations seems to be maximal after 2-3 cigarettes daily in males and 4-5 cigarettes daily in females 7
Clinical Implications
- Reductions of clozapine dose of 30% are recommended when a patient on clozapine stops smoking, with adjustments informed by clozapine steady-state trough levels and clinical risk-benefit evaluation 3
- Smoking patients treated with clozapine should be monitored regularly for changes in smoking consumption to adjust doses accordingly 4, 6
- The optimum target range for predose plasma clozapine may be different in smokers (0.35-0.45 mg L-1) compared to non-smokers (0.50-0.60 mg L-1) 7