From the Guidelines
Clozapine toxicity is a medical emergency that presents with signs such as seizures, agranulocytosis, sedation, weight gain, hypersalivation, elevated liver enzyme levels, orthostatic hypotension, tachycardia, and fever, requiring immediate attention and potential discontinuation of the medication.
Signs and Symptoms of Clozapine Toxicity
The signs of clozapine toxicity can be severe and life-threatening, including:
- Seizures, which occur in approximately 3% of patients, with the risk increasing as the dose increases, especially if dosage changes are made rapidly 1
- Agranulocytosis, which occurs in approximately 1% of patients and is potentially fatal, with the risk being higher in youth 1
- Sedation, weight gain, hypersalivation, elevated liver enzyme levels, orthostatic hypotension, tachycardia, and fever, which are common side effects of clozapine 1
- Extrapyramidal side effects, which have been noted in some case reports, particularly in youth 1
Monitoring and Prevention
To prevent and monitor clozapine toxicity, the following guidelines are recommended:
- Weekly blood cell counts during the first 6 months of treatment, then every 2 weeks thereafter, including testing during the 4 weeks after the medication is stopped 1
- Monitoring of white blood cell count (WBC) and absolute neutrophil count (ANC), with immediate discontinuation of the medication if the WBC drops below 2,000/mm3 or the ANC drops below 1,000/mm3 1
- Avoidance of concurrent medications that can lower blood cell counts, such as carbamazepine 1
- Gradual dose escalation, with starting doses of 6.25 to 25 mg/day, depending on the patient's weight, and subsequent increases of no more than 25 to 50 mg once or twice per week 1
From the FDA Drug Label
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. The signs of Clozapine (Clozaril) toxicity are:
- Sedation
- Delirium
- Coma
- Tachycardia
- Hypotension
- Respiratory depression or failure
- Hypersalivation
- Aspiration pneumonia
- Cardiac arrhythmias
- Seizure 2 2
From the Research
Signs of Clozapine Toxicity
The signs of clozapine toxicity can be severe and varied, including:
- Hematological complications, such as agranulocytosis 3, 4
- Cardiovascular complications, such as myocarditis, congestive heart failure, and arrhythmias 5, 4
- Neurological complications, such as seizures, delirium, and obsessive-compulsive symptoms 3, 5, 6
- Gastrointestinal complications, such as constipation, nausea, and bowel ischemia 3, 4
- Other complications, such as weight gain, sialorrhea, elevated liver enzymes, enuresis, and fever 3, 4
Delayed Complications
Delayed complications can occur after severe clozapine intoxication, and may include:
- Delayed clinical presentations, which can occur up to 5 days after intoxication 6
- Severe complications, such as cardiac arrhythmias, seizures, and respiratory failure 5, 6, 4
Risk Factors
Risk factors for clozapine toxicity include:
- High doses of clozapine 5, 6
- Acute medical illness, which can impair CYP1A2 function and lead to toxic levels of the drug 7
- Combination with other medications, which can increase the risk of adverse effects 3
Treatment
Treatment for clozapine toxicity may include:
- Supportive care, such as vital support and monitoring of clinical symptoms and vital functions 5, 6
- Extracorporeal techniques, such as CytoSorb hemoadsorption, which can help to quickly and efficiently reduce clozapine levels to non-toxic serum levels 5
- Measurement of clozapine levels, which can help to identify patients at risk of toxicity 7