- USES: Clozapine is used for treatment-resistant schizophrenia. It was first synthesized in 1969, but not widely used until the 1970s. It was withdrawn from the market in 1974 due to cases of fatal agranulocytosis associated with its use, but was reintroduced in 1990. It improves both the positive and negative symptoms of schizophrenia and has a lower likelihood of producing extrapyramidal symptoms compared to typical antipsychotics. PHARMACOLOGY: Unlike typical antipsychotic medications, clozapine has little affinity for dopamine receptors. Clozapine is an antagonist of muscarinic and serotonin receptors at clinically effective doses and blocks peripheral alpha1-adrenergic receptors. In addition, it interferes with the reuptake of catecholamines and antagonizes GABA A receptors. TOXICOLOGY: Overdose is usually an extension of pharmacology effects, which primarily affects the cardiovascular system and central nervous system, including anticholinergic toxidrome (antagonizes muscarinic receptors), hypotension (blocks peripheral alpha1-adrenergic receptors) and, less commonly, seizures (GABA antagonism). Many adverse reactions occur with therapeutic use, and are not dose-dependent. EPIDEMIOLOGY: Clozapine is only indicated for the treatment of resistant schizophrenia and not commonly prescribed. Therefore, poisoning is rare, but may be life-threatening. MILD TO MODERATE POISONING: Somnolence, anticholinergic effects (eg, mydriasis, flushing, fever, dry mouth, decreased bowel sounds), tachycardia, mild hypotension, and nausea and vomiting are common after overdose. Pinpoint pupils are often observed. Agitation, nystagmus, ataxia, confusion, and hallucinations may develop with moderate poisoning. SEVERE POISONING: Generally, toxicity appears to be greater in patients who are not chronically taking clozapine, particularly children. Severe effects involve the central nervous system and cardiovascular system and may include delirium, seizures, coma, hyperthermia, severe hypotension, myoclonus, muscle rigidity and, rarely, ventricular dysrhythmias. Clozapine has a relatively low affinity for cardiac sodium channels, and there is little evidence suggesting cardiac dysrhythmias as a direct effect of clozapine toxicity. Clozapine prolongs the QT interval and, therefore, may cause torsades de pointes, although this has not been reported after overdose. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma, or seizures. ADVERSE EFFECTS: Mild anticholinergic effects are common, including mild sedation, constipation, and urinary retention. Ironically, clozapine can cause increased salivation. Dyslipidemia, hepatic steatosis, and glucose intolerance can occur with long-term antipsychotic use. Clozapine can cause life-threatening agranulocytosis in 0.38% to 2% of patients. Myocarditis and cardiomyopathy have rarely been reported. Extrapyramidal syndrome (ie, acute dystonia, akathisia, parkinsonism, and tardive dyskinesia) more commonly results from typical antipsychotic use but may occur with clozapine administration. Neuroleptic malignant syndrome (ie, muscular rigidity, autonomic instability, altered mental status, and hyperthermia) is potentially life-threatening and may occur following overdose, but is much more likely to occur with therapeutic use, usually within the first 2 weeks of treatment or after a dose increase.
Range of Toxicity:
- TOXICITY: SUMMARY: CHILD: A dose of more than 50 mg is potentially toxic in a drug naive child less than 12 years old. A dose of more than 62.5 mg is potentially toxic in a drug naive child aged 12 years or greater. In children on chronic clozapine therapy an acute ingestion of more than 5 times their current single dose (not daily dose) of clozapine is potentially toxic. ADULTS: Fatal overdoses have been reported following ingestions of greater than 2.5 g. The minimal dose ingested for development of moderate to severe toxicity was 0.1 g. CHILDREN: Overdoses as small as 50 to 200 mg have been associated with serious symptoms (ie, altered mental status and muscle tone, tachycardia, and extrapyramidal effects) in children. THERAPEUTIC DOSE: ADULTS: 12.5 mg once or twice daily initially, and then increase by daily dosage increments of 25 to 50 mg/day to a target dose of 300 to 450 mg/day by the end of 2 weeks. Maximum daily dose is 900 mg. CHILDREN: Safety and efficacy have not been established.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: The majority of clozapine overdoses require only supportive care. Administer activated charcoal if patients can protect their airway and if they present shortly after ingestion. Mild sedation is common. Hypotension and tachycardia are generally mild and well tolerated, and do not require specific treatment except IV fluids. MANAGEMENT OF SEVERE TOXICITY: Orotracheal intubation for airway protection should be performed early. Patients with laryngeal dystonia may require intubation and mechanical ventilation until symptoms resolve. Administer activated charcoal in patients who can protect their airway or who are intubated. Severe delirium may develop and require large doses of benzodiazepines for sedation. Seizures (which may progress to status epilepticus) may require aggressive use of benzodiazepines, propofol and/or barbiturates. Monitor core temperature and treat hyperthermia with external cooling and with aggressive benzodiazepine sedation to control agitation. Clinical manifestations may be prolonged due to prolonged absorption in the setting of anticholinergic ileus. Agranulocytosis is a potentially life-threatening complication of clozapine use, but it does not appear to be dose-related. Care is largely symptomatic and supportive, including administration of granulocyte colony stimulating factors.
- Decontamination: PREHOSPITAL: Not recommended because of potential for somnolence and seizures. HOSPITAL: Administer activated charcoal if recent, substantial ingestion, and if patient is able to protect their airway. If patient is intubated and has a recent, large ingestion, charcoal may be given via NG or OG tube, if no ileus is present.
- Airway management: Perform early in patients with severe intoxication (eg, seizures, dysrhythmias, severe delirium, laryngeal dystonia, or hyperthermia).
- Antidote: None
- Conduction disorder of the heart: Although the risk of torsades de pointes appears to be low, patients with QTc prolongation should be monitored, and, if the patient develops torsades, they should be treated according to ACLS protocols (magnesium, overdrive pacing).
- Dystonia: Treatment is symptomatic and supportive, including airway protection, if needed. Administration of anticholinergic agents often produces rapid alleviation of symptoms. Benztropine (ADULTS: 2 mg IV or IM; CHILDREN: 0.05 mg/kg) or diphenhydramine (ADULTS: 50 to 100 mg IV; CHILDREN: 1 mg/kg) may be given. Benzodiazepines may be given as adjunctive therapy. Be aware that the duration of action of clozapine may exceed the duration of action of treatment, so symptoms may recur.
- Akathisia: Antipsychotic dose should be reduced or the medication changed. Benzodiazepines may be helpful in alleviating symptoms. Anticholinergics such as benztropine or diphenhydramine may be given.
- Neuroleptic malignant syndrome: Treatment of neuroleptic malignant syndrome (NMS) is largely symptomatic and supportive. The offending agent should be removed. Great care should be taken to treat hyperthermia, hypotension, and to protect the patient’s airway. Benzodiazepines should be used liberally and are the pharmacologic mainstay of therapy. Dantrolene and bromocriptine may be adjunctive measures but their efficacy is not well-proven in the treatment of NMS. Dantrolene, a skeletal muscle relaxant, is given as 1 mg/kg rapid IV push, may repeat every 1 to 3 min until no detectable rigidity, or up to a total dose of 10 mg/kg; can also be given orally 100 mg to 400 mg/day in 2 to 4 divided doses. Bromocriptine, a centrally acting dopamine agonist, can be given orally, or via NG tube, 5 mg 3 times daily, up to a maximum of 20 mg every 6 hours. Electroconvulsive therapy has been used for treatment in severe cases, but is not of proven benefit.
- Coma: Treat symptomatically and supportively. Perform orotracheal intubation to protect airway. Administer dextrose, thiamine, naloxone, and oxygen if etiology of altered mental status is uncertain.
- Seizure: Intravenous benzodiazepines, propofol, and/or barbiturates.
- Hyperthermia treatment: Control agitation with benzodiazepines; initiate aggressive external cooling measures. If needed, intubate, sedate, and paralyze.
- Delirium: Sedate patient with benzodiazepines as necessary; large doses may be required. Minimize external stimuli; place in quiet, dark room.
- Tachycardia: May occur from a combination of agitation and catecholamine release or reflex tachycardia from hypotension. Give IV fluids as indicated. Treat with benzodiazepines. Beta-blockers are generally avoided in these patients.
- Hypotensive episode: Should be treated with initial normal saline bolus, if patients can tolerate a fluid overload, then adrenergic vasopressors, if necessary to raise mean arterial pressure.
- Monitoring of patient: An initial leukocyte count with differential should be obtained at admission following a potential clozapine overdose. The leukocyte and granulocyte count should then be monitored once or twice weekly for four weeks following overdose. Monitor vital signs and mental status. Clozapine plasma concentrations are not clinically useful or readily available. Obtain a basic chemistry panel to ensure optimization of electrolytes. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, delirium, seizures, coma, hypotension). Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma. Monitor renal function and urine output in patients with rhabdomyolysis. Monitor respiratory function including respirations, airway, pulse oximetry, and/or ABGs in symptomatic patients.
- Enhanced elimination procedure: Hemodialysis and hemoperfusion are not of value because of large volume of distribution and high protein binding.
- Patient disposition: HOME CRITERIA: Children less than 12 years of age who are naive to clozapine can be observed at home following an unintentional ingestion of 50 mg or less and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to clozapine, can be observed at home following an unintentional ingestion of 62.5 mg or less and are experiencing only mild sedation. All patients who are taking clozapine on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of clozapine. Patients who have not developed signs or symptoms more than 6 hours after ingestion are unlikely to develop toxicity. OBSERVATION CRITERIA: Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to clozapine should be referred to a healthcare facility following an unintentional ingestion of more than 50 mg. All patients, 12 years of age or older, who are naive to clozapine should be referred to a healthcare facility following an unintentional ingestion of more than 62.5 mg. All patients who are taking clozapine on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of clozapine. ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (ie, hallucinations, somnolence) or persistent tachycardia should be admitted. Patients with dysrhythmias, seizures, delirium, or coma should be admitted to an intensive care setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, seizures, dysrhythmias, severe delirium, coma) or in whom the diagnosis is not clear. Consult a hematologist for agranulocytosis.